INTERCOSTAL MUSCLE ACTIVITY IN THE CAT DURING SLEEP
by THOMAS EDWARD DICK, B.S.
A DISSERTATION IN PHYSIOLOGY
Submitted to the Graduate Faculty of Texas Tech University Health Sciences Center in Partia.l Fulfillraent of the Requirements for the Degree of DOCTOR OF PHILOSPHY
ADoroved
August, 1983 V i-fj- ACKNOWLEDGMENTS I thank my teachers, my friends, and the people who are both. Specifically, I acknowledge the influence of my parents who instilled in me an interest in science; Dr. Enrique Silva who first showed me the excitement of a successful experiment; Dr. P. Reed Larsen who gave me a second chance; and Dr. Pier L. Parmeggiani whose conversations with Dr. Orem and me were an initial impetus behind this dissertation.
I thank my committee, Dr. John Orem, Dr. Charles Barnes, Dr. Michael Kopetzky, Dr. James Pirch, and Dr. Donald Davies. I also thank Dr. Maysie Hughes who served on the committee until her recent retirement. I appreciate their participation and contributions. Tarbox Parkinson's Disease Institute of Texas Tech University School of Medicine gave me a Predoctoral Research Fellowship for which I am very grateful. There are two people who helped tremendously on this project. Ms. Elizabeth Orem edited the entire manuscript making it understandable for the reader and enjoyable for me to read. Ms. Alma Wood assisted in every phase of this project giving me excellent technical support. I am greatly indebted to my advisor, Dr. John Orem, and my wife, Anne. Without their support, this dissertation would not have been possible.
11 i TABLE OF CONTENTS
ACKNOWLEDGMENTS LIST OF TABLES ^^ LIST OF FIGURES ^ I. INTRODUCTION •] Respiratory Alterations in Sleep 3 Mechanisras T5 Summary and Proposal 23 II. METHODS 25 Surgery 25 Recording Sessions 30 Lesions 33 Histology 34 Data Analysis 35 III. RESULTS 41 Augmentation of Expiratory IMA 42 Postural Effect on IMA 44 IMA During PGO Waves Before and After Pontine Tegmental Lesions 46 IV. DISCUSSION 83 Augmentation of Expiratory IMA 83 Postural Effect on IMA 90 IMA During PGO Waves Before and After Pontine Tegmental Lesions 97 Sumraary and Conclusions 103 BIBLIOGRAPHY 105
111 LIST OF TABLES
1. Correlation Between Integrated IMA and EEG Total Power 54 2. Intercostal Muscle Activity During NREM Sleep 63 3. Intercostal Muscle Activity During REM Sleep 65 4. PGO Wave and IMA Correlation in REM Sleep .... 76
IV LIST OF FIGURES
1. Brainstera coronal-sections of five cats having positive correlations between IMA and PGO waves during REM sleep 40
2. The augmentation process recorded frora expiratory intercostal muscle (bottom two tracings) as the animal went from wakefulness to NREM sleep. ... 51 3. Integrated expiratory intercostal EMG (solid) and EEG total power (diagonal lines) are plotted against time (5.12-s bins) 53
4. The cycle-triggered histograra of expiratory inter- costal raotor unit activity in NREM sleep (heavy line) is rauch greater than cycle-triggered histogram attained in the previous waking episode (diagonal area) 56
5. Cycle-triggered histograms of inspiratory inter- costal motor unit activity show various altera- tions in activity with change in state from wakefulness (thin line, diagonal lined area) to NREM sleep (heavy line, open area) 58 6. Cycle-triggered histograras (CTH) plotted to represent each muscle recording 60 7. The postural effect recorded frora the left inspiratory intercostal rauscles 62
8. Inspiratory IMA was recorded during NREM sleep with the aniraal in two different positions. ... 67 9. Expiratory IMA was recorded during NREM sleep with the animal in two different positions. ... 69 10. Inspiratory IMA was recorded in two different sleeping positions during REM sleep 71 11. Expiratory IMA was recorded during REM sleep with the aniraal in two different positions. ... 73 12. Inspiratory IMA persisted into REM sleep in intact animals more than expiratory IMA which became atonic in REM sleep 75 13. Inspiratory IMA (second and fourth tracing in A and B) recorded during REM sleep in an intact animal (A) and in the sam animal (Cat D) after bilateral, pontine-tegmental lesions. ... 78 14. IMA (third tracing in A and B) was recorded during REM sleep before (A) and after bilateral, pontine- tegmental lesions (B) in cat E 80 15. IMA was cross-correlated with PGO-wave activity during REM sleep in intact animals (top half of A, B, and C) and in lesioned animals (bottom half of A, B, and C) 82
VI CHAPTER I
INTRODUCTION
The physiology of an aniraal changes from wakefulness to sleep and within sleep, from non-rapid eye movement (NREM) to rapid eye raoveraent (REM) sleep (Orera and Barnes, 1980). Researchers report there are neural, hormonal, and raetabolic changes in sleep which influence various organ systems. In NREM sleep, the animal has lost consciousness and is quiescent. Parasympathetic tone predominates (Baust and Bohnert, 1969; Parmeggiani, 1980a,b), and anabolic hormones are released (Takahashi et al., 1968; Boyer et al., 1972; Parker et al., 1980; Mendelsohn, 1982). Also in NREM sleep, reflex arcs tightly regulate metabolic factors such as P(C0(2)) (Phillipson et al., 1977; Phillipson, 1978) but in wakefulness, voluntary acts can overwhelra reflex raechanisras and alter arterial P(C0(2)). A slow, rhythmic respiration, a regular heart rate and a decreased metabolic rate and 0(2) consumption raark the "stability" of an animal in NREM sleep.
In REM sleep, neural control is more coraplex than in NREM sleep. The possible neural raechanisrastha t influence bodily functions are: 1) a high level of parasympathetic activity with brief periods when sympathetic activity increases dramatically and parasyrapathetic tone diminishes 1 (Baust et al., 1968; Baust and Bohnert, 1969; Mancia et al., 1971; Parmeggiani, 1980a,b; Guilleminault et al., 1981), 2) voluntary mechanisms elicited by dreara content (Deraent and Wolpert, 1958; Hobson et al., 1965), and 3) "state-con- trolled" mechanisms from pontomedullary reticular formation nuclei, which increase their activity in REM sleep
(Aserinsky, 1965; Hobson, 1965; Hobson et al., 1975; Siegel and McGinty, 1977; Netick et al., 1977). The existence of each mechanism has not been verified, but changes in breath- ing, heart rate, and rauscle tone persist in decerebrate animals (Hobson, 1965; Morúzzi, 1972). Therefore, neural controls arising frora brainstem structures do explain some of the observed physiological changes during REM. There are no reports of the secretion of hormones specifically during REM sleep. However, the increase in prolactin level in the early raorning (Parker et al., 1980) when REM sleep is concentrated suggests that hormonal changes raay occur in REM sleep. Metabolic influences, espe- cially the P(C0(2)) influence on respiration, are reportedly depressed (Phillipson, 1978). Breathing becoraes rapid and irregular in REM sleep. Heart rate generally decreases, but phasic increases occur during rapid eye movements. There is a generalized vasodilatation with a decrease in mean arteri- al pressure, but again, there are variations in blood pressure associated with phasic REM events. Apparently, baroreceptors do not regulate blood pressure (Guazzi and Zanchetti, 1965a,b; Mancia and Zanchetti, 1980).
The physiological changes which occur during sleep, especially during REM sleep, are often nonhoraeostatic. The regulatory reflexes are attenuated partially because of less effective afferent input, but in addition, neural raechanisms actively inhibit efferent systems. For exaraple, during REM sleep, inhibitory activity from the area of Magoun and Rhines (1946) presumably inhibits postural, skeletal muscles (Morrison and Pompieano, 1965; Pompieano, 1967, 1972).
In this dissertation, the eraphasis is on the respirato- ry changes occurring in sleep. In 1926, Reed and Kleitman (p. 607) questioned the very existence of these changes: "The classical notion of very marked and constant changes in respiration symptomatic of sleep should, in our opinion, be abandoned." But recent evidence points both to verifiable changes in respiration as well as to pathologies associated with these changes. Gastaut's report of hypnic hypoventila- tion and sleep apnea in Pickwickian subjects (Gastaut et al., 1965, 1966) indicated that respiratory failure may occur in sleep. For both clinical and scientific reasons, it is important to extend the investigation of the influence of sleep on respiration and to exaraine further the underlying mechanisms of these effects. Respiratory Alterations in Sleep
Basically, sleep alters these 13 respiratory variables:
1) breathing frequency. 2) ratio of the duration of inspiration to the duration of expiration, 3) peak airflow rate,
4) upper airway resistance, 5) tidal volume, 6) minute volume,
7) ratio of thoracic to abdominal displaceraent, 8) sensitivity to carbon dioxide,
9) sensitivity to oxygen, 10) sensitivity of pulraonary receptors, 11) sensitivity of upper airway receptors, 12) response to respiratory load, and 13) response to airway occlusion. Note also, that because sleep is not a homogeneous state, NREM sleep and REM sleep affect these variables differently,
1) Breathing Frequency
Frequency of breathing is lower and more regular in
NREM sleep than in wakefulness or REM sleep (Bulow, 1963;
Phillipson et al., 1976; Reramers et.al., 1976; Orem et al.,
1977a). In a representative study using cats (Orem et al.,
1977a), breathing rate decreased 31.2 t 0.7 percent from quiet wakefulness to NREM sleep. From NREM to REM sleep, the rate increased to levels coraparable to those in quiet wakefulness. Aserinsky and Kleitraan (1953) noted an increase in respiration associated with eye movements when they first 5 reported the existence of REM sleep in humans. In mammals during REM sleep, average breath durations are similar to those in wakefulness, but variability from breath to breath is greater in REM sleep than in wakefulness (Phillipson et al., 1976; Remmers et al., 1976; Orera et al., 1977a). In studies on humans, Snyder et al. (1964) calculated the variability in breathing frequency within 5-rain epochs during REM and NREM sleep. They noted that the variability increased 55 percent in REM sleep. Aserinsky (1965) associ- ated this variability in breathing with other REM-sleep changes, such as bursts of rapid eye moveraents and myoclonic twitches.
2) Ratio of the Duration of Inspiration to the Duration of Expiration
Changes in breathing frequency are dependent on changes in the duration of inspiration (Ti) and expiration (Te). Clark and von Euler (1972) postulated that Te is dependent on Ti. But the relationship between these two variables appears to change across states of consciousness. Orem (1978a,b) plotted Te versus Ti for different states. The equations for the regression lines are: in quiet wakeful- ness, Te = 1.38 x Ti + 0.13; in NREM sleep, Te = 0.08 x Ti + 1.16; in REM sleep, Te = 1.45 x Ti - 0.17. Thus during wakefulness and REM sleep, Te and Ti were directly related.
3) Peak Airflow Rate Peak airflow rate is also dependent on state of consciousness. In wakefulness, peak airflow rate is the highest, decreasing progressively in sleep. In a study by Orem et al. (1977a), it decreased 30 ± 8.3 percent in NREM sleep. From NREM to REM sleep, it decreased another 14 ± 4.9 percent (Orem et al., 1977a). In wakefulness, a rapid shift in the airflow tracing to the inspiratory phase raarked the end of expiration. Just before the terraination of inspiration, a brief, sharp increase in airflow occurred. During NREM sleep, the transition frora expiration to inspi- ration was attenuated. During NREM and REM sleep, the increase at the end of inspiration disappeared.
4) Upper Airway Resistance Upper airway resistance is raodulated with respiration. During inspiration, airway resistance is lower than during expiration. With sleep, there are changes in raodulation and in the baseline resistance during expiration. In NREM sleep, baseline resistance is rauch greater than in wakeful- ness (Orera et al., 1977b, Lopes et al., 1983), but during inspiration, upper airway resistance drops almost to wake- fulness levels. In REM sleep, expiratory resistance reraains elevated and inspiratory modulation disappears (Orem et al., 1977b) causing an increase in mean upper airway resistance across the respiratory cycle. The increase in upper airway resistance is secondary to a decrease in upper airway muscle tone (Berger, 1961; Sauerland and Harper, 1976; Orem and Lydic, 1978; Orem et al., 1979; Sherrey and Megirian, 1980; Lopes et al., 1983). The decrease in muscle tone occurs in the laryngeal abduc- tors, the posterior cricoarytenoid muscles (Orem and Lydic, 1978; Orem et al., 1979; Sherrey and Megirian, 1980), and the genioglossus (Sauerland and Harper, 1976). There is a progressive decrease in tone frora wakefulness into NREM sleep and then, into REM sleep.
5) Tidal Volume
Alterations in airflow and Ti produce tidal volume (Vt) changes in sleep. In NREM sleep, Vt is slightly greater than in wakefulness because the increase in Ti raore than compensates for the decrease in airflow rate. In REM sleep, when breath duration is shortest and peak flow is lowest, Vt is also lowest. In cats (n=7), determined values were: 35.1
± 0.43 ml in NREM sleep; 33.2 t 0.73 ral in wakefulness; and 24.4 t 0.63 ml in REM sleep (Orem et al., 1977a).
6) Minute Volume Minute volume or ventilation (Ve) reflects the changes in Vt and breathing rate. Ve is higher in wakefulness than in sleep. Orera et al. (1977a) reported these values in
cats: 1081 ± 25 ral/min in wakefulness, 883 *= 9.9 ml/min in NREM sleep, and 806 ± 19 ml/min in REM sleep.
