fMRI signal changes in response to forced expiratory loading in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses to CO2 and hypoxia and reduced drive to breathe during sleep but retain appropriate breathing patterns in response to volition or increased exercise. Breath-by-breath influences on heart rate are also deficient. Using functional magnetic resonance imaging techniques, we examined responses over the brain to voluntary forced expiratory loading, a task that CCHS patients can perform but that results in impaired rapid heart rate variation patterns normally associated with the loading challenge. Increased signals emerged in control (n = 14) over CCHS (n = 13; ventilator dependent during sleep but not waking) subjects in the cingulate and right parietal cortex, cerebellar cortex and fastigial nucleus, and basal ganglia, whereas anterior cerebellar cortical sites and deep nuclei, dorsal midbrain, and dorsal pons showed increased signals in the patient group. The dorsal and ventral medulla showed delayed responses in CCHS patients. Primary motor and sensory areas bordering the central sulcus showed comparable responses in both groups. The delayed responses in medullary sensory and output regions and the aberrant reactions in cerebellar and pontine sensorimotor coordination areas suggest that rapid cardiorespiratory integration deficits in CCHS may stem from defects in these sites. Additional autonomic and perceptual motor deficits may derive from cingulate and parietal cortex aberrations.

State influences on ventral medullary surface and physiological responses to sodium cyanide challenges.

Intravenous sodium cyanide (NaCN) administration lowers ventral medullary surface (VMS) activity in anesthetized cats. Sleep states modify spontaneous and blood pressure-evoked VMS activity and may alter VMS responses to chemoreceptor input. We studied VMS activation during peripheral chemoreceptor stimulation by intravenous NaCN using optical procedures in six cats instrumented for recording sleep physiology during sham saline and control site trials. Images of scattered 660-nm light were collected at 50 frames/s with an optical device after 80-100 microg total bolus intravenous NaCN delivery during waking and sleep states. Cyanide elicited an initial ventilatory decline, followed by large inspiratory efforts and an increase in respiratory rate, except in rapid eye movement sleep, in which an initial breathing increase occurred. NaCN evoked a pronounced decrease in VMS activity in all states; control sites and sham injections showed little effect. The activity decline was faster in rapid eye movement sleep, and the activity nadir occurred later in waking. Sleep states alter the time course but not the extent of decline in VMS activity.

Optical imaging of the ventral medullary surface across sleep-wake states.

We hypothesized that spontaneous activity declines over widespread areas of the cat ventral medullary surface (VMS) during rapid eye movement (REM) sleep. We assessed neural and hemodynamic activity, measured as changes in reflected 660- and 560-nm wavelength light, from the VMS during sleep and waking states in five adult, unrestrained cats and in two control cats. Relative to quiet sleep, overall activity declined, and variability, assessed by standard deviation, increased by 25% during REM sleep. Variability in activity during waking also increased by 45% over quiet sleep, but mean activity was unchanged. REM sleep onset was preceded by a reduction in the hemodynamic signal from 5 to 60 s before neural activity decline. The activity decline during REM sleep, previously noted in the goat rostral VMS, extends to intermediate VMS areas of the cat and differs from most neural sites, such as the cortex, hippocampus, and thalamus, which increase activity during REM sleep. The activity decline during REM sleep has the potential to modify VMS responsiveness to baroreceptor and chemoreceptor challenges during the REM state.

Optical imaging of the ventral medullary surface of developing kittens during ventilatory challenges.

We used large-array optical recording procedures to examine maturation of regional neural activity within the ventral medullary surface (VMS) of anaesthetized kittens during graded hypercapnic and hypoxic challenges. The VMS was exposed through a ventral surgical approach in 10, 20, 30, and 45-day-old kittens and in adult cats under sodium pentobarbital anaesthesia. Arterial pressure, costal diaphragmatic EMG, and ECG were continuously monitored. A coherent image conduit with 12 mu fibre resolution was attached to a charge-coupled-device camera and positioned over the VMS. Reflected 660 nm light was digitized continuously at 2-s intervals during a baseline period, hyperoxic hypercapnia, (3, 5, and 10% CO2 in O2), and poikylocapnic hypoxia (6%, 9%, and 12% O2 in N2), and recovery. Sixty to seventy-five images within each epoch were averaged, and subtracted from baseline. Regional differences within the image were determined by ANOVA procedures (alpha = 0.05). During hypercapnia, an overall decrease in neural activity (increase in scattered light) occurred, which was marginally age-dependent. By 30 days, regional bidirectional reflectance changes in response to CO2 emerged in a small proportion of animals, and were similar to adult responses. Hypoxia induced a dose- and age-dependent decrease in overall scattered light. Transient "on" and "off" responses were common under both ventilatory stimuli. In 20-30-day kittens, marked rebound responses in reflectance accompanied cessation of hypoxic stimuli; such patterns were absent at other ages. At 30 days, a caudal-rostral bidirectionality in response to mild hypoxia (12% O2) began to emerge in a subset of animals. We conclude that dose-dependent response to ventilatory stimuli occur in the VMS at all post-natal ages of the kitten; however, in hypoxia, the magnitude of the overall reflectance changes is diminished relative to adult patterns. Rebound responses to hypoxia are present at particular ages, and older kittens begin to show a topographical organization of neural activation.

