John J. Chelonis

Attention deficit/hyperactivity disorder: characteristics, interventions and models

An epidemiological study of Attention Deficit/Hyperactivity Disorder (ADHD) suggests that the prevalence may be two to three times higher than the figure of 3-5% often cited. In addition, the data suggest that both underdiagnosis and overdiagnosis occur frequently. Rodent animal models of ADHD, like the Spontaneously Hypertensive Rat (SHR) and other rat models such as those with chemical and radiation-induced brain lesions and cerebellar stunting, and the Coloboma mouse model exhibit clear similarities with several aspects of the human disorder and should prove useful in studying specific traits. Operant behavioral tasks that model learning, short-term memory and simple discriminations are sensitive to ADHD and methylphenidate has been shown to normalize ADHD performance in a short-term memory task. Recent findings challenge not only the current postulate that response inhibition is a unique deficit in ADHD, but also the concepts of ADHD and its treatment, which presume intact perceptual abilities. Time perception deficits may account, in part, for the excessive variability in motor response times on speeded reaction time tasks, motor control problems and motor clumsiness associated with ADHD. The Multimodality Treatment Study of ADHD (MTA) provided data suggesting that pharmacological interventions that included systematic and frequent follow-up with parents and teachers, with or without psychosocial interventions, are superior to psychosocial interventions or standard community care alone. Additionally, the MTA was one of the first studies to demonstrate benefits of multimodal and pharmacological interventions lasting longer than 1 year. Imaging studies have demonstrated differences in brain areas in children with ADHD: anterior corpus callosum, right anterior white matter, and cerebellar volumes are all decreased in children with ADHD and there is less brain asymmetry in ADHD subjects. Additionally, functional imaging studies, coupled with pharmacological manipulations, suggest decreased blood flow and energy utilization in prefrontal cortex and striatum and the dysregulation of catecholamine systems in persons with ADHD.

Symposium overview: the use of delayed matching-to-sample procedures in studies of short-term memory in animals and humans.

Behavioral paradigms applicable for use in both human and nonhuman subjects for investigating aspects of working/short-term memory are presented with a view towards exploring their strengths, weaknesses, and utility in a variety of experimental situations. Such procedures can be useful in teasing out specific aspects of mnemonic processes including discrimination, encoding, and retention. Delayed matching-to-position, delayed matching-to-sample (DMTS), and titrating matching-to-sample procedures are highlighted. Additionally, the application of DMTS tasks in preclinical and clinical settings is presented: drug effects on memory processes can be explored preclinically in animal models; normative data have been developed in human populations where they have been used in adults to explore the relationships between mnemonic processes and specific clinical entities such as Parkinsonism, senile dementia of the Alzheimers type, schizophrenia, and depression. Studies in children indicate that encoding and retention processes improve rapidly in the early years, plateauing prior to puberty. Noninvasive imaging techniques such as positron emission tomography (PET) indicate that activity in specific brain areas is associated with DMTS task performance and may serve to confirm roles for such structures in mnemonic processes.

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.

Developmental aspects of delayed matching-to-sample task performance in children

The influence of age, sex, and intelligence (IQ) on performance of a delayed matching-to-sample (DMTS) task, commonly used with animals and adult human subjects to study aspects of short-term memory, was examined for 674 children, 5 to 13 years old. The data suggest that younger children were less accurate at short delays and displayed a greater decrease in accuracy as recall delay increased than older children. Children with lower IQs demonstrated consistent impairment in recall of information when compared to children with higher IQs. No significant differences in task performance were observed between boys and girls. These normative data provide insights into the developmental time course of behaviors thought to serve as metrics of short-term memory. These data will be critical for ongoing and future studies in determining whether specific clinical diagnoses, drug treatments, or other risk factors (e.g., perinatal drug exposure, pregnancy complications, exposure to toxicants) are associated with differences on specific aspects of task performance. The use of tasks that are also applicable to animal models provides great opportunities for the conduct of important comparative studies.

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.

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.

Stimulant medication improves recognition memory in children diagnosed with attention-deficit/hyperactivity disorder.

The effect of stimulant medication on recognition memory was examined in 18 children with attention-deficit/hyperactivity disorder (ADHD). Recognition memory was assessed using a delayed matching-to-sample task at 6 delays ranging from 1 to 32 s. Each child was tested on 2 separate occasions, once 60 to 90 min after taking stimulant medication and the other at least 18 hr after taking medication. Children performed significantly better on medication than off. Stimulant administration significantly increased accuracy and the number of nickel reinforcers earned. Decreases in observing response latency and correct choice response latency occurred after taking stimulant medication. The results indicate that stimulant medication improved recognition memory for children with ADHD.

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.

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.

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.