7) Ratio of Thoracic to Abdominal Displacement The ratio of thoracic displacement to abdominal displacement is also state dependent. Since first reported 8 (Mosso, 1878; Bechterew, 1910; Shepard, 1914; Reed and Kleitman, 1926), this finding in huraans has been controver- sial because of artifacts that may arise frora postural changes occurring with sleep and limitations in the differ- ent methods of measuring thoracic and abdominal displace- ment. However, in a study where sleep onset occurred with- out the human subjects changing from the supine position Naifeh and Kamiya (1980) showed an increase in thoracic breathing during NREM sleep linked to an increase in the displacement of the thorax and a decrease in the displace- ment of the abdomen with inspiration. In wakefulness, approximately 40 percent of Vt was accounted for by the thoracic displacement while the other 60 percent was the result of expansion of the abdomen. In NREM sleep, the ratio was reversed: 60 percent of the tidal volume was caused by thoracic displacement, 40 percent by abdorainal displacement (Naifeh and Kamiya, 1980). Reports by Timmons et al. (1972), O'Flaherty et al. (1973), Mortola and Anch (1978), Tabachnik et al. (1981), Gothe et al. (1981), and Iber et al. (1982) confirmed this finding.
8) Sensitivity to Carbon Dioxide In sleep there are changes in the influence of sensory input as well as in the effectiveness of motor output. Straub (1915) was the first to report an increase in alveo- lar P(C0(2)) during sleep. Subsequent reports (Magnussen, 1944; Birchfield et al., 1958, 1959; Reed and Kellogg, 1958, 1960b; Bulow and Ingvar, 1961; Bulow, 1963; Ingvar and Bulow 1963; Duron et al., 1966; Duron, 1972; Townsend et al., 1973; Phillipson et al., 1977; Coccagna and Lugaresi, 1978) have supported this finding. But few reports differentiate the changes occurring in REM sleep from NREM sleep. Phillipson et al. (1977) reported a decrease of 2 mra Hg in alveolar P(C0(2)) during the transition from NREM to REM sleep in dogs. The decrease was attributed to an increase in breathing rate. However, Orem et al. (1977a) did not associate the increase in breathing rate with an increase in ventilation. Therefore, C0(2) production should decrease with the transition from NREM to REM sleep.
During NREM sleep, an increase in alveolar P(C0(2)) coincides with a decrease in sensitivity to arterial P(C0(2)) changes. To delineate sensitivity, ventilation is plotted against alveolar P(C0(2)). During NREM sleep, this function shifts to the right (Reed and Kellogg, 1958, 1960b; Phillipson et al., 1977), indicating decreased sensitivity. In three humans, Reed and Kellogg (1958, 1950b) showed that this shift to the right persisted at high altitude (14,250 ft). The shift was algebraically superiraposed on the increased responsiveness associated with high altitude or hypoxia.
9) Sensitivity to Oxygen Changes in blood oxygen (0(2)) saturation occurring with sleep are difficult to measure because, as the 0(2) 10 dissociation curve shows, there must be large changes in alveolar P(0(2)) for decreases in blood 0(2) saturation to be observed. Nevertheless, Birchfield et al. (1958, 1959) reported statistically significant decreases in blood 0(2) percent saturation with sleep onset. In nine, normal, adult (21-26 yrs.) males, blood 0(2) percent saturation dropped from a mean 95.1 percent saturation in wakefulness to 93.7 percent saturation with sleep onset. Some investigators (Henderson-Sraart and Read, 1979; Jeffery and Read, 1980; Berthon-Jones and Sullivan, 1982; Douglas et al., 1982) have reported an accorapanying decrease in the hypoxic ventilatory response; other investigators studying dogs and humans (Phillipson et al., 1978; Reed and Kellogg, 1960a,b; Gothe et al., 1982) have found no differences between ventilatory responses to hypoxia during NREM sleep and wakefulness, while Pappenheimer (1977) studying rats found responses to hypoxia increased in NREM sleep. However, in an editorial review, Anthonisen and Kryger (1982) considered recent studies and concluded that the response to hypoxia decreased during NREM sleep. They noted first, that the increased arterial P(C0(2)) would increase the sensitivity of the animal to hypoxia, thus obscuring the decrease in the hypoxic ventilatory response; and second, that arousal was a part of the response to hypoxia. The arousal response to hypoxia is clearly different in NREM and in REM sleep. Although the ventilatory response to 11 hypercapnia and hypoxia is intact in REM sleep (Phillipson et al., 1978), the arousal response is greatly delayed when compared to that of NREM sleep. In the Phillipson et al. study (1978), arousal occurred in four dogs at a mean arterial 0(2) saturation of 87.5 * 2.6 percent during NREM sleep. During REM sleep, the mean arterial 0(2) saturation necessary for arousal was significantly lower, 70.5 * 3.4 percent.
10) Sensitivity to Pulmonary Stretch Receptors
Lung inflation elicits the Hering-Breuer reflex. This reflex is mediated by pulraonary stretch receptors and consists of inhibition of inspiratory efforts and an excita- tion of expiratory efforts. The Hering-Breuer reflex was studied during sleep in the opossum (Farber and Marlow, 1976) and the dog (Phillipson et al., 1976b). Evidently, the reflex is present in NREM sleep. However, during REM sleep, it is highly variable (Farber and Marlow, 1976) or even absent (Phillipson et al., 1976b).
11) Sensitivity of Upper Airway Receptors Sullivan (1980) and Sullivan et al. (1978, 1979a,c)
exarained the sensitivity of laryngeal and tracheal irritant receptors in sleeping dogs by squirting water in the airway or by having thera inhale acetic acid vapors. Stiraulation of these receptors elicited a cough reflex during wakefulness. When these stimuli were applied in sleep, they elicited an apnea and an arousal followed by a cough. The threshold for 12 arousal and a subsequent cough increased frora NREM to REM sleep.
12) Response to Respiratory Load
Phillipson et al. (1976a) have studied indirectly the sensitivity of the chestwall afferents by examining the respiratory response to increased load. They compared the responses to graded elastic loads during wakefulness and NREM sleep and with the vagus nerves intact and blocked. The loads were generated by having the dog inspire from rigid containers. End-inspiratory tracheal pressure (Ptr) and Vt measured the response to the load at three points: 1) control Vt with the dog inspiring normally (Ptr is zero), 2) Vt and Ptr generated with the dog inspiring against load, and 3) Ptr generated with the dog inspiring against occluded airway (Vt is zero). In pressure-volume plots, the slope of the line connecting these points has compliance dimensions (liters/cm H20). The reciprocal of compliance is elastance. With intact vagus nerves in wakefulness, the mean elastance (n=3) was 55.8 cra H20/1, and in NREM sleep, it was 54.7 cm H20/1. With vagal blockade in wakefulness, the value was 57.8 cm H20/1, and in NREM sleep, it was 56.0 cm H20/1. None of these values were statistically different. Clearly, this reflex is intact during NREM sleep and is not dependent
on intact vagus nerves. Knill et al. (1976) studied respiratory load compensa-
tion in 15 infants during both NREM and REM sleep. A closed 13 rigid container connected to a raask worn by the infant provided the elastic load. The size of the container was chosen so that the elastic load would decrease Vt about 50 percent on the first breath in NREM sleep. The infant reraained connected to the load for five breaths. During this time, the infant was also rebreathing. This procedure tested both immediate and progressive load corapensation. During NREM sleep, a progressive load compensation was present. Vt averaged over all five loaded breaths was 70 percent of the unloaded, control Vt. After the first breath, increased central respiratory drive corapensated for the load. In contrast, during REM sleep, the progressive load compensation was attenuated. The average percent compensation for Vt was only 58.5 percent over the five loaded breaths. Knill et al. (1976) observed that when they applied the load during REM sleep, the rib cage diameter decreased through inspiration, According to the researchers, this "paradoxical" rib cage raotion caused an over-estimation of the compensation.
13) Response to Airway Occlusion Complete airway occlusion results in a respiratory load of infinite resistance allowing no airflow. There are reports on the response to increases in resistive loads (Santiago et al., 1981; Iber et al., 1982) and to airway occlusions (Henderson-Smart and Read, 1976; Phillipson and Sullivan, 1978a; Orem et al., 1980) during sleep. The data 14 of Iber et al. (1982) showed that increased resistive loads in either wakefulness or NREM sleep decreased minute venti- lation. However, in wakefulness, the decrease in Ve was only 12 percent, whereas, in NREM sleep, the decrease was 23 percent. Santiago et al. (1981, p. 385) reported similar findings stating: "sleep abolished the augmentation of respiratory effort normally elicited by increased inspiratory resistance."
Orem et al. (1980) showed that responses to airway occlusion during wakefulness and sleep were an increase in electromyographic activity in respiratory muscles (recording from the diaphragm and posterior crico-arytenoid muscle) and an increase in endotracheal pressure, both reflecting an increase in central respiratory drive potential. Muscle activity augmented imraediately and progressed frora breath to breath during the occlusion. This study (Orera et al., 1980) deraonstrated that arousal produced a major discontinuity in the response to occlusion. Thus, recorded activity of the diaphragm and posterior cricoarytenoid muscle increased with wakefulness. The authors considered that the increased activity reflected a "wakefulness stimulus" for respiration (see also Fink, 1961). In REM sleep, the duration before
arousal was reported as highly variable and generally prolonged. Although there was a progressive response to occlusion, it varied greatly and was weaker than in NREM sleep. 15 Mechanisras
The underlying raechanisraso f these respiratory changes are unknown, but several have been proposed. After altera- tions in respiration are examined, it is evident that the changes during NREM sleep result from different mechanisms than those observed during REM sleep. For exaraple, during
NREM sleep the increased alveolar P(C0(2)) and decreased sensitivity to arterial P(C0(2)) may be simply the result of decreased excitability of the respiratory centers, or a loss of the wakefulness stimulus. In contrast, during REM sleep the decrease in alveolar P(C0(2)) may result from a decreased production of C0(2) rather than an increased sensitivity to arterial P(C0(2)) or increased alveolar ventilation. The shift in the thoracic-abdorainal displace- ment ratio during NREM sleep also points to state-specific changes in respiration. Most of the changes in REM sleep are state-dependent. For example, the highly variable breathing pattern of REM sleep does not depend upon afferent input (Guazzi and Freis, 1969; Dawes et al., 1972; Remmers et al., 1976; Foutz et al., 1979; Netick and Foutz, 1980) or cortical input (Hobson, 1965), but instead, it is related to events that occur phasically throughout REM sleep
(Aserinsky, 1965; Sullivan et al., 1979; Orem, 1980a,b). There are also tonic influences on breathing during REM sleep (Morrison and Pompieano, 1965a,b,c; Netick et al., 1977). 16 Wakefulness Stimulus
Reed and Kellogg (1958a,b) showed that the C0(2) sensitivity curve shifted to the right with sleep onset. This phenomenon occurred even after exposure to high alti- tude, which shifts the curve to the left. In 1961, Fink reported that posthyperventilation apneas occurred only after anesthesia or sleep and not during wakefulness. Based on this and previous findings, he postulated that with sleep onset, a nonchemical stimulus for breathing, a wakefulness stimulus, was lost. Further studies, cited earlier, showed that the loss of the wakefulness stimulus plays a major role in the decreased effectiveness of afferent input (Reed and Kellogg, 1958; Phillipson, 1978; Orem et al., 1980; Remmers, 1981) and efferent output (Orem and Dement, 1976; Orem et al., 1977a,b; Krieger and Kurtz, 1978) during sleep, especially NREM sleep.
The neural substrate for the wakefulness stimulus has not been identified, and many brainstem nuclei could be involved. Certainly, the structures influencing the state of consciousness should be considered. For example, the ascending reticular activating system (ARAS), located in the midbrain reticular formation (MRF), has a strong arousing, EEG activating, influence (Moruzzi and Magoun, 1949). Cohen and Hugelin (1965) studied the influence of the ARAS on respiration. They stimulated the MRF with long trains (5-30 sec) of high frequency impulses (30 Hz) in decerebrated 17 aniraals. This stiraulation increased the slope and peak of the integrated phrenic activity and shifted the relationship between Ti and Te to that seen in arousal. Orem and Lydic (1978), recording from the posterior cricoarytenoid muscle, reported similar findings. They observed that ARAS stimula- tion increased the frequency of as well as recruited addi- tional posterior cricoarytenoid motor unit discharges. The short latency of the response (~6 ms) revealed a direct influence of the ARAS on the posterior cricoarytenoid motoneurons.
Although stiraulation experiments reveal an excitatory relationship between ARAS and the respiratory groups, addi- tional evidence is either lacking or contradicting. Edwards (1975) showed only sparse and scattered projections from the ARAS to the ventral respiratory groups. Plum and Posner (1972) reported that lesions in the MRF produce a central neurogenic hyperventilation in humans. Finally, Beck et al. (1958) dissociated cortical activation and a conditioned excitatory respiratory response. In their experiment, to condition the animal, foot shock which increased breathing was paired with tones. Once the aniraal was conditioned, the tones alone increased breathing. Initially, the conditioned respiratory response occurred with an arousal, but with continued training it occurred without cortical activation. Additionally, the conditioned response was still present in aniraals with lesions that prevented arousal (Doty et al.. 18 1959). Therefore, the ARAS raay partially mediate the wake- fulness stimulus, but a cortical arousal is not absolutely necessary. Other structures raust be involved. Active Processes During NREM Sleep
The increase in thoracic displaceraent in NREM sleep (Naifeh and Kamiya, 1981) indicates that state-specific, neural processes may occur during that state. The neural substrate of this process is unknown. However, Gassel (1965, 1966) noted increased red nucleus activity which coincided with sleep spindles in the EEG. In general, red nucleus activity facilitates flexors. The expiratory, internal intercostal muscles could reflect increased facilitation frora the.red nucleus because they are flexors and are raoderately not maximally active during NREM sleep. Alternatively, the increased costal breathing may be a reflex response to the increased resistance in the airway which increases respiratory load. Phasic REM Sleep Influences
Early studies (Hobson et al., 1964; Aserinsky, 1965) associated irregularities in breathing during REM sleep with intermittent, phasic events such as rapid eye movements and myoclonic twitches. Baust et al. (1972) correlated changes in respiration and heart rate with pontogeniculo-occipital (PGO) waves which are elemental, phasic REM-sleep events positively related with rapid eye movements. Orem (1980a,b) correlated PGO waves with medullary respiratory neural 19 activity alterations. A positive correlation between PGO wave activity (number and frequency) and medullary respira- tory unit activity was present in 105 out of 109 100-s episodes in REM sleep (Orem, 1980a,b). This correlation suggested that phasic REM sleep processes facilitated medullary respiratory activity. However, facilitation did not appear in diaphragmatic EMG recordings which showed an inconsistent inhibition of activity occurring within 300 ms of a PGO wave.
