Detection of early FXTAS motor symptoms using the CATSYS computerised neuromotor test battery.

BACKGROUND: Carriers of the FMR1 premutation allele are at a significantly increased risk for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder is distinct from fragile X syndrome (FXS) in its molecular aetiology and clinical presentation. The primary features of FXTAS are late-onset intention tremor and gait ataxia. Associated features include parkinsonism, neuropsychological dysfunction, autonomic dysfunction and peripheral neuropathy. AIM: To investigate the usefulness of a quantitative neurological test battery implemented through the CATSYS instrument to identify preclinical symptoms of FXTAS. METHODS: Both premutation carriers with 70-199 repeats (62 men) and their low-repeat allele carrier siblings (27 men), identified through families with an individual affected with FXS, were tested. RESULTS: As expected, because of its sensitivity, use of the instrument allowed identification of tremor in 23% of men who had not self-reported tremor, and ataxia in 30% of men who had not self-reported ataxia. Among subjects with self-reported tremor and ataxia, we found significant concordance between measures of the CATSYS system and the self-report. CONCLUSION: Rates of these traits among premutation carriers and low-repeat allele carrier siblings could be identified, and are presented in this paper, along with the minimum estimates of age-related prevalence.

Health effects of long-term mercury exposure among chloralkali plant workers.

BACKGROUND: Inorganic mercury is toxic to the nervous system, kidneys, and reproductive system. We studied the health effects of mercury exposure among former employees of a chloralkali plant that operated from 1955 to 1994 in Georgia. METHODS: Former plant workers and unexposed workers from nearby employers were studied. Exposure was assessed with a job-exposure matrix based on historical measurements and personnel records. Health outcomes were assessed with interviews, physical examinations, neurological and neurobehavioral testing, renal function testing, and urinary porphyrin measurements. Exposure-disease associations were assessed with multivariate modeling. RESULTS: Exposed workers reported more symptoms, and tended toward more physical examination abnormalities, than unexposed workers. Exposed workers performed worse than unexposed subjects on some quantitative tests of vibration sense, motor speed and coordination, and tremor, and on one test of cognitive function. Few findings remained significant when exposure was modeled as a continuous variable. Neither renal function nor porphyrin excretion was associated with mercury exposure. CONCLUSIONS: Mercury-exposed chloralkali plant workers reported more symptoms than unexposed controls, but no strong associations were demonstrated with neurological or renal function or with porphyrin excretion.

Neurobehavioral test performance in the third National Health and Nutrition Examination Survey.

The third National Health and Nutrition Examination Survey (NHANES III) contained three computerized neurobehavioral tests from the Neurobehavioral Evaluation System (NES): simple reaction time, symbol-digit substitution and serial digit learning. The neurobehavioral data that were collected came from a nationally representative sample of adults 20-59 years old. Performance on the tests was related to sex, age, education level, family income and race-ethnicity. Performance decreased as age increased, and increased as education level and family income increased. Differences in performance between sexes, levels of education and racial-ethnic groups tended to decrease as family income increased. The relationship between age and performance on the symbol-digit substitution test varied by education level and by racial-ethnic group. The relationship between age and performance on the serial digit learning test varied by racial-ethnic group. Questionnaire variables that were related to performance on one or more of the tests included the reported amount of last night's sleep, energy level, computer or video game familiarity, alcoholic beverages within the last 3 h and effort. Persons who took the tests in English or Spanish performed differently on the symbol-digit substitution and serial digit learning tests. Performance on all the tests decreased as test room temperature increased.

Validity of a computer-assisted neurobehavioral test battery in toxicant encephalopathy.

The computer-assisted Neurobehavioral Evaluation System 2 (NES2) test battery provides an efficient method of measuring neurobehavioral effects in epidemiological studies, and a newer computer-assisted battery, NES3, has been developed to assist in neuropsychological assessment. This study assesses the validity of some NES2 and NES3 tests in patients diagnosed with toxicant encephalopathy (TE) following exposure to lead or to mixed solvents. This information can be used to improve the interpretation of NES test results in research studies and clinical evaluations examining central nervous system function. Performance on a battery of computer-assisted tests, consisting of several NES2 and NES3 tasks, by persons diagnosed with TE was compared to that of control subjects to determine if performance differences reflected a priori hypothesized brain-behavior relationships. Performance on the NES2 and NES3 tests was also correlated with performance on analogous standard neuropsychological tests. Significant performance differences between the patient cases and controls were observed in most of the predicted domains on the NES tests. Overall, moderate correlations were obtained between standard neuropsychological tests and NES2 and NES3 tests from the same functional domains. The results suggest that a test battery composed of NES2 and NES3 tests can identify clinically significant performance deficits in solvent-exposed patients who have been diagnosed with TE using traditional clinical neuropsychological test methods. The results with lead-exposed TE patients are less robust. Possible explanations for these differences are discussed.

