Stability of coupled fluctuations in movement and visual attention in infants.

Fluctuations in body movement and visual inspection were measured over minutes in 3-month-old infants to look for evidence of coupling. In Experiment 1, infants (n = 12) looked ad libitum at two identical pictures for an average of 7.3 min. Analysis of the spontaneous fluctuations in movement and inspection revealed that they were inversely coupled: Moment-to-moment changes in movement and inspection occurred in opposite directions. In Experiment 2, after 4 min of free looking, infants (n = 33) were presented with a new pair of stimuli, a temporary change in the stimuli, or no change in stimuli. The inverse coupling between the fluctuations in body movement and visual inspection found in Experiment 1 was present before and after the stimulus changes, even in infants whose body movement decreased transiently in response to the stimulus changes. The reappearance of inversely coupled fluctuations in body movement and visual inspection following the stimulus changes was led by increases in movement. The results demonstrate the stability of the inverse coupling between spontaneous fluctuations in body movement and visual inspection, and suggest that changes in movement may lead changes in inspection.

Structure and irregularity in the spontaneous behavior of young infants.

Persistent, irregular fluctuations in spontaneous motor activity are common in the young of many vertebrate species, but whether the irregularity is intrinsic to the dynamics of motor activation or the result of random perturbations is not known. Analysis of the second-by-second variation in the general body movement of awake human infants 1 and 3 months after birth revealed low dimensional structure in the characteristically irregular motor activity and exponential rates of divergence of initially similar states of motor activation. Results support the conclusion that irregularity is an intrinsic property of the dynamics of motor activation involving relatively few effective degrees of freedom and raise questions about the advantages or disadvantages of irregularity built into early behavioral organization.

Effects of warmth on newborn rats' motor activity and oral responsiveness to an artificial nipple.

Temperature is a powerful regulator of the behavior and physiology of newborn altricial animals. The effects of warmth on newborn rats' oral responsiveness to suckling stimuli and spontaneous motor activity in a thermoneutral environment were investigated. Newborn rat pups' oral grasp responses to an artificial nipple and overall motor activity were recorded for 18 min. Near-term pups were delivered by cesarean section so that their 1st experiences with suckling stimuli could be observed. Experimental pups were warmed for 15 s every 2 min; control pups were not warmed. Warmed pups grasped the nipple fewer times than the not-warmed pups. However, oral grasp durations became longer for the warmed pups but not for the not-warmed pups. Warmth increased pups' motor activity but only while the heat was applied. Warmth in a thermoneutral environment may promote longer nipple attachment during newborns' early feeding experiences.

The integration of body movement and attention in young infants.

The normal development of adaptive behavior in humans depends on the integration of visual attention and body movement, yet little is known about the initial state of movement-attention coupling at the beginning of postnatal life. We studied 1- and 3-month-old infants during extended periods of visual exploration and found that spontaneous shifts of gaze are preceded by rapid changes in general body movement. The results reveal a tight link between motor activation and overt attention on a time scale of seconds or less. This link undergoes substantial developmental change in the first few weeks after birth. During that time, phasic motor activation may play a key role in visual exploration by helping to unlock gaze when the environment is unchanging.

An intrinsic source of behavioral regulation that influences discrete responses to cues important for the initiation of suckling.

The present experiment investigated the relationship between motor activity and oral grasping of an artificial nipple in newborn rats. Pups orally grasped the artificial nipple, and they performed more and longer oral grasps in the latter portion of the nipple presentation. Motor activity was cyclical, and this cyclicity was evident before and during presentation of the artificial nipple. The onset of an oral grasp response was preceded by a period of relatively low motor activity, and the termination of a grasp was followed by relatively high motor activity. The newborn rat pup's intrinsic oscillations in motor activity may regulate the expression of discrete responses to cues important for the initiation of suckling.

Blood pressure and heart rate in the ovine fetus: ontogenic changes and effects of fetal adrenalectomy.

