Prenatal manganese biomarkers and operant test battery performance in Mexican children: Effect modification by child sex.

BACKGROUND: Manganese (Mn) is essential to healthy neurodevelopment, but both Mn deficiency and over-exposure have been linked to prefrontal cortex (PFC) impairments, the brain region that regulates cognitive and neurobehavioral processes responsible for spatial memory, learning, motivation, and time perception. These processes facilitated by attention, inhibitory control, working memory, and cognitive flexibility are often sexually dimorphic and complex, driven by multiple interconnected neurologic and cognitive domains. OBJECTIVE: We investigated the role of child sex as an effect modifier of the association between prenatal Mn exposure and performance in an operant testing battery (OTB) that assessed multiple cognitive and behavioral functional domains. METHODS: Children (N = 575) aged 6-8 years completed five OTB tasks. Blood and urinary Mn measurements were collected from mothers in the 2nd and 3rd trimesters. Multiple regression models estimated the association between Mn biomarkers at each trimester with OTB performance while adjusting for socio-demographic covariates. Covariate-adjusted weighted quantile sum (WQS) regression models were used to estimate the association of a Mn multi-media biomarker (MMB) mixture with OTB performance. Interaction terms were used to estimate modification effect by child sex. RESULTS: Higher blood Mn exposure was associated with better response rates (more motivation) on the progressive ratio task and higher overall accuracy on the delayed matching-to-sample task. In the WQS models, the MMB mixture was associated with better response rates (more motivation) on the progressive ratio task. Additionally, for the linear and WQS models, we observed a modification effect by child sex in the progressive ratio and delayed matching-to-sample tasks. Higher prenatal Mn biomarker levels were associated with improved task performance for girls and reduced performance in boys. CONCLUSION: Higher prenatal blood Mn concentrations and the MMB mixture predicted improved performance on two of five operant tasks. Higher prenatal Mn concentrations regulated executive functions in children in a sexually dimorphic manner. Higher prenatal Mn exposure is associated with improved performance on spatial memory and motivation tasks in girls, suggesting that Mn's nutritional role is sexually dimorphic, and should be considered when making dietary and/or environmental intervention recommendations.

Prenatal metal mixture concentrations and reward motivation in children.

Reward motivation is a complex umbrella term encompassing the cognitions, emotions, and behaviors involved in the activation, execution, and persistence of goal-directed behavior. Altered reward motivation in children is characteristic of many neurodevelopmental and psychiatric disorders. Previously difficult to operationalize, the Progressive Ratio (PR) task has been widely used to assess reward motivation in animal and human studies, including children. Because the neural circuitry supporting reward motivation starts developing during pregnancy, and is sensitive to disruption by environmental toxicants, including metals, the goal of this study was to examine the association between prenatal concentrations of a mixture of neurotoxic metals and reward motivation in children. We measured reward motivation by administering a PR test to 373 children ages 6-8 years enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) Study in Mexico City. Children were asked to press a response lever for a token reward; one press on the response lever was required to earn the first token and each subsequent token required an additional 10 lever presses. Maternal blood concentrations of lead, manganese, zinc, arsenic, cadmium, and selenium were measured using inductively-coupled plasma mass spectrometry during the 2nd and 3rd trimesters of pregnancy. We performed generalized Weighted Quantile Sum (gWQS) regression analyses to examine associations between the prenatal metal mixture and reward motivation; adjusting for child sex, birthweight and age; and maternal IQ, education, and socioeconomic status. The prenatal metal mixture was significantly associated with higher motivation as indicated by more lever presses (ß = 0.02, p < 0.001) and a shorter time between receiving the reinforcer and the first press (ß = 0.23, p = 0.01), and between subsequent presses (ß = 0.07, p = 0.005). Contributions of different metals to this association differed by trimester and child sex. These findings suggest that children with increased exposure to metal during the 2nd and 3rd trimesters of gestation demonstrate increased reward motivation, which may reflect a tendency to perseverate or hypersensitivity to positive reinforcement.

