Methodological Issues in the Study of Drug Effects on Cognitive Skills in Mental Retardation

Methodological Issues in the Study of Drug Effects on Cognitive Skills in Mental Retardation DEAN C. WILLIAMS AND KATHRYN J. SAUNDERS PARSONS RESEARCH CENTER UNIVERSITY OF KANSASSCHIEFELBUSCH INSTITUTE FOR LIFE SPAN STUDIES PARSONS, KANSAS

I.

INTRODUCTION

Despite the widespread use of psychoactive drugs in the treatment of individuals with mental retardation (MR), little is known about their effects on cognitive functioning and adaptive behavior. Progress has been limited by methodological difficulties and a paucity of studies. In their seminal review of pharmacotherapy in MR, Sprague and Werry (1971) noted that few studies had measured cognitive effects. Since then, virtually every discussion of this topic has called for more andor better research on cognitive effects (e.g., Aman & Singh, 1988; Aman & White, 1986; Ellis, Singh, & Landrum, 1993; Werry, 1988). Because there is little information on the cognitive effects of specific drug classes, we will not organize this review by drug or attempt to summarize the evidence for the effects of particular drugs on specific functions. Our goal, instead, is to facilitate the growth of this knowledge base by focusing on methodological issues. We will discuss some of the broader issues relating to measurement of the cognitive effects of drugs in this population and critically examine methods and procedures. Specific measurement procedures will be examined in detail. Informative research has been limited by difficulties developing measures of learning and performance that are sensitive to drug effects, comparable across a range of functional levels (Aman & White, 1986; Evenden, 1988), and show some degree of external validity. Procedures traditionally used to study drug, psychiatric, and physiological variables on information processing and cognitive performance typically deINTFRNATIONAL REVIEW OF RESEARCH IN MENTAL RJ7TARDATION. Vol. 21 u o 7 4 7 7 m S2S.M

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pend on intact, sophisticated verbal abilities. Often, these procedures cannot be adapted for individuals with poor instruction-followingabilities.Thus, we will review promising procedures from the basic literature on behavioral pharmacology and stimulus control that are not dependent on verbal repertoires.

A.

Why Study Drug Effects on Cognitive Functioning in Mental Retardation?

The underdeveloped state of this research literature belies the importance of the topic. Cognitive effects of drugs in persons with MR are studied for three overlapping reasons: (a) as side effects of pharmacotherapy for behavior control or seizure control; (b) to develop drug treatments to enhance cognitive abilities; and (c) to establish the mechanisms of drug action in this population. The specific questions that an experiment is designed to answer and the methods and procedures used will depend on which of these rationales is primary. Ideally, however, all research should be conducted in a way that contributes to an understandingof drug mechanisms of action. 1. COGNITIVE SIDE EFFECTS OF PHARMACOTHERAPY Most of the research on the cognitive effects of drugs is designed to assess the side effects of commonly prescribed drugs. Psychoactive drugs are frequently administered to control undesirable or aberrant behaviors such as self-injury, aggression, property destruction, and stereotypy (i.e., as psychotropic medications). The drugs used to treat seizure disorders (which occur in a high proportion of individuals with mental retardation)are also psychoactive and can affect behavior directly. In a review of prevalence surveys, Aman and Singh (1988) reported that 26-50% of individualswith MR receive some form of psychotropic drug (i.e., psychoactive drugs given to alter behavior). The prevalence of such pharamcotherapy is not generally decreasing. Baumeister,Todd, and Sevin (1993) reviewed the reported drug prescription rates and concluded that the use of psychoactive drugs to control undesirable behavior in individuals with MR has remained stable from 1977 to 1992.In both community-based and institutional treatment settings, typical neuroleptics (e.g., chlorpromazine, thioridazine, and haloperidol) are still the most commonly prescribed psychotropic medications (e.g., Baumeister et al., 1993;Weny, 1988). Increasingly, however, the trend has been to use a wider range of medication classes to control aberrant behaviors in this population. These include anticonvulsives such as carbamazepine and valproic acid used as mood stabilizers, lithium, antidepressants (including the newer serotonin reuptake inhibitors), antianxiety agents, beta-adrenergic antagonists, stimulants, and opiate antagonists (see Baumeister & Sevin, 1990; Gadow, 1986; Gadow & Poling, 1988; Gualtieri, 1991; Schaal & Hackenberg, 1994; Schroeder, 1988; N. Singh, Singh, & Ellis, 1992;