Ontogenic changes in baseline and 24-h rhythms of fetal arterial blood pressure (FABP) and heart rate (FHR) and their regulation by the fetal adrenal were studied in 18 fetal sheep chronically instrumented at 109-114 days gestation (GA). In the long-term study, FABP and FHR were continuously recorded from 120 days GA to spontaneous term labor (>145 days GA) in five animals. Peak times (PT) and amplitudes (Amp) of cosinor analysis were compared at 120-126, 127-133, and 134-140 days GA. Consistent, significant linear increases in FABP and linear decreases in FHR were observed in all fetuses. Significant 24-h rhythms in FABP and FHR were observed during all the time windows. In the adrenalectomy study, to test the hypothesis that fetal cortisol plays a key role in cardiovascular maturation, fetal adrenals were removed in eight animals (ADX); sham fetal adrenalectomy was performed on five animals (Con). Cortisol (4 microgram/min) was infused intravenously in four ADX fetuses from day 7 postsurgery for 7 days (ADX+F). No significant changes in PT and Amp in FABP and FHR were observed. Plasma cortisol levels remained low in Con and ADX fetuses (<4.9 ng/ml). Cortisol infusion increased fetal plasma cortisol to 22.3 +/- 3.2 ng/ml (mean +/- SE) on day 13 in ADX+F fetuses. FABP increased in control and ADX+F but not ADX fetuses; FHR decreased in control and ADX but rose in ADX+F fetuses. These results suggest that, in chronically instrumented fetal sheep at late gestation, 1) increases in FABP and decreases in FHR are maintained consistently from 120 to 140 days GA, with distinct 24-h rhythms, the PT and Amp of which remain unchanged, and 2) the physiological increase in FABP is dependent on the fetal adrenal; bilateral removal of the fetal adrenals does not prevent the ability of cortisol to produce a sustained increase in FABP.

Variation in motor activity on different time scales and responsiveness to oral stimulation in the rat fetus.

The near-term rat fetus exhibits brief oral grasp responses to discrete presentations of an artificial nipple. In the present experiment, an artificial nipple was presented to individual fetal subjects 10 times. Five of the presentations were timed to occur when spontaneous fetal motor activity was low and five while activity was high, as determined by the baseline activity for the individual fetus. The likelihood of responding to the artificial nipple was increased when the fetus was relatively inactive at the moment of stimulus presentation. Furthermore, stimulus presentations that resulted in oral grasping of the artificial nipple were associated with greater point-to-point variability (2-s intervals) in motor activity during the 30-s period preceding the presentation of the artificial nipple. This pattern of results indicates that the recent history of general motor activity as well as the level of activity at the instant of stimulus presentation may contribute to variation in responding to biologically relevant stimuli early in development.

The development of nuchal atonia associated with active (REM) sleep in fetal sheep: presence of recurrent fractal organization.

The behavioral state of active or rapid eye movement sleep (REMS) is dominant during fetal life and may play an important role in brain development. One marker of this state in fetal sheep is neck nuchal muscle atonia (NA). We observed burst within burst NA patterns suggestive of recurrent fractal organization in continuous 13 day in utero recordings of NA during the third trimester. Consistent with fractal renewal processes, the cumulative mean and standard deviation (SD) diverged over this time and the tail of NA distributions fit a stable Lévy law with exponents that remained invariant over the periods of development examined. The Hurst exponent, a measure of self-affine fractals, indicated that long-range correlations among NA intervals were present throughout development. A conserved complex fractal structure is apparent in NA which may help elucidate ambiguities in defining fetal states as well as some unique properties of fetal REMS.

Variability in general activity and the expression of complex behavior in the fetal rat (Rattus norvegicus).

Rat fetuses exhibit intrinsic fluctuations in general motor activity and respond to an artificial nipple (AN) with mouthing and oral grasping behavior. The present study examined the relation between the organization of general activity and the expression of these specific responses to an AN on Embryonic Day 21. In Experiment 1, continuous exposure to the AN resulted in nonspecific behavioral activation characterized by an increase in amplitude and high-frequency variability. In Experiment 2, increased amplitude and variability in general activity preceding discrete presentations of the AN resulted in more mouthing and oral grasping responses to the AN. These results suggest that presentation of the AN triggers behavioral reorganization in which the level and variability of overall activity may facilitate expression of well-defined action patterns.

