Cerebral resuscitation: pathophysiology and therapy.

The interest in the possibility of cerebral resuscitation has been growing exponentially during the last decade. It became clear that pharmacotherapeutic interaction can possibly alter the outcome of cerebral hypoxia/ischemia. The present review is an attempt to provide an organizational framework for a systematic integration of studies specifically dealing with pharmacological treatment post-insult.

Aging of core and optional sleep.

Two consecutive 24-hr ambulatory recordings of 14 healthy elderly persons (7 women, 7 men, ages 88-102) and of 19 healthy young adults (10 women, 9 men, ages 25-35) were evaluated. In addition to the classical sleep parameter analysis, sleep structure was also analyzed in terms of a proposed distinction between "core" and "optional" sleep (Horne 1989). Core sleep is the essential part of the sleep and is mainly slow wave sleep. This type of sleep is composed of stages 3 and 4 on non-REM sleep (NREM 3-4). Core sleep is obtained during the first three sleep cycles and the remainder of the night sleep is considered optional sleep. Optional sleep is more altered than core sleep. However, in both optional and core sleep, NREM sleep and REM are reduced. There is also an increase in drowsiness and in the time spent awake after sleep onset; however, the extent of these effects are more obvious in elderly men. Aging effects of slow wave sleep probably represent an amplification of the changes as observed in awake electroencephalic (EEG) patterns in healthy seniors. The decrease in slow wave sleep (stages NREM 3-4) is gender related and prevails in elderly men. REM sleep diminishes with increasing age. In the elderly, most REM sleep occurs at the beginning of the night. This contrasts to younger persons where the duration of REM sleep is longer at the end of the night. Furthermore, a decrease in REM sleep latency is particularly obvious in elderly men and probably secondary to the curtailment of slow wave sleep. The ultradian NREM-REM cycle rhythm (as defined by the periodic occurrence of REM sleep) shows a monophasic trend suggesting a diminished adaptive function of aged sleep. The informative value of true, continuous ambulatory recordings in the assessment of sleep-wakefulness patterns in normal and pathological aging is stressed.

Sleep disruption in Parkinson's disease. Assessment by continuous activity monitoring.

OBJECTIVE: To assess differences in activity and immobility during sleep between patients with Parkinson's disease (PD) and healthy subjects and to evaluate the relations of clinical variables with the motor activity measures in patients with PD. DESIGN: Survey, case series. SETTING: University hospital outpatient neurology department and urban population in Leiden, the Netherlands. Motor activity was recorded during 6 successive nights at home with a wrist-worn activity monitor. PARTICIPANTS: Eighty-nine patients with PD and 83 age-matched healthy controls. MAIN OUTCOME MEASURES: For each subject, three mean measures reflecting activity or immobility during the nocturnal period were calculated. RESULTS: Compared with the healthy elderly subjects, patients with PD have an elevated nocturnal activity level and an increased proportion of time with movement, indicating a more disturbed sleep. The mean duration of nocturnal immobility periods was similar for both groups. This measure, however, did reflect the self-reported disturbed sleep maintenance in both groups. The daily dose of levodopa or the use of dopamine agonists in patients not receiving levodopa, rather than disease severity, proved to be the best predictors of nocturnal activity. CONCLUSIONS: We hypothesize that in mildly to moderately affected patients with PD, levodopa or dopamine agonists cause sleep disruption by their effects on sleep regulation. In more severely affected patients, the beneficial effects of these drugs on nocturnal disabilities that cause sleep disruption in PD prevail.

Differential effects of the new antipsychotic risperidone on sleep and wakefulness in the rat.

The effects of risperidone, a new antipsychotic with potent 5-hydroxytryptamine2 (5-HT2) and dopamine-D2 (DA-D2) antagonistic properties, were studied on sleep-wakefulness patterns in rats. Administration of low doses (0.01-0.16 mg/kg i.p.) resulted in a significant increase of deep slow wave sleep (SWS2) and a decrease of wakefulness (W) and light slow wave sleep (SWS1). High doses (0.63-2.5 mg/kg) produced opposite effects. Paradoxical sleep (PS) was significantly reduced over the dose range tested. The increase of SWS2 after low doses of risperidone could be related to a predominant and potent 5-HT2 receptor blocking activity.