Acetyl-l-carnitine does not prevent neurodegeneration in a rodent model of prolonged neonatal anesthesia.

Many studies have shown that prolonged or repeated use of general anesthesia early in life can cause an increase in neurodegeneration and lasting changes in behavior. While short periods of general anesthesia appear to be safe, there is a concern about the neurotoxic potential of prolonged or repeated general anesthesia in young children. Unfortunately, the use of general anesthesia in children cannot be avoided. It would be a great benefit to develop a strategy to reduce or reverse anesthesia mitigated neurotoxicity. The mechanisms behind anesthesia related neurotoxicity are unknown, but evidence suggests that mitochondrial dysfunction and abnormal energy utilization are involved. Recent research suggests that a class of compounds known as carnitines may be effective at preventing anesthesia related neurotoxicity by influencing fatty acid metabolism in the mitochondria. However, it is unknown if carnitines can provide protection against changes in behavior associated with early life exposure to anesthesia. Accordingly, we evaluated the neuroprotective potential of acetyl-l-carnitine in 7-day old rats. Rat pups were exposed to 6 h of general anesthesia with sevoflurane or a control condition, with and without acetyl-l-carnitine. The oxygenation level of animals was continuously monitored during sevoflurane exposure, and any animal showing signs of hypoxia was removed from the study. Animals exposed to sevoflurane showed clear signs of neurodegeneration 2 h after sevoflurane exposure. The hippocampus, cortex, thalamus, and caudate putamen all had elevated levels of Fluoro-Jade C staining. Despite the elevated levels of Fluoro-Jade C, few behavioral changes were observed in an independent cohort of animals treated with sevoflurane. Furthermore, acetyl-l-carnitine had little impact on levels of Fluoro-Jade C staining in animals treated with sevoflurane. These data suggest that acetyl-l-carnitine may offer little protection again anesthesia related neurotoxicity in fully oxygenated animals.

Performance on the Operant Test Battery in young children exposed to procedures requiring general anaesthesia: the MASK study.

BACKGROUND: It is not known whether the neurotoxicity produced by anaesthetics administered to young animals can also occur in children. Exposure of infant macaques to ketamine impairs performance in selected domains of the Operant Test Battery (OTB), which can also be administered to children. This study determined whether a similar pattern of results on the OTB is found in children exposed to procedures requiring general anaesthesia before age 3 yr. METHODS: We analysed data from the Mayo Anesthesia Safety in Kids (MASK) study, in which unexposed, singly-exposed, and multiply-exposed children born in Olmsted County, MN, USA, from 1994 to 2007 were sampled using a propensity-guided approach and prospectively underwent OTB testing at ages 8-12 or 15-20 yr, using five tasks that generated 15 OTB test scores. RESULTS: In primary analysis, none of the OTB test scores depended upon anaesthesia exposure status when corrected for multiple comparisons. Cluster analysis identified four clusters of subjects, with cluster membership determined by relative performance on the OTB tasks. There was no evidence of association between exposure status and cluster membership. Exploratory factor analysis showed that the OTB scores loaded onto four factors. The score for one factor was significantly less in multiply-exposed children (mean standardised difference -0.28 [95% confidence interval, -0.55 to -0.01; P=0.04]), but significance did not survive a sensitivity analysis accounting for outlying values. CONCLUSIONS: These findings provide little evidence to support the hypothesis that children exposed to procedures requiring anaesthesia show deficits on OTB tasks that are similar to those observed in non-human primates.

Sevoflurane exposure has minimal effect on cognitive function and does not alter microglial activation in adult monkeys.