Pontine neural activity generates many of the phasic phenomena characterizing REM sleep. For example, rapid eye raoveraents and PGO waves are generated from the pontine reticular formation (Jouvet, 1972; Sakai and Jouvet, 1980; Mergner and Pompeiano, 1981; Fuchs and Kaneko, 1981). Siegel and McGinty (1977) reported that pontine-tegmental neurons showed intense firing patterns in association with specific movements of the pinna, head, and neck in wakeful- ness and REM sleep, demonstrating that neuronal discharges of the pontine reticular formation correlated with the phasic, motor events in REM sleep (Siegel, 1979).
Bilateral lesions in the dorsolateral pontine tegmentura alter dramatically the pattern of motor behavior observed during REM sleep (Henley and Morrison, 1969, 1974; Sakai et al., 1976; Hendricks et al., 1976, 1981, 1982; Morrison, 1979a,b; Sakai, 1980; Hendricks, 1982). Animals with these lesions have lost the tonic muscle-atonia associated with 20 REM sleep. These aniraals retain their skeletal muscle tone into REM sleep. Some raise their heads and a few even walk during REM sleep (Hendricks et al., 1982; Hendricks, 1982). Tonic REM Sleep Influences
A generalized skeletal-muscle atonia occurs in the postural muscles throughout REM sleep. This atonia is evident in respiratory rauscles. For example, Sieck et al. (1982a,b) reported a decrease in the recruitraent of large, diaphragmatic raotor units during REM sleep; and Parmeggiani and Sabattini (1972) noted an intercostal muscle atonia during REM sleep. Knill et al. (1976) reported that in infants, intercostal rauscle atonia detrimentally affects ventilation when infants inspired against an increased load in REM sleep. With this paradigra, Knill et al. (1976) observed a "paradoxical" rib cage raovement. The chest wall collapsed during inspiration because of its high compliance. In infants, intercostal rauscle tone provides rigidity to the chest wall. Generalized atonia affects accessory respiratory muscles also. Sauerland and Harper (1976) reported that during REM sleep in humans, motor units of the genioglossus ceased activity for several respiratory cycles. Orem
(1977b) reported that laryngeal abductor activity decreased 40 percent during REM sleep in the cat. Remmers et al. (1978) hypothesized that decreased tone in the upper airway was a contributing factor in the pathogenesis of obstructive 21 sleep apneas. Decreased tone increased upper airway resist- ance and predisposed individuals to occlusion. Giaquinto et al. (1964), Gassel et al. (1964a,b, 1965a,b), Morrison and Pompieano (1965a,b), and Pompeiano (1967) published a series of reports concluding that the inhibitory area of Magoun and Rhines (1946) generated the rauscle atonia in REM sleep. The area raay cause both an inhibition and a disfacilitation of alpha motoneurons. Inhibition may result from the generation of inhibitory postsynaptic potentials in alpha motoneurons. Disfacilita- tion may be the result of two mechanisms: 1) Inhibition of gamma motoneurons, thereby blocking autofacilitation via contraction of intrafusal fibers and subsequent stiraulation of Group la and II fibers of rauscle spindles. 2) Presynap- tic inhibition of raany types of afferent endings including Group la afferent endings. In 1978, two groups (Glenn et al., 1978; Morales and Chase, 1978; Glenn and Dement, 1981) recorded chloride-reversible, hyperpolarized membrane poten- tials in identified motoneurons during REM sleep. These recordings from motoneurons innervating postural, skeletal muscles provide an explanation for the loss of tone in respiratory muscles during REM sleep, especially in those that have both a postural and respiratory function.
Duron (1973), Jung-Caillol and Duron (1976), and Duron and Marlot (1980) related tonic activity and the extent of REM-sleep hypotonia in a respiratory-related rauscle to the 22 density of muscle spindles in the muscle. They found that the greater the number of spindles per gram muscle, the more tonically active the muscle was during wakefulness and the more atonic it was during REM sleep. Muscles that had very phasic respiratory-related activity (diaphragra, interchon- drals, and triangularis sterni) had minimal losses of tone during REM sleep and few muscle spindles. For example, diaphragmatic activity continues relatively unchanged throughout REM sleep although high-threshold diaphragmatic motor units cease firing in REM sleep (Sieck et al., 1982). Duron's studies suggest that autogenic facilitation is important in activating intercostal muscles in all states of consciousness and that disfacilitation is iraportant in inactivating intercostal muscles in REM sleep.
Another tonic influence on respiration during REM sleep was recorded by Netick et al. (1977) in the raedullary reticular formation. They found cells (6) that were "REM- specific," firing tonically only during REM sleep. The discharge frequencies of the cells were also positively correlated with respiratory frequency. The highest discharge rates occurred with bursts of eye movements, linking the tonic and phasic influences. Sakai et al. (1979a, 1980, 1981) have confirmed and extended these results. They showed input from the pontine tegmentum (peri-locus coeruleus alpha area) and output to the cord. They hypothesized that this REM-sleep specific, medullary 23 unit activity is related to the muscle atonia of REM sleep. Summary and Proposal
The influence of sleep on respiration includes a range of variables. Effectiveness of both motor output and sensory input is attenuated. During NREM sleep, a decrease in upper airway muscle tone and an increase in arterial P(C0(2)) reflect the loss of the wakefulness stimulus. In REM sleep, intercostal muscle atonia and a diminished response to hypercapnia indicate state-specific processes influence respiration.
In addition to these depressive effects, there are changes in respiration which suggest there may be active, stimulatory processes occurring during sleep. During NREM sleep, the thoracic component increases in breathing. During REM sleep, medullary respiratory activity increases with PGO wave bursting.
I propose to record intercostal muscle activity during sleep, exaraining potential state-specific effects on respi- ration. Reported changes suggest that state affects inter- costal muscle tone. First, changes in the thoracic-abdomi- nal breathing pattern during NREM sleep suggest state-spe- cific changes in intercostal muscle activity. Second, sleeping position, stereotypical of sleeping behavior, may affect the postural component of intercostal muscle activi- ty. Third, phasic REM-sleep events which are positively correlated with raedullary respiratory unit activity raay be 24 associated with changes in intercostal muscle activity.
This possibility will be investigated before and after pontine-tegmental lesions which are reported to produce REM
sleep without atonia. CHAPTER II
METHODS
Adult cats were the subjects for all of the experiments in this study. The animals were operated upon and cared for strictly in accord with the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80-23). Surgery
A separate animal operating room, sterilized instru- ments, drapes, and gowns provided an aseptic environment for all the surgical procedures. To prevent infection, the incision site was cleaned, the sutures coated with iodine, and a long-acting antibiotic, Bicillin (200,000 units) injected intramuscularly. During surgery and recovery, a heating pad maintained the animal's body temperature.
In the first six aniraals, electrodes to monitor state and to record IMA were implanted in one operation. This procedure proved unsatisfactory because recordings of phasic, respiratory-related activity were rarely obtained from the intercostal muscles after the long (1-2 months) recovery period. Thereafter, 14 animals were prepared, first, with a tracheal fistula and electrodes for monitoring sleep-wakefulness and, second, 1-2 months later, with elec- trodes for recording intercostal muscle activity (IMA).
25 26 Sodiura pentobarbital (Nembutal, 50 rag/ral) was the anesthetic agent. In the first operation, a dose of 35 rag/kg was administered intraperitoneally. Subsequent intra- venous (0.5 ml) injections were necessary in 9 animals during the 5-7-h operation. In the second operation, the dose was reduced to 30 mg/kg for the shorter (<3 h) and less traumatic procedure. Supplementary anesthesia was not necessary.
In the first surgical procedure, forraation of the tracheal fistula, the cat was placed in a dorsal decubitus, supine position, with its limbs stretched and taped lateral- ly. A cylinder (5-cm d) was placed under the animal's neck to support and elevate the trachea. This position exposed completely the ventral surface of the neck. A 4-cm midline incision, extending caudally from the cricoid cartilage, exposed the underlying neck muscles (sternomastoid, sterno- hyoid, and sternothyroid). These muscles were retracted to expose the trachea which was opened by raidline incision across five cartilaginous rings. The cut-end of each ring was sutured to the overlying wound margin with fine (000) silk. Heavier silk (0) was used to close the wound margins beyond both ends of the tracheal fistula. In the second surgical procedure, electrodes were placed to record the electroencephlogram (EEG), the electro- oculogram (EOG), and pontogeniculo-occipital (PGO) waves. Electrodes for recording the nuchal electromyograra (EMG), 27 also used to distinguish state of consciousness, were placed each recording day and not during this operation.
The EEG and EOG were recorded with raacroelectrodes consisting of 3/16 in., 4-40, stainless-steel screws with copper-wire leads. A female amphenol-connector pin was soldered to the other end of the copper wire. These screws were placed in pairs for bipolar recordings. Electrodes used to record PGO waves were formed by twisting together three strands of insulated, stainless-steel wire (.010-in. d). The bared ends of each strand were separated vertically by 0.5-1.0 mm, and female araphenol-connector pins were soldered to the other ends.
PGO-wave recording electrodes were placed in the later- al geniculate body of the thalaraus. The Horsley and Clark (1908) stereotaxic apparatus oriented the cat's head in a defined space, allowing estiraations of the location of deep brain structures. This apparatus also iramobilized the cat's head and simplified placement of the EEG and EOG electrodes and formation of the dental-acrylic-headcap.
Once the head was in the stereotaxic apparatus, a 10 cm midline incision from the rostral border of the frontal plate to the occipital crest exposed the skull. First, the skin and its associated musculature were retracted and the dorsal portions of the temporal muscles bilaterally reraoved. Second, the skull was scraped with a curet to remove the periosteum and cleaned with hydrogen peroxide. Third, the 28 frontal plates overlying the frontal sinus were removed and holes for the electrodes and screws (4-40, 3/16 in.) were drilled. The screws anchored the dental acrylic to the skull.
The EEG electrodes were placed approximately 1 cm apart over the anterior and posterior sigmoid gyrus. The EOG electrodes were placed laterally and raedially in the frontal sinus behind the bony orbit. Rostral in the nasal bone, a hole was drilled for a unipolar, screw electrode that served as a ground. Electrodes for recording PGO waves were placed according to the stereotaxic coordinates of the lateral geniculate body (anterior, 6.5; lateral, 10.5; vertical, +2.5).
Holes for the securing screws were placed laterally so the shafts of the screws were perpendicular to the surface of the skull and not parallel to an upward force on the headcap. These holes were sized to ensure that the screws would tap the holes during insertion but would not cause degeneration of the surrounding bone.
After the electrodes and screws were placed, dental acrylic was applied to the skull to cover the screws and support the PGO electrodes. When the acrylic dried, the PGO electrode carriers were removed, the feraale connecting pins plugged into a 15-pin amphenol connector, and a metal plate positioned over the skull. This plate was mounted on a stereotaxic carrier's base and included three bolts (4-40, 29 1.5 in.). The bolts and the amphenol connector were incor- porated into the headcap, the edges of the headcap smoothed and cleaned to rainimize irritation, and the rostral and caudal aspects of the incision sutured to draw the skin around the edges of the headcap.
In the second operation, the intercostal muscles were exposed, and four bipolar electrodes were implanted into them. The electrodes' leads were passed anteriorly and subdermally, and placed in a nine-pin, amphenol connector that was added to the headcap. A modified version of the Basmajian and Stecko (1962) technique was used to form and implant the intercostal electrodes. These electrodes were bipolar electrodes, constructed frora pairs of fine (.006-in. d), insulated, stainless-steel wires, bared 1 mm at the tip.
A 10-cm incision was made on the lateral chest wall to expose the intercostal muscles. It angled from behind the forelimb caudally and dorsally, following approximately the raargin of the latissimus dorsi. Retraction of the sheath of the latissimus dorsi revealed the external oblique and the dorsal serratus rauscles, which cover the external intercos- tal rauscles. The fibers of these rauscles were separated to expose the intercostal muscles. Again, electrodes were inserted into the muscles with a hypodermic needle. But, the electrode wire was passed along the outside of the shaft of the needle so that the barb was on the inside of the beveled lumen. The needle and wire could pass together into 30 the rauscle, and when the needle was removed, the barbed tip remained in the rauscle.