Long-term neurological assessment of the post-resuscitative effects of flunarizine, verapamil and nimodipine in a new model of global complete ischaemia.

In anesthetized rats, global complete ischaemia lasting for 9 min was induced by controlled hydraulic compression of the chest. A neurological score, based on cranial and spinal reflexes, postural tone, gait, movement and limb placement, was determined at 2 hr and 1, 2, 3, 7, 14, 21 and 28 days after resuscitation. Three doses of three calcium antagonists, flunarizine, verapamil and nimodipine and their respective solvents, were given intravenously during the resuscitation. The total neurological score was significantly better than solvent with 0.16 and 0.63 mg/kg of flunarizine and 0.04 and 0.16 mg/kg of verapamil; it was significantly better with solvent (10% ethanol) than with 0.04 and 0.16 mg/kg of nimodipine. The deficiency in tactile placing reactions of the hindpaws was the most resistant to therapy. This non-invasive model of global ischaemia in rats seems useful for the evaluation of drugs, since it requires minimal anesthesia and allows assessment of neurological recovery over an extended period of time.

Topographical and temporal patterns of brain activity during the transition from wakefulness to sleep.

Changes in electroencephalographic (EEG) spectral power, coherence and frequency were examined for the last minute of wakefulness and the first minute of sleep via topographical mapping. Data were also analyzed across sequential 1-minute samples of wake, stage 1 and stage 2 sleep. Not all brain regions exhibited the same EEG changes during the transition and not all brain regions were found to change at the same time. Brain sites closest to the midline (e.g. F4, C4, P4, O2) showed significant changes in EEG power (increases in theta and decreases in alpha power) during the transition to sleep, whereas brain sites most lateral to the midline (e.g. Fp2, F8, T4) showed little change. Decreases in alpha coherence were observed from wakefulness to sleep for brain site comparisons furthest away from each other (e.g. T3 vs. T4, T5 vs. T6, F7 vs. F8, F3 vs. O1, F4 vs. O2). Spectral analysis of EEG activity revealed that the time of significant change in EEG power varies among brain regions. Decreases in alpha power continued to occur later into the transition period for the posterior regions of the brain (O2, P4).

Ambulatory monitoring of sleep-wakefulness patterns in healthy elderly males and females (greater than 88 years): the "Senieur" protocol.

OBJECTIVE: The study was designed to investigate sleep-wake patterns in healthy elderly men and women (greater than 88 years) using ambulatory recording techniques. DESIGN: Cross-sectional observations on 2 consecutive days. METHODS: Two consecutive 24-hour recordings were made. Each 30-second period of the recording was scored as characteristic of wakefulness, REM, and non-REM sleep (stages 1-4). SETTING: Interviews and recordings were done in the home of the elderly, not interfering with the habitual routine. PARTICIPANTS: Among eligible members of the "Senieur" protocol, screened for wellness, seven females (88-102 years) and seven males (88-98 years) volunteered to participate. MAIN OUTCOME MEASURES: Organization of sleep, sleep structure, and daytime mapping. RESULTS: There was no difference between the first and second night recording. Important gender differences were observed: males had significantly less total sleep, shorter REM latency, more transitions to wake from REM, less NREM 3 sleep, and virtually no NREM 4. Daytime napping, REM amount, and distribution did not show sex differences. Although the variability in the amount of napping was considerable, it occupied less than 10 percent of the total sleep time in both women and men. Daytime napping was unrelated to sleep characteristics. CONCLUSIONS: Ambulatory sleep-wake recordings allow an objective and critical evaluation of sleep function in normal aging. Interesting findings include a shift of REM sleep to the first part of the sleep period an increased cycle variability, and non-correlation of night-time sleep with daytime napping. In contrast to earlier findings in elderly persons, a polygraphic and subjective first-night effect was lacking.

Nocturnal activity and immobility across aging (50-98 years) in healthy persons.