Postoperative Cognitive Dysfunction (POCD) is a complication that has been observed in a subset of adult and elderly individuals after general anesthesia and surgery. Although the pathogenesis of POCD is largely unknown, a growing body of preclinical research suggests that POCD may be caused by general anesthesia. A significant amount of research has examined the effects of general anesthesia on neurocognitive function in rodents, yet no studies have assessed the adverse effects of general anesthesia on brain function in adult nonhuman primates. Thus, this study sought to determine the effects of an extended exposure to sevoflurane anesthesia on cognitive function and neural inflammation in adult rhesus macaques. Five adult rhesus macaques (16-17 years of age) were exposed to sevoflurane anesthesia for 8 h and, and micro-positron emission tomography (PET)/computed tomography (CT) imaging and a battery of operant tasks were used to assess the effects of anesthesia exposure on 18F-labeled fluoroethoxybenzyl-N-(4-phenoxypyridin-3-yl) acetamide ([18F]-FEPPA) uptake, a biomarker of microglia activation, and aspects of complex cognitive function. Exposure to sevoflurane anesthesia for 8 h did not increase [18F]-FEPPA uptake in the adult monkey brain. Sevoflurane anesthesia significantly decreased accuracy (mean difference = 22.79) on a learning acquisition task 6 days after exposure [t(3) = 6.92, p = 0.006], but this effect did not persist when measured 1 week and 2 weeks after additional exposures. Further, sevoflurane anesthesia had no impact on performance in 4 additional cognitive tasks. These data suggest that exposure to anesthesia alone may not be sufficient to cause persistent POCD in adult populations.

Early life exposure to extended general anesthesia with isoflurane and nitrous oxide reduces responsivity on a cognitive test battery in the nonhuman primate.

Despite the widespread use of general anesthesia, a growing body of research suggests that anesthesia exposure early in life may be associated with acute neurotoxicity and lasting behavioral changes. To better evaluate the risk posed by early life anesthesia on cognitive development, infant rhesus monkeys were exposed to an anesthesia regimen previously shown to be neurotoxic and their cognitive development was subsequently measured using a translational operant test battery. On postnatal day 5 or 6, animals were exposed to 8 h of isoflurane (n = 6, 1% isoflurane in a vehicle gas of 70% nitrous oxide and 30% oxygen) or a control condition (n = 8). Starting at 7 months of age, the monkeys were continuously trained and assessed on the NCTR Operant Test Battery (OTB). The OTB consists of cognitive tests which also exist in near identical forms for use in rats and humans, and includes tests of learning, memory, color discrimination, and motivation. Monkeys previously exposed to anesthesia showed a clear decrease in responding in a measure of motivation, as well as a lower response rate in a learning task. These data further support the hypothesis that prolonged anesthesia early in life may increase the risk of developing cognitive impairments later in life.

Neuropsychological and Behavioral Outcomes after Exposure of Young Children to Procedures Requiring General Anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study.

BACKGROUND: Few studies of how exposure of children to anesthesia may affect neurodevelopment employ comprehensive neuropsychological assessments. This study tested the hypothesis that exposure to multiple, but not single, procedures requiring anesthesia before age 3 yr is associated with adverse neurodevelopmental outcomes. METHODS: Unexposed, singly exposed, and multiply exposed children born in Olmsted County, Minnesota, from 1994 to 2007 were sampled using a propensity-guided approach and underwent neuropsychological testing at ages 8 to 12 or 15 to 20 yr. The primary outcome was the Full-Scale intelligence quotient standard score of the Wechsler Abbreviated Scale of Intelligence. Secondary outcomes included individual domains from a comprehensive neuropsychological assessment and parent reports. RESULTS: In total, 997 children completed testing (411, 380, and 206 unexposed, singly exposed, and multiply exposed, respectively). The primary outcome of intelligence quotient did not differ significantly according to exposure status; multiply exposed and singly exposed children scoring 1.3 points (95% CI, -3.8 to 1.2; P = 0.32) and 0.5 points (95% CI, -2.8 to 1.9; P = 0.70) lower than unexposed children, respectively. For secondary outcomes, processing speed and fine motor abilities were decreased in multiply but not singly exposed children; other domains did not differ. The parents of multiply exposed children reported increased problems related to executive function, behavior, and reading. CONCLUSIONS: Anesthesia exposure before age 3 yr was not associated with deficits in the primary outcome of general intelligence. Although secondary outcomes must be interpreted cautiously, they suggest the hypothesis that multiple, but not single, exposures are associated with a pattern of changes in specific neuropsychological domains that is associated with behavioral and learning difficulties.