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Y.Singh, Ricketts, Ellis, & Singh, 1993; Sokol & Campbell, 1988; Thompson, Hackenberg, & Schaal, 1991). In addition, the newer “atypical” neuroleptics (clozapine, risperidone, and olanzapine) have been shown to reduce the destructive and bizarre behaviors of psychosis at doses that may produce fewer of the devastating movement and other side effects of typical neuroleptics(e.g., Baldessarini & Frankenburg, 1993; Meltzer, Lee, & Ranjan, 1994). Preliminary studies with clozapine and risperidone in persons with mental retardation have indicated that atypical neuroleptics may be efficacious in this population as well (Cohen & Underwood, 1994; Hammock, Schroeder, & Levine, 1995; Vanden Borre et al., 1993).Thus, in the near future, a number of drugs including atypical neuroleptics (especially risperidone) may replace typical neuroleptics as the drugs of choice in the MR population. Phmacotherapy may reduce undesirable behaviors (the primary effect), but there is little evidence that the effects of neuroleptic and other psychotropic medications are specific to the targeted, problematic behavior classes (see, for example, Baumeister et al., 1993; Thompson et al., 1991). One concern is that psychotropic drugs may interfere with motor and cognitive functioning and with learning and performing adaptive behaviors (Baldessarini, 1990; Hartlage, 1965; Schroeder, 1988; Waters, Hardy, & Cohen, 1987). Potential reductions in cognitive abilities would be a serious concern (Wolfensberger & Menolascino, 1968). Presumably, behavioral side effects of psychotropic drug treatment are at least as severe as the effects demonstrated in populations without MR. Beyond sedation, treatment with typical neuroleptics is associated with a host of decrements in cognitive skills that are important for learning and memory, as well as loss of motivation (anhedonia), flattened affect, social withdrawal, and alogia that can interfere with functioning despite alleviation of the primary (positive) symptoms (Bustillo, Kirkpatrick, & Buchnan, 1995; Goldman, Tandon, Liberzon, Goodson, & Greden, 199 1 ;Moller, 1993; Moller, Muller, Borison, Schooler, & Chouinard, 1995).Given that the acquisition and maintenance of language and appropriate social interaction may lead to a reduction of aberrant behaviors (e.g., Carr & Durand 1985), the use of psychotropic drugs without sound knowledge of their cognitive effects might be counterproductive. Antiepileptic drugs (e.g., phenobarbital, phenytoin/Dilantin, carbamazepine/ Tegretol, and valproic acidlDepakene)are currently one of the most frequently prescribed class of psychoactive drugs in individuals with MR. Aman and Singh (1 988) estimated that 25-45% of persons living in institutionsand 18-24% of persons living in the community received some form of antiepileptic medication (also see Baumeister, et al., 1993). In addition to their use for seizure disorders, these drugs are increasingly prescribed to treat aberrant behaviors in the absence of documented seizure disorder (Gadow, 1986; Gadow & Poling, 1988; Gualtieri, 1991; Poling, Gadow, & Cleary, 1991; N. Singh & Winton, 1984; Sovner, 1991). Given their frequent use, it is important to understand the effects of antiseizure medica-

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tions on cognitive performance (e.g.. Durwen, Hufnagel, & Elger, 1992; Novelly. Schwartz, Mattson, & Cramer, 1986; Poling & Picker, 1987). In studies of the efficacy of a drug in reducing undesirablebehaviors or seizures, effects on cognitive skills and performance are usually treated as side effects, and their measurement is often of secondary concern. Subject selection, experimental design, and effort put into measurement may reflect this emphasis. The experimental question is: Are there untoward effects of the therapeutic dose on learning, memory, or performance? The tactics necessary to verify reliability of cognitive effects, such as extended baseline measures, measures across a range of doses, placebo controls, and reversals to previous drug conditions, are seldom a part of efficacy studies. 2. SEARCH FOR COGNITIVE ENHANCEMENT Drugs may produce cognitive enhancement (i.e., nootropics). Historically, this has been the impetus for the assessment of the cognitive effects of drugs. Early “magic bullet” approaches had the goal of normalizing IQ (Louttit, 1965; Share, 1976 Wolfensberger & Menolascino, 1968) and curing the mental disability. Following the lead of pediatric pharmacotherapy, current research is focused more narrowly on enhancing specific cognitive functions and adaptive performances. Stimulant medications are frequently prescribed to children with normal IQs for the purpose of enhancing attention, learning, and performance. Cognitive enhancement may be plausible in persons with developmental disabilities as well (Wolfensberger & Menolascino, 1968). Given that attentional problems may be considered a primary deficit in MR (Memll, 1990;Warm & Berch, 1985;Zeaman & House, 1963),the pharmacological enhancement of attentional capacities could have a major impact on treatment (Ratey & Gualtieri, 1991).Other drugs studied for treating the cognitive and adaptive deficits of developmental disabilities are fenfluramine (see Aman & Kern. 1989, for a review), haloperidol, and opiate antagonists such as naltrexone (M. Campbell et al., 1990). Drugs could enhance learning and performance directly or indirectly by reducing stereotyped behavior, self-injurious behavior, or hyperactivity (Anderson et al., 1984; M. Campbell et al., 1982; Wittenborn, 1978). The indirect effects may depend on the drug decreasing disruptive target behaviors at doses that do not decrease desirable behaviors (e.g., Campbell et al., 1982). When cognitive enhancementis the goal, studies seek to demonstrate the medications and dosages that will produce the maximum positive effect. This requires examining a wide range of doses with cognitive functioning as the primary measure.

