Sleep-waking states develop independently in the isolated forebrain and brain stem following early postnatal midbrain transection in cats.

We report the effects of permanently separating the immature forebrain from the brain stem upon sleeping and waking development. Kittens ranging from postnatal 9 to 27 days of age sustained a mesencephalic transection and were maintained for up to 135 days. Prior to postnatal day 40, the electroencephalogram of the isolated forebrain and behavioral sleep-wakefulness of the decerebrate animal showed the immature patterns of normal young kittens. Thereafter, the isolated forebrain showed alternating sleep-wakefulness electrocortical rhythms similar to the corresponding normal patterns of intact, mature cats. Olfactory stimuli generally changed forebrain sleeping into waking activity, and in cats with the section behind the third nerve nuclei, normal correlates of eye movements-pupillary activity with electrocortical rhythms were present. Behind the transection, decerebrate animals showed wakefulness, and after 20 days of age displayed typical behavioral episodes of rapid eye movements sleep and, during these periods, the pontine recordings showed ponto-geniculo-occipital waves, which are markers for this sleep stage, together with muscle atonia and rapid lateral eye movements. Typically, but with remarkable exceptions suggesting humoral interactions, the sleep-waking patterns of the isolated forebrain were dissociated from those of the decerebrate animal. These results were very similar to our previous findings in midbrain-transected adult cats. However, subtle differences suggested greater functional plasticity in the developing versus the adult isolated forebrain. We conclude that behavioral and electroencephalographic patterns of non-rapid eye movement sleep and of rapid eye movement sleep states mature independently in the forebrain and the brain stem, respectively, after these structures are separated early postnatally. In terms of waking, the findings strengthen our concept that in higher mammals the rostral brain can independently support wakefulness/arousal and, hypothetically, perhaps even awareness. Therefore, these basic sleeping-waking functions are intrinsic properties of the forebrain/brain stem and as such can develop autochthonously. These data help our understanding of some normal/borderline sleep-waking dissociations as well as peculiar states of consciousness in long term patients with brain stem lesions.

Neuroamine related compounds in the CSF of hydrocephalic rabbits.

The effects of neonatal hydrocephalus on the levels of tyrosine, tryptophan, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) in CSF were determined by high-performance liquid chromatography (HPLC) with fluorometric detection in normal and chronically hydrocephalic rabbits. The hydrocephalic rabbits showed a highly significant increase in both the serotonin metabolite 5-HIAA and the dopamine metabolite HVA. There were no significant effects of the hydrocephalus on either tyrosine or tryptophan levels. There was a significant positive correlation between the intracranial pressure (ICP) and the increase in 5-HIAA and HVA, but not with the two precursor amino acids. There was a significant decrease in these amino acid precursors with age in both groups. A trend towards higher levels of 5-HIAA and HVA in older rabbits was also evident, however this change was not to the degree found in the hydrocephalics. These data indicate that increased ICP affects the mechanism of removal of 5-HIAA and HVA from the cerebrospinal fluid.

Neurological and neurobehavioral development of the mutant 'twitcher' mouse.

The present study described the neurological and locomotor development of the mutant 'twitcher' mouse (B57BL/6J-twi), an enzymatically authentic model of globoid cell (Krabbe) leukodystrophy. Comparisons were made on a neurological developmental battery and a series of behavioral tests, including open field, rotorod, and hangtime performance. Homozygous affected (twi/twi), heterozygous carriers (+/twi) and homozygous normals (+/+) were compared. Neurological development was slowed in twi/twi with some subtler differences between +/twi and normals. Twi/twi reached all functional milestones except grasp. There was a rapid deterioration of motor indices after 20 days of age. However, most sensory markers were preserved. On hangtime, there were significant differences from normal for both twi/twi and +/twi at 15 days of age and across the 15-30 day developmental stage, with the +/twi males slightly more impaired. On the rotorod, all animals were equally unable to stay on the rod at 15 days of age and neither male nor female twi/twi showed significant development. Male +/twi lagged significantly behind male +/+. In the open field, all groups were equally inactive at 13-15 days and showed similar increases in activity, rearing, and grooming until weaning. All groups peaked immediately after weaning and declined thereafter, with twi/twi showing the lowest activity. The data were discussed in terms of the relationship between the human disease and the animal model.

Recovery of function after neonatal or adult hemispherectomy in cats: I. Time course, movement, posture and sensorimotor tests.