Single and repeated exposures to the volatile anesthetic isoflurane do not impair operant performance in aged rats.

Postoperative Cognitive Dysfunction (POCD) is a complication that can occur in the elderly after anesthesia and surgery and is characterized by impairments in information processing, memory, and executive function. Currently, it is unclear whether POCD is due to the effects of surgery, anesthesia, or perhaps some interaction between these or other perioperative variables. Studies in rodents suggest that the development of POCD may be related directly to anesthesia-induced neuroactivity. Volatile anesthetics have been shown to increase cellular inflammation and apoptosis within the hippocampus of aged rodents, while producing corresponding impairments in hippocampal-dependent brain functions. However, it is unclear whether volatile anesthetics can affect additional aspects of cognition that do not primarily depend upon the hippocampus. The purpose of this study was to use established operant tests to examine the effects of isoflurane on aspects of behavioral inhibition, learning, and motivation in aged rats. Twenty-one adult Sprague-Dawley rats (11 male, 10 female) were trained to perform fixed consecutive number (FCN), incremental repeated acquisition (IRA), and progressive ratio (PR) tasks for a minimum of 15 months prior to receiving anesthesia. At 23 months of age, rats were exposed to 1.3% isoflurane or medical grade air for 2h. Initial results revealed that a 2h exposure to isoflurane had no effect on IRA, FCN, or PR performance. Thus, rats received 3 additional exposures to 1.3% isoflurane or medical grade air: 2, 4 and 6h exposures with 2 weeks elapsing before exposure two, 3 weeks elapsing between exposures two and three, and 2 weeks elapsing between exposures three and four. These additional exposures had no observable effects on performance of any operant task. These results suggest that single and repeated exposures to isoflurane do not impair the performance of aged rats in tasks designed to measure behavioral inhibition, learning, and motivation. This lack of significant effect suggests that the impairments associated with isoflurane exposure may not generalize to all aspects of cognition, but may be selective to tasks that primarily measure spatial memory processes.

Neurodevelopment of children exposed to anesthesia: design of the Mayo Anesthesia Safety in Kids (MASK) study.

There is increasing evidence that exposure of developing brains in animals, including nonhuman primates, to commonly-utilized anesthetic agents may cause adverse effects on cognition and behavior. In this paper, we summarize our methodology for a population-based, propensity-matched study to evaluate possible anesthesia-related sequelae in preschool children when evaluated in elementary or high school. A cohort of all children born in Olmsted County, Minnesota between the years 1994 and 2007 who are currently local residents has been identified. Existing medical records are being used to identify all episodes of exposure to general anesthesia prior to the age of 3 years (i.e., prior to their 3rd birthday). Children with multiple, single, and no anesthesia exposure are sampled for testing between the ages of 8 and 12 years or 15 and 19 years during the period 2012-2016. To match children in different exposure groups as closely as possible, sampling is guided by propensity-matching for the likelihood of receiving anesthesia. Selected children are invited to participate in a single 4-hour session of neuropsychological testing, including the National Center for Toxicological Research-Operant Test Battery, which has been used to study anesthetic neurotoxicity in nonhuman primates. The results of this testing will be compared among children with different anesthetic exposure histories. The expected products of this research will be a detailed phenotype of possible anesthetic-associated neurotoxicity in humans, utilizing a robust patient database and neuropsychological testing battery, and the first comparison of effects of anesthetic exposure in children and nonhuman primates performing nearly identical behavioral tasks.

Comparison of delayed matching-to-sample performance in monkeys and children.