3. PSYCHOPHARMACOLOGICAL RESEARCH Psychopharmacology seeks to understand mechanisms of drug action, with the goal of understanding why an effect occurs. By mechanism, we mean how drugs

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interact with basic processes-biological, cognitive, or behavioral-to produce a given effect on performance. The first step is to determine whether a drug affects cognitive performance directly, or indirectly (e.g.. by reducing stereotypy, hyperactivity,or combativeness;Campbell et al., 1982; T. Thompson, 1982; Wittenborn, 1978). Subsequent research is directed at a more precise description in terms of more isolated processes. For example, increased accuracy and speed on a continuous performance task might be due to more efficient processing of information, less interference from irrelevant stimuli, increased efficacy of the reinforcer, increased compliance, or a general increase in alertness. Pharmacological research is less concerned with why a given drug is administeredand more concerned with precisely characterizing effects. Procedures are selected for relevance to theory. Drug manipulations can also provide information on the behavioral and neurochemical bases of cognitive deficits and of the aberrant behaviors characteristics of MR and developmental disabilities (Aman & Kern, 1989; Herman, 1991; Poling, Henningfield, & Wysocki. 1986; Schroeder, 1988).

B.

Unifying Themes

Studies narrowly designed to achieve one of the three goals may limit interpretation to that specific question. For example, assessing cognitive side effects of therapeutic drug use may involve only one dose, so results cannot be used to characterize effects of the drug in general-a basic pharmacology issue. To make general statements about a drug’s effects, a range of doses must be assessed. Moreover, assessing the effects of a single dose will not indicate the maximal efficacy of the drug, which is important in investigating enhancement of cognitive function. Regardless of specific goals, the minimal requirements for a methodologically sound clinical drug study set forth by Sprague and Werry (197 1) must be followed to produce interpretable results. These include the random assignment of subjects, a placebo control, double-blind procedures, standardized dosages, standardized evaluation,and appropriate statisticalanalysis. To this list, Aman and Singh (1980) and Thompson et al. (1991) have added the absence of concurrent additional medication. It. GENERAL CONSIDERATIONS OF METHOD AND PROCEDURE A.

Choosing a Measurement Procedure

In a discussion of psychopharmacologyof normal children, Weny (1978) noted that a useful measure must be reliable, valid, sensitive, relevant, practicable,

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safe, and ethical. After briefly discussing the concepts of accuracy, reliability and validity we will address the sensitivity and selectivity of a measure (see Aman, 1984,1991; Werry, 1978). 1. ACCURACY, RELIABILITY, AND

VALIDITY OF MEASUREMENT Indirect measures (e.g., rating scales, global clinical impressions)are safe, practical, and generally relevant to clinical practice. However, methods using human observers present problems for guaranteeing and measuring reliability and accuracy. They are susceptible to “instrument drift” (Aman, 1984; D. Campbell & Stanley, 1969), that is. the criteria for scoring change over observations. These problems are often overcome by the precise specification of the operations of measurement (operational definition). This task is made much easier when observable behaviors are the dependent measures, as when learning is defined as a change in the proportion of button presses that occur in the presence of a stimulus versus in its absence. Automated measurement offers the advantage of being the most accurate, reliable, and stable of behavioral measurement strategies. A valid measure is one that can be demonstrated to measure what it is purported to measure. Inaccurate and unreliable measurement precludes validity. A measure is also invalid if the dimensions measured are irrelevant to the property that the measure is purported to assess. For example, the number of corrective prompts given to a subject may not be a valid measure of learning when the rate of responding is variable. Measures of drug effects on cognitive functions should be weighed in terms of construct validity, face validity, and predictive validity. To have construct validity, a measure should fit the theoretical or conceptual assumptions about the cognitive skill being tested and map on to other accepted measures of the cognitive function in question. Idiosyncratic measures of learning, memory, and attention must be logically and empirically linked to more generally accepted measures. A measure will have face validity to the extent that it formally resembles a generally agreed upon application of the cognitive skill. Learning discriminations between pictures of common objects or assembling a bicycle brake may have more face validity than discriminating the left or right button or matching arbitrary shapes. Predictive or empirical validity reflects the degree to which drug effects on the cognitive measure correlate with clinical drug effects. Predictive validity would be demonstrated if accuracy on a paired associates task and school grades changed similarly as a function of methylphenidatedose. The weight placed on the different types of validity will depend on the relevance to the task at hand. 2. SENSITIVITY AND SELECTIVITY A good measure is both sensitive and selective. Sensitivity means that the measure can be affected by the drug or that drug effects can be detected when they oc-

