Vernon A. Benignus

Carbon monoxide and the nervous system

Carbon monoxide (CO) is a colorless, tasteless, odorless, and non-irritating gas formed when carbon in fuel is not burned completely. It enters the bloodstream through the lungs and attaches to hemoglobin (Hb), the bodys oxygen carrier, forming carboxyhemoglobin (COHb) and thereby reducing oxygen (O(2)) delivery to the bodys organs and tissues. High COHb concentrations are poisonous. Central nervous system (CNS) effects in individuals suffering acute CO poisoning cover a wide range, depending on severity of exposure: headache, dizziness, weakness, nausea, vomiting, disorientation, confusion, collapse, and coma. At lower concentrations, CNS effects include reduction in visual perception, manual dexterity, learning, driving performance, and attention level. Earlier work is frequently cited to justify the statement that CO exposure sufficient to produce COHb levels of ca. 5% would be sufficient to produce visual sensitivity reduction and various neurobehavioral performance deficits. In a recent literature re-evaluation, however, the best estimate was that [COHb] would have to rise to 15-20% before a 10% reduction in any behavioral or visual measurement could be observed. This conclusion was based on (1) critical review of the literature on behavioral and sensory effects, (2) review and interpretation of the physiological effects of COHb on the CNS, (3) extrapolation from the effects of hypoxic hypoxia to the effects of CO hypoxia, and (4) extrapolation from rat behavioral effects of CO to humans. Also covered in this review article are effects of chronic CO exposure, the discovery of neuroglobin, a summary of the relatively new role for endogenous CO in neurotransmission and vascular homeostasis, groups which might be especially sensitive to CO, and recommendations on further research. The interested reader is directed to other published reviews of the literature on CO and historically seminal references that form our understanding of this ubiquitous gas.

Toluene levels in blood and brain of rats during and after respiratory exposure

Eighty rats were exposed to 575 ppm toluene by inhalation for up to 240 min. Animals in one group were sacrificed during exposure at 15, 30, 60, 120, or 240 min. Following a 240-min exposure, groups of rats were sacrificed at 15, 30, 120, or 240 min. Blood was drawn from the vena cava of sacrificed subjects. Brains were extracted and homogenized. Blood and brain tissue were assayed for toluene by gas chromatography. One-compartment pharmacokinetic models were fitted to predict toluene levels in blood and whole brain as a function of time. Estimated asymptotes were 10.5 ppm (μg/g) for venous blood and 18.0 ppm (μg/g) for brain. Blood and brain toluene levels achieved 95% of estimated asymptotes in 53 and 58 min, respectively. Brain and blood toluene levels did not rise at significantly different rates. Though the difference was small, brain toluene level fell significantly more rapidly than toluene level in blood. In cases where other data were available in the literature on rodents or man, the results reported here agreed well with earlier data.

Effects of age and body lead burden on CNS function in young children. I. slow cortical potentials.

The effects of body Pb burden on slow cortical potentials were studied in 63 children aged 13-75 months. Slow wave (SW) voltage during sensory conditioning varied as a linear function of blood lead (PbB) level. The slope of this function, moreover, changed systematically with age. For children under 5 years of age, SW voltage tended to be positive at low PbBs and to be negative above 30 micrograms/dl. For children over 5 years of age, SW voltage tended to be negative at low PbBs and to be less negative (or positive) above 30 micrograms/dl. These results provide evidence of altered CNS function at the lowest Pb effect level ever reported.

Active and passive avoidance in rats as a function of age

Rats of four age groups: young (30 days of age), adolescent (180 days of age), adult (365 days of age), and old (547 days of age) were trained on active and passive avoidance tasks. There was impaired acquisition and 30-day rentention of passive-avoidance learning in both young and old rats, compared to the intermediate age groups, and marked impairment of acquisition and retention of active-avoidance learning in the old rats. Learning impairment is thus associated with immaturity as well as senescence.

Increasing scientific power with statistical power.

A survey of basic ideas in statistical power analysis demonstrates the advantages and ease of using power analysis throughout the design, analysis, and interpretation of research. The power of a statistical test is the probability of rejecting the null hypothesis of the test. The traditional approach to power involves computation of only a single power value. The more general power curve allows examining the range of power determinants, which are sample size, population difference, and error variance, in traditional ANOVA. Power analysis can be useful not only in study planning, but also in the evaluation of existing research. An important application is in concluding that no scientifically important treatment difference exists. Choosing an appropriate power depends on: a) opportunity costs, b) ethical trade-offs, c) the size of effect considered important, d) the uncertainty of parameter estimates, and e) the analysts preferences. Although precise rules seem inappropriate, several guidelines are defensible. First, the sensitivity of the power curve to particular characteristics of the study, such as the error variance, should be examined in any power analysis. Second, just as a small type I error rate should be demonstrated in order to declare a difference nonzero, a small type II error should be demonstrated in order to declare a difference zero. Third, when ethical and opportunity costs do not preclude it, power should be at least .84, and preferably greater than .90.