Although research has consistently demonstrated that accuracy on a variety of memory tasks decreases as delay increases, relatively little research has been conducted to quantify this relationship across development in humans or directly compare rates of forgetting between humans and monkeys. This study utilized a delayed matching-to-sample (DMTS) task to compare the relative contributions of proactive interference and attention on the rate of forgetting in monkeys and children. The performance of 1125 children from four to fourteen years of age and 10 adult rhesus monkeys was compared. For this DMTS task, a shape was displayed on the center one of three press-plates. After a delay, the subjects were required to match the original shape with one of three choice shapes to receive a banana-flavored food pellet for monkeys, or a nickel for children. A modified power function provided an excellent fit for the data for monkeys and children. The forgetting rates in children decreased with age, and the forgetting rates for monkeys were most comparable to those of younger children. The data also suggest that proactive interference did not significantly contribute to the forgetting rates for monkeys or younger children. Further, the monkeys appeared to attend to the task at a level similar to that of younger children as evidenced by the similarities in response latencies. The results from this study indicate that the rate of forgetting in monkeys, as well as the mechanisms underlying this rate, appears to share more similarities with that of younger children than of older children.

The use of an incremental repeated acquisition task to assess learning in children.

The development of valid animal models of learning is especially important since learning is critical for nearly all aspects of human behavior and identifying appropriate surrogates provides additional opportunity to study various aspects of learning. Examining the factors that affect learning is often complicated by the need to administer the same task repeatedly across experimental conditions. Incremental repeated acquisition (IRA) tasks have been used extensively in animal research because they circumvent this problem by requiring a subject to learn different response chains repeatedly across sessions. The present study examined the association of age, sex of the participant, and IQ on the performance of an incremental repeated acquisition task in 837 children, aged 5-13 years. This task required children to learn to press four response levers in a specific sequence that was randomly chosen. Illumination of colored indicator lights signaled position in the required response chain. Initially, for the first link, only one of the four levers was correct: a response to it resulted in the delivery of a monetary reinforcer (5 cents). After mastery of the first link (i.e. three correct presses), the children were presented with a two-link response chain: a different lever had to be pressed before pressing the previously correct lever. After mastery of the two-link chain, the response chain length was once again increased, and so on until a response chain consisting of six links was completed or until the task timed out. Older children and children with higher IQs mastered longer response chain lengths and were more accurate in performance of this learning task than younger children. In addition, older children and children with higher IQs had higher effective response rates and lower ineffective response rates. No significant effects of the sex of the participant were demonstrated for any of the variables on this task, except overall response rate. The results indicate that this test is sensitive to developmental variables in children, with the degree of sensitivity of certain dependent variables being age-dependent. Characterization of performance of this task by humans facilitates comparisons with animal models employing the same task, thus enhancing its translational utility.

Assessing motivation in children using a progressive ratio task.

The association of age and sex on the performance of a progressive ratio task was studied in 847 children, ages 4-14 years. Variations of this task have been used extensively with animals and to a lesser extent with humans to study factors that affect aspects of motivation. The participants in this study were required to press a response lever for nickel reinforcers during a 10 min period. One response was required to earn the first nickel and each subsequent nickel required an additional 10 more responses. Older children had a significantly higher breakpoint than younger children. This appeared to be mostly the result of older children having significantly shorter inter-response times than younger children. In addition, boys had significantly higher breakpoints than girls, especially at older ages. The results of this study illustrate that both age and sex influence the performance of this task and thus suggest that age and sex influence aspects of motivation in children. Further, characterization of performance of this task by humans facilitates comparisons with animal models and, thus, enhances its translational utility.

Effect of methylphenidate on motivation in children with attention-deficit/hyperactivity disorder.

The effects of methylphenidate (MPH) on motivation were examined using a progressive ratio (PR) task in children who were prescribed MPH for the treatment of ADHD. Twenty-one children, 7 to 12 years of age, completed two test sessions, one under the effects of medication and one not. During each session, children pressed a lever to earn nickel reinforcers, where the first press resulted in a reinforcer and 10 additional presses were required for each subsequent reinforcer. Children on MPH had a significantly higher breakpoint than when off medication. This MPH-associated increase in the breakpoint manifested as a significant decrease in the interresponse times (IRT). Further, MPH administration resulted in a significant decrease in IRT variability. In contrast, MPH administration had no significant effects on the means and variability of postreinforcement pause duration. These results suggest that MPH increased motivation in children being treated for ADHD. Further, the inability of MPH to significantly reduce postreinforcement pause duration while simultaneously decreasing IRTs suggests that while MPH may increase motivation to perform an ongoing task, it may have little effect on the initiation of that task.