Two wires of a bipolar electrode were implanted indi- vidually under the external oblique muscle, and two others were placed more dorsally, in the sarae intercostal space under the dorsal serratus. Four more wires (two pairs) were implanted similarly into another intercostal space. There were eight total wires or four bipolar electrodes implanted. The fifth through seventh intercostal spaces were the most accessible with this approach. Recording Sessions
At the start of each recording session, I implanted EMG electrodes into the neck musculature using the technique of Basmajian and Stecko (1962). These paired electrodes were fine (.006-in. d), insulated, stainless-steel wire, bared 2-3 mra at the tip. The wire, passing through the lumen of a hypodermic needle (21 guage), was inserted into the rauscle, and the needle was withdrawn, leaving the electrode in the muscle. These electrodes were removed when the recording session ended.
A Beckman six-channel polygraph (5411B) recorded neck EMG, EEG, PGO waves, and respiration and IMA from two sources. During some recording sessions, EOG was substitu- ted for nuchal EMG. During NREM sleep, the EEG, respira- tion, and IMA from two bipolar electrodes were recorded on a Hewlett-Packard four-channel tape recorder (3964 A). During 31 REM sleep, I substituted a PGO wave recording for the EEG recording. Channels 1 and 2 on the tape recorder were FM channels and recorded the low-frequency signal of the EEG and of respiration.
Before a signal was recorded, it was conditioned by either a Beckman (Type R-411) amplifier (EEG, EOG, and resp- iration) or a Grass (P511) preamplifier (PGO waves, nuchal EMG, and IMA). For the EEG, low-frequency and high-frequen- cy response controls were set at 1.6 Hz and 30 Hz, respec- tively. The signal in the bandwidth between 1.6 Hz and 30 Hz was transmitted unaltered to the amplifier, but the signal beyond the bandwidth was "cut-off" and only partially amplified. For low-frequency EOG signals, the controls were set on .15 Hz and 3 Hz; for PGO waves, the amplified bandwidth was between 1 Hz and 10 kHz; and for the EMG recordings, the amplified bandwidth was between 3 Hz and 10 kHz. The Grass (P511) amplifiers contained a 60 Hz filter which decreased "60-Hz noise" in PGO wave and EMG signals. Signals from all the araplifiers were transmitted to Beckraan polygragh pen drivers and to the Hewlett-Packard tape
recorder. For recording respiration, airflow through a sraall-ani- mal pneumotachograph (Grass PT5 A) was monitored by a volu- raetric pressure transducer which measured changes in pres- sure across a screen in the pneuraotachograph. The differen- tial pressure is proportional to airflow. A 14-cra, French, 32 endotracheal tube (RUSCH) connected the pneumotach with the respiratory tract. The endotracheal tube was inserted into the upper airway through the tracheal fistula at the start of each recording session, and it was reraoved at the end of the session. The signal frora the pressure transducer went to a coupler on the Beckraan polygraph. Filters were set on DC and 30 Hz, cutting off frequencies above 30 Hz, and the araplified output was recorded on paper and tape.
Before raost recording sessions, the aniraals were deprived of sleep, particularly REM sleep, by placing them in a cold (7-12 degrees C) environment for 10-14 h (Parraeggiani, 1980). They had access to food, water, and a litter box. The recording sessions lasted 5-8 h. During raost sessions, the animal's body was restrained by a loose, canvas bag and its head was held by a plate into which the three bolts in the head cap were secured. These restraints prevented the cat from removing the endotracheal tube. In the first few sessions, the cats adapted to the apparatus, and the best recordings of EEG, PGO waves, and IMA were selected. Once the cat had adapted to the recording envi- ronraent, IMA was recorded during different states of consciousness in two to four sessions for each animal.
Eight animals were recorded unrestrained. They moved in the Faraday cage, tethered to the recording equipment by a commutator with long leads to a male-amphenol connector 33 which was plugged into the head-cap's araphenol connector. During these sessions, I noted: 1) sleeping position, 2) the correlation between bursts of IMA and chest wall raoveraents, and 3) behavioral events such as grooming in wakefulness or myoclonic jerks in REM sleep.
After the initial, control recordings, the dorsal pontine tegmentura was coagulated bilaterally. Recording sessions resuraed three to five days after the lesion. They continued interraittently until the recordings indicated a resumption of REM sleep or until a cat's sleep/wakefulness pattern had stabilized. In some animals when REM sleep resumed, the brainstem was lesioned again in attempts to get REM sleep without atonia. Lesions
The general target area for the lesion was the left and right dorsal pontine tegmentum. To reach this area, I anesthetized the animal (30 rag/kg, Nembutal) and placed it in the stereotaxic apparatus. The exact coordinates of the target site were posterior, 3.1; lateral, 2; and vertical, -1.5, -2.5, and -3.5 (Berman, 1968). The lesions were DC electrolytic, and the lesioning electrode was the anode. For the lesion, 1.25 mAmp was applied for 45 s through a 0.80-mm d stainless-steel probe. The lesion was done in three steps on each side, moving the lesioning electrode down 1 mra each step.
The target area for the lesion, the peri-locus coerule- 34 us alpha area (Sakai, 1980), was slightly caudal, raedial, and ventral to the locus coeruleus (Fig. 1). Because this area lies directly below the tentoriura, the lesioning elec- trode projected through the cerebellura at a 45 degree angle. A craniotomy at the occipital crest exposed the dorsocaudal cerebellum and provided an opening for the electrode. Histology
The aniraals were killed with an overdose of Nembutal. A canula was inserted into the brachiocephalic artery. The brain was perfused through the canula, first, with saline ("100 cc) and, second, with 10 percent forraalin ("100 cc). After perfusion, the brain was reraoved and stored in 10 percent formalin. After storing the tissue for at least one week, the brainstem was blocked and frozen for sectioning. Coronal sections, 40 microns thick, were cut on a freezing raicrotorae (Araerican Optical Model 888). These sections were raounted on slides and stained by cresyl violet (Kluver and Barrera, 1953). The extent of the lesion was deterrained after I examined all the sections, selecting representative sections for close inspection. A photographic enlarger projected these sections onto drawing paper. By tracing the projected sections, I produced an enlarged permanent record (Fig. 1). Key nuclei and the lesion site were identified and labelled according to Berraan's atlas (Berman, 1968) and Taber's noraenclature (Taber, 1951). 35 Data Analysis
The data were stored in analog forra on Ampex (797 15DW11) magnetic tape and analyzed with a microcoraputer (Motorola, 6800 microprocessing chip). Analysis of the data was done in three discrete stages: 1) EEG total power was correlated with IMA, 2) IMA was compared in two different sleeping positions, and 3) IMA was correlated with PGO wave activity during REM sleep before and after bilateral, pontine-tegmental lesions.
Cycle-triggered histograms (CTH) were constructed for each rauscle recording to characterize IMA as either inspira- tory or expiratory. To form a CTH of IMA, I used intercos- tal muscle action potentials and the airflow tracing. The muscle action potentials were passed through an amplitude analyzer (Frederic Haer) which converted the discriminated, analog, motor unit activity to standard pulses of 3.3 V lasting 50 microseconds. A counter in the microcomputer tabulated the number of pulses, Simultaneously, an analog-to-digital (A/D) converter digitized the airflow signal. The microcomputer read the counter and digital airflow signal and reset the counter every 20 ms. A floppy disk received and stored these values. Inspiration and expiration were determined from the airflow signal, with a zero-crossing algorithm. Each breath was divided into 20 bins of equal duration. For histograms, equivalent bins were sumraed across 50 breaths. 36 In the first stage of analysis, total EEG power was correlated with half-wave rectified and integrated IMA (tirae constant=0.1 s). The EEG and integrated IMA were passed to A/D converters. The raicrocoraputer read the A/D converters every 20 ms and stored the values on disk. A 7.158-min sample of data filled the disk; the sample consisted of 84 5.12-s periods. For each period, total EEG power was calculated with a fast-Fourier transform algorithra on the frequencies between 0.5 and 25 Hz, and the amount of IMA was calculated by summing the values read from the integrated activity. These values were stored in a 2 X 84 matrix, and from this raatrix, the microcomputer determined the correla- tion between IMA and total EEG power. In the second stage of analysis, I examined the postural affect on IMA. Again, IMA was half-wave rectified and integrated (time constant=0.1 s). The microcomputer read a value from the integrated EMG curve every 20 ras and summed the activity in 9-s epochs. The raean and standard deviations were calculated for all epochs in which the cat was in a given state and position (e.g., in NREM sleep, with electrodes recording IMA from the chest wall on which the cat lay) during the same recording session. The signifi- cance of the difference between IMA recorded from two postures was tested by the Student's t_ test.
In the third stage of analysis, PGO waves and siraulta-
neous changes in IMA were defined before and after 37 lesioning. First, PGO waves were correlated with the amount of IMA. An amplitiude analyzer discriminated PGO waves and sent a standard pulse to the counter which tabulated the pulses. IMA was half-wave rectified and integrated (time constant=0.05 s). This signal went to the A/D converter. Every 20 ras, the raicrocoraputer read values frora the A/D converter and the counter and reset the counter. When a floppy disk was full, the araount of IMA and the number of PGO waves were calculated for 50 6.38-s periods. These figures were stored in a 2 X 60 matrix. From this matrix, the correlation coefficient between PGO wave frequency and IMA was determined.
In another microprocessing program in this analysis, I examined the average amount of IMA during the average PGO wave. A histogram was constructed of PGO wave activity and of the IMA showing this relationship. The raicrocoraputer received input through three channels: one channel contained the signal from the araplitude analyzer, discrirainating the occurrence of PGO waves. A second channel transmitted a digitized PGO wave signal from the A/D converter. The third channel delivered the digitized half-wave rectified and integrated IMA signal frora the A/D converter. The raicro- computer sampled all three channels every 10 ras, reset the counter, and sent the data to disk for storage. Because the sampling rate was much faster than the period of PGO waves, the counter read either one or zero. When the counter read 38
1 , the microcomputer stored the previous and following 25 values from PGO wave and IMA channels in a 50 X 2 matrix. Frora the raatrix, two histograras were constructed: one, of the average PGO wave; the other, of the average IMA occurring during the PGO waves. The data base for this analysis contained both short episodes of REM sleep with bursts of PGO waves and long periods of REM- sleep. 39
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RESULTS
There were three priraary results: 1) an augraentation of expiratory IMA occurred during NREM sleep, 2) a strong postural effect on IMA existed during sleep, and 3) IMA increased, decreased, or rhythmically increased and decreased in association with PGO waves both before and after bilateral dorsal pontine tegmental lesions.
The intercostal rauscles were exposed to iraplant the electrodes. However, the origin of the recorded rauscle activity could not be determined because it may have arisen from either the external or the internal intercostal rauscles. The uncertainty existed because of the proximity of these rauscles and the possibility of recording activity at a distance; therefore, phasic, respiratory-related, intercostal activity was defined as inspiratory or expirato- ry based on the tiraing of the activity in the respiratory cycle. It is most probable that inspiratory activity arose frora the external intercostal muscles and that expiratory activity arose from the internal intercostal muscles. These assumptions follow Hamberger's (1748) theory based on the anatomical orientation of the rauscle fibers. Many studies recording IMA frora intact and partially isolated intercostal
41 42 muscles (Taylor, 1960; Viljanen, 1967; Campbell, et al., 1970; Duron, 1973) support Hamberger's theory. Augmentation of Expiratory IMA
Expiratory IMA increased progressively throughout NREM sleep, peaking in deep NREM prior to REM sleep (Figs. 2, 3, and 4). In REM sleep, as Parmeggiani and Sabattini (1972) reported, expiratory intercostal muscles became atonic or hypotonic. Inspiratory IMA changed unpredictably in NREM sleep (Fig. 5): in the various inspiratory intercostal rauscle recordings, activity increased, decreased, or remained constant frora wakefulness to NREM sleep. In raost cases, inspiratory IMA decreased in REM sleep.
The activity of both expiratory and inspiratory inter- costal rauscles was correlated with the total power of the EEG (0.5-25 Hz frequency spectrura) in 64 7,168-rain intercos- tal EMG recordings. Each recording consisted of 84 5.12-s periods and contained periods of wakefulness and NREM sleep. In 24 recordings from 5 cats, expiratory IMA was correlated with EEG power; in the remaining 40 .recordings frora 8 animals, inspiratory IMA was analyzed. The results of this analysis showed consistently positive correlations between expiratory IMA and total EEG power in the period from quiet wakefulness into NREM sleep (Fig. 3, Table 1). The corre- lation coefficients of the individual episodes (n=84 periods) ranged from 0.08 to 0.70 with a grand mean equal to 0.44 (N=24 episodes, Table 1). 43 The correlations between the integrated inspiratory IMA and EEG total power varied considerably among cats. The mean _r values were scattered between -0.34 and +0.38 (n = 84 periods). Changes in inspiratory IMA with sleep were gener- ally unpredictable from animal to animal and frora episode to episode (Table 1: Cats J, F, D, E-(B), T, C-(B)), but the activity of some inspiratory muscles either increased or decreased consistently with increasing depth of NREM sleep (Table 1: Cat P, G-(A)).
Cycle-triggered histograms (CTH) of IMA in NREM sleep were corapared with those in wakefulness (Fig. 4 and 5). Altogether 201 CTH were constructed: 62 of expiratory IMA and 139 of inspiratory IMA. Nineteen of 20 coraparisons between pairs of CTH of expiratory IMA showed increased activity in NREM sleep. CTH revealed that the augraentation of expiratory IMA involved a generalized increase in activi- ty throughout the respiratory cycle (Fig. 4). The shape of NREM-sleep CTH was similar to the shape of wakefulness CTH (Fig. 4). In the single case which did not show an increase, the activity was largely tonic in wakefulness, but became more phasic and respiratory-related in NREM sleep.