OBJECTIVE: To measure the influence of age on measures of nocturnal activity and immobility in 100 healthy subjects aged 50 to 98 years. DESIGN: Cross-sectional study. SETTING: Urban population in Leiden. Recordings were performed at home while the subjects maintained their habitual 24-hour pattern of activities. PARTICIPANTS: 100 subjects without a history of major medical disorders and a normal neurological examination and performance-oriented assessment of gait (Tinetti). MEASUREMENTS: Motor activity was recorded during six successive nights with a wrist-worn activity monitor. The occurrence of supra-threshold motor activity was recorded over 15-second epochs. A questionnaire was used to evaluate sleep habits and the occurrence of sleep disturbances. Four mean measures reflecting activity or immobility during the nocturnal period were calculated for each subject. RESULTS: Only one out of four measures, (ie, the nocturnal proportion of time with movement, increased with age for females. For males, no age effects emerged. The mean duration of nocturnal immobility periods was higher in females than in males. Also, for females, the use of hypnotics increased with successive decades. Sex and the use of hypnotics were significantly related to the mean duration of immobility periods. CONCLUSION: If care is taken not to confound aging with illness, measures of nocturnal activity and immobility reveal only marginal effects of aging.

Metrazol-produced impairment of passive avoidance retention specifically antagonized by anti-petit mal drugs.

In a single session, naive female 250-g Wistar rats were trained to remain for 3 min on a platform located above an electrifiable grid. During training, animals were shocked (4 mA) after they stepped down. Retention of the step-down avoidance was tested 24 h later in rats treated SC 30 min before the session with saline or a subconvulsive dose of metrazol (40 mg/kg). During the retention test no shock was delivered. The latency to step down and the time on the grid were recorded. The metrazol rats significantly failed to retain the avoidance task. Groups of six rats per dose were trained and 24 h later pretreated, 5 min before metrazol, with an IP injection of the following antiepileptics (dose range in mg/kg): Ethosuximide (20--320); trimethadione (20--320); clonazepam (0.04--0.63); sodium valproate (20--320); carbamazepine (1.25--20); phenobarbital (5--80); or diphenylhydantoin (5--80); or high dose of haloperidol (0.16) and amphetamine (0.63). Only ethosuximide, trimethadione, and clonazepam significantly increased the latency to step down and significantly shortened the time on the grid. Sodium valproate only shortened the time spent on the grid. The results suggest that only anti-petit mal drugs antagonize the retention impairment of passive avoidance produced by metrazol.

A putative multipartite model of haloperidol interaction in apomorphine-disturbed behavior of the dog.

The interaction between various doses of apomorphine and haloperidol on intracranial self-stimulation in the dog was studied using a pradigm in which reinforcing brain-stimulation was controlled by a discriminative auditory stimulus. Reinforced lever-pressing was decreased by low doses of apomorphine and completely suppressed by stereotypogenic doses. At various doses of apomorphine, low doses of haloperidol either increased response inhibition by enhancing stereotypy, or increased lever pressing by reducing stereotypy while concomitantly increasing the number of nonreinforced responses. Intermediate to relatively high doses of haloperidol antagonized stereotypy and the response inhibition produced by apomorphine. High doses of haloperidol antagonized stereotypy but also suppressed self-stimulation. Thus, haloperidol is not only able to restore performance capability, but also disturbed reinforcing and discriminative stimulus control.

Effects of ritanserin on sleep disturbances of dysthymic patients.

Ritanserin, a selective and potent serotonin-2 antagonist, is effective in the treatment of a variety of syndromes related to anxiety and depression, including dysthymic disorder. In animals and healthy volunteers, ritanserin specifically increases slow-wave sleep and the hypothesis arises that this effect on sleep may contribute to its therapeutic properties. Therefore, we studied the effects of ritanserin on sleep in a group of dysthymic patients (DSM-III). Polygraphic recording as well as subjective evaluations of the quality of sleep were performed before and at the end of a 4-week period of double-blind medication with either ritanserin (10 mg o.d. in the morning) or placebo. At baseline, patients showed at fragmented and superficial sleep, with low amounts of slow wave sleep. Ritanserin significantly increased Slow Wave Sleep and changed the frequency and distribution of some stage transitions during the night. No other sleep parameters were modified by ritanserin treatment.