Contractile activity of the uterus prior to labor alters the temporal organization of spontaneous motor activity in the fetal sheep.

Contractile activity of the uterus before the onset of labor (uterine contractures) has been described in a number of species and provides a powerful source of repeated stimulation for the fetus throughout much of gestation. To understand how fetal behavior responds to this dynamic aspect of the intrauterine environment, we investigated the effects of uterine contractures on the temporal organization of spontaneous motor activity in the fetal sheep during the last fifth of gestation. Eleven fetuses were instrumented on 113-116 days of gestation (dGA). Electromyogram (EMG) activity was recorded from flexor and extensor muscles in the fetal forelimbs and hindlimbs, and from the uterus. Pooled limb EMG activity from 2300 hr to 0700 hr on 118, 125, 132, and 139 dGA before, during, and after uterine contractures was spectral analyzed to detect and quantify the cyclic organization in fetal motor activity. There was strong evidence of cyclic organization in fetal motor activity (CM) at each gestational age, similar to what has been described in the fetal rat and human. There was no evidence of developmental changes in the baseline spectral measures of CM. The most prominent feature of the response of CM to uterine contractures was a transient decrease in irregularity at 118-132 dGA. The strength of CM increased during contractures at 125 and 132 dGA, and a slight acceleration of CM during contractures was detected at 118 and 139 dGA. The results demonstrate that the stimulation associated with contractures influences an important source of complexity in early behavioral organization. The results are consistent with speculation by others that uterine contractures might induce transient cerebral hypoxemia in the fetus, and suggest that conditions established in the first few minutes of sustained uterine activity constitute the effective perturbation of CM.

Behavioral responses of the chronically instrumented sheep fetus to chemosensory stimuli presented in utero.

Fetal sheep were surgically prepared on Days 113-114 of gestation with an array of chronic instruments for recording electromyographic data (EMG) in oral--facial, axial, and limb muscles and heart rate (FHR). Fetuses also were fitted with an intraoral catheter for infusion of chemosensory fluids (isotonic saline, quinine, colostrum, sucrose) onto the surface of the tongue. Individual subjects received chemosensory infusions on Days 134-137. Fetuses showed consistent oral responses to quinine and milk, but did not respond to isotonic saline or sucrose. Different patterns of motor responses suggest that fetuses discriminated among different concentrations of quinine. The expression of tachycardia to quinine and bradycardia to milk also suggested differential responding to chemosensory fluids that differ in hedonic qualities. Detailed characterization of fetal responses to these stimuli in utero confirm the functionality of the gustatory system in the sheep fetus near term.

Oscillation and complexity in early infant behavior.

Cyclic fluctuation is a ubiquitous property of spontaneous motor activity in the human fetus and neonate. Oscillation occurs on the scale of minutes, and irregularity is one of its most characteristic properties. To determine whether cyclic motor activity (CM) persists beyond the neonatal period (1 month after birth), and beyond what has been called the period of the fetus ex utero (2-3 months after birth), 30 infants were studied at monthly intervals from 1 to 4 months after birth during active sleep and awake. Spectral analysis was used to quantify the rate, strength, and irregularity of CM. To examine the characteristic irregularity of awake CM more closely, a nonlinear forecasting technique, developed to study chaotic dynamic in other fields, was used to estimate the predictability of spontaneous movement in a state space reconstructed from the time series. The rate and irregularity of CM during active sleep and awake, and its strength during active sleep, did not change across the first 4 postnatal months. However, there was a pronounced drop in the strength of awake CM from 2 months onward and a concurrent increase in the broad-band power of fluctuations faster than 2 cycles/min. The predictability of awake CM also dropped abruptly between 1 and 2 months, especially for prediction intervals less than 20 sec. The changes at 2 months reflect the introduction of a source of variation with a shorter time constant than fetal-neonatal CM, and which is specific to awake periods. The source of these effects may be moment-to-moment interactions between CM and attention.