Effects of age and body lead burden on CNS function in young children. II. EEG spectra

This study explored the effects of age and PbB upon EEG power spectra and various measures of hemispheric laterality in children, aged 13-75 months, watching a display (cartoon). The following are the principle conclusions: (1) The delta- and theta-band amplitude decreased with age. (2) When only bilaterally synchronized EEG between P3 and P4 was considered, the amplitude of P3 was estimated as greater than P4 in all frequency bands and for all ages. Previous reports have not shown lateral EEG dominance in children below 75 months. (3) When lateral dominance measures consider only the relationship between synchronized EEG at P3 and P4, bilateral communality in the delta band increased with age. (4) Increased PbB generally produced an increase in the relative amplitude of synchronized EEG between P3 and P4 in all frequency bands. This was true for PbB levels well below 15 micrograms/dl, among the lowest level PbB effects previously reported. No clinical or behavioral effects of PbB values have been reported below 15 micrograms/dl. It appears to be theoretically and practically important to understand the functional significance of bilaterally synchronized activity. The signal processing of the CNS can be explored using these methods. Greater understanding of these data would help define the extent and etiology of PbB effects on the CNS

Signal detection behavior in humans and rats: a comparison with matched tasks

Animal models of human cognitive processes are essential for studying the neurobiological mechanisms of these processes and for developing therapies for intoxication and neurodegenerative diseases. A discrete-trial signal detection task was developed for assessing sustained attention in rats; a previous study showed that rats perform as predicted from the human sustained attention literature. In this study, we measured the behavior of humans in a task formally homologous to the task for rats, varying two of the three parameters previously shown to affect performance in rats. Signal quality was manipulated by varying the increment in the intensity of a lamp. Trial rate was varied among values of 4, 7, and 10 trials/min. Accuracy of signal detection was quantified by the proportion of correct detections of the signal (P(hit)) and the proportion of false alarms (P(fa), i.e. incorrect responses on non-signal trials). As with rats, P(hit) in humans increased with increasing signal intensity whereas P(fa) did not. Like rats, humans were sensitive to the trial rate, though the change in behavior depended on the sex of the subject. These data show that visual signal detection behavior in rats and humans is controlled similarly by two important parameters, and suggest that this task assesses similar processes of sustained attention in the two species.

Human Neurobehavioral Effects of Long-Term Exposure to Styrene: A Meta-Analysis

Many reports in the literature suggest that long-term exposure to styrene may exert a variety of effects on the nervous system, including increased choice reaction time and decreased performance of color discrimination and color arrangement tasks. Sufficient information exists to perform a meta-analysis of these observations quantifying the relationships between exposure (estimated from biomarkers) and effects on two measures of central nervous system function: reaction time and color vision. To perform the meta-analysis, we pooled data into a single database for each end point. End-point data were transformed to a common metric of effect magnitude (percentage of baseline). We estimated styrene concentration from biomarkers of exposure and fitted linear least-squares equations to the pooled data to produce dose–effect relationships. Statistically significant relationships were demonstrated between cumulative styrene exposure and increased choice reaction time as well as increased color confusion index. Eight work-years of exposure to 20 ppm styrene was estimated to produce a 6.5% increase in choice reaction time, which has been shown to significantly increase the probability of automobile accidents. The same exposure history was predicted to increase the color confusion index as much as 1.7 additional years of age in men.

Toluene levels in blood and brain of rats as a function of toluene level in inspired air

The relationship of toluene concentration in blood and brain to the concentration of toluene in inspired air has not been explicitly studied. Sixty rats were exposed by inhalation to 50, 100, 500, or 1000 ppm toluene for 3 hr. Immediately following exposure, venous blood samples and whole brains were collected and assayed for toluene levels. For several empirical reasons, the natural logarithm (log) of toluene tissue levels were predicted in a linear model from log toluene levels in air. An additional 10 rats were exposed to 550 ppm toluene for 8 hr in order to verify that the 3-hr exposure was sufficient to produce near-asymptotic levels of toluene in blood and brain. Log brain toluene concentration was significantly higher than log blood concentration by an additive constant. The ratio of brain to blood toluene level was estimated as 1.56/1. Three- and eight-hour exposure results did not differ, thus indicating that these results would hold for toluene exposures of 3 hr or greater.

Age related changes in the effect of electroconvulsive shock (ECS) on the in vivo hydroxylation of tyrosine and tryptophan in rat brain

A single electroconvulsive shock (ECS) was applied to 40 young (9 months) and 40 old (24 months) male rats. The effect on brain catecholamine synthesis was determined at intervals after ECS by measuring the accumulation of dihydroxyphenylalamine (DOPA) and 5-hydroxytryptophan (5-HTP) in rats pretreated with a central decarboxylase inhibitor (M-hydroxybenzyl hydrazine, NSD 1015). This accumulation permitted an estimation of the in vivo rates of hydroxylation of tyrosine and tryptophan. Control brain DOPA and 5-HTP concentrations were both lower in the older animals. Following ECS there was an increase in brain DOPA concentration (maximal at 60 min after ECS) in both young and old rats, but the increase was much smaller in the older animals. There were no changes in brain 5-HTP at any time after ECS, in either age group. It appears that aging selectively affects the response of the brain dopaminergic neurotransmitter system to stress, and we suggest that this may be a factor in the decreased resistance to stress in older subjects.