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cur (Poling et al., 1991). Selectivity means that the effect occurs with a limited range of manipulations. A highly sensitive measure that is not selective may change with changes in any variable, increasing 5 p e 1 errors. Placebo controls help rule out oversensitivity as a factor in an apparent drug effect. Nonselective measures that are affected by many drugs give little useful information for characterizing particular drugs. Insensitive measures may also be nonselective in that they do not change under a wide variety of manipulations, increasing Type 2 errors. An example will illustrate the relative nature of sensitivity and selectivity. Avoidance behavior is sensitive to the disruptive (rate reduction) effects of neuroleptic and anxiolytic drugs. If all drugs decreased avoidance responding, it would be a nonselective preparation. However some drugs increase avoidance response rates (e.g., amphetamine),making avoidance behavior a selective measure. It is difficult to determine sensitivity and selectivity a priori. However, hypersensitiveor reactive measures will yield low “test-retest’’ reliability because of excessive influence by uncontrolled variables. Insensitive measures will yield high test-retest reliability. Global performance measures such as IQ tests are designed to be highly stable across administrations and are considered to be generally insensitive to drug manipulations (Aman, 1984; Wolfensberger & Menolascino, 1968). One does not know if a measure is insensitive or nonselective until it has been used across a variety of conditions. Studies involving a range of parameters must be conducted to determine how the measure will be affected by different drugs across doses. This can be a time-consuming and costly endeavor (Novelly et al., 1986). The sensitivity and selectivity of a preparation can be influenced by the performance generated in individual subjects. This represents a major challenge in adapting tasks to a range of ability levels. For example, highly accurate or otherwise maximally controlled performance only allows detection of the deleterious effects of a drug manipulation (ceiling effect). Conversely, if accuracy is at chance levels in the control condition, the preparation cannot detect deleterious effects. Procedures that may yield potentially sensitive and selective measures might be found in the behavioral pharmacology literature with animal subjects and with other human populations. These literatures have larger databases on the behavioral effects of drugs than does the psychopharmacology of MR. Well-studied procedures might be adapted for use with persons with MR. Procedures may not translate directly across species and populations, however. For example, procedures used with human subjects with normal verbal abilities may yield quite different results when adapted to persons with limited or nonexistent receptive and expressive language abilities. Their sensitivity may depend on drug interactions with behaviors that are not operative in less language-capable people. Similarity of drug effects across species and across human populations is likely to depend on the degree to which the procedures involve homologous processes. Uncritical transfer of

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procedures will yield measures of unknown sensitivity. There is much empirical work to be done in the development of sensitive drug-assessmentprocedures, especially for subjects below the mild level of MR.

B. Pharmacological Variables Drugs can have different qualitative and quantitative effects on behavior depending on the dose. The relation of dose administered and the amount of drug available at the site of action is influenced by many factors that can produce variation in drug effects across subjects and studies. Some of these variables can be controlledor documented. For example, the drug’s form (liquid or solid, sustained release, crushed or whole), and route of administration will influence rate of absorption,duration of action, and peak blood level. The subject’sdrug history, physiological condition, and maturation level can affect metabolism and excretion of the drug as well as neurotransmitterand receptor response. Variation in the functional dose administered may be a major factor in the variability in the observed effects of drugs. Since Sprague and Werry (1971), many reviewers have called for standardized measures of drug dose. In basic pharmacology research, doses are standardized in terms of milligram per kilogram of body weight per unit time, or in terms of blood levels. This practice is necessary to compare dosages across subjects and studies.Additionally, the particular pharmacokinetics of different drugs determine the time course of drug blood levels. Studies should control and specify the time of testing relative to the most recent drug administration, the dosing schedule, the length of time the current dosing schedule has been followed prior to testing, and the time relative to the start of a drug condition (both drug initiatiodincrease and withdrawddecrease).As a rule of thumb, drugs with linear kinetics take five half-lives of consistent, continuous dosing for blood levels to reach steady state, and five half-lives to clear from the body. Drugs also differ in the time course of various therapeutic and side effects. Similar dynamics should be expected with respect to the direct and indirect effects on cognitive functioning.For example, antidepressantsmay take several weeks to alleviate depressive symptoms, tolerance to the sedating effects of neurolepticsmay take 1 to 2 weeks, and neurolepticsproduce both immediateand late (tardive dyskinesia) withdrawal effects that may interact with cognitive abilities across time. Thus, the duration and timing of cognitive assessments will influence outcomes. General conclusionsabout the effects of a given drug on a cognitive domain can only be made with confidence when the database is large enough to identify consistent effects separate from variation in experimentalcontrol of dosage variables. It is currently unknown whether the large amount of variability in the literature on drug effects in MR is due to idiosyncratic responses to a given dose or to pervasive problems in the experimental control of dosage. Because individual variability in responsiveness to a given drug cannot yet be