Reliability of some tremor measurement outcome variables in field testing situations.

OBJECTIVE: Many summary measures of data obtained from tremor measurement procedures are commonly reported. The reliability of many of these summary measures of tremor measurements made in field testing situations is unknown. The purpose of the present investigation was to assess the reliability of a number of summary measures produced by the software of a widely used, commercially available tremor measurement instrument using data collected in three field epidemiologic studies. METHODS: Tremor data were obtained from 689 participants in 3 previously conducted studies of groups exposed to elemental mercury or arsenic. A widely used, commercially available tremor measurement instrument was used. Two-axis accelerometer measurements were obtained on 2 or more trials from each hand for each participant. Estimates of trial-to-trial and internal consistency reliability were calculated for 5 summary measures calculated by instrument manufacturer's software and 5 additional summary measures calculated from data output by the software. RESULTS: An RMS acceleration measure had the highest reliability in all 3 studies. The average over 4 trials of RMS acceleration and its logarithm had high reliability (>0.9). Recalculation of a tremor summary index and a harmonicity index as suggested by Edwards and Beuter (1999) resulted in measures with higher reliability and better distributional shape than the corresponding measures provided by the instrument manufacturer's software. The results in all three studies were similar. CONCLUSIONS: For the tremor measurement instrument and testing procedure that we employed, we recommend using the common logarithm of the RMS accelerations and recalculated tremor index as summary measures. We also recommend employing multiple trials of each type (e.g., with each hand) and averaging summary measures from those trials to derive outcome measures of tremor for use in epidemiologic studies. We recommend at least 2 trials for RMS acceleration measures and more for less reliable measures, particularly for designs employing repeated measurements of individuals. Summary measures averaged over at least 4 trials for mean frequency, dispersion of frequency, and power in the 3-6.5 and 6.6-10 Hz frequency ranges have sufficiently high reliability for use in epidemiologic studies.

Relationships between quantitative measures and neurologist's clinical rating of tremor and standing steadiness in two epidemiological studies.

OBJECTIVE: The purpose of the present investigation was to 1) compare a neurologist's physical examination (NPx) rating of severity of postural tremor to several summary measures derived from quantitative measurements of tremor and 2) compare a NPx rating of standing steadiness and related clinical findings to quantitative sway speed measurements. METHODS: Comparisons were performed on data obtained from two epidemiological field studies: 1) retired heavy industrial workers (n= 198, approximately half previously exposed to elemental mercury), and 2) small town residents (n=234, approximately 40% with environmental exposure to arsenic). A commercially available tremor measurement instrument was used in both studies. To obtain standing steadiness measures, a head position monitoring device was used in the mercury study, and a force platform was used in the arsenic study. The NPx included assessment of postural tremor, as well as evaluation of vibration perception and proprioception of the great toe, Achilles tendon reflex activity, Romberg test status, and tandem gait. One neurologist performed all the NPx in both studies and results were graded as normal, equivocal, or abnormal. The square root of the proportion of variance accounted for by a linear trend term in ANOVA models was used as an estimate of association between quantitative tests and clinical examination grade. An estimate of agreement, kappa, was also calculated after both NPx and quantitative test results were dichotomized. RESULTS: Most tremor summary measures varied monotonically with NPx tremor severity grade. Moderately good associations were observed between the tremor acceleration measure and NPx postural tremor grade (correlations up to approximately 0.5). Sway speed with eyes open and with eyes closed increased monotonically with NPx grade for most of the clinical signs. The NPx signs showing the strongest relationships with sway speed were Romberg test performance, tandem gait, and proprioception and vibration sensation of the great toe (correlations up to approximately 0.5). CONCLUSIONS: Quantitative tremor measurements were related to a neurologist's grading of postural tremor. Sway speed was associated with several NPx findings related to standing stability. Quantitative measurements of tremor and standing stability may provide more precise and objective measures of neurological function than NPx by a neurologist and are likely to be more consistent across times and examiners.

