Morphological plasticity in an infant monkey model of temporal lobe epilepsy.

PURPOSE/METHODS: Seizures in early life are thought to contribute to the development of human temporal lobe epilepsy. To examine the consequences of early seizures, we elicited status epilepticus in immature, 5.5- to 7.0-month-old pigtailed macaques by unilateral microinfusion of bicuculline methiodide into the entorhinal cortex. RESULTS: This report focuses on neuropathological changes in the hippocampus. Bicuculline infusion consistently elicited limbic-like seizures with prolonged, relatively localized electrographic activity. Magnetic resonance imaging revealed enhanced signal intensity in the ipsilateral hippocampus after seizures; in some cases, there was also progressive hippocampal atrophy. Histological changes were variable; in two of five monkeys, there was significant hippocampal neuron loss, gliosis, granule cell dispersion, and mossy fiber reorganization. CONCLUSIONS: The histopathological findings and associated magnetic resonance imaging abnormalities after bicuculline-induced status epilepticus in infant monkeys mimic common aspects of human temporal lobe epilepsy.

Development of a model of status epilepticus in pigtailed macaque infant monkeys.

Seizures, particularly multiple episodes and/or status epilepticus (SE) are prevalent in pediatric patients. Pediatric SE is associated with brain changes that have been hypothesized to contribute to the onset of temporal lobe epilepsy (TLE). In order to gain insight into the effects of seizures on the immature brain and the risk for later TLE, we have developed a model of limbic SE in the pigtailed macaque monkey. In separate studies, bicuculline methiodide or a bicuculline 'cocktail' was infused into three regions of the brain (area tempestas, hippocampus, entorhinal cortex) to induce seizures. Measures included MRI, electrophysiology, behavior and morphology. Our results suggest that monkey models of SE may provide useful tools for understanding the effects of prolonged seizures during infancy and the origins of TLE in humans.

Infant monkeys' visual responses to drawings of normal and distorted faces.

Face-like patterns attract attention from both human and nonhuman primates. The present study explored the facial preferences in infant pigtailed macaques (Macaca nemestrina). Twenty-five subjects looked at 20 paired drawings of adult conspecific monkey faces, and their looking time was recorded. The facial features in the drawings were arranged in positions ranging from a normal to a scrambled face. The subjects looked at the normal face more than expected by chance (P < .02), suggesting a preference, whereas the distorted faces were observed randomly. The normal face may have been preferred because the eyes were in a normal position within the facial outline.

Cognitive and behavioral deficits in nonhuman primates associated with very early embryonic binge exposures to ethanol.

This study was undertaken to evaluate teratogenesis associated with early weekly ethanol exposure followed by later gestational abstinence. Ethanol, 1.8 gm/kg, was orally administered weekly to gravid nonhuman primates (Macaca nemestrina) for the first 3, 6, or the entire 24 weeks of pregnancy. Control animals received weekly sucrose solution as did the 3- and 6-week cohort animals in subsequent weeks. Thirty-five viable infants were assessed for growth, malformations, and behavioral and cognitive dysfunction. Animals in the 6-week and 24-week cohorts were uniformly abnormal in behavior and inconsistently abnormal in physical development relative to the control animals. Animals in the 3-week cohort were equivocally normal. These results demonstrate ethanol's capacity to produce behavioral teratogenesis (brain dysfunction) in isolation from physical anomalies in the rest of the body. The results strongly suggest that binge drinking in the first 6 to 8 weeks of pregnancy (a period when women may not know that they are pregnant), followed by later gestational abstinence, is as dangerous to the fetus as exposure throughout gestation.

Behavioral assessment of young nonhuman primates: perceptual-cognitive development.

The Infant Primate Research Laboratory at the University of Washington utilizes a range of test procedures to study perceptual-cognitive development in nonhuman primate infants at high and low risk for poor developmental outcome. These test procedures rely on the visual preferences of infants and are employed in research with both human and animal subjects. The forced-choice preferential looking technique is based on the primate infants' preference for patterned over plain stimuli and allows the early measurement of visual acuity. The novelty paradigm is based on the preference that infants show for novel over familiar stimuli and is used to study intramodal and cross-modal recognition memory. Tests of recognition memory have shown sensitivity in detecting subtle functional alterations associated with perinatal risk factors such as teratogen exposure. The use of measures which assess early patterns of visual attention should be considered in both human and nonhuman primate studies in behavioral teratology.

Deficits in visual recognition in low birth weight infant pigtailed monkeys (Macaca nemestrina).

15 low birth weight and 15 normal birth weight pigtailed monkey infants were administered an adaptation of a standardized test of visual recognition memory, originally developed for human infants. Animals were given a series of problems in which 2 identical black-and-white patterns were presented for a familiarization period. The previously exposed pattern was then paired with a novel one, and looking time to each pattern was recorded. The normal birth weight animals directed a significant amount of their visual attention to the novel stimuli, thus demonstrating recognition abilities. As a group, the performance of the low birth weight infants remained at chance. These findings have important implications for an animal model to examine factors contributing to poor cognitive outcome in low birth weight human infants.

Visual recognition memory deficits in methylmercury-exposed Macaca fascicularis infants.

Infant Macaca fascicularis exposed prenatally to maternal subclinical levels of methylmercury (MeHg) and their nonexposed controls were administered a test of visual recognition memory beginning at 210 days postconception (mean postnatal age = 51.88 days, SD = 5.30). The test consisted of a series of problems in which two identical 35 mm slides of a monkey's face were presented for a study period, followed by a test trial in which the previously exposed stimulus was paired with a novel one, and the looking time to each was recorded. The nonexposed group showed differential visual attention to the novel stimuli, indicating visual recognition abilities. The exposed group's visual attention to the novel stimuli was random. These results, in conjunction with earlier findings, suggest that prenatal MeHg exposure is associated with impaired visual recognition memory performance.

Auditory evoked heart rate responses in pigtailed macaques (Macaca nemestrina) raised in isolation.

Heart rate (HR) responses evoked by 1 sec of 85-dB white noise were studied in 12 1-year-old pigtailed macaques, 6 of which were raised in social isolation and 6 with mothers and peers. Tests were given for 5 days, with 25 trials each day. Although baseline HR did not differ between groups, the pattern of change from baseline was not the same. Isolates showed only HR acceleration, returning to baseline within 10-11 sec of stimulus onset. Socially reared monkeys had a 10- to 11-sec biphasic response of acceleration followed by deceleration, with subsequent return to baseline. The same group difference in HR pattern occurred when subjects were tested with a less intense 65-dB stimulus. These findings were discussed in terms of activity, emotionality, and autonomic regulatory functions. It was concluded that early rearing experiences may affect later physiological processes involving autonomic nervous system balance. This conclusion was related to observations of persistent individual differences in HR by human children classified as inhibited.

The effect of low-level prenatal methylmercury exposure on visual recognition memory in infant crab-eating macaques.

Infant crab-eating macaques exposed in utero to maternal subclinical levels of methylmercury (MeHg) and their nonexposed controls were administered an adaptation of a standardized test of visual recognition memory. Exposed animals showed recognition deficits in that they directed significantly less visual attention to novel stimuli than did controls. These results parallel those obtained by other investigators with high-risk and teratogen-exposed human infants.