Cycle-triggered histograms of inspiratory IMA revealed, variously: 1) no change (Fig. 5A, 56 percent of the cases), 2) a decrease (Fig. 5B, 21 percent of the cases), 3) an increase (Fig. 5C, 16 percent of the cases) in the respira- tory activity, or 4) a change in the amount of tonic nonres- 44 piratory activity (Fig. 5D, 7 percent of the cases) between wakefulness and NREM sleep. Postural Effect on IMA
The IMA recording electrodes were iraplanted only on one side of the cat. Generally, this was the left side. When the cat was lying on his left side, the left chest wall was stretched on the convex side of the curl and bore the animal's weight. When an animal was in this position with electrodes implanted on the left side, the electrodes were down. I compared IMA recorded with the electrodes down to IMA recorded with the electrodes up.
The intercostal rauscles were defined according to the relationship of their activity to respiration. Cycle-trig- gered histograms (n=56) correlating IMA with respiration were constructed from data collected when the animals were in NREM sleep. For a representative profile of IMA, four 50-breath CTH were normalized and averaged for each rauscle recording (Fig. 6). An index of the phasic respiratory coraponent was obtained by calculating the ratio of peak to nadir in the CTH. The range of ratios was frora 5.3 to 14 for inspiratory IMA and 2.2 to 8.3 for expiratory IMA. When the aniraals were recorded unrestrained, IMA was correlated with chest raoveraents. Peak IMA occurred in the sarae phase of respiration as indicated by the CTH. In the curled, semiprone posture, left IMA was less when the animal was lying on his left rather than his right 45 side (Fig. 7). This postural effect occurred in NREM and in REM sleep, but in the latter state the effect was much smaller and raore variable (Figs. 8, 9, 10 and 11; Tables 2 and 3). Although the postural effect was evident also in quiet wakefulness, it was not analyzed. These periods were very short because alpha waves and spindles appeared in the EEG recording soon after the cat assumed a curled, sleeping position.
The analysis of the effect of posture on IMA was based on 24 recordings from 14 different rauscles in 7 unrestrained cats. These recordings yielded a total of 6860 9-s epochs. Of these, 5272 9-s. epochs were from animals in NREM sleep. All inspiratory IMA recordings (n=13) showed greater activi- ty when the recorded side was upward. Seventy-three percent of the expiratory IMA recordings (n=11) also increased activity when they were upward. Two of the expiratory recordings (sarae electrodes, different sessions) showed an opposite pattern: their IMA showed greater activity when the electrodes were down rather than up.
The decrease in IMA frora NREM to REM sleep raasked the postural effect; however, in seven of ten recordings of inspiratory IMA in REM sleep, activity on the upward side was greater than activity on the downward side (Fig. 10, Table 3). In four of six expiratory IMA recordings in REM sleep, the postural effect was also significant. In the other two recordings, expiratory IMA was greater on the 46 downward side than on the upward side.
There was no correlation between the araount of change in activity between the two positions and the amount of phasic versus tonic activity in the IMA recording: for inspiratory IMA, r_ = -0.13 (n = 7), and, for expiratory IMA, r^ = 0.13 (n=7). IMA During PGO Waves Before and After Pontine Tegraental Lesions
During REM sleep in the intact animals, the intercostal muscles became either atonic with episodic bursts of activi- ty or hypotonic with the persistence of rhythraic, respirato- ry-related activity. In REM sleep, inspiratory IMA persisted more than expiratory IMA (Fig. 12). An analysis of the relationship between IMA and PGO wave activity in REM sleep failed to show a consistent pattern of IMA occurring with PGO activity (Table 4, Figs. 13, 14, and 15). Corre- lation coefficients between the araount of IMA and the density of PGO activity varied around zero (Table 4). Sirailarly, the cross-correlation histograms (CCH) did not reveal consistent increases or decreases in IMA related to PGO waves (Fig. 15). Bilateral, pontine tegmental lesions produced various disturbances in REM sleep. In five lesioned animals, REM sleep did not reappear during the recording sessions for periods of 8 to 63 days (specifically, 8, 21, 26, 28, and 63 days). During these sessions, PGO waves appeared in wake- 47 fulness and throughout NREM sleep. In three of these animals, arousal occurred just as they entered REM sleep and was associated with violent jerks. Four of the five animals recovered, returning to REM sleep with atonia. The fifth was killed after 63 days without REM sleep.
Five lesioned aniraals (including two of the recovered animals from the previously mentioned group) had REM sleep and showed a decrease in IMA with REM sleep onset; however, they showed increases in IMA associated with PGO waves (Table 4, Figs. 13, 14, and 15), The patterns of IMA around PGO waves varied, but in some cases, CCH revealed an inhibition followed by an excitation in IMA after the occurrence of a PGO wave (Fig. 15). Correlation coefficients were determined between the araount of IMA and density of PGO activity in 24 REM episodes from 5 intact animals. Because the REM episodes had differ- ent durations, the number of 6.38-s periods upon which the correlations were based ranged from 20 to 60 (Table 4). The correlation coefficients between IMA and PGO waves varied about zero and had a raean r_ and standard deviation equaling -0.3 t 0.26 (Table 4). The mean _r and standard deviation
frora inspiratory and expiratory IMA were -0.02 t 0.22 (15 REM episodes) and -0.05 ± 0.33 (9 REM episodes), respec- tively, and were not significantly different frora zero or each other (Student's _t test). In the five lesioned animals, the coefficient correlat- 48 ing IMA and PGO waves shifted to consistent, positive values in REM sleep (Table 4). The raean and standard deviation of the correlation coefficients were 0.37 * 0.19 for 28 REM episodes (Table 4). In this case, mean jr was significantly different from zero (P<0.005; Student's t_ Test) and raore positive than that obtained in the unlesioned animals. The mean correlation coefficient for inspiratory IMA was 0.35 ± 0.19 (N=21 REM episodes) and was not different from the expiratory-IMA r_, which was 0.41 ± 0.17 (N=7 REM episodes). In intact animals, 163 CCH relating IMA to a PGO wave were constructed by averaging IMA every 10 ms in the period 250 ms before and 250 ras after the occurrence of a PGO wave. The analyzed data consisted of both short bursts of PGO waves and long periods of REM sleep. Even though CCH revealed no consistent increase or decrease in IMA concur- rent with PGO waves in the intact animals, patterns were evident (Fig. 15). There were CCH showing: 1) peaks in the IMA histograms, 2) troughs in the IMA histograms following PGO waves, and 3) alternating peaks and troughs in the IMA histograms (Fig. 15), In raost cases, however, CCH were flat, revealing no change in the pattern of IMA, This was most apparent when the CCH was based on a large nuraber of PGO waves (Fig. 15).
In the lesioned aniraals, 30 of 148 CCH indicated distinct patterns in association with bursts of PGO waves. With bursts of PGO waves, IMA decreased and then increased 49 rhythraically. Another pattern consisted of a sustained augmentation in IMA which lasted beyond the 250 ras chosen for the cross-correlation histograra (Fig. 15). Simultane- ous twitches in other rauscles were also noted during these episodes.
Other behavior alterations occurred in these lesioned animals. These included: 1) increased motility, essentially an "obstinate locomotion," 2) increased appetite, 3) increased breathing frequency, and 4) increased aggressive behavior in one raale and one female cat. 50 0 ^-N ro >, o r-i •o 3 w o CD 0 •o a. 4J 10 •H 0 N—^ to CD to cH • . o 0 0 o a iH .^-. O í. s_ to 0 CD a i- o 3 0 4J o 0 c 4J E îH •H 4J 4-> •H ro tO a c x: l-< •H 4-5 •H >. 4->
0 lo g 0 lim a to hi s ram ; ator ; i- nj s:: c CD 4-> •o i. 3 •H a to a c •H 3
deterra i tO proces s a s th e c roencep h vit y i n C crease d ^ •H 4-» o •oH •H ni Th e augmentatio r (botto m tw o tracings ) moveraent s (EOG) , ele c wave s wer e recorde d t Respiratio n (inspira t muscl e activity . Ac t NRE M slee p an d the n < activit y i n RE M slee p 51
lU GC
oCA O cc UJ >- oc < o < oc oc 0. o a X o 20 •• ÍS UJ Q uj 100 200 TIME (SECONDS) 54 Table 1 Correlation Between Integrated IMA and EEG Total Power Expiratory IMA Inspiratory IMA Correlation Correlation Coefficient Coefficient Recording (N) (Mean + SD) Recording (N) (Mean + SD) I (5) .36 ± .22 P (5) -.34 ± .04 G-(3) (6) .42 ± .18 J (5) -.12 ± .18 C-(A) (6) .46 ± .13 F (5) -.08 ± .26 E-(A) (2) .49 ± .08 D (7) -.02 ± .30 M (5) .50 ± .16 E--(B) (3) .06 ± .31 T (4) .18 ± .13 C--(B) (6) .24 ± .28 G--(A) (5) .38 ± . 10 TOTAL (24) .44 ± .16 » TOTAL (40) .03 ± .09 e N: The nuraber of 7.168-min episodes, each consisting of 84 5.14-s periods, that were anaiyzed to determine the mean correlation between IMA and EEG total power. *: p<0.001, Student's 't' Test, Ho: r(x,y)=0 ê: not significantly different frora zero. 55 Figure 4 The cycle-triggered histograra of expiratory intercostal motor unit activity in NREM sleep (heavy line) is much greater than the cycle-triggered histogram attained in the previous waking episode (diagonal area). Total number of discriminated intercostal-rauscle action potentials per bin over 50 breathes is plotted on the ordinate. The 20 bins are on the abscissa denoting inspiration and expiration. The peak of the NREM activity is 2.67 times the wakefulness peak. 56 '60-1 CAT I iZZ Wakefulness J L NREM Sleep 57 Figure 5 Cycle-triggered histograms of inspiratory intercostal motor unit activity show various alterations in activity with change in state from wakefulness (thin line, diagonal lined area) to NREM sleep (heavy line, open area). The ordinate and abscissa are the same as Figure 4. In A, activity stayed the same. This occurred in 56 percent of the cases. In B, activity decreased from wakefulness to NREM sleep. This is representative of 21 percent of the cases. In C, activity increased from wakefulness to NREM sleep in 16 percent of the cases. In D, only the activity in the expiratory phase of respiration increased. This happened in seven percent of the cases. A total of 57 pairs were compared. 58 B \^/A Wakefulness 600-1 .NREM Sleep 3001 >- I- > 450- < CAT P 200 2 300- O o oc liJ H- 00-1 S 150- o-" 200i 200 / / / 150- 150 /_, // // CAT F CAT D-A 100- 100- / / VH / 50- 50- r f ' > r~r-^^^~^~^-' ^ ^ ' Q //7/?^ > > / > > 11 I j 0-" -I 1- 59 Figure 6 Cycle-triggered histograras (CTH) plotted to represent each intercostal muscle recording. The inspiratory muscles are shown in A; the expiratory muscles in B. Each CTH is an average of four normalized CTH. The arrows point to the transition from inspiration to expiration. 60 B TXT 1100 75 75 50 ftMÍ! 50 llOO 50 100 X 25 u- so O 100 5 10 15 20 BINS 61 Figure 7 The postural effect recorded from the left inspiratory intercostal muscles. In A, the aniraal was restrained in the sphinx position. The tracheal fistula was intubated and respiration was recorded (second line, inspiration up) . This showed that IMA (third and fourth lines) was inspira- tory. In B and C, the animal was unrestrained, lying curled on the left side, electrodes down (B) and lying on the right side, electrodes up (C). IMA was significantly greater when the activity was recorded from the concave upward side versus the convex downward side. In.A, B and C, the EEG (top line) showed that the state of consciousness was NREM sleep in each case. 62 •A A Sphinx position NREM Sleep ^ EEG <^«ifp|Hii||l|M^^ Resp.llnspup) Left Intercostal EMG mmtimmmm^mmêBêtitmi t-^.7 D Curled left side DOWN t EEG ti4pt# \ í Left Intercostal E/V\G >- > »•—•-*—*—»^ »»••»»> > »--«•—-«^-»—•—•-»—-•.- — >••*- —t-j—(~f-+- >J--|H^-4- K- ^Curledleftside UP EEG Left Intercostal EMG mÊimmåÉmmmmmÊÊttmm 10 s. 63 Table 2 Intercostal Muscle Activity During NREM Sleep Inspiratory IMA Recording Electrodes DOWN Electrodes UP N Mean ± SD N Mean ± SD 1-(A) 210 34.5 ± 3.1 196 92.3 ± 9.6 * 164 43.1 ± 6.3 216 148.8 ± 20.1 * 1-(B) 210 26.2 ± 0.9 196 80.3 ± 7.0 164 46.8 ± 3.9 216 107.5 ± 10.1 * 2-(A) 34 38.8 ± 8.4 204 102.1 ± 22.1 * 162 58.2 ± 8.7 202 81.3 ± 8.5 * 3-(A) 18 40.6 ± 3.1 72 76.0 ± 7.9 * 100 42.6 ± 5.4 170 138.9 ± 10.8 * 4-(A) 44 34.0 ± 2.6 168 86.1 ± 11.8 * 46 47.9 ± 10.1 42 66.1 ± 9.8 * 5-(A) 104 20.9 ± 2,5 82 68.9 + 15.4 * 5-(B) 104 95.0 ± 4.3 82 117.7 ± 11.4 * 48 42.5 ± 2.9 70 54.3 ± 6.5 * 64 Table 2 continued Expiratory IMA Recording Electrodes DOWN Electrodes UP N Mean ± SD N Mean ± SD 2-(B) 34 33.2 ± 7.5 206 101.1 ± 17.6 * 162 26.0 ± 6.4 204 104.2 ± 7.9 * 3-(B) 100 26.6 ± 5.7 170 91.4 ± 9.9 * 4-(B) 44 89.4 ± 12.3 170 69.0 ± 16.5 •!