Epidemiological case definitions of peripheral neuropathy: experience from two neurotoxicity studies.

OBJECTIVE: The purpose of this investigation was to develop and apply case definitions of peripheral neuropathy (PN) derived from a set of individual measures of peripheral nerve function obtained in two epidemiological studies. METHODS: In the first study, retired workers of an industrial plant who were either previously exposed to mercury or not underwent a set of peripheral neurological tests. In the second study, persons living in an arsenic contaminated community in rural Georgia, USA, and unexposed comparison subjects were tested. In both studies all participants received a neurological physical examination, functional quantitative tests of vibrotactile thresholds and standing stability, and nerve conduction measurements. Two types of analyses were performed. First, the effect of exposure group status was examined for each individual test. For tests with continuous outcomes, the effect of exposure group was estimated while controlling for covariates. For tests with categorical outcomes (all of the neurological examination outcomes), exposure group effects were estimated by comparison of the proportion of abnormal test results among the exposed and unexposed groups. Second, case definitions of PN were constructed using combinations of results of the tests performed. Each of the continuous measures was categorized as normal, equivocal, or abnormal on the basis of adjusted standardized scores. Separate "abnormality scores" were constructed for 1) the nerve conduction tests and 2) the functional quantitative tests and physical examination findings. Five case definitions for PN were constructed based on combinations of these two abnormality scores. RESULTS: Generally, small differences were observed between exposed (n=79 arsenic exposed and 85 mercury exposed) and unexposed (n=84 arsenic unexposed and 118 mercury unexposed) groups when results of each clinical, functional or electrophysiological test were examined separately. Clearer group differences were observed in the proportions of each group who met case definitions for PN, however. For example, for both studies, the largest difference in nerve conduction measures between exposed and unexposed groups was approximately 0.33 SD, while the composite case definition showed an odds ratio of more than 3.1 for the mercury study and 5.1 for the arsenic study. CONCLUSIONS: These results suggest improved efficiency (and avoidance of the multiple-comparisons problem) for detecting peripheral nerve effects when case definitions of PN are constructed rather when results of individual tests of PN function are compared.

Residual neurologic deficits 30 years after occupational exposure to elemental mercury.

A battery of tests of peripheral and central nervous system function was administered to 205 former workers of a large heavy industrial plant, 104 of whom were previously exposed to inorganic mercury. The mean age of those examined was 71 years. Exposed subjects had participated in a urine-mercury exposure monitoring program during the time of operation of a process that required the use of mercury and its subsequent clean-up. Mercury exposure had been high (mean peak urine mercury concentration was >600 microg/l) and had ended 30 years or more prior to the investigation. Peripheral nerve function outcomes that were statistically significantly associated with cumulative mercury exposure after controlling for covariates included classification as having peripheral neuropathy, peroneal motor nerve conduction velocity, ulnar motor nerve conduction velocity, and peroneal motor nerve F-wave latency. Quantitative assessment of resting tremor was nearly significantly associated with cumulative mercury exposure (p=0.07). Among tests of central nervous system function, results of the Handeye Coordination test were significantly associated with cumulative mercury exposure after controlling for covariates. Cumulative mercury exposure was not observed to be associated with a quantitative measure of dementia or with a number of cognitive neurobehavioral test outcomes. The statistically significant associations with mercury exposure were observed in spite of greater mortality among the exposed group than the unexposed group. These results suggest that substantial occupational mercury exposure can have long-term adverse effects on the peripheral nervous system detectable decades after cessation of exposure. Such long-term adverse effects were not observed for a measure of dementia or other measures of cognitive function.

Neurological effects of environmental exposure to arsenic in dust and soil among humans.