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predicted, each subject should be exposed to a predetermined range of doses distributed across the full therapeutic range with a varied order of administration. In this way, the peak eficacy (the maximum effect that a given drug can produce), the potency (the dose required to produce a given effect), and the median eflective dose (in an individual this is the dose required to produce half of the maximum effect) can be determined for each subject (see Poling et al., 1986).These three properties enable quantitative comparison across individuals, populations, and medications. In the psychopharmacologicalliterature in MR, none of these properties has been described for any effect of any drug. A frequently used alternative for studying cognitive side effects is to individually titrate the dosage to the optimal therapeutic dose for the target behavior, and then hold dose constant while cognitive measures are taken. When this tactic is employed, it is critical that optimal therapeutic effect be defined precisely and reported. Although this singledose strategy does not yield dose-effect information (allowing general statements about the drug’s effects), it can demonstrate cognitive effects at clinically relevant doses. In clinical practice, however, it may be desirable to arrive at some balance between the maximal effect on the targeted behavior and acceptable adverse side effects. Taking measures at only one dose removes the opportunity to achieve this balance and limits information on cognitive effects. Moreover, single-dose assessments are more likely to show nonsignificant effects than studies that assess multiple doses. Rapport and Kelly (1991) reviewed the literature on effects of stimulant drugs on measures of cognition in children with normal IQ and attention deficit disorder (ADD). The majority of the tasks were studied under single doses. Of these, approximately 60% showed significant effects (regardless of whether the dose was considered therapeutically optimal). In contrast, 100% of the tasks studied under three doses showed significant effects. Thus, greater variability in results can be expected across single-dose studies.

C.

Behavioral Variables

Variables maintaining the behavior of interest are as important as phmacological variables in determining the effects of drugs on behavior. Behavioral pharmacology has shown that drug effects depend critically on the specifics of variables responsible for the behavior being examined. Seemingly minor characteristicsof stimulus circumstances,scheduling of consequences,and other variables can contribute to a drug’s action on behavior. (Branch, 1991, pp. 48-49)

The basic behavioral pharmacology literature is replete with examples of the mediation of drug effects at given doses by environmental determinants of the pattern, rate, and topography of the measured behavior (see Branch, 1991, for a thor-

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ough discussion).Describing the effects of the drug in a single context limits complete characterizationof the drug’s effects just as does describing the effects of a single dose. The role of procedural variables in determiningdrug response has not been studied in clinical populations. Four variables that may be relevant to interpreting research in MR are: (a) performance factors (e.g., rate dependency), (b) stimulus control, (c) behavioral history, and (d) consequencesof behavior (e.g.. schedule of reinforcement,whether primary or conditioned reinforcement is used, or whether positive or negative reinforcement is used). In addition, the potential for nonspecific behavioral effects and withdrawal effects must be considered. 1. PERFORMANCE FACTORS The effect of a drug on behavior may be determined by the subject’s baseline performance. The classic example is rate dependency, in which a given dose of a drug can produce stimulation or depression depending on the rate of responding in control (nondrug) conditions. Dews (1958) showed (in pigeons) that methamphetamine decreased relatively high response rates generated under either a fixed ratio (FR) 50 schedule (in which a reinforcer was delivered after every 50th response)or under a variable interval (VI) l-min schedule (in which a reinforcer was delivered for the first response following an interval of varied length that averaged 1 min). The same doses increased or did not affect lower rate responding under fixed interval (FI) 15min and FR 900 schedules.Rate-dependenteffects have been shown across drugs, species, and preparations,and can be seen with “depressants” including barbiturates, and phenothiazine neuroleptics (see reviews by Dews, 1981; Kelleher & Morse, 1968; Lander, 1981; McKearney, 1981). Rate-dependent effects of methylphenidate have been studied in hyperactive children responding under a multiple variable ratio (VR) 5, FI 30-sec schedule (Rapport, DuPaul, & Smith, 1985). Rate dependency is itself conditional on many factors (see McKearney, 1981) and, in itself. is not an explanation for behavioral effects of drugs (see Branch, 1984). It is, however, a well-documented description of performance-drug interactions. Rate dependency illustrates that any analysis of drug effects on behavior that does not control for performance factors will be susceptible to limits on interpretation. In addition, variation in performance levels may introduce variability in observed effects of drugs on formally identical tasks.Many group-comparison studies of the effects of drugs on cognitive measures in subjects with MR involve subjects with diagnosesranging from profound to mild. Unless care is taken to produce equivalent performance levels across subjects, such groupings are likely to involve widely different levels of performance on the task of interest. If these different levels are affected differently by the drug, consistent effects on the group mean will be virtually impossible to detect. A better strategy is to assert ex-