Aberrant temporal patterning of slow-wave sleep in siblings of SIDS victims.

We assessed the patterning of slow-wave EEG activity during sleep in siblings of sudden infant death syndrome (SIDS) victims over the first 6 months of life. Twelve hour overnight physiologic recordings were obtained from 25 apparently healthy subsequent siblings of SIDS victims and 25 control infants at 1 week, and 1, 2, 3, 4 and 6 months of age. The EEG activity was electronically bandpass filtered, leaving primarily activity ranging from 0.5 to 2.5 Hz (the delta frequency), and the filtered traces were full-wave rectified and integrated over 1 min periods. The recordings were divided into four 3 h segments beginning at sleep onset, and the mean integrated delta activity during quiet sleep was determined for each segment of the night. At 3 and 4 months postnatal age, SIDS siblings displayed increased integrated delta amplitude in the early morning hours relative to control infants. Most SIDS deaths occur in the early morning hours during the 2-4 month age range. We thus speculate that increased delta activity may be indicative of increased arousal thresholds in the early morning, which may contribute to SIDS deaths.

Distribution of slow-wave EEG activity across the night in developing infants.

Adults show distinctive patterns of slow-wave (delta) electroencephalogram (EEG) activity across each sleep cycle and across the night. We examined the ontogeny of slow-wave EEG patterning in infants. Twelve-hour overnight physiological recordings were obtained from 25 normal infants at 1 week and 1, 2, 3, 4 and 6 months of age. The EEG activity was band-pass filtered, leaving primarily activity ranging from 0.5 to 2.5 Hz (the delta frequency). Filtered EEG traces were full-wave rectified and integrated over 1-minute periods. Nighttime recordings were divided into four 3-hour segments, beginning at sleep onset, and the mean integrated delta activity during quiet sleep was determined for each segment of the night. In addition, patterns of delta activity across extended periods of quiet sleep (15 minutes or longer) were determined. Beginning at 2 months of age, integrated delta activity declined significantly over the night. Moreover, beginning at 3 months of age, delta activity increased significantly over individual periods of quiet sleep; in neonates up to 1 month of age, delta activity decreased significantly within epochs of quiet sleep. Beginning at 2-3 months of age, infants show patterns of delta activity similar to those found in adults.

Development of heart rate dynamics during sleep-waking states in normal infants.

Previous studies show alterations in the dynamic patterns of cardiac rate in several "at-risk" populations, including apparently healthy infants who subsequently die of the sudden infant death syndrome. In the present study, we examined the maturation of cardiac rate dynamics in normal infants during sleep-waking states over the first 6 mo of life. Instantaneous changes in cardiac R-R intervals were examined in 12-h recordings of 24 normal full-term infants; each infant was recorded at 1 wk and at 1, 2, 3, 4, and 6 mo of age. Scatter plots, consisting of each cardiac R-R interval plotted as a function of the previous interval (Poincaré plots), were constructed for each sleep-waking state in each recording. Analyses of variance were performed on the dispersion of intervals after long and short R-R intervals. In neonates, Poincaré plots showed significantly more next-interval dispersion after a long R-R interval than after a short interval, a pattern similar to those observed in older infants and in healthy adults. However, between 1 wk and 1 mo of age, this pattern disappeared and returned gradually beginning at 2 mo of age. The scatter of points in Poincaré plots of infants 1 mo of age approached the patterns of at-risk populations, including infants who subsequently died of the sudden infant death syndrome. These patterns at 1 mo may be indicative of increased vulnerability in normal infants after the neonatal period.

Respiratory patterning following cerebral ventricular administration of cocaine.

Intravenous (IV) cocaine in the conscious cat causes extreme tachypnea and reduction in breath-to-breath variability. In this study, we examined respiratory patterning following administration of cocaine into the cerebral ventricles. Intraventricular cocaine elicited a tachypnea that was nearly identical to that for IV cocaine. At the high dose, peak respiratory rate increased by 380%. Breath-to-breath variability was dramatically reduced by cocaine, especially in the early stages of the intoxication; during these stages, the tachypnea was occasionally interrupted by prolonged inspiratory efforts. Procaine was administered as a control for the anesthetic effects of cocaine and caused an initial tachypnea that was similar to that for cocaine. For both cocaine and procaine, the mean ratios of inspiratory to expiratory durations were unaffected, indicating that the tachypnea was accomplished by approximately equal reductions in inspiratory and expiratory durations. We conclude that the tachypnea following cocaine administration results principally from central rather than peripheral mechanisms. In addition, the data suggest that anesthetic actions mediate the principal respiratory effects of cocaine.