Cats with removal of the left hemitelencephalon (hemispherectomy) as neonates (n = 12) or in adulthood (n = 14), were compared using a battery of 16 neurological and behavioral tests given when they were young adults (kittens) or at least 5 months after the lesion (adults). The neonatal-lesioned subjects grew normally and performed markedly and significantly better than adult-lesioned cats in 13 tests covering the wide range of movement, posture and sensory functions which were assessed. None of the animals recovered tactile placing of the right forelimb or a normal vision in the right visual field. However, the overall recovery was outstanding for all cats such that the neonatal-lesioned were hard to differentiate from intact controls in their spontaneous, daily activities. Because the lesions were similar in the two age-at-lesion groups, and since numerous functions were followed for prolonged, comparable postlesion time, we conclude that, after hemispherectomy in the cat, there definitely is greater functional recovery if the lesion is sustained early in life. We propose that the enhanced recovery of function in neonatal-lesioned cats is largely due to the extensive anatomical reorganization which we have demonstrated in ongoing studies, and which contrasts with a lesser remodeling in adult-lesioned cats.

Maturation of pyrogen-elicited fever in the kitten.

The febrile response to the endotoxin Salmonella typhosa was studied in developing kittens. We found that kittens younger than 30 days of age generated only a small rise in temperature in response to a standardized endotoxin challenge that consistently causes fever in adult cats. Some degree of febrile response was present at birth, but the dose of pyrogen necessary to elicit a fever was 10-15 times greater than that required in the adult. There was a gradual increase in both the magnitude and duration of fever as a function of age with the largest change occurring after 30 days of age. There was a direct relationship between the ability of the kitten to maintain its body temperature (Tbo) at the room ambient (Ta) and the magnitude of the elicited fever. However, increasing the Ta to thermoneutral (Ta = 30-32 degrees C) did not enhance the thermal response indicating that the failure to elicit the fever is not due to passive effects of Ta. These data suggest that the febrile response to an endotoxin develops over the first 6-7 weeks of the kitten's life and are discussed in relation to other physical variables of development.

Striatal lesions change the behavioral effects of morphine in cats.

Cats injected with a relatively low single dose of morphine sulfate (0.5-3.0 mg/kg i.p.) exhibit a long-lasting group of behaviors which we quantified via a time-sampling video technique. The dominant events are complex head movements accompanied by discrete paw, ear and body movements with the animal in a quiet posture, all of which appeared to be visually mediated. Cats with extensive lesions of the caudate nuclei do not show this profile; instead they show unspecific locomotor activity proportional to the size of the ablation and to the dose of morphine. These effects are blocked by naloxone in both intact and lesioned animals. The robustness of these results indicate that (i) the striatum is involved in the behavioral effects of morphine, and (ii) that the cat is a useful, sensitive model for the study of the behavioral effects of opiates.

Reorganization of cerebellorubral terminal fields following hemispherectomy in adult cats.

Tritiated amino acids were injected into the right nucleus interpositus of the cerebellum and the projections to the red nucleus were mapped autoradiographically in adult cats with ablation of the left cerebral hemisphere and in intact controls. In intact animals cerebellorubral terminals were found along the entire rostrocaudal extent of only the left red nucleus. The fields occupied a larger area and were apparently more dense toward the middle third of the nucleus. An outstanding change in hemispherectomized cats was a significant expansion of the terminal fields into the dorsal quadrants. Possibilities for morphological reorganization are discussed.

Residual cerebellothalamic terminal fields following hemispherectomy in the cat.

Tritiated amino acids were injected into the nucleus interpositus, both the anterior (INA) and posterior (INP) divisions, and the projections to the ventrolateral nucleus (VL) of the thalamus mapped autoradiographically in 7 intact and 8 hemispherectomized adult cats. Five hemispherectomized cats receiving injections into the antero-medial one-third of INP, exhibited terminal fields in lateral portions of the contralateral VL. These terminals were patchy and appeared qualitatively identical to those seen in intact animals. In 3 hemispherectomized cats sparse terminal fields were also observed in both normal and gliotic regions of the parafascicular, central lateral, anterior pretectal and posterior thalamic nuclei. The presence of these terminal fields was specific to the injections into the INP. The density of the terminal labeling was greater in the hemispherectomized than in the intact cats. The VL areas receiving these terminals were conspicuously gliotic and devoid of large thalamocortical relay neurons. These results indicate that the INP projections to the VL persist despite degeneration of the thalamocortical neurons, suggesting that the site of the residual terminals is not directly upon such neurons. Attempts at reorganization are discussed.