Post-marketing drug surveillance--concepts, insights and applications.

At the present drug approval process consists of preclinical animal testing, followed by three phases of clinical testing. Phase I is usually conducted on non-patient volunteers; phase II involves administration of the drug to a small number of selected patients; and phase III is the final premarketing test of the drug's safety and efficacy. These trials have major limitations, such as restricted patient populations, limited duration of patient exposure, and limited patient numbers. Considerable information remains unknown after the end of phase III testing, including: less common adverse effects; delayed adverse effects; efficacy and toxicity in types of patient usually excluded from premarketing testing, e.g. children, pregnant women and old people; efficacy and toxicity in patients with other illnesses and/or ingesting other drugs; efficacy and toxicity relative to other drugs used for the same purpose; efficacy and toxicity when used for indications other than those initially tested; the toxic effects of a massive overdose; physicians' prescribing habits, etc. The attempt to obtain this information after marketing is postmarketing drug surveillance.

The neural control of cyclic motor activity in the fetal rat (Rattus norvegicus).

The spontaneous behavior of rat fetuses (in a saline bath with fetal-placental-uterine connections intact) was observed directly for 30 minutes on Day 20 of gestation. Rearleg and nonrearleg movements from fetuses with a mid-thoracic spinal cord transection or sham operation were analyzed for cyclic organization. Oscillations in rearleg activity occurred at the same frequency in fetuses with spinal cord transections (0.74 cycle/min) and sham-operated fetuses (0.72 cycle/min). However, oscillations in nonrearleg activity were much slower in the fetuses with spinal cord transections (0.30 vs. 0.77 cycle/min). Other characteristics of the cyclic patterns in motor activity were unaffected. The findings demonstrate 1) the caudal half of the spinal cord can generate cyclic output in the absence of descending input from the brain, 2) there is no single timing center, and 3) rostral sources are slower.

Infants of diabetic mothers: late normalization of fetal cyclic motility persists after birth.

The prenatal development of cyclic motility (CM) in the human is disrupted by maternal diabetes, but appears normal by the end of gestation. To determine whether birth and adaptation to postnatal life reveal new or persisting abnormalities in CM, 24 newborn infants of insulin-dependent diabetic mothers (IDMs) and 24 normal newborns were studied for 2-4 hr in a controlled environment. Spectral analysis of spontaneous movement revealed that CM was common in both groups. Measures of its cyclic organization in each state did not differ between IDMs and controls. State differences were the same in the two groups, and replicated the pattern found in a previous study of normal newborns. For IDMs, there were no differences associated with neonatal evidence of increased glucose supply in utero (macrosomia, postnatal hypoglycemia), or with determinations of prenatal maternal hyperglycemia. IDMs had also been studied as fetuses, and the pattern of continuity and change in CM across birth replicated the pattern previously reported for normal fetuses. The results suggest that the development and control of CM is buffered from the prenatal metabolic insults suffered by IDMs, and support speculations that cyclic activation is a general and robust property of the developing motor system in the human.

Increasing arterial carbon dioxide tension: influence on transcutaneous carbon dioxide tension measurements.

Despite widespread use of transcutaneous PCO2 (TcPCO2) monitoring, the precise relationship between TcPCO2 and PaCO2 remains unclear. It has been widely assumed that theoretical correction of TcPCO2 (combining temperature correction with a constant metabolic factor of 4 mm Hg) accounts for the elevation of TcPCO2 over PaCO2. To test this assumption, TcPCO2 was measured with a 44 degrees C electrode and compared to PaCO2 in 60 normotensive infants with cardiorespiratory disease during the first four +/- six days of life (mean +/- SD) (range one to 36 days). During hypocapnea, from PaCO2. In contrast, during normocapnea, theoretically corrected TcPCO2 exceeded PaCO2 by 5 +/- 4 mm Hg (P less than .001), and similarly during hypercapnea, theoretically corrected TcPCO2 exceeded PaCO2 by 9 +/- 6 mm Hg (P less than .001). These data suggest that, as PaCO2 increases, there may be an imbalance between tissue CO2 production and removal, resulting in a progressively increasing gradient between TcPCO2 and PaCO2. Clarification of the relationship between TcPCO2 and PaCO2 should enhance the interpretation of TcPCO2 measurements in infants.

Human cyclic motility: fetal-newborn continuities and newborn state differences.

The spontaneous movement of 41 healthy human newborns was analyzed for cyclic patterns during different behavioral states and also compared to similar data obtained during their last few months of gestation. Spectral analysis was used to identify and quantify the motility cycles, except in quiet sleep, for which the instantaneous frequency of the isolated movements was analyzed. Cyclic motility (CM) was common in all states, and measures of its cyclic organization were similar in the non-sleep states in spite of very large differences in the total amount of movement. During active sleep, CM was weaker and less regular than during the non-sleep states, but similar to fetal CM during the last month of gestation. Thus cyclic variation in spontaneous motor activity, a basic feature of fetal behavior, is also a nearly constant feature of newborn spontaneous movement. Fetal CM persists relatively unchanged in the newborn during active sleep, and the cyclic organization of newborn movement is independent of the level of motor output.

Effects of social support during parturition on maternal and infant morbidity.

Because continuous social support during labour is a component of care in many societies but inconsistent in our own, the clinical effect of support during labour on maternal and neonatal morbidity were studied. Social support was provided by female companions. Four hundred and sixty five healthy primigravidous women were enrolled using a randomised design. Compared with 249 women undergoing labour alone 168 women who had supportive female companions throughout labour had significantly fewer perinatal complications (p less than 0.001), including caesarean sections (7% v 17%, p less than 0.01) and oxytocin augmentation (2% v 13%, p less than 0.001), and fewer infants admitted to neonatal intensive care (p less than 0.10). Of the women who had an uncomplicated labour and delivery requiring no interventions, those with a companion had a significantly shorter duration of labour (7.7 hours v 15.5 hours, p less than 0.001). This study suggests that constant human support may be of great benefit to women during labour.

The development of cyclic motility in fetuses of diabetic mothers.

The cyclic organization of spontaneous movement was studied longitudinally in 22 fetuses of diabetic mothers (FDMs) during the third trimester of gestation and quantified with spectral analysis. Cyclic motility at frequencies between .08 and 1.22 cycles/min was found in all fetuses, although it was temporarily absent in 12 of the 22 fetuses at some time between 25 and 38 weeks. While some parameters of cyclic motility changed little, the frequency of the dominant motility cycle doubled from .24 to .48 cycle/min between 28 and 36 weeks, and the relative strength of motility cycles in the band between .18 and 1.02 cycles/min decreased temporarily at 36 weeks. These developmental changes and the common absence of cyclic motility contrast sharply with previous findings in normal fetuses, and (except for its absence) are accounted for by a subgroup of FDMs whose mothers' blood glucose levels were least well controlled during the third trimester of gestation. The presence of cyclic motility in all FDMs provides further evidence that cyclic activation is a basic property of the developing central nervous system in the human, as it appears to be in other vertebrates. However, the differences between FDMs and normal fetuses suggest that the development of cyclic motility is sensitive to disturbances in the fetal metabolic environment.

Interaction between nonnutritive sucking and respiration in preterm infants.

The effect of nonnutritive sucking bursts (NNSBs) on respiratory frequency was sequentially evaluated in 12 healthy preterm infants. Studies were performed during active sleep in infants between 32 and 37 weeks postconceptional age. The duration of NNSBs was classified as follows: (a) less than 3 s, (b) between 3 and 6 s, and (c) greater than 6 s. NNSBs of each duration were found at all ages, although NNSBs greater than 6 s were the least frequently observed. Respiratory rate increased significantly during NNSBs of less than 3 s, and also in those of 3-6 s duration. There was no significant effect on respiratory frequency of sucking bursts longer than 6 s. Our results document an early interaction between these two motor rhythms, which is influenced by the length of the NNSB. Moreover, they indicate that the decrease in respiratory frequency reported in a similar group of preterm infants during feeding should not be interpreted as an effect of sucking per se.