• 42 102.2 ± 23.6 42 77.3 ± 9.9 + 5-(C) 48 62.0 ± 6.4 70 81.8 ± 6.4 * 6-(A) 20 63.0 ±11.8 44 76.2 ± 18.9 * 56 58.4 ± 12.5 88 89.7 ± 23.8 * 6-(B) 20 94.8 ±11.7 44 99.7 ± 20.8 @ 56 31.4 ± 7.3 88 108.1 ± 19.7 * 20 66.5 ± 2.9 58 88.2 ± 21.7 * N: The number of 9-s periods averaged from a recording session. *: p<0.05, that IMA with electrodes up is significantly greater than with electrodes down. @: The difference in IMA between positions is not signif- icant at p<0.05. +: p<0.05, that IMA with electrodes down is significantly greater than with electrodes up. All differences were tested by the Student's 't' test. Ho: x-y=0 65 Table 3 Intercostal Muscle Activity During REM Sleep Inspiratory IMA Recording El ectrodes DOWN El ectrodes !J P N Mean ± SD N Mean :t SD 1-(A) 122 47.7 ± 9.9 76 46.0 ± 11.0 § 78 52.2 ± 12.9 90 66.6 ± 13.8 * 1-(B) 122 38.9 ± 10.7 76 37.8 ± 4.2 § 78 65.0 ± 19.7 82 76.3 ± 11.2* 2-(A) 60 35.9 ± 2.9 86 39.8 ± 6.2 » 3-(A) 12 53.7 ± 20.8 42 85.5 ± 16.5 * 4-(A) 28 21.0 ± 0.9 80 24.6 ± 4.9 * 5-(A) 18 26.1 ± 7.2 26 70.6 ± 17.8 » 5-(B) 18 88.7 ± 4.7 26 108.3 ± 21.0 * 14 39.8 ± 12.7 52 34.4 ± 12.7 @ E>:pirator y IMA 2-(B) 60 15.3 ± 1.7 86 25.7 ± 7.2 « 3-(B) 12 35.2 ± 13.7 42 43.6 ± 9.3 * 4-(B) 28 23.8 ± 3.2 80 21.4 ± 0.6 + 5-(C) 14 59.4 ± 8.2 52 31.0 ± 8.1 + 6-(A) 12 17.2 ± 1.6 2 25.7 ± 9.0 » 6-(3) 12 17. 1 ± 0.4 2 37.9 ± 11.9 * Symbols are defined in Table 2. 66 (U T3 c 4-5 •D o C 4-> i. S 3 CD CD 4-> -P O x: T3 1 x; tO C w Q. •H d) w CD 4-3 -C o i- C M J-> t. bO (U cc o T3 E E to 13 •rH O (U •H 4-3 C í. s: s: CO cu c^H H +> (U (U to t- JC Ji^ b • O 4-3 -P C w CH •H 0) >, -C "C! T3 ro X3 +> i- O 4J •H O t. (tJ ,^ 3 O 4-> XJ LH 0) O O C í. (U (U (U i-H s: O 0) «a; (U E- sy --1 s: CL ÍO hH J= N—' 4-> s: 4J> •H (U 4-> CX3 UJ c 3 T) c oc o •H (D 0) 2 V) T3 (0 o i. . 0) 0) Q. •H 3 bo s_ -P 3 Cw tiO C Q. C • H •i-f •H (1) CTJ •H T3 n E tO i- •H E "O CD O (U o UIO C T3 i- s: n -I m Q. m 13 yi t/t •= e e < (/> r"o. "(r3. 3^ < 3, ;;-s^; o o o in o if) vvNi AaoivaidSNi 2 68 -T |S CO eep n UJ 8 ect rode ^DE] tl-^M • ^^' -''•-: ::^^M^x#^^"^^ < J m H-:v:>N-Ss;>:y::s<:.j;^-J < H I ^ H I cM {->^:WilI§\^xv: ••v-.x..:- :v.."" m co HZiiI^HEM3 - i^:»:t^^:a>a:>^m::^i^^ cn §#fii#i»a o O in O o lO vi^i AaoivdidSNi s: 72 0 s: >. 4J> XI s: T3 4J> 0 0 •H s: 4-3 •~ o 3 4-3 o LO 3 c O 4J TJ • C • • 0 tO •H tO o C^ c T3 0 to s/ •H S- T3 M 0 a 0 o O ro M >_.• M M o S- E c XI ro 0 4-3 •H ZD 0 ra E c O c T3 E- •H 0 ra •H c 1- æ íiS^^i>^^-^^^^ I ^ Slee p ectrode s ectrode s S lU LJJ J.v>-''-^\:\>W. :••• v\\\\\\\v\\\V\\\\\»\ < UJ DH H ^«»« o D f w CD oL o o lO V^Ni Ad01VdldX3 S 74 CO 0 4J M to XI a bO CH i- o c 0 C o 3 4J> ro 0 •H JO to CH T3 c -^ M X> 0 ro bO >, ro c X3 >, .c c • XI s: ra i- i. 4-> •H to o 0 o o to T3 XI O O -C 4-3 0 ra 0 C c CxJ 0 4-3 ro i. i- c ra o Lú i- i_ o 4-3 to o c • H 3 E O 0 0 to •H CL. a o U) to XJ ro X •H to o UJ 3 3 >, 0 M 4-3 o 0 4-> 4-3 tO ro ^^ >. -C •H í^'-N •H 0 E c o 4-> M a > •H to o c a 3 •H • H c 0 o 0 c E 4-3 s: ra > 3 M ro to o 3 ro c« cr 1 ra •a; 4-3 3 o 0 3 3 a O i. . O 0 ro o 0 Cw bO M c 4-> , 0 o 4J 1 c o 0 ,—1 c D. n: 3 •H 0 •H M (0 •H 4J O XI x: 4-> O c to M 4J to 3 UJ •H a 0 co r >, ir a E cc 0 c 0 0 X3 a 0 •H a XI i- X M o '—• 3 CM 0 E XI 0 ro 4-) «— M 0 tO +> •H lUTO B bd n _ CiJ 0 3 s: X! CH b Lú o c o -am p cte r H cc terc ( 3te d •H 4J> ro i- c O i. 4-3 4-3 •H ig h o T3 al f ra x: 0 ,<- 4-) >, .û rauscl e persi : r e record h e firs t ícam e aton i T3 ccurre d ch i io n (thir d as e o f th 0 0 4-3 o 4J> M persiste d i n XI N x: 3 ro a ra Inspirator y IM A (secon d tracing ) wave s occurre d i n record , RE M slee p G O waves . Respi r rmin e th activ irator y intercost : Lrator y IM A whic h vit y diminished . 03 3 CH exp ; NRE M slee p character i PG O th e ins p det e o act i 75 76 Table 4 PGO Wave and IMA Correlati on in REM Sleep Recording Prelesion Postlesion Correlation Cat/Channel Correlation Coefficient n Coefficient D 60 -.41 32 .19 44 -.33 60 .50 60 -.29 60 60 .53 -.53 26 .30 60 -.52 44 -.03 60 .37 60 .52 20 -.37 60 .18 60 .10 26 .30 53 -.16 47 .30 44 .18 38 .55 26 .22 14 .66 59 .32 3 60 -.10 11 .67 4 60 -.10 14 .25 59 -.07 5 .23 47 .02 28 .29 23 .06 14 .32 26 .33 14 .42 59 ,06 5 .21 47 03 26 ,47 23 41 23 .53 14 .73 3 38 04 26 .26 56 06 20 31 29 35 4 32 15 23 12 56 33 20 10 29 49 Total N = 24 -.03 N = 28 .37 The number of 6.38-s periods for the basis of the correlation between IMA and PGO wave activity. The total number of REM episodes in which IMA and PGO waves were correlated. p<0.005, Student's 't' Test, Ho 'r'(x,y) = 0 77 x> s: c UJ ra XJ c cc 0 •H M bO enc ; es s IM A 4J> Duri r inta c inhib i ator y menta l tivel y a l (A ) ikeful n i- c bO ra lU E • >, i n freq u •H ro 0 b •H M 3 a 4-> 0 c CQ 0 XI XJ tO c r c ra 4-3 c •H 0 c M slee p pontin ( B ) wa s intac t anima l altern a increa s slee p a 78 79 T3 C XJ ra < 0 0 s: x: to • c ^^ M jj> ro M 0 < 3 ro •H v-^ .- — E to CQ 0 to •H 0 0 to 0 c M i. XJ M > ro o c < ro 0 CH ro 3 XI x: 0 0 4J> Xi «3; • 0 c ^^ 0 0 C a x: C . •H •H 0 4-> to 0 0 XI tw 0 >. M X3 c 0 M 0 10 ra C C to 0 0 s M .a; 4.3 JC 3 UJ to 4-> cr cc c i. 0 • •H 3 c i. w UJ .0 •H Cw c bO •H 4-3 c 0 0 •0 i. ro •H x: 4-3 0 3 0 0 4-> ro to XI ra c ra c i- x: •H 0 T3 •H 4J> 4J E k-. 0 •H 0 0 XI ^-N XI 3 X3 c t. CD c 0 •H =r o •«-' 0 XI i. >- o 0 0 a c 0 to 0 4J ra 0 t. c to ro 0 i. 0 ^-^ •H i. XJ 3 to •H 0 0 ra bo ro to 10 0 E x: •H 3 0 0 to [i.. M > to x: .—, -^ ra ro bC CQ CQ M 3 3 " . ro c 0 XJ a XI 4J 0 i. (—• c 0 C c 0 0 ro 0 ro 0 Q- 4-> M3 M E 4-3 ra <£ to • bO 0 ro 0 4J a .. C s: c +3 to •H UJ •H 1 T3 >, bO D= 0 0 i. c bO bO c 4-3 0 •H c C c •H ra 4-> XJ •H •H •H 4J> M •H i. 0 o C 0 .D 0 ro >, ro 0 i- •H 0 i- M i. a i- s: 0 4-> M 4-> 0 c i- ra .* 0 •H a •H XI M x: 0 0 i. ro >> XI 4-3 4J 0 •H i. M c 0 v-^ a x: 0 0 ro X3 10 4J) 4J> c 0 s-^ > ro •H >, C 0 M 4-3 i. •H •H c cí •H •H 0 4-3 0 2: XI to 4-3 4-3 ra •H M 0 ro C i- 4JI i- a 4J> 0 •H •H 0 •H T3 a X3 4J tO 0 •H to C CH ra X > 0 0 ro 3 0 0 ee 0 80 81 bO 4-3 0 c c O CQ i. o o 10 ro o c t. E 4-3 CH to o o 0 ro c 0 0 XI o •H bO t. J3 > c CL, 4-3 c bO CH ro ra 0 •H o O O tO o 3 i- •H JO 4-3 E 4-3 ra tO E •H tO O i. M x: x: 0 a o o o 0 ro 4-> c x: 0 ro in D- x: i. E >, 4-3 0 s: c\i to 0 •H x: E CH JC i- XI O E bo O C s: 4J> c 4-> O 4-> ro c T3 ra 4-3 4-3 •H i. o X3 C O Lú 4-3 0 cn i. u 0 ra c XJ CC O i- XJ C o to XI 3 E XI o •H M bO 3 O c •H 4J> ro c O C E ra CQ tO (0 ra E •H ra 4-3 •H tl M o 0 0 i. i. •H c c ro Sl bO CQ 3 c o ro -H XI >, O X3 o X 4J> 4-> C >, c 0 X3 o 10 ro 4J 0 4-> ra ro •H 0 C •H 4-3 T3 CH 4-3 X3 -C o > T3 O 0 O o E- •H 0 ro 4-> s: ro x: to 4-3 C ro o a 4J c 0 t. O o 0 c ra o bû c ro ro •H 0 0 LPi to ro 0 0 M 0 i. >, 0 > 0 i. XI x: to o 0 ro > o 0 i. ro to JC 3 XI 4J> to 3 0 c 4-3 bO I 0 M 4-3 to o 10 4-3 •H O X3 x: c 0 •H c •H O o c 4-3 c 0 u. > 4-> t. 0 Q- ro 0 0 ro 0 bO C^-i x: to 0 ra ra i. XI 3 Jj) c Cw 4-3 4-> XI 4J 3 0 •H 4-3 o 0 bO u c to N O ra 0 to o t. •H >, a 4-3 CH X3 10 ro o X 4-3 T3 c 0 x: 0 to C XI ra Cw 0 ro i. 0 DL, ro 4-3 c x: O a 0 to ro 4J) c ro 0 > ro CH •H i. t- E M cc ro X3 0 o ra 0 3 c O i. 10 M ra i- E to 0 O T3 E T3 3 0 x: i. ro O •H 3 ro 0 O t. o i- O 4-3 40 o C^-i O. i. •H a E bO E a bO ro 4-3 I o ra 0 O O O •H i- ro 4-) to 4J> ro i- 0 4-) o ro 4-> 10 bO M x: to to o a CtH o o s. o to to c i. o JD ro 0 4-3 tO o 4J> to x: to 0 ro T3 ra x: CH •H 0 XI 10 a UJ > C 3 o c o ro x: •H ra o ro oc 0 ro c ra 4-3 XI 3 4J Lú to 0 JC Cw ra c u XI a E o 4J> >, ro o O •H o to c ro •H > 4-3 o 0 0 M to E 4-3 c 0 ro tO ro i- 0 u s: X3 0 to E o O 4J 0 x: i. 0 •H 4-3 4J •H XI XI •H •H to a > o 4-) c c c x: i- ro c ro ro ro 0 0 X ra 3 i- 3 0 a 3 a t. 82 CHAPTER IV DISCUSSION Augmentation of Expiratory IMA Expiratory IMA was augmented during NREM sleep, peaking in deep NREM sleep when single PGO waves occurred. Inte- grated expiratory IMA correlated positively with EEG total power in periods containing only wakefulness and NREM sleep. During REM sleep, expiratory IMA decreased as did other skeletal muscle activity. In contrast to expiratory IMA, inspiratory IMA changed unpredictably during transitions from wakefulness to NREM sleep and in NREM sleep. For instance, in some cases, IMA increased in both inspiratory and expiratory phases; in others, it increased specifically in the expiratory phase. Other cases showed decreased IMA in both phases, or no change across the respiratory cycle during NREM sleep. In REM sleep, some recordings showed that inspiratory IMA became hypotonic. But in others, inspiratory activity persisted in REM sleep. The inconsistent behavior of inspiratory IMA during NREM sleep does not agree with the results of Tabachnik et al. (1981), who recorded a consistent, 34-percent increase in human inspiratory IMA during NREM sleep. There are 83 84 important methodological differences between this study and that of Tabachnik et al. (1981) which may explain this discrepancy. Tabachnik et al. (1981) used surface elec- trodes and recorded activity parasternally from the second intercostal space. On the other hand, in this study, bipo- lar, chronically implanted electrodes were used and recorded IMA laterally in the fifth to seventh intercostal spaces. In the parasternal region, the inspiratory interchondral rauscles have a low density of muscle spindles (17 spin- dles/g dry weight muscle in cat). Laterally, in the lower intercostal spaces, the spindles of the inspiratory (exter- nal) intercostal muscles are more dense (113 spindles/g dry weight muscle in cat) (Huber, 1902; Duron, 1973; Jung- Caillol and Duron, 1975; Duron et al., 1978; Duron and Marlot, 1980). Therefore, parasternal interchondral muscles with few spindles show little tonic activity and marked phasic, inspiratory activity, whereas, the lateral, external intercostal muscles with many spindles show tonic as well as phasic activity (Jung-Caillol and Duron, 1976; Duron and Marlot, 1980). Accordingly, interchondral, inspiratory muscles have a greater respiratory function than the exter- nal intercostal muscles, and they may respond more to increases in arterial P(C0(2)) occurring in NREM sleep than the external intercostals do. Secondly, the results of Tabachnik et al. (1981) could have been influenced by a reflex response to increased upper 85 airway resistance. This increased resistance occurs during sleep in both huraans (Remmers et al., 1978; Lopes et al., 1983) and cats (Orem et al., 1977). In our study, the animals breathed through an endotracheal tube bypassing their upper airway. Therefore, upper airway resistance changes usually associated with sleep were not a factor. A species difference also exists in these two studies. One can expect differences in the raechanics of breathing between species and especially between a bipedal versus a quadripedal animal. For exaraple, huraans show an increase in the thoracic coraponent in breathing during sleep (Mortola and Anch, 1978; Tabachnik et al., 1981; Naifeh and Karaiya, 1981). It is not known if the increase in parasternal IMA is iraportant in this behavior; nor is it known if cats display similar changes in their breathing pattern. Other species-specific differences, as yet undiscovered, may explain the discrepancy between the studies. In contrast to the inconsistencies in inspiratory IMA in NREM sleep, the progressive augmentation of expiratory IMA was a consistent finding. The respiratory consequences of this augmentation are unknown. It does reflect a progressively greater participation of the expiratory inter- costal muscles in breathing during NREM sleep. But, inter- costal muscle recordings correlated only with airflow are insufficient data to determine the respiratory function of the recorded rauscle. For instance, De Troyer et al. (1983, 86 p. 88) postulate "the electrical activity observed during quiet expiration in the interosseous portion of the lower- most internal intercostals may be regarded as an antagonis- tic activity which tends to prevent collapse of the lower rib cage, rather than as an agonistic activity which deflates the rib cage." Chest wall motion is complex, requiring the simultaneous contraction of many muscles (De Troyer et al. , 1983). Therefore, to associate the increase in expiratory IMA with increases in the thoracic component of Vt will require data on chest wall compliance. Nevertheless, state-specific increases in thoracic breathing in NREM sleep (Mortola and Anch, 1978; Tabachnik et al., 1981; Naifeh and Kamiya, 1981) may cause an increased expiratory IMA. In a representative study, thoracic displacement accounted for 40 percent of the tidal volurae in wakefulness but 70 percent of it in NREM sleep (Tabachnik et al., 1981). Proposed causes for this shift in the breathing pattern include the changed posture for