Analysis of beat-to-beat heart rate changes during sleep-waking states in normal infants.

Summary measures of heart rate variation describe those aspects of heart rate change that can be averaged over relatively long periods of time. We examined the postnatal maturation of a dynamic feature of cardiac rate--the dependency of each beat-to-beat change in cardiac interbeat interval on the previous beat-to-beat change. In each sleep-waking state, the number of delta RR (the difference between two successive R-R intervals) 4msec was determined as a percent of the total number of intervals (delta RR > 4ms/total delta RR), and each pair of successive interval differences was categorized based on the directions of the two changes (whether they reflected increases or decreases in cardiac intervals). Analysis of variance was used to identify alterations in the proportion of interval differences exceeding the minimum over ages and sleep-waking states, and to describe developments in the temporal patterns of cardiac interval changes. At all ages, infants showed fewer beat-to-beat interval changes during waking than during either sleep state. In all states, older infants showed significantly more beat-to-beat cardiac interval changes and a higher proportion of sustained changes (intervals increasing or decreasing consistently over several beats) than did young infants. Furthermore, infants 2 months and younger showed significantly more sustained increases than decreases in interbeat intervals, indicating gradual declines in heart rate and rapid increases, while older infants showed the opposite pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Discharge dependencies of amygdala central nucleus neurons to the cardiac and respiratory cycle following local cocaine administration.

We examined dependencies of amygdala central nucleus neuronal discharge to the cardiac and respiratory cycles in freely behaving cats following local microinjection of cocaine (100 micrograms/0.2 microliter). Cross-correlation histograms showed cycle-by-cycle dependencies between neuronal discharge and the cardiac and respiratory cycles in 10 of 30 cells and 7 of 30 cells, respectively, during baseline periods. After cocaine delivery, the discharge rate of half of the central nucleus of the amygdala cells (16/30, 53%) were partly or completely inhibited in a reversible manner. Excluding cardiac- and respiratory-dependent neurons which ceased firing after cocaine, more than half (5/8) of the remaining cardiac and two-thirds (4/6) of respiratory-dependent neurons altered discharge dependencies following cocaine administration. Of the cells that did not exhibit cardiac and respiratory dependencies pre-cocaine, 2 of 20 developed cardiac correlations and 3 of 23 developed respiratory correlations following cocaine administration. We speculate that a portion of the cardiac and respiratory responses induced by cocaine may be mediated through the central nucleus of the amygdala.

Dynamic analysis of cardiac R-R intervals in normal infants and in infants who subsequently succumbed to the sudden infant death syndrome.

Infants who subsequently succumb to the sudden infant death syndrome (SIDS) have higher heart rates and reduced heart rate variation compared with other infants. We examined dynamic changes in cardiac interbeat intervals to explore these differences in cardiac control. Recordings of electrocardiographic activity and respiratory movement were acquired from 13 SIDS victims before their deaths. Moment-to-moment changes in R-R intervals during quiet sleep, rapid eye movement sleep, and waking were compared with values of 13 matched control infants. For each sleep-waking state, every R-R interval was plotted against the previous interval (Poincaré plots), and each change in interbeat interval was plotted against the previous change. Dispersion of interbeat intervals at different heart rates was reduced in SIDS victims, resulting in Poincaré plots markedly different from those of controls. The dispersion, sampled at the 10th and 90th percentiles of heart rates, was reduced across all sleep-waking states in SIDS victims. At high heart rates, the difference between groups disappeared after correcting for basal rate; however, the reduced range at low heart rates was independent of basal rate. SIDS victims also showed smaller beat-to-beat changes in heart rate and fewer sustained runs of consistent heart rate changes during waking relative to controls. The differences in cardiac rate dynamics suggest altered autonomic control in infants who succumb to SIDS. We speculate that the autonomic disturbance may lead to cardiac instability or may indicate CNS alterations with the potential to affect other vital functions.

Dynamic properties of respiratory timing following cocaine administration.

We assessed the timing and amplitude characteristics of diaphragmatic muscle activity following administration of intravenous cocaine HCl (10 mg/kg) to awake, unrestrained cats. Cocaine produced a pronounced tachypnea which was interrupted by deep inspiratory efforts coincident with tonic-clonic movements over the first 10 min following cocaine administration. Following that period, diaphragmatic cycle rates slowly increased for up to 1 h and were interrupted occasionally by longer inspiratory efforts which were not associated with other overt motor activities. As respiratory rate increased, breath-to-breath variability decreased, and the incidence of deep inspiratory efforts decreased. As total cycle time decreased, the ratio of inspiratory time to expiratory time remained the same between precocaine and early, intermediate and late intoxication periods. The amplitude of diaphragmatic EMG activity increased with the extreme tachypnea. A number of neural mechanisms may mediate the changes in diaphragmatic muscle activity, including hyperthermia and alteration of rostral brain influences on brainstem timing mechanisms.