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perimental control over performance where possible to reduce variability in performance factors rather than rely on statistical control (see Sidman, 1960). Rate dependency also shows that interpretations in terms of a topographical description (lever pressing) or in terms of broad categorizations such as operant or learned behavior will be misleading. For example, if high-rate FR responding is studied, one might conclude that the drug decreases operant behavior. If only lowrate responding is studied, one might conclude that the drug increased operant behavior. In more clinical terms, the rate decrease might be seen as either a reduction in hyperactive responding or a decrease in adaptive behavior, and the increase as either a drug-induced hyperactivity or an increase in adaptive responding. 2. STIMULUS CONTROL VARIABLES When the probability of a response is very high in the presence of a stimulus and very low in its absence, the behavior may be said to be under “strong” stimulus control. The effects of drugs on a given performance can be influenced by the “strength” of stimulus control over that performance. One example involves drug effects on established conditional discriminations in pigeons (Katz, 1982, 1983). When sample stimuli were altered to decrease discriminability, promazine and pentobarbital decreased control by the samples relative to nondrug conditions, although these drugs had no effect on the originally trained conditional discrimination. Another drug class, amphetamines, did not affect either condition. Another example: Animal and human subjects reliably show greater disruption of the acquisition of stimulus control than of the maintenance of well-established stimulus control (e.g., Bickel, Higgins, & Griffiths, 1989). 3. HISTORY EFFECTS

The training history on a discrimination task can affect a procedure’s sensitivity to drug effects. For example, Terrace (1970) established a successive discrimination between vertical (S+) and horizontal (S-) lines in pigeons using either differential reinforcement of the terminal performance (trial and error) or an errorless training procedure. Chlorpromazine and imipramine greatly increased S- responding (i.e., decreased accuracy) in birds that had been trained with trial-and-error procedures, but had no effect on the S- responding of birds trained with errorless procedures. Thus, the drug increased the frequency of stimulus-response relations that had been demonstrated previously in the trial-and-error birds. The errorlessly trained birds had not previously demonstrated control by the S -, and they did not do so under drug conditions. These results show that it is not only important to describe results in terms of baseline performance level, but it is also important to describe the subject’s history with a particular task. The potential differential effects based on history span all of the measures discussed in this chapter.

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4. CONSEQUENCES OF BEHAVIOR

Topographically identical behaviors maintained by different environmental events may be affected differently by drugs. For example, “anxiolytics” can reduce behavior maintained by shock at doses that increase behavior maintained by food in the same subject (e.g., Barrett, 1976). Galizio and Allen (1991) found that amphetamine and morphine differentially affected avoidance responding and responding that produced time out from avoidance in rats. A drug may affect behavior by enhancing conditioned reinforcer effectiveness. Files, Branch, and Clody (1 989) showed that methylphenidate increased responding that occasionally produced stimuli previously paired with food delivery, but did not increase responding when no consequences were produced (extinction) in pigeons. Preliminary data from our laboratory are suggestive of conditioned reinforcer enhancement. A man with severe MR showed greater accuracy on a discrimination task with a food reinforcer as compared to pennies (exchangable for a variety of items, including food). When tested at a time corresponding to peak blood propranolol levels, accuracy with pennies was equal to accuracy with a food reinforcer at a time correspondingto low blood propranolol levels. 5. NONSPECIFICBEHAVIORAL EFFECTS ANDWlTHDRAWALEFFECTS

Drugs can affect responding in an indirect or nonspecific manner. For example, a drug can serve as a discriminative stimulus or as part of the context that controls behavior, as any environmental stimulus can. Behavior learned in the presence of a given drug can be disrupted if tested in the absence of that drug or vice versa. This is state dependency (see Overton, 1971). Without taking repeated measures for long enough periods under the different drug conditions, such an effect might be mistakenly interpreted as a specific effect of the medication. Studies that examine the effects of drugs under withdrawal designs are subject to confounded findings due to short-term drug withdrawal symptoms, tardive dyskinesias, and short-term effects from emergent behaviors (Schroeder. 1988). Withdrawal phases (or any drug condition) must be long enough to allow acute withdrawal effects to dissipate.