Persons living in a small town in Georgia, USA, were studied because of known environmental exposure to arsenic-containing dust. To assess the effects of this exposure on the nervous system, a cross-sectional epidemiological study was performed. The health outcome assessments of the study were based on a priori selected clinical examination results and quantitative electrophysiologic and behavioral outcome measures. Because the primary goal was to identify cases of peripheral neuropathy, a clinically relevant case definition, based on results of these outcomes was created. Historical exposure reconstructions were performed on a subset of the exposed subjects for whom such information was available. Of the 238 persons enrolled in the study, 133 were classified as non-exposed (i.e., did not reside in the area of known exposure) and 105 were classified as exposed (i.e., did reside in the area of known exposure). Following exclusions of persons with occupational exposure to neurotoxicants, pre-existing conditions associated with peripheral nerve impairment, or age below 18 years, 118 unexposed subjects and 85 exposed subjects were available for inclusion in the analyses of peripheral nerve outcomes. A total of 4 (3.4%) of the unexposed subjects and 13 (15.3%) of the exposed subjects met the case definitions for peripheral neuropathy (OR=5.1; p=0.004). Comparison of three exposure groups (none, low, high) did not yield statistically significant differences. Statistically significant exposure group differences were observed on quantitative tests of standing steadiness, vibrotactile threshold and tremor intensity but not for nerve conduction measures. These results demonstrate a strong association between community arsenic containing dust exposure and peripheral neuropathy among participants in this investigation.

Neurotoxicity in young adults 20 years after childhood exposure to lead: the Bunker Hill experience.

OBJECTIVES: An epidemiological study of young adults was conducted to determine whether environmental exposure to lead during childhood was associated with current adverse neurobehavioural effects. METHODS: The exposed group consisted of 281 young adults who had been exposed environmentally to lead as children and the unexposed referent group consisted of 287 age and sex frequency matched subjects. Information on demographics, past and current health, and past exposures to neurotoxicants, and responses to the Swedish Q16 questionnaire were collected by interview. Standard neurobehavioural and neurophysiological tests were administered by computer or trained technicians. K x ray fluorescence was used to estimate tibial bone lead concentrations among the exposed and unexposed groups. Associations were examined between the exposed group and referents and tibial bone lead concentration and the neurobehavioural and neurophysiological outcomes of interest. RESULTS: Among the measures of peripheral nerve function, after controlling for confounders, sural sensory nerve evoked response amplitude, peroneal motor nerve compound motor action potential amplitude, vibrotactile thresholds of fingers and toes, and standing steadiness were significantly associated with exposure group. Among the neurobehavioural tests, hand-eye coordination, simple reaction time latency, trails B latency, symbol digit latency, serial digit, and learning error score were also significantly associated with exposure group after controlling for confounders. Exposed subjects had significantly more neuropsychiatric symptoms than the referents. Associations between tibial bone lead concentration and scores for vocabulary, vibrotactile thresholds of the fingers, and vibrotactile thresholds of the toes approached significance. CONCLUSIONS: Significant adverse central and peripheral neurological effects were found in a group of young adults 20 years after childhood environmental exposure to lead when compared with non-exposed controls. The absence of a significant association between neurological outcomes and tibial bone lead concentration, and the presence of significant associations between neurological outcomes and exposure group may be due to either the magnitude of measurement uncertainty in K x ray films relative to the actual tibial bone lead concentration in these young non-occupationally exposed subjects, or uncontrolled confounding of the exposure group.

The sensitivity and specificity of tests for carpal tunnel syndrome vary with the comparison subjects.

The performance of a variety of common office-based clinical tests for detection of carpal tunnel syndrome (CTS) was assessed in 119 subjects with and without electrophysiological evidence of CTS. Symptoms compatible with CTS and electrophysiological tests positive for median mononeuropathy at the wrist were observed in 57 hands, symptoms compatible with CTS and normal electrophysiological test results were observed in 58 hands, and no symptoms compatible with CTS and normal electrophysiological test results were observed in 123 hands. For all the diagnostic tests studied, the proportion of subjects who had a false positive clinical test result was much higher in the electrophysiologically normal subjects who had CTS compatible hand symptoms than in the electrophysiologically normal subjects who were asymptomatic. These results suggest that many studies that have evaluated diagnostic tests for CTS have produced falsely optimistic estimates of the test's performance because of their use of asymptomatic comparison subjects.

Tolerance of mefloquine by SwissAir trainee pilots.

Due to presumed adverse performance impact, a World Health Organization clause currently restricts the use of mefloquine malaria chemoprophylaxis in individuals requiring fine coordination and spatial discrimination. We conducted a double-blind, placebo-controlled, cross-over study to quantitatively assess the effects of mefloquine at steady state on performance in 23 trainee airline pilots. Flying performance was assessed using a flight simulator, psychomotor function was evaluated, sleep and wake cycles were monitored, and symptoms and moods were assessed using standardized questionnaires. A simplified postural sway meter recorded sway in three test positions. In the mefloquine loading dose phase, there was one withdrawal due to dizziness, diarrhea, and flu-like symptoms, and three volunteers reported nonserious, sleep-related adverse events. There was no significant difference in flying performance, psychomotor functions, or mean sway for any test position. Nonsignificant reductions in mean total nocturnal sleep (mefloquine = 450 min versus placebo = 484 min) and poorer sleep quality were detected in the mefloquine phases. The mood findings indicated a predominance of positive states, with vigor the predominant mood in all phases. No significant performance deficit was documented under laboratory conditions during use of mefloquine at steady state.