Evidence for a crossed corticorubral projection in cats with one cerebral hemisphere removed neonatally.

Tritiated amino acids were injected into the right pericruciate cortex and the projections to the red nucleus were mapped autoradiographically in 10 intact and 6 adult cats with one cerebral hemisphere (left side) removed neonatally. In the intact cats only projections to the ipsilateral red nuclei were seen. The terminals were distributed along the entire rostrocaudal extent, but the density of the label was greater in the ventral and medial aspects of the nucleus. In the hemispherectomized cats projections to both red nuclei were found. The topography of the terminals was similar to that seen in intact animals. This finding, together with other changes which we have described, suggests that an extensive structural reorganization may occur after removal of one cerebral hemisphere in cats.

Hippocampal theta rhythm persists in the permanently isolated forebrain of the cat.

In cats with high mesencephalic transections surviving for up to 90 days, the hippocampal EEG shows exaggerated percentages of 3-5 Hz theta activity. The theta rhythm has similar waveform and frequency characteristics to that seen in the intact cat and can be selectively enhanced or abolished by systemic physostigmine or atropine respectively. These data demonstrate (1) that the caudal brainstem is not essential for the spontaneous appearance of the hippocampal theta rhythm, and (2) the integrity of a major cholinergic system in the chronically isolated forebrain.

Hypothalamic dysthermia in persons with brain damage.

Brain injury causing dysthermia has appeared to be not uncommon in institutionalized people with mental retardation. We sought to determine the characteristics and risks of patients of one institution. Of 1100 residents surveyed over 10 years 92 were reported to have unexplained high or low body temperatures, and 48 were monitored. Core temperatures were taken by non-invasive thermometers recording continuously for 24 h. Results were related to clinical conditions and aetiologies of mental retardation. Twenty-one per cent of the residents monitored showed hyperthermia, often related to prenatal metabolic or chromosomal abnormalities. Forty-two per cent had hypothermia, related to other causes of brain injury. Seventy-five per cent had abnormal patterns, including flat or exaggerated rhythms, reversed day-night cycle, unusual fluctuations, or sleep phase delay. Sixty-two per cent of 21 deaths to date have occurred in hypothermic patients. Occasional discrepancies between history of dysthermia and monitored results are best explained by fluctuations of temperature control over several days, probably due to changes in timing of hypothalamic rhythmicity. This could be better delineated by longer periods of monitoring.

Neurological development of kittens.

The neurological development of the kitten was studied from birth to 120 days of age. Three motor features present at birth disappeared within the 1st 45 days of life. The labyrinthine head and body righting reactions were present at birth; the latter matured only by 25 days of age when the air righting reaction (mature by 35 days) started to appear. Limb placing reactions developed progressively with proprioceptive components being present at birth whereas tactile components evolved slowly from early contact lifting to forepaws contact placing (60 days) and narrow plank walking (75 days). Standing and walking were well developed by 45 days. Eye opening occurred at 9.5 days and several eyeblink reactions (including blink to light) were present at birth. Adequate binocular coordination was seen by 47 days. Vision progressed parallel to the clearing of the ocular media which were fairly transparent by 32 days. Visually guided paw placing and the visuopalpebral blink reflex matured later (by 37 and 59 days, respectively). The external auditory canal and pinna were fully developed by 12 and 31 days, respectively; spontaneous and tactile pinna movements were present at birth; orienting to animal and nonanimal sounds was well developed by 6.5 and 18 days, respectively; spatial sound localization was developed by 16 days and differential responding to animal sounds matured by 24.5 days. Somatic responses and olfaction were present at birth but matured further thereafter. Playful interactions between kittens started by 10--15 days and well developed play behavior was seen by 36--40 days. In brief, all neurological functions mature progressively during the 1st 3 postnatal months.

Mortality and the acquisition of basic skills by children and adults with severe disabilities.