6. THE IMPORTANCE OF PREPARATION VARIABLES The preceding description of factors that may interact with pharmacological variables does not reflect the scope of research in behavioral pharmacology on these variables. We presented this cursory treatment to suggest the complexity involved in interpretingbehavioraldata. Lack of experimentalcontrol over these and other procedural variables will produce variability across subjects. Pooling data from subjects with different histories, motivations, and performance levels can mask real effects in individual subjects.

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Experimental Designs

The final issue is the design used to evaluate the reliability and generality of an effect and allow attribution of the effect to the drug manipulation.All experiments. regardless of the design used, must defend against similar threats to internal and external validity (for discussions, see Perone, 1991; Poling & Cleary, 1986). Threats to internal validity are the presence of extraneous variables that confound the interpretation of the results of a given experiment. External validity is the extent to which the results can be generalized beyond the study to different settings, subjects, and behaviors. The primary method of resolving issues of internal and external validity is replication of the treatment within and across subjects. Sidman (1960) described two types of replication. Direct replication involves repeating the treatment or experiment exactly. Systematic replication involves repeating the treatment with specified changes. Reproducingthe original effects across replications demonstratesthe internal validity of an experiment and increases confidence in attributing an observed change to the drug manipulation. Three research strategies are the case report, across-subject or group comparisons, and within-subject comparisons. Each has uses and limitations. A healthy literature on cognitive effects has a place for all three strategies. 1. CASE REPORTS Case reports are used extensively in the clinical therapeuticdrug literature.They involve general narrative statements of procedures, and results are typically nonquantitativestatementsof clinical global impressions.They include no control procedures and thus no defense against alternative factors operating. As a scientific tool, their usefulness is limited to suggesting more specific experimental questions. 2. BETWEEN-GROUPS DESIGNS

The between-groups design is the workhorse of the clinical psychopharmacological literature. As well, the majority of the drug literature in MR uses group designs. Group designs allow assessments of the effectiveness of efficacy of treatments in specified populations. They are the standard procedure for clinical trials to establish the safety and effectiveness of new or experimental drugs in treating a given condition. They are also used to assess novel uses of existing drugs. The logic of group designs is straightforward.One group is given the medication and its primary and secondary effects are measured. A second group is not given the drug, but is treated identically in all other ways. Differences in measures of interest between the control group and the treatment group are attributed to the drug. The reliability of this attribution is determined by appropriate statistical analysis. The validity of the inference depends on how well the

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experiment removed or equated the influence of extraneous variables that would confound the effects of drug manipulations. Because of the prevalence of group designs in the literature on drug effects in MR, methodological issues have been well covered (e.g., Aman, 1984; Sprague & Werry, 1971; Whalen & Henker, 1986). We will focus on advantages and disadvantages of their use with cognitive measures. Apractical problem of using group designs is the requirement for adequate numbers of subjects to meet the requirements and assumptions of statistical analyses. Difficulties compounded by having to recruit large numbers of subjects include ethical concerns over placebo control groups and side effects, control of dosing regimens, and finding subjects that meet research diagnostic criteria. The costs (in time and money) of meeting the requirement of large numbers of subjects make research on procedural development especially difficult. A more fundamental problem arises because the population of persons with retardation is highly heterogeneous in etiology and level of disability. Performance on cognitive tasks is highly variable across subjects (e.g., Detterman et al., 1992). In group comparisons,the defenses of internal and external validity depend on adequate group size and random assignment to ensure that individual differences are distributed equally across groups. External validity is protected to the extent that subject selection across the population is randomized. Given the heterogeneity of performance capacities inherent in the population, tremendous between-subject variability on standardized tasks is to be expected. This large background or error variance against which the drug effect must be measured makes it difficult to discover drug effects. Furthermore, the drug will be tested on different performance levels in different subjects. This is a problem because drug effects are determined by an interaction of performance and drug. Finally, if different training procedures are necessary to equate the performance of individualswith different levels of ability, there is the potential of differential history effects interacting with drug effects contributing to variability of effect. Variability may be decreased by increasing the number of factors included in the design to control more variables such as IQ. This will multiply the subject requirements or lead to reduced subjects per group. The latter will increase the likelihood of nonsignificant results. The prevalence of reported effects that “approach significance” attests to this problem. Another limitation of between-groups designs is that group mean performance cannot be generalized to the individual (see Sidman, 1960, pp. 46-54). which is the unit of clinical interest. Therefore, the external validity of these results to the very setting to which they are to be applied is questionable.A related limitation of group means is that they obscure effects on individual subjects (Sidman, 1960, pp. 145-190). A powerful effect in some subjects may be hidden in a statistically nonsignificant group effect (Barlow & Hersen, 1984).