Sleep improvement in dogs after oral administration of mioflazine, a nucleoside transport inhibitor.

Mioflazine, a nucleoside transport inhibitor, was given PO to dogs at doses of 0.04-10 mg/kg. Sixteen hour polygraphic sleep recordings were made and analysis and sleep stage classification was done by computer. Mioflazine decreased wakefulness and increased slow wave sleep, but did not affect the latencies of either REM sleep or slow wave sleep. This increased sleep was due to an increase in the number of light and deep slow wave sleep epochs. The effect lasted for about 8 h. The decreased wakefulness and increased slow wave sleep could be antagonized by the adenosine antagonist caffeine (2.5 and 10 mg/kg, PO); however, there was not a pure antagonistic effect. It might be that the enhancement of slow wave sleep is due to an activation of brain adenosine receptors. This is the first report of a drug acting on adenosine that given orally improves sleep. Mioflazine might be the prototype of substances worth considering for the treatment of a variety of sleep disorders.

Functional role of 5-HT2 receptors in the regulation of sleep and wakefulness in the rat.

Recently developed agents specifically acting on different 5-hydroxytryptamine (5-HT) receptor populations were used to analyze the functional role of 5-HT2 receptor subtypes in the sleep-wakefulness cycle of the rat. The 5-HT2 receptor antagonist ritanserin injected intraperitoneally (IP) (0.04-2.5 mg/kg) induced an increase in deep slow wave sleep (SWS2) duration at the expense of wakefulness (W), light slow wave sleep (SWS1) and paradoxical sleep (PS). The stimulation of 5-HT2 receptors by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) produced a dose-related increase in W and a dose-dependent decrease in both SWS2 and PS. Pretreatment with ritanserin (0.16-2.5 mg/kg) or with cinanserin (2.5-5 mg/kg), another 5-HT2 receptor antagonist, dose-dependently reversed the W enhancement and the SWS2 deficit produced by DOM, but not the PS deficit. Sleep-wakefulness alterations (increase in W and SWS1 combined with a suppression of SWS2 and PS) observed after IP injection of two putative 5-HT1 receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (2.5 mg/kg) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969) (0.63 mg/kg), were not modified by ritanserin pretreatment (0.16-2.5 mg/kg). These results further support the hypothesis that the serotonergic system plays an active role in the regulation of the sleep-wakefulness cycle in the rat and that 5-HT2 receptors are involved in this action. In addition, it is suggested that 5-HT1 receptor subtypes are unlikely to interact with 5-HT2 receptors in the sleep-wakefulness modulation mediated through 5-HT2 receptors.

Effects of zolpidem and flunitrazepam on nocturnal sleep of women subjectively complaining of insomnia.

Eighteen non-pregnant woman complaining about insomnia were polysomnographically investigated for 3 nights with weekly intervals. They received placebo, 2 mg flunitrazepam or 10 mg zolpidem according to a cross-over double blind design. The patients were selected by general practitioners on the basis of subjective complaints. Zolpidem is a recently introduced short-acting imidazopyridine hypnotic, binding to a subunit of the benzodiazepine 1 receptor. Flunitrazepam is a well-known hypnotic, binding to both the benzodiazepine 1 and 2 receptor subtypes. Objective recording did not substantiate the subjective complaint of insomnia. Sleep patterns during placebo differed only little from that expected from age matched healthy persons. Both flunitrazepam and zolpidem significantly shortened sleep onset (5 min of continuous sleep beginning with NREM 1 sleep). The sleep composition following flunitrazepam was characterized by an increase in NREM 2, a prolongation of the time of REM sleep, a reduction of REM sleep and an increase in NREM 3-4 sleep during the first 2 h of sleep. The sleep composition following zolpidem resembled more than seen in persons without sleep complaints. However, as compared to placebo, there was a decrease of the time spent awake during sleep and an increase in NREM 3-4 during the first 2 of sleep.

Experimental evidence of penile erections during paradoxical sleep in the rat.