sleep (Tusiewicz et al., 1977) and the increased upper airway resistance (Tabachnik et al., 1981; Lopes et al., 1983). In huraans, the change from standing to supine decreases the passive expansion of the chest secondary to diaphragraat- ic contraction (Goldman and Mead, 1973); therefore, when one is supine, a greater IMA is required to produce a given rib cage expansion than when standing (Tusiewicz et al., 1977). This mechanical uncoupling suggests that the increased IMA 87 in sleep is compensatorv anH iri-fv, 4-u- F ûdoory and with this compensation, the araount of thoracic as opposed to abdominal displaceraent accounting for the tidal volurae also increases. However, Naifeh and Karaiya (1981) showed that thoracic breathing was actually greater in sleeping than in awake supine humans. Our experiments controlled the possible effects of changes in posture. The cats maintained a sphinx position through- out sleep and wakefulness because of the manner in which they were restrained. Although increased upper airway resistance did not affect these IMA recordings, intrathoracic resistance changes may have. The endotracheal tube, inserted below the cricoid cartilage, projected only three to four centimeters into the airway. However, widespread changes in airway sraooth muscle tone would have to occur to increase airflow resistance enough to affect IMA because these intrathoracic small airways function as parallel resistors. Other causes of the increased expiratory IMA during NREM sleep must be considered. One.potential factor is the increased duration of the respiratory cycle in NREM sleep. But, in the periods examined for correlation of integrated IMA with total EEG power, the changes in the breath duration were small. Second, inspiratory IMA was also subject to possible changes because of longer respiratory cycles, but it did not show a consistent augmentation. Longer breath duration can not account for the increases in expiratory 88 IMA. Another possibility is that the augmenting expiratory IMA is a response to chemical stimuli which develop during sleep. Arterial P(C0(2)) increases from quiet wakefulness to NREM sleep. However, in Dial-urethane anesthetized cats, Arita and Bishop (1983) deraonstrated a depression of inter- nal intercostal raotor units during normoxic hypercapnia. The hypercapnia, induced by adrainistration of 3, 5, or 7 percent C0(2) in 21 percent 0(2) and the balance N(2), was greater than the slight hypercapnia occurring during NREM sleep, Arita and Bishop (1983) concluded that hypercapnia does not affect substantially descending facilatory inputs from brainstem expiratory neurons onto spinal expiratory motoneurons. Indeed, Mitchell and Herbert (1974) and Baker et al. (1979) have shown that in the brainstem inspiratory activity is raore sensitive than expiratory activity to changes in arterial P(C0(2)). Arita and Bishop (1983) reraarked that during inspiration, when inspiratory neurons inhibit expiratory neurons (Sears, 1977; Cohen, 1968, 1979; Merrill, 1974), hypercapnia may increase this inhibition, slowing the rate of depolarization of expiratory motoneurons in early expiration. In contrast, Bainton et al. (1978) reported excitatory effects of C0(2) on both inspiratory and expiratory IMA in artificially ventilated, decerebrated cats. In summary, the cause of the increased expiratory IMA 89 is unknown. A prolonged respiratory cycle is not a suffi- cient reason for increased IMA. Although available data conflict, increased arterial P(C0(2)) does not cause a specific augmentation of expiratory IMA and raay even inhibit expiratory activity. The other two factors, postural changes and increases in upper airway resistance, were cited in earlier studies and were controlled for in this study. It is not known whether other expiratory rauscles show similar increases in activity in NREM sleep. Sherrey and Megirian (1977, 1980) observed in rats changes in the activ- ity of the cricothyroid muscles with changes in the state of consciousness. In wakefulness, the cricothyroid showed expiratory activity; in NREM sleep, recordings showed only inspiratory activity or both inspiratory and expiratory activity. Duron and Marlot (1980) studied the triangularis sterni muscle (an expiratory rauscle) across states of consciousness and did not report an augraentation process during NREM sleep. However, these rauscles have very few muscle spindles (Duron and Marlot, 1980) unlike the lateral internal intercostals. Therefore, direct functional coraparisons are difficult. Finally, comparisons of the cycle-triggered histograms of expiratory IMA in wakefulness and NREM sleep showed a generalized increase in activity in NREM sleep. The increase in expiratory IMA did not coincide with one phase of respiration. Rather, activity increased throughout the 90 respiratory cycle suggesting a tonic, nonrespiratory-raodu- lated stimulus. It is interesting that activity in the red nucleus increases with bursts of synchrony in the EEG (Gassel et al. 1966a,b). The red nucleus is facilitatory for flexors and projects to the thoracic cord in cats (Brodal, 1969). Potentially, the red nucleus may affect expiratory IMA during NREM sleep. But clearly, the neuronal substrate mediating the augmentation is unknown. Possibili- ties exist for mechanical and chemical reflexes as well as state-specific, central neural generation. Postural Effect on IMA The animal's sleeping position dramatically influenced IMA. A generalized, although variable, increase in activity was recorded from intercostal muscles when they were on the upward chest wall as opposed to being on the downward chest wall with the animal lying curled on its side. This differ- ence in muscle tone raay reflect a difference in postural rather than respiratory influences on IMA. The response affected the inspiratory and expiratory IMA equally. This increase was recorded in NREM sleep, and although sraaller and more variable, it persisted in REM sleep. The postural effect was evident both in muscle recordings which showed a strong respiratory signal and in those which showed raore tonic activity. IMA has at least two coraponents: 1) phasic, respiratory (either inspiratory or expiratory) activity, and 2) tonic. 91 postural activity (Duron, 1973; 1981). Not all intercostal muscles have the same pattern of activity. Jung-Caillol and Duron (1976) have shown that the amount of tonic, postural IMA is related to the concentration of muscle spindles with- in that muscle. There is a rostral-caudal gradient in the distribution of muscle spindles in the intercostal muscles. The rostral intercostal muscles have the highest concentra- tion of muscle spindles and the greatest amount of tonic activity. The concentration of muscle spindles decreases caudally. The interchondral or parasternal muscles have the lowest concentration of muscle spindles in the chest wall and very phasic, inspiratory muscle activity. The sterni triangularis or tranverse thoracic muscles show phasic, expiratory, activity and have very few muscle spindles (Jung-Caillol and Duron, 1976; Duron and Marlot, 1980; Duron, 1981). There is also a dorsal-ventral gradient in muscle mass. The internal intercostal rauscles are thickest in the para- sternal region where they are referred to as the interchon- dral muscles. Their muscle sheath thins laterally, and there are no internal intercostal muscle fibers paraverti- brally. In contrast, the external intercostal muscles are thickest paravertebrally. Their sheath thins ventrolater- ally and is thinnest at the costochondral junction. External intercostal rauscle fibers are not present between the costal cartilages. In suraraary, the internal and 92 external intercostal rauscles are present at the mid-axillary line, an imaginary line at the intersection of the ribs with the axial plane of the body. The internal intercostals, specifically, those in the lower intercostal spaces and lying on the raid-axillary line, show phasic, expiratory activity. They possess spindles also and have a tonic, postural component in their recordings. Their counterparts, the external intercostals, are sirailar but show phasic, inspiratory activity. In these experiraents, bipolar electrodes recorded activity from the lateral chest wall in the fifth to seventh intercostal spaces. This position was near the raid-axillary line. I assurae that expiratory IMA carae from the internal intercostal rauscles, whereas inspiratory IMA was from exter- nal intercostal motor units. This is the first report of a postural effect on IMA in chronic, sleeping animals. It is in agreeraent with the results of studies by Massion (1976) and Massion et al. (1960) on decerebrate cats, by Duron and Marlot (1980) on chronic, intact, awake aniraals and by Frankstein et al. (1973) on humans. Massion noted an increase in IMA on the side towards which he turned the animal's head. Duron and Marlot observed that in bilateral, external intercostal muscle recordings (third space), activity was symraetrical when the cat was sitting with its head straight. When the cat turned its head, IMA became asymmetrical with activity 93 greater on the side toward which the head turned. Frankstein et al. (1973) reported that when a subject leaned forward, rotation of the head to the side increased IMA on that side. Clearly, these postural reflexes are similar to the response reported in this paper, and the underlying mechanisms may be similar also. However, because the sleeping position of the cat involves more than a simple turn of the head, other mechanisms and influences may be involved. The cat lies curled against a surface, stretching the intercostal spaces contralateral to the direction of the curl and compressing the ipsilateral spaces. The cat also turns his head in the curled direction, resting it on his front paws. Massion et al. (1960), Frankstein et al. (1973), and Massion (1976) hypothesized that cervico-labyrinthine reflexes caused the postural effect on IMA. The influences of cervico-labyrinthine reflexes on brainstem respiratory- related units have been studied. Ghelarducci et al. (1974a,b) recorded 30 medullary respiratory neurons in a decerebrate cat but could not alter neuronal discharge frequency by tilting the animal. These cells were located in the dorsal respiratory group and in the nucleus arabiguus of the ventral respiratory group (VRG). No attempt was made to record and identify specifically those cells which project to the thoracic cord. Therefore, it is possible but unlikely that a cervico-labyrinthine reflex acts through 94 respiratory bulbo-spinal neurons to increase activity on the upward side. It is more likely that these influences act at the segmental level. Corda et al. (1966) recorded alpha and garama intercos- tal raotoneurons in decerebrate cats. They, like Massion et al. (1960), noted that turning of the head increased the discharge frequency of the motoneurons on the ipsilateral side. Both external and internal intercostal muscle spindle activity increased on the ipsilateral side and decreased on the contralateral side. They atterapted to isolate cervi- cal joint receptor influences from vestibular influences by inactivating the vestibular apparatus with lignocaine injections into the inner ear. The response to head turning was not dirainished after lignocaine injections. Duron (1981) and Jung-Caillol and Duron (1976) recorded external IMA bilaterally in a decerebrate cat. They reported that passive lateral curving of the thoracic wall, widening the intercostal spaces on the convex side of the curve, increased tonic IMA on this side and decreased tonic activity in the rauscle on the concave side. This pattern is opposite to the one recorded in this study and was probably influenced by the generalized increased gamma activation associated with decerebration. Corda et al. (1966) exarained the influence of joint receptors located in regions other than the cervical verte- brae on intercostal rauscle tone. In a decerebrated and 95 paralyzed cat, lateral flexions of the back in the lumbar region coactivated the alpha and tonic gamma intercostal raotoneurons on the concave side of the cat. On the convex side, motoneuronal activity decreased. Also, flexing the hindlimb at the hip increased intercostal motoneuronal activity on the ipsilateral side and decreased activity on the contralateral side. They noted that all the reflexes with the exception of those elicited by lateral flexion of the head persisted after cervical cord transection. There- fore, it seems that joint receptors coactivate alpha and gamma motoneurons in a pattern similar to that recorded in sleeping animals. Sumi and Kotani, (1959) and Surai (1963) defined reflex- ogenic skin areas for both inspiratory and expiratory inter- costal muscles. The response of intercostal motor units