Early detection of Alzheimer disease: methods, markers, and misgivings.

There is at present no reliable predictive test for most forms of Alzheimer disease (AD). Although some information about future risk for disease is available in theory through ApoE genotyping, it is of limited accuracy and utility. Once neuroprotective treatments are available for AD, reliable early detection will become a key component of the treatment strategy. We recently conducted a pilot survey eliciting attitudes and beliefs toward an unspecified and hypothetical predictive test for AD. The survey was completed by a convenience sample of 176 individuals, aged 22-77, which was 75% female, 30% African-American, and of which 33% had a family member with AD. The survey revealed that 69% of this sample would elect to obtain predictive testing for AD if the test were 100% accurate. Individuals were more likely to desire predictive testing if they had an a priori belief that they would develop AD (p = 0.0001), had a lower educational level (p = 0.003), were worried that they would develop AD (p = 0.02), had a self-defined history of depression (p = 0.04), and had a family member with AD (p = 0.04). However, the desire for predictive testing was not significantly associated with age, gender, ethnicity, or income. The desire to obtain predictive testing for AD decreased as the assumed accuracy of the hypothetical test decreased. A better short-term strategy for early detection of AD may be computer-based neuropsychological screening of at-risk (older aged) individuals to identify very early cognitive impairment. Individuals identified in this manner could be referred for diagnostic evaluation and early cases of AD could be identified and treated. A new self-administered, touch-screen, computer-based, neuropsychological screening instrument called Neurobehavioral Evaluation System-3 is described, which may facilitate this type of screening.

Human neurobehavioral research methods: impact of subject variables.

Behavioral tests are used in work site and community research to detect and characterize the effects of neurotoxic chemical exposures in human populations, but the influence of subject variables on test performance has not been well studied in normal adult populations. This research sought to evaluate the impact of two variables, education and cultural group, on 18 widely used tests of neurotoxic insult. Behavioral tests from the two consensus neurotoxicity test batteries (established by the World Health Organization and the U.S. Agency for Toxic Substances and Disease Registry) were administered to 715 people aged 26-45 with 0-18 years of education, drawn from European descent United States majority, American Indian, African American, and Latin American populations. Education, cultural group, age, and gender affected the outcome of behavioral tests as revealed by ANOVA, MANOVA, and multiple regression techniques. Education, followed by cultural group, accounted for the most variance in the tests studied. More importantly, years of education and cultural group had 13-25% shared variance on the cognitive tests and highly significant interactions derived from ANOVA tests. This suggests that these factors should be controlled in the design of a study rather than in the statistical analysis. Because these factors can mimic a neurotoxic insult, failure to adequately control and analyze them could lead to inaccurate conclusions about the association between poor performance and neurotoxic insult.

Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance.

This longitudinal study of travellers to Africa taking mefloquine (MQ) chemoprophylaxis aimed to quantify and assess non-serious adverse events (AE) occurring during short-term prophylaxis and relate these to concentrations of racemic MQ, its enantiomers and metabolite. A total of 420 volunteers (52% F) participated. AEs with some impact on activities were reported by 11.2% of participants including 7.9% of neurological/psychiatric symptoms. Women were more likely to report AEs (P = 0.02). The standardized questionnaires used showed more pathological indicators in travellers who reported subjective AE with significantly more dizziness, distress, sleep disturbances and a high total mood disturbance (TMD) in the AE group. There was, however, no significant performance deficit in computerized psychomotor tests in those experiencing AE. Furthermore, no significant differences were observed in enantiomer ratios, metabolite concentrations, or racemic MQ levels in participants with or without AEs suggesting that these factors are not the main predictors of mefloquine intolerability.

Symposium on computerized behavioral testing of humans in neurotoxicology research: overview of the proceedings.