OBJECTIVE: To determine normative data on age-related probabilities of children with severe disabilities acquiring mobility or self-feeding skills, or dying during a 5-year follow-up period. RESEARCH DESIGN: A 5-year follow-up study of three mutually exclusive subgroups formed on the basis of severe, profound, or suspected levels of retardation and incontinence and the following combinations of feeding and mobility skills. PARTICIPANTS: The sample was made up of 7836 children and adults distributed among the three subgroups being served in California between January 1981 and December 1985. MEASUREMENTS/MAIN RESULTS: Subjects who were tube-fed and immobile showed very little likelihood of becoming mobile or feeding themselves and had a high probability of death. Individuals who had some mobility experienced a better outcome. CONCLUSIONS: After age 6 years, the most probable outcome for children who are immobile and cannot feed themselves is death or no improvement in self-help skills.

Tumor volume and growth kinetics in hypothalamic-chiasmatic pediatric low grade gliomas.

Pediatric low grade gliomas evidence a tendency towards quiescent growth, thus complicating the clinical management of nonresected tumors whose clinical behavior may be difficult to predict. We decided to explore the hypothesis of possible correlation in pediatric low grade glioma between tumor volume and growth rate. We identified 6 children with hypothalamic chiasmatic lesions. Five of these patients were treated only with biopsy and 1 with repeated partial tumor resection. All of 6 patients had 10-15 sequential brain MRI over a time span of 3-8 years. Tumor volume was determined using Sigma Scan Image software. The results were analyzed utilizing two equations for modeling tumor growth: exponential and Gompertz. In 4 patients whose tumor volume was approximately 80-100 cm(3) at the time of diagnosis, slow spontaneous partial regression was observed. In the other patients deceleratory or exponential tumor growth was volume-dependent. Our results suggest that growth of pediatric low grade glioma decelerates as tumor becomes large and that the Gompertz model for tumor growth is useful for understanding the growth kinetics of pediatric low grade glioma.

An enzyme immunoassay for neuron-specific enolase in cerebrospinal fluid.

A direct (as opposed to competitive) enzyme immunoassay (EIA) was developed to detect neuron-specific enolase (NSE) in cerebrospinal fluid (CSF). Most common methods of evaluating NSE levels have utilized radioimmunoassay. These are highly sensitive, but cannot be employed in laboratories not equipped or licensed for the use of radioisotopes. The EIA developed here shows sensitivity within the physiological range of values for CSF-NSE (> I ng/ml) and can be used in laboratories with appropriate densitometric scanning capabilities. The assay was applied to CSF samples obtained from patients with a variety of diagnoses at the time of surgical intervention for their respective disorders. While there were no diagnostically significant differences between the level of NSE in CSF from patients with different neurological disorders utilized in the development of this procedure, we were able to differentiate between marginally different levels of NSE. We conclude that we have developed a safe, fast, reliable, and sensitive assay for NSE in the CSF that can be used to study NSE levels in a variety of neurological cases.

Metabolic responses of the neonatal rabbit brain to hydrocephalus and shunting.

The metabolic changes that occur in the neonatal brain as a result of hydrocephalus, and the response to ventriculoperitoneal shunting, vary with the maturational stage of the brain. In this study, local glucose utilization (LCMRglu) and oxidative metabolic capacity were estimated using 2-deoxyglucose autoradiography and cytochrome oxidase histochemistry, respectively. Hydrocephalus was induced in rabbit pups via intracisternal kaolin injections at 4-6 days of age. Shunting occurred at 19-26 days of age and the animals were sacrificed at ages ranging from 33 to 331 days. In normal animals there was a high glucose demand early in life which showed a decrease at about 60 days of age. In rabbits sacrificed prior to 60 days of age the controls showed the highest LCMRglu with significant decreases in both the hydrocephalic and shunted animals. After 60 days of age the shunted animals had higher LCMRglu than both the hydrocephalic and control subjects. Oxidative metabolic capacity peaked before 50 days of age in normal animals. At the youngest age, both the hydrocephalic and shunted animals showed higher cytochrome oxidase density rates than the control rabbits. In the older group, the hydrocephalic animals remained high while the shunted animals approximated the control densities. Neither the changes seen in the LCMRglu nor the oxidative metabolic capacity were correlated with changes in cell packing density or increased intracranial pressure. These data suggest that when the brain is compromised by hydrocephalus, there is an initial compensatory increase in oxidative metabolic capacity. The development of the glycolytic pathway appears to be retarded by hydrocephalus, but with shunting and the passage of time, the LCMRglu rebounds to levels above that of controls.