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3. SINGLE-SUBJECT DESIGNS Single-subject designs are used extensively in the study of learning and stimulus control. They are also extensively used in behavioral pharmacology (Branch, 199 1). a melding of the experimental analysis of behavior and psychophannacology. The logic of single-subject designs has been discussed extensively elsewhere (Johnston & Pennypacker, 1980;Perone, 1991; Sidman, 1960).Single-subject designs replace statistical control with experimental control over subjects’behavior. Single-subject designs are rarely used in psychopharmacology(Poling & Cleary, 1986).This is unfortunate because they can solve many of the practical and interpretational problems of between-groups comparisons.Their distinguishingfeature is that the independent variable effect is assessed and reported by changes in the dependent variable within a subject. The reliability of effects is demonstrated by replication within the individual subject and through direct and systematic replications across subjects. Within-subject designs have several advantages for dealing with issues of internal and external validity in psychopharmacological assessment in MR in general, and especially for the assessment of cognitive effects. A major benefit is that the aforementioned concerns of group composition are eliminated. In within-subject designs it is not necessary to recruit large numbers of subjects to meet the requirements of equivalence between groups and adequate statistical power. As a result, more attention can be paid to developing satisfactory task performance in individual subjects.Another benefit is that generality to the clinical setting is more direct. Additionally, subgroups of people that show particular effects can be identified and potentially characterized for greater prediction of drug effects. Because single-subject designs are uncommon in the psychopharmacology literature, we will briefly summarize some designs that will be useful for assessing drug effects on cognitive performance. See Poling and Cleary (1986) and Barlow and Hersen (1 984). for a discussion of designs applicable to clinical psychopharmacology, and see Johnston and Pennypacker (1980) and Sidman (1 960) for comprehensive discussions of single-subject designs. The most common designs are successive comparisons designs (Perone, 1991). In these designs, the reliability of effects is demonstrated by establishing a baseline (a starting comparison level) and then introducing the drug manipulation (AB design). The power of a demonstration is increased by adding replications (e.g., ABAB). Variations can include any combination of additional treatments, for example ABACA D, where different letters indicate different treatments or different levels of treatment (e.g.. doses of drug). A multiple-baseline-across-subjectsdesign is useful when reversals in drug dose are not permitted or when a drug produces irreversible changes in performance. In this form of multiple-baseline design, replication occurs across subjects but the drug manipulation is introduced at

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different points in time under baseline. This controls for extraneous variables related to length of exposure to the task while allowing analysis of individual subject data. The most widely used design in behavioral pharmacology is the probe design, in which drug probes are introduced on stable baseline performance for brief periods and then withdrawn. However, this design is seldom applicable to clinical psychopharmacology, in which continuous dosing over long periods is common.

111.

SPECIFIC MEASURES AND PROCEDURES

Early studies of drug effects on cognitive performancerelied extensively on IQ tests and other standardizedmeasures of achievement (see Aman, 1984). There has been a growing realization of the drawbacksof such measures (Aman, 1984; Werry & Sprague, 1972; Wolfensberger & Menolascino, 1968). IQ tests are designed to measure long-term achievement, not basic cognitive processes. By design, scores are highly stable over time, and resistant to local changes in capacity or motivation. A number of authors have called for increased use of specific and objective laboratory measures of functioning. As noted earlier, the lack of information on cognitive effects of drugs in MR is due in part to difficulties developing measures of learning and performance that are sensitive. adaptable to a range of functional levels. comparable across a range of functional levels, and show some degree of external validity. In this section we evaluate procedures that may meet these criteria. Some of these procedures have had limited use in the literature on pharmacology and MR. Others are taken from the basic literatures on behavioral pharmacology and on stimulus control. In addition to having features that seem suited to drug assessment, we seek tasks that can be trained without verbal instruction. The current literature is compromisedby difficulties in establishing baseline performances in individuals with lower functioning. In building a literature on drug effