Behavioral assessment of visual deficits in the taiep mutant.

Taiep (tremor, ataxia, immobility, epilepsy, paralysis) mutants show a significant increase in myelin thickness from 10 to 30 days of age but then demonstrate a decrease in myelin thickness from 1 to 6 months. The severity of the demyelination in the optic nerve suggests that visual deficits may exist in the taiep mutants. Animals were trained on a discrimination task, in which responses to a light stimulus (the SD period) were reinforced on a fixed ratio (FR)-1 schedule, and responses in the absence of the light stimulus (the SΔ period) were not reinforced. Following training, the light intensity presented during the SD period was gradually reduced between sessions until -6.0 candela/m2 was reached. Both groups of animals - taiep mutants and control Sprague Dawley rats - successfully recognized and responded in the presence of the stimulus near perfectly by the final day of training, suggesting that taiep mutants demonstrated normal learning, at least under this paradigm. Despite the severe demyelination of the taiep optic nerve, no visual deficits were detected as both groups of animals performed similarly as the light intensity decreased. Though the myelin loss of the optic nerve may have negatively affected signal transduction, this did not result in an increase in visual threshold.

Active sleep and its role in the prevention of apoptosis in the developing brain.

The aim of this study is to identify a possible function of Active Sleep (AS), also known as Rapid Eye Movement Sleep (REM) in humans, as a protective state during early Central Nervous System (CNS) development. Previous research suggest pharmacological agents that inhibit high levels of neuronal activity in the CNS (e.g., benzodiazepines, ethanol, and anesthetics) precipitate massive CNS programmed cell death (PCD), in developing mammals. AS is characterized by high levels of CNS activity at levels comparable to waking. AS occupies up to 75% of the circadian cycle in developing mammals (rodents from postnatal days 1-14 days (p1-p14), and humans from prenatal month seven to postnatal year one). Many studies have implicated AS as having an active role in the normal development of the visual system and have documented myriad behavioral anomalies as a result of AS deprivation. Reduced adult brain mass has also been observed after AS deprivation in developing rats during this period, however, no study to date has documented this process as it occurs (i.e., the cellular mechanisms that result in behavioral anomalies or reduced adult brain mass). The purpose of this study is to begin documentation of this process by utilizing histological techniques that identify the PCD process, if it occurs, after acute and prolonged AS deprivation in rats from ages p7 to p14 (a time of active synaptogenesis). Our methodology includes utilization of the alpha2-adrenergic receptor agonist clonidine, to deprive rat pups of AS at ages varying from p7 to p14. Pilot data from our laboratory has shown that an acute exposure to clonidine significantly reduces time spent in AS. The animals that were AS deprived also showed a statistically significant decrease in brain mass and have stained positively for PCD. If our hypotheses are correct, this research will have major implications with regard to determining the function(s) of REM sleep.

Behavioral effects of chronic melatonin and pregnenolone injections in a myelin mutant rat (taiep).

The taiep (tremor, ataxia, immobility, epilepsy, and paralysis) myelin mutant displays a number of locomotor deficits. Taiep rat gait is characterized by shorter stride and step lengths as well as by larger stride widths. Thirty-day-old taiep mutants were placed under a regimen of daily hormone injections for 60 days. Animals in Condition 1 received melatonin, those in Condition 2 received pregnenolone sulfate, and those in a third control condition received injections of saline. Following the injections, each taiep mutant's gait was analyzed. The animals that received melatonin and pregnenolone displayed significantly larger stride and step lengths than did the controls. In addition, the animals that received hormones displayed shorter stride widths than did the controls. These experimental effects are consistent with a normalization of gait. Possible cellular mechanisms of this behavioral effect are discussed.

Locomotor analysis of the taiep rat.

Locomotor activity (tremor, ataxia, immobility, epilepsy, and paralysis) in the taiep rat, which suffers from a myelin deficient disorder, has not been previously documented. This study used walking track analysis of footprints to analyze locomotor activity in the taiep rat in comparison to normal, age-matched controls. The results confirmed differences between normal and taiep rats in terms of stride length, step length, and stride width. In addition, we found significant interactions between age and condition for stride and step length. The results suggest that locomotor analysis is a sensitive indicator of myelin deficiency. The results are discussed in terms of the underlying myelin deficiency and possible treatment regimens.

Rat sleep and eye movement density as biological markers of demyelinating disease.

Myelin mutants provide an opportunity to study neurophysiological and behavioral effects of demyelination. The taiep rats are myelin mutants with progressive demyelination of the central nervous system (CNS), resulting in five neurological symptoms: tremor, ataxia, immobility, epilepsy, and paralysis. The demyelination affects the brainstem, an important area in the control of sleep. This study compared eye movement density (EMD) in taiep vs. normal control rats during paradoxical sleep (PS). It was hypothesized that taiep rats would have significantly reduced EMD during PS in comparison to normal controls due to their demyelinating disease. In addition, demyelination of brainstem structures would suggest possible changes in sleep-wake structure. Hence, we compared sleep-wake stages in taiep vs. normal, control rats. The results confirmed significantly reduced EMD during PS in taiep rats compared to normal rats during the 12-h (light) recording period. In addition, analysis of EMD values across the 12-h light period revealed significant differences in EMD values as a function of time of day in the taeip rats only. Comparison of waking and sleep values across the 12-h light phase revealed an "immobility episode" in three taiep rats, which was not present in normal controls. In addition, PS percentage was significantly lower and low-voltage sleep was significantly higher in taiep rats. These results suggest that EMD, immobility episodes, and sleep architecture may be useful as measurable biological events in the study of demyelinating disease. The results were discussed in terms of possible mechanisms underlying these differences, as well as possible implications for future studies.

The splay angle: A new measure for assessing neuromuscular dysfunction in rats.

This report describes a new method, the splay angle measures, to determine neuromuscular dysfunction. Splay angles are measured from a standard splay test and define hind limb orientation quantified, in degrees, by the paw strike of the hind limbs. We used mutant rats, presenting with a chronic central nervous system demyelinating disease, characterized by tremor, ataxia, immobility, epilepsy, and paralysis (taiep). Significant differences between taiep (n = 12) and normal control rats (n = 10) were found for Linear Splay, AngleLeft, AngleRight, and AngleBoth. These results suggest that the splay angles are a sensitive measure of hind limb orientation and may reflect an underlying pathology.

Two- and 4-hour bright-light exposures differentially effect sleepiness and performance the subsequent night.

The effect of two durations of bright light upon sleepiness and performance during typical night shift hours was assessed. Thirty normal, healthy young adults participated in a 2-night protocol. On the 1st night subjects were exposed to bright or dim light beginning at 2400 hours, under one of the following three conditions: bright light for 4 hours, dim light for 2 hours followed by bright light for 2 hours or dim light for 4 hours. Following light exposure, subjects remained awake until 0800 hours in a dimly lit room and slept in the laboratory between 0800 and 1600 hours, during which time sleep was estimated with actigraphy. Throughout the 2nd night, the multiple sleep latency test (MSLT), simulated assembly line task (SALT) performance, and subjective sleepiness were recorded. The single, 4-hour exposure to bright light was found to significantly increase MSLT scores and improve SALT performance during the early morning hours on the night following bright-light exposure. No significant effects were noted with a 2-hour exposure. The most likely explanation for these findings is a phase delay in the circadian rhythm of sleepiness-alertness.

Sleep physiology and psychological aspects of the fibrositis (fibromyalgia) syndrome.

Fibrositis (fibromyalgia) patients were compared with normal controls in terms of electrophysiology (EEG), self-report indicants of awakening, quality of sleep, behaviourally signalled awakenings, and Symptom Check List 90R (SCL-90R) scores. The results differentiated fibrositis patients from normal controls in terms of SCL-90R scores, with fibrositis patients showing significantly more psychopathology. Fibrositis patients had more alpha EEG sleep and less REM and Stage 1 sleep. They were better able to recall their behaviourally signalled awakenings the following morning and reported qualitatively less satisfying sleep than the normal controls. The alpha EEG sleep anomaly may reflect a vigilant arousal state during nocturnal sleep and result in the daytime experience of unrefreshing sleep, psychologic distress, that re-enforces the perpetuation of the sleep-related symptoms.

Sleepiness/alertness on a simulated night shift following sleep at home with triazolam.

Physiological sleep tendency during a simulated night shift schedule was examined in 15 middle-aged subjects following daytime sleep after administration of triazolam or placebo. A double-blind, counterbalanced, crossover design involving two tours of five laboratory nights and four daytime home sleep periods was used. Triazolam lengthened daytime sleep as measured by wrist actigraph and improved nighttime alertness as measured by the MSLT. Sleepiness was most profound during the early morning hours (0430 to 0630) but improved significantly across nights for both conditions. Repeated test of sustained wakefulness latencies and simulated assembly line task performance decreased slightly across the night, but there were no significant condition effects. Subjective data tended to support objective measures, although Stanford Sleepiness Scale ratings indicated that subjects did not perceive improved alertness at night after triazolam-aided daytime sleep.

Induction of the obstructive sleep apnea syndrome in a woman by exogenous androgen administration.

We documented airway occlusion during sleep and an abnormally high supraglottic resistance while awake in a 54-yr-old woman who had developed physical changes and the syndrome of obstructive sleep apnea while being administered exogenous androgens. When the androgens were withdrawn, the patient's physical changes, symptoms, sleep study, and supraglottic resistance all returned to normal. A rechallenge with androgen produced symptoms of obstructive sleep apnea that abated upon withdrawal of the hormone. Previous reports have favored a role of androgens in the pathogenesis of sleep apnea. Our report provides direct evidence for this role. Structural and functional measurements indicate that androgens exert a permissive or necessary action on the structural configuration of the oropharynx that predisposes to obstruction during sleep. Development of the obstructive sleep apnea syndrome must be considered a possible side effect of androgen therapy.

Supraglottic airway resistance in normal subjects and patients with occlusive sleep apnea.

We assessed the flow-impeding properties of nose and pharynx combined in four normals and five patients with occlusive sleep apnea (OSA) while awake by measuring supraglottic pressure and airflow at the nose. We calculated two indices of impedance presented by the supraglottic airway: the second coefficient (K2) of Rohrer's equation and supraglottic resistance (Rsg) at 0.4 l/s. The influence of posture and nasal mucosal circulation was evaluated by measuring these indices in sitting and supine position before and after administration of a nasal decongestant. The effects of changes in posture were similar in both normals and patients: K2 and Rsg values were significantly larger in supine than in sitting position. The nasal decongestant significantly decreased both values in sitting and supine positions for normals and patients but did not eliminate the posturally induced changes. Patients had significantly greater K2 and Rsg values than normals in all conditions. These results indicate supraglottic airway narrowing in OSA patients. This narrowing probably results from structural encroachment on the pharyngeal airway.

Chest wall configuration in supine man: wakefulness and sleep.

We measured the anteroposterior and lateral diameter of the rib cage (RC), the anteroposterior diameter of the abdomen (ABD) and the cranio caudal abdominal dimension during breathing in supine posture, in order to analyze the shape of the chest wall in both awake and sleep conditions. By comparing the active breath holding and relaxation curves, it appeared that during activity of the respiratory muscles the RC is both expanded and distorted at the highest volumes and mainly distorted at the lowest volumes. During sleep the abdominal protrusion is smaller and the lateral sides of the rib cage expand more than during wakefulness. This might explain the higher rib cage motion during sleep found by some authors who measured the rib cage circumference and not confirmed by others who measured only its anteroposterior diameter. The motion of the rib cage is similar during sleep and wakefulness, its lateral parts leading the anteroposterior ones, showing that the pattern of motion of the rib cage is not affected by the different activation of the respiratory muscles. The possibility of a distorsion within the front part of the rib cage has been also discussed.

Effects of high ambient temperature on sleep in young men.

Each of 10 normal subjects had 4 nights of laboratory-monitored sleep, consisting of adjustment, baseline, high blanket temperature (HBT), and recovery nights. EEG-EOG recordings were made on each night; rectal temperature, heart rate, body weight, and ambient temperatures were monitored throughout the last 2 nights. On the HBT night, subjects had less total sleep time, more frequent and longer awakenings, greater shifting among sleep stages, decreased amounts of stage 1 REM and stages 3 + 4, and delayed onset of deep sleep (stages 3 and 4). Body temperature was elevated to a relatively constant level of 37 degrees C on the HBT night, but gradually decreased from 36 degrees C to 34.5 degrees C across the recovery night. Heart rate decreased at a linear rate on both the HBT and recovery nights, but was 15 beats/min faster on the former. Subjects experienced liquid loss of 1.25 kg on the HBT night, but had a full recovery by the following evening.