Upper airway and diaphragmatic muscle activity following acute cocaine administration.

These studies examined activity of the diaphragm and a laryngeal dilator, the posterior cricoarytenoid, following 3 levels of intravenous and cerebral ventricular administration of cocaine. Both administration routes induced extremely high respiratory rates with enhanced tonic and phasic electromyographic activity, and affected patterning similarly in upper airway and diaphragmatic muscles. Both intravenous and intraventricular administration induced a rise in core and brain temperature related to the route of administration; however, the tachypnea was only loosely related to the hyperthermia. Intraventricular administration resulted in a more rapid onset of peak respiratory rates, and a faster decline than an intravenous route. Different dose levels elicited similar elevated respiratory rates, but higher intravenous doses also resulted in extensive hypertonicity with intermittent phasic movements. Tachypnea continued between these phasic efforts. The phasic events associated with high doses were accompanied by sustained inspiratory efforts; however, no evidence of obstructive apnea was found. These data suggest that cocaine can modify respiratory patterning by inducing a centrally mediated tachypnea and by eliciting sustained, intermittent inspiratory efforts.

Non-linear dynamics of electrocardiographic waveforms following cocaine administration.

We examined dynamics of ECG waveforms preceding and following 10 mg/kg intravenous administration of cocaine in freely moving cats. Cocaine induced substantial variation in ECG waveforms, as demonstrated by non-linear procedures of phase-plane plots and Poincaré analyses. Phase-plane plots revealed that waveform variation following cocaine administration was not randomly or uniformly distributed, but instead followed patterns of clustered organization with unvisited regions. These patterns are characteristic of chaotic distributions, and support the hypothesis that ECG waveform variation following cocaine does not degenerate into random patterns; instead, the variation follows deterministic, though chaotic patterns.

Frequency-related, bidirectional limbic responses to cocaine: comparisons with amphetamine and lidocaine.

Dual effects of cocaine on the electrical excitability of limbic structures were investigated by determining current thresholds for afterdischarges (AD) evoked by low and high frequency electrical stimulation. Cocaine, lidocaine and D-amphetamine treatments were compared in order to assess the extent to which cocaine's local anesthetic and monoaminergic actions contribute to its effects on limbic afterdischarges. Afterdischarge threshold, duration and propagation for both 3 and 50 Hz stimulation of the amygdala, hippocampus and septal area were tested following saline, cocaine (5 mg/kg), lidocaine (5 mg/kg) and D-amphetamine (2.5-5 mg/kg). Results provide clear evidence that cocaine has a bidirectional effect on hippocampal and amygdalar AD thresholds--significantly increasing sensitivity to low frequency stimulation while significantly decreasing sensitivity to high frequency stimulation at identical brain sites. A frequency-dependent threshold effect also occurred at the septal area. In addition, cocaine reduced limbic AD duration and propagation; these effects proved unrelated to the direction of AD threshold changes. Cocaine effects on afterdischarges differed significantly from those of amphetamine and lidocaine. Comparisons with amphetamine and lidocaine suggest that cocaine's local anesthetic action, but not its monoaminergic properties, may contribute to reductions in limbic afterdischarge duration and propagation. However, it is unlikely that either monoaminergic or local anesthetic actions are responsible for cocaine's pronounced dual effect on the electrical excitability of major limbic structures. This bidirectional drug effect has interesting neurobiological implications and, in addition, offers a potentially valuable tool for new research on frequency-related functions of the limbic system.

Regional effects of ethanol on limbic afterdischarge activity.

This study assessed the effects of acute administration of ethanol on afterdischarge (AD) activity evoked by electrical stimulation of the amygdala, septum and hippocampus. Limbic AD thresholds, duration and propagation were determined in cats following intravenous infusions of saline or ethanol (0.4, 0.8 and 1.6 g/kg). Ethanol administrations significantly increased septal and amygdalar, but not hippocampal AD thresholds. This effect was dose-related and most pronounced at the septum. Reductions in AD duration followed ethanol treatment and demonstrated similar regional differences. In addition, projected discharges were reduced, propagation of AD from stimulation sites to limbic and neocortical projections sites were suppressed and ictal episodes were attenuated following ethanol treatment. Afterdischarge activity was affected even by the 0.4 g/kg dose which produced no observable change in behavior. These findings indicate that ethanol reduces the responsiveness of limbic structures to electrical stimulation--suppressing the initiation, maintenance and propagation of limbic afterdischarges. The amygdala, septum and hippocampus proved differentially sensitive to ethanol.