We have developed a new technique to chronically monitor penile erections in the rat across behavioural states. This technique, involving chronic erectile tissue pressure monitoring and simultaneous ischiocavernosus and bulbospongiosus (IC-BS) muscle electromyography, demonstrates for the first time that rats exhibit penile erections during paradoxical sleep (PS). No erectile events were observed during slow wave sleep. These PS-related erectile events were similar to visually confirmed, waking state, erections in that they were associated with an increase in baseline erectile tissue pressure and, with IC-BS muscle bursts, dramatic suprasystolic penile pressure peaks often greater than 1000 mmHg. PS-related erections were 11 +/- 7 s in duration and were observed in 28.5% of all PS episodes. This method of chronic penile erection monitoring in the rat provides a new animal model for investigating neural mechanisms of sleep-related erections.

Effects of temperature and temperature gradients on ion-sensitive microelectrodes.

Ion-sensitive microelectrodes are widely used in studies of mammalian tissues. Often the tissue is maintained at 37 degrees C, some 10-15 degrees C above room temperature. The temperature difference between the room and the preparation was found to be capable of altering the measured ion potential by as much as 10 mV. The change depended on 3 factors: the temperature dependence of the Nernst slope, the temperature dependence of the interference factor, and the thermoelectric potential induced by the temperature difference between the two ends of the ion-exchanger column. Certain combinations of these changes can cancel each other, resulting in spurious but apparently temperature-insensitive readings. The first two factors can produce errors when the temperature of calibration differs from the temperature of the tissue being measured. Serious errors in measurements of ion concentration can also occur, due to all 3 factors, if a temperature gradient exists across the ion exchanger column; this situation can easily occur when recording from exposed mammalian tissues. The use of a short ion-exchanger column will reduce but not eliminate effects due to a temperature gradient.

The effect of hypoxia on the acquisition of a two-way avoidance task in the guinea-pig.

Male guinea-pigs learned conditioned two-way shuttle behaviour to acoustic stimuli. Training was given during 5 consecutive days. Two daily training sessions were held with intersession intervals of 120 (Experiment 1) and 60 (Experiment 2) min. In each experiment one group was given post-session hypoxia (H) and another group received no hypoxia (NH). In the NH group the performance during the second session was higher than during the first session on the same day. In the H group this gain was abolished but the course of acquisition was unchanged. The induced amnesia confirmed the selective effect of hypoxia on medium-term memory (MTM) formation previously observed in rats. The results are discussed with reference to the validity of the multistage model of memory formation.

Pharmacological protection against hypoxia-induced effects on medium-term memory in a two-way avoidance paradigm.

Male guinea-pigs were trained in a two-way avoidance task. They were exposed for 1 min to 100% nitrogen after each of the two daily sessions on 5 consecutive days. Eight groups of 10 animals were pretreated with a single dose of either flunarizine (0.16 or 0.63 mg/kg), nimodipine (0.16 or 0.63 mg/kg), nifedipine (0.16 or 0.63 mg/kg) or verapamil (0.63 or 2.5 mg/kg) 1 h before the first daily session. Only flunarizine protected against the hypoxia-induced amnesia. The results are discussed with reference to protective effects in other paradigms and the utility of the paradigm for pharmacological research purposes.

Ambulatory first night sleep effect recording in the elderly.

The concept of a first night effect on sleep patterns, specifically in relation to age is a controversial topic in the literature. Our data are obtained during two consecutive 24-h ambulatory home sleep-wake recording in 10 elderly persons with a mean age of 85.5 years. Polysomnographic recordings indicated that a first night effect is present in old age, even using home recording, and that several types of insomnia can be differentiated, stressing that sleep cycle parameters should be taken into account. It is suggested that the first night effect is a 'miniature' replication of a psychophysiological insomnia.

The benzodiazepine antagonist, Ro 15-1788, increases REM and slow wave sleep in the dog.

The benzodiazepine antagonist, Ro 15-1788, increases REM and deep slow-wave in dogs at a dose of 10 mg/kg orally. These actions are opposite to that of diazepam. This suggests either that Ro 15-1788 possesses hitherto undescribed intrinsic partial inverse agonist activity or that it is antagonizing an endogenous benzodiazepine-like substance which is involved in modulating sleep-wakefulness.