Estimates of the validity and utility of the Conners' Continuous Performance Test in the assessment of inattentive and/or hyperactive-impulsive behaviors in children.

This study evaluated the validity and classification utility of the Conners' Continuous Performance Test (CCPT) in the assessment of inattentive and hyperactive-impulsive behaviors in children. Significant, positive correlations between the CCPT parameters and behavioral ratings of ADHD behaviors were hypothesized. In addition, it was hypothesized that the CCPT parameters would perform better than a random test (chance) and show fair to moderate utility of classification across the different indices. Participants were 104 children between 6 and 12 years of age who were referred for evaluation of attention problems. The first hypothesis was not supported. There were no significant, positive correlations between the CCPT parameters and parent and teacher ratings of inattentive and hyperactive-impulsive behaviors. The second hypothesis was only partially supported. The CCPT Overall Index and the Omission Errors (84th percentile cutoff) performed better than a random test; however, the utility of the CCPT Overall Index only ranged from poor to slight. Receiver operating characteristic analyses showed the accuracy of the CCPT to be low. The implications and limitations of this study and future research directions are discussed.

The relationship between behavioral inhibition and time perception in children.

PURPOSE: To test one component of Barkley's (1997) model of executive functions by examining the relationship between behavioral inhibition and time perception in children. METHOD: Correlation analysis was used to determine the relationships between measures of behavioral inhibition and time perception for the entire sample, and for boys (n = 34) and girls (n = 26) separately. FINDINGS: For both parent and child measures, behavioral inhibition and time perception scores were correlated for the total group and for girls. Child measure of behavioral inhibition and time perception were not correlated for boys. CONCLUSIONS: The findings of this study support Barkley's theory and indicate a relationship between poor behavioral inhibition and poor time perception in children.

Stimulation of the semicircular canals via the rotary chair as a means to test pharmacologic countermeasures for space motion sickness.

OBJECTIVE: Space motion sickness is currently treated pharmacologically with the empiric use of the H1 antihistamine promethazine, but use of this intervention is limited by the side effect of significant sedation. This creates a dilemma, as full cognition is particularly important during the same conditions likely to exacerbate the symptoms of space motion sickness. Using overstimulation of the semicircular canals with a rotary chair as a paradigm for space motion sickness, we evaluated four medications, commonly used for the treatment of terrestrial motion sickness and vertigo, for their efficacy in alleviating the simulated symptoms of space motion sickness. STUDY DESIGN: Randomized, prospective, double-blind study. SETTING: Tertiary referral center. PATIENTS: Healthy male and female volunteers, 18 years of age or older, without history of neurologic or psychiatric disorders, and with no known allergies or any previous adverse reactions to the drugs used. INTERVENTIONS: Lorazepam 1 mg, meclizine 25 mg, promethazine 25 mg, scopolamine 0.4 mg, or placebo. MAIN OUTCOME MEASURE: The ability of each treatment to control the nausea and vomiting associated with our paradigm for space motion sickness was evaluated by measuring time of rotation pre- and posttreatment and time of symptom onset pre-and posttreatment. RESULTS: Only scopolamine effected a mean change in duration of rotation that reached statistical significance when compared with placebo (p <0.008), with a greater than 40% increase in rotation time. Results with promethazine were not statistically significant. CONCLUSION: Results showed a rank order of efficacy of scopolamine > promethazine > placebo > meclizine > lorazepam. Scopolamine significantly increased rotation time, but none of the treatments resulted in a significant delay to onset of symptoms.

Effects of drug countermeasures for space motion sickness on working memory in humans.