to stimulation of slowly-adapting pressure receptors was complex because both inhibitory and excitatory effects could be elicited from overlapping areas. For the expiratory motor units, the inhibitory receptive field surrounded a specific excitatory area. Activation of receptors over a large area of skin inhibited the underlying expiratory intercostal muscle activity. In summary, there are several possible mechanisras which contribute to changes in IMA. The postural influence may be the result of reflex raechanisrasbecaus e it has been recorded in decerebrate animals (Massion et al., 1960; Corda et al.. 96 1966; Massion, 1976). Corda et al. (1966) showed that the joint receptors in the neck, lumbar cord and hind limb can coactivate alpha and gararaa motoneurons. In addition to the gamma loop, there are complementary reflexes elicited by pressure receptors and Golgi tendon organs (Critchlow and von Euler, 1963) which may play a role in this IMA response to postural changes. In contrast, the postural effect may be the result of voluntary mechanisras. In these experiraents, the animals assumed their positions; they were not manipulated as in the studies demonstrating the above reflexes in decerebrate cats. The assuraed posture itself may be the result of the animal's therraal regulatory behavior (Parmeggiani, 1978). The hypothalamus, regulating teraperature while conserving energy, may control the sleeping posture assuraed by the cats (Parmeggiani, 1978). Whatever the reason, the curled semi- prone sleeping position raay require the patterns of IMA recorded in this study. The postural effect on IMA allows tidal volume to be maintained with the least araount of work. The chest wall that is free and up has the greatest displacement, whereas the one bearing the weight of the body shows minimal activ- ity. This efficiency complements postulations by Otis et al. (1952) and evidence presented by Mead (1960) that breathing pattern changes under different conditions to minimize respiratory muscle work. 97 IMA During PGO Waves Before and After Pontine Tegmental Lesions In normal animals during REM sleep, inspiratory IMA persisted more than expiratory IMA. There was no consistent relationship between PGO waves and the remaining IMA, although various patterns were evident. Correlation coeffi- cients between the amount of IMA and the density of PGO wave activity varied around zero. Cross-correlation histograras did not reveal consistent increases or decreases in IMA related to PGO waves, but inhibition and excitation patterns were apparent during bursts of PGO waves. Bilateral, pontine-tegraental lesions caused various disturbances in REM sleep. Five aniraals showed a decrease in IMA with the transition frora NREM to REM sleep but also a consistent increase in IMA associated with PGO waves. The teraporal relationship of IMA to PGO waves varied, but sorae cross-correlation histograms revealed an inhibition followed by an excitation in IMA. Others showed only the excitation in IMA after the occurrence of PGO waves. Our report that expiratory and some inspiratory IMA decreased in REM sleep agrees with earlier studies (Parmeggiani and Sabatini, 1972; Duron and Marlot, 1980). Parmeggiani and Sabatini (1972) reported a generalized muscle atonia occurring in the intercostal muscles during REM sleep. However, in sorae of our recordings, inspiratory IMA persisted in REM sleep. Duron and Marlot (1980) 98 reported also the persistence of IMA activity during REM sleep. They correlated this with the muscle spindle density of the tissue. In muscles with few spindles, respiratory- related activity persisted in REM sleep. In tissue with many spindles, activity became atonic during REM sleep. The external intercostal muscles even in the lower intercostal spaces have a moderate spindle density and should show rauscle atonia in REM sleep. Although the placement of our electrodes was lateral to the parasternal region, the inspiratory activity persisting into REM sleep may arise frora the lateral edge of the inspiratory internal intercos- tal muscles. Studies on the mechanisra of tonic REM-sleep atonia report both supraspinal inhibition and disfacilitation of motor neurons. Post-synaptic inhibition of alpha raotoneu- rons may arise frora the inhibitory area of Magoun and Rhines (1945) located in the ventral medulla. Stimulation of this area inhibits both flexor and extensor muscle activity (Magoun and Rhines, 1945; Jankowska.et al., 1968). More recently, Netick et al. (1977) in restrained animals; and Sakai et al. (1979) and Kanamori et al. (1980), in unre- strained aniraals, recorded ventral raedullary neurons during REM sleep. Sorae of these units were tonically activated, specifically, in REM sleep. These units may be part of a neural substrate which hypothetically generates REM sleep atonia by inhibiting alpha and gamraa motoneurons. Other 99 data supporting this hypothesis are: 1) The ventral medullary neurons have been antidromically activated by stimulation of the ventrolateral column (Sakai et al., 1979, Kanamori et al., 1980). Transecting this column blocked REM-sleep atonia (Giaquinto et al., 1964). 2) These units have been orthodroraically activated by stimulation of the peri-locus coeruleus alpha area (Sakai et al., 1979; Kanaraori, et al. , 1980). Lesioning this area blocked REM- sleep atonia (Henley and Morrison, 1969, 1974; Hendricks et al., 1982). A disfacilitation of motoneurons in REM sleep results from inhibition of brainstem nuclei which facilitate raoto- neurons (Morrison, 1979, 1983). Again, the dorsal pontine tegmentum is involved. Theoretically, activity of this area inhibits the locomotor center (Morrison, 1979, 1983). Simi- larly, dorsal raphe activity which is positively related with muscle tone decreases in REM sleep (Trulson et al., 1981), Bilateral lesions of the dorsal pontine tegraentum (peri-locus coeruleus alpha area) block the decrease in dorsal raphe activity (Trulson et al., 1981). Trulson et al. (1981) reported a positive correlation between raphe unit activity and the araount of raotor unit activity in the lesioned aniraal during REM sleep without atonia. Thus, active inhibitory and disfacilitatory supraspinal mechanisms generate REM-sleep muscle atonia. In intact animals, the changes in IMA with PGO waves 100 are consistent with previous reports of strong excitatory and inhibitory activity which influences alpha-motoneurons during phasic REM sleep (Arduini et al., 1963; Gassel et al., 1964a,b, 1965a,b, 1966; Morrison and Pompeiano, 1955a, b,c; Pompeiano and Morrison, 1965; Kubota and Tanaka, 1966; Pompeiano, 1967, 1970; Jouvet, 1967, 1972; Gassel and Pompeiano, 1968; Chase, 1974a,b; Steriade and Hobson, 1976; Siegel and McGinty, 1977; Glenn et al., 1978; Morales and Chase, 1978, 1981; Nakaraura et al., 1978; Sakai et al., 1979, 1981; Siegel et al., 1979; Kanaraori et al., 1980; Orem, 1980b,c). During phasic REM sleep, monosynaptic and polysynaptic reflexes are depressed more than during tonic REM sleep (Gassel et al., 1964a,b). Morrison and Pompeiano (1965a,b) showed that the response of alpha motoneurons to antidromic and orthodromic stimulation is less in phasic than in tonic REM sleep. Recent reports (Glenn et al., 1978; Morales and Chase, 1978, 1981; Nakaraura, 1978; Glenn and Dement, 1981) demonstrated that phasic increases in hyperpolarization of the alpha motoneuron are associated with increases in synaptic activity. Thus, in addition to the tonic inhibition of alpha motor units, there is phasic inhibition. Simultaneous with phasic inhibition, there is phasic excitation of alpha motoneurons from many sources. Arduini et al. (1963) and Morrison and Pompeiano (1965b) demon- strated an increase in pyramidal tract activity associated 101 with phasic REM events. Gassel et al. (1965a,b; 1966) recorded increased activity in the red nucleus during phasic REM activity. Pompeiano and Morrison (1965) and Morrison and Pompeiano (1966) demonstrated the role of the vestibular nuclei in the generation of rapid eye movements and myoclon- ic twitches. Transections of the vestibular nerve and lesions of the vestibular nuclei abolished both rapid eye movements and rayoclonic twitches. Additionally, Siegel and McGinty (1977) and Siegel et al, (1979) have reported activity of units in the brainstera reticular forraation associated with head and neck movements in REM sleep, In summary, there are raany phasic inhibitory and excitatory influences as well as tonic inhibitory influences affecting motor units during REM sleep, The effect of these influences on brainstera respiratory neurons and spinal respiratory raotor neurons are both excitatory and inhibitory. Irregular breathing is a hall- mark of REM sleep (Aserinsky and Kleitman, 1953) and is associated with other phasic eventssuch as rapid eye move- ments (Aserinsky, 1963; Snyder et al. 1964; Duron and Marlot, 1980). This irregularity seeras to be controlled by REM sleep processes (Reramers et al., 1977; Orera, 1980). In 1980, Orem reported that medullary respiratory activity is positively correlated with PGO waves. This excitation was not evident in diaphragraatic EMG recordings (Orera, 1980b; Duron and Marlot, 1980). In fact, the diaphragm was more 102 consistently inhibited than excited (Orera, 1980; Duron and Marlot, 1980). However, both reports included figures (Orem, 1980b, Figure 7; Duron and Marlot, 1980, Figure 9) and showed an excitation-inhibition pattern in the diaphragm during bursts of PGO waves (Orera, 1980b) or rapid eye raove- raents (Duron and Marlot, 1980). This pattern was evident also in IMA recorded from our intact animals. In summary, the data frora the intact animal are consistent with the hypothesis of an integration at the spinal level of both excitatory and inhibitory input on motoneurons. In the lesioned animals, the excitatory and inhibitory influences still exist, but their balance has been altered. Jones (1979) reported that radio-frequency lesions in the pontine gigantocellular tegmental field eliminated REM sleep. Five cats in our study had large electrolytic pontine-tegmental lesions which prevented the appearance of REM sleep. However, kianic acid lesions of this area do not affect REM sleep (Sastre et al,, 1979), Theoretically, kianic acid lesions preserve the fibers of passage, destroy- ing only cell bodies, whereas electrolytic lesions of the tegmentum destroy the projecting fibers from other areas traversing the tegmentum, and specfically those from the peri-locus coeruleus alpha area (Sastre et al,, 1979; Sakai et al., 1980, 1981; Morrison, 1979, 1983). These fibers project to the inhibitory area of Magoun and Rhines (1946) in the ventral raedulla (Tohyama et al., 1979a,b). When the 103 tonic inhibitory system is not activated by peri-locus coeruleus activity, the response to phasic activation asso- ciated with PGO waves can be observed. Thus, some of the animals in our experiments aroused themselves with violent jerks as soon as they entered REM sleep. In railder cases, where the inhibitory system was not blocked totally, the animals were affected less by phasic excitatory events. The positive correlations between PGO waves and rauscle activity observed in our lesioned aniraals reflect the increased effectiveness of phasic excitatory activity, Sumraary and Conclusions Functions of the intercostal muscle are both postural and respiratory, The,recorded rauscle activity results from an integration of input related to these two functions, The effect of sleeping posture on intercostal muscle emphasizes an integration of these inputs and the recorded pattern of activity demonstrates a postural influence on respiration. During REM sleep, intercostal muscle atonia results from generalized skeletal muscle inhibition. When muscle atonia is partially prevented by pontine tegmental lesions, varia- tions in IMA associated with PGO waves during REM sleep reveal a state influence on rauscle activity controlled by respiratory and postural systems. The augmentation of expiratory IMA in NREM sleep may be a result of excitatory inputs that project to many skeletal muscles rather than respiratory reflexes that only affect the intercostal 104 muscles. Recently, Lydic et al. (in press) reported an augmentation of skeletal muscle activity associated with EEG synchrony. The interrelationship between postural and respiratory functions of the intercostal rauscles is a simple yet eloquent example of the integrative power of the central nervous system. BIBLIOGRAPHY Author's Note: For completeness, additional references, not cited in . the text, are included in the Bibliography. Arainoff, M., and Sears, T. A. Spinal integration of segmen- tal, cortical and breathing inputs to respiratory moto- neurones. J. Physiol. 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