The Symposium on Computerized Behavioral Testing of Humans in Neurotoxicology Research, held in Portland, OR (USA), on June 21-23, 1995, is the subject of the 23 articles in this issue of Neurotoxicology and Teratology. It is the first open forum to focus exclusively on computer-implemented behavioral test methods for neurotoxicology. Both the Symposium and this proceedings have been organized around the topics: new technologies and new batteries, confounders and methodologic factors, special populations (children), sensory and motor testing, clinical applications, and neurotoxicology research. The Symposium emphasized common approaches to computerized testing, highlighted fundamental differences in strategies for the selection of tests, and produced tangible evidence that the NES2 test battery has become a pervasively used instrument for presenting valid tests in human neurotoxicology research. However, the dominant impression drawn from the Symposium is that there is a methodologic vigor in the field of computerized behavioral testing. This is revealed by the appearance of new test batteries, criticism of existing procedures, challenges to the existing order of test selection, and the identification of analytic covariates for commonly used tests.

NES test performance in a large US Army veteran sample: relationships with both demographic factors and traditional neuropsychological measures.

A large sample of Vietnam-era US Army veterans completed a set of 16 neuropsychological tests, including six computer-based tests from the Neurobehavioral Evaluation System (NES), during medical examinations supervised by the US Centers for Disease Control (CDC). Data for 881 participants of the Agent Orange Validation Study (AOV) and Vietnam Experience Study (VES) were available for analysis from public access data tapes provided by CDC. Information was available for several potential covariates from demographic questionnaires, a medical examination, and a medical history. Explorator, principal components factor analysis of 16 test variables yielded four factors, including one on which most of the NES tests loaded. The single best predictor of most neuropsychological performance variables was an index of general intellectual level as measured at entry into the Army almost 20 years before the neuropsychological examinations. Alcohol drinking variables were not related to neuropsychological performance. Several measures of general intelligence were compared for use as covariates of neuropsychological test performance. All were superior to years of education in statistically controlling for general intellectual level.

Development of a computer-based battery designed to screen adults for neuropsychological impairment.

The initial step in the development of a new computer-based neuropsychological testing system is described. A new hardware-software system and a screening battery consisting of an orientation task and five cognitive tests has been implemented. This novel screening battery is designed for use in identifying individuals among exposed groups who may require more extensive follow-up neuropsychological evaluation. Sophisticated, but currently available, and relatively inexpensive hardware and software technology are employed, introducing an improvement over existing computer-based batteries. Use of a digitized speech production device for producing instructions facilitates testing of illiterate subjects, use of auditory stimulus materials, and relatively easy translation of the testing instructions to other languages. Use of a pen-based notebook computer enables responding by the subject in a manner that is both natural and analogous to that used in existing paper-and-pencil testing instruments. Five neuropsychological tests were developed to cover a range of cognitive domains: 1) verbal list learning and recognition memory, 2) visual memory span, 3) conceptual and motor tracking, 4) psychomotor speed and accuracy, and 5) delayed verbal recognition. The screening instrument has been pilot-tested for feasibility of use among outpatients at an occupational medicine clinic and among community-dwelling older adults. This instrument is intended to provide a standardized efficient, cost-effective method for widespread use in occupational medicine and public health to detect and track subclinical neurotoxic effects and to prevent additional harmful exposure. Additional aspects of development of the computer-based testing system are discussed.

Feasibility and validity of three computer-assisted neurobehavioral tests in 7-year-old children.

Three tests from the computerized Neurobehavioral Examination System (NES) were administered to a group of 917 Faroese children at approximately 7 years of age. The NES Continuous Performance Test (CPT) was modified to use animal silhouettes as stimuli instead of letters. Almost all children completed Finger Tapping (FT), the modified CPT, and Hand-Eye Coordination (HE). However, 18% of the children missed at least 25% of the stimuli on the CPT (full test period), and 37% of the children did not improve their HE performance by at least 10%, as compared to the first trial. Boys obtained better results than girls, and older children performed better than younger ones. However, both factors were confounded by acquaintance with computer games. Children who used glasses, who had strabismus, or who had decreased contrast sensitivity obtained less satisfactory scores, especially on CPT and HE. The NES performance was significantly associated with functional neurological performance, including catching a ball, diadochokinesia, and finger agnosia. Slight, though statistically significant, decrements were seen with increased levels of prenatal exposure to neurotoxicants, as indicated by the mercury concentrations in cord blood obtained at the time of birth. In conclusion, the tests were feasible in this age group after slight modifications, and the test results showed meaningful associations with major predictors, thus supporting the validity of the data.