Space motion sickness (SMS) is a problem during the first 72 h of space flight and during transitions from different gravity environments. There currently are no effective drug countermeasures for SMS that also accommodate the retention of optimal cognitive function. This creates a dilemma for astronauts because cognitive skills are particularly important during gravity transitions (e.g., take-off and landing). To quantify the cognitive side effects of potential drug countermeasures, an automated delayed matching-to-sample (DMTS) procedure was used to assess visual working memory before and after drug countermeasures (meclizine 25 mg, scopolamine 0.4 mg, promethazine 25 mg, or lorazepam 1 mg, given orally approximately 45 min prior to testing) and/or the induction of SMS by vestibular stimulation in a rotary chair (spinning). Sixty-seven normal healthy volunteers (mean age, in years, 26.6+/-4.8 S.D.; 24 females and 43 males) each participated in two test sessions, one 'off' drug and one 'on' drug. Spinning by itself significantly decreased task accuracy (Acc) and choice response speed, especially at longer recall delays. Meclizine alone had no effect on Acc or speed with or without spinning. Scopolamine alone decreased Acc, and with spinning, slowed speed. Promethazine alone had no adverse effect, but combined with spinning, decreased Acc and speed. Lorazepam alone decreased speed, and with spinning, decreased Acc. The data suggest that, at clinically useful doses, the rank order of the drugs with the best cognitive profiles is meclizine>scopolamine>promethazine>lorazepam.

Developmental aspects of timing behavior in children.

This research examined the association of age, sex, and intelligence on the performance of a time production (temporal response differentiation, TRD) task. Variations of this task have been used extensively with both animals and humans to study factors that affect aspects of timing ability. The participants in this study (720 children, ages 5 to 13 years) were required to hold down a response lever for at least 10 s, but no more than 14 s, to receive a nickel. Older children made more correct lever holds and exhibited less variability in the duration of their lever holds than did the younger children. Boys and girls performed similarly on this task, whereas children with higher IQs made more correct lever holds. Young children with below average IQs exhibited increased variability in lever hold duration compared with young children with average and above average IQs. The results of this study illustrate that both age and intelligence influence timing ability. The use of this timing task in children, which also has been widely used in animal models, provides unique opportunities for interspecies comparisons.

Effect of methylphenidate on time perception in children with attention-deficit/hyperactivity disorder.

The effects of methylphenidate (MPH) on performance of a time-production task were studied in 17 children with attention-deficit/hyperactivity disorder who participated in 1 test session on and 1 off MPH. Participants held a response lever down for at least 10 but no longer than 14 s. Administration of MPH had no effect on the number of correct responses or on the mean duration of lever holds. MPH administration significantly decreased timing response variability, increased holds of 10- to 11-s duration, and decreased lever holds of extremely short durations. These results indicate that administration of MPH resulted in more precise timing performance without changing the mean duration of lever holds, suggesting an enhancement in working memory.

The effects of prenatal cocaine exposure on reversal learning using a simple visual discrimination task in rhesus monkeys.

The purpose of this research was to determine if adult animals that were exposed to cocaine prenatally would be able to adapt to changes in the rules of reinforcement for a simple discrimination task. Treatment groups included 0.0, 1.0, and 3.0 mg cocaine/kg/day and an escalating-dose group that began treatment at 3.0 mg cocaine/kg/day, after which the dose was increased by 0.5 mg cocaine/kg/day every 2 weeks throughout the pregnancy. All animals performed a color and position discrimination task for food reinforcers for approximately 6 years before the present study. For this task, subjects were presented with colored stimuli that determined the correctness of subsequent position choices: left for red or yellow and right for blue or green. At 7 years of age, the rules for obtaining reinforcement were reversed. Animals exposed to all doses of cocaine showed impaired reversal performance. Further, animals exposed to the escalating doses of cocaine continued to show this impairment for over 285 sessions (about 21/2 years). The number of sessions required by subjects to master these contingency changes indicated that, using a task with which they have an extensive history, cocaine-exposed animals have greater difficulty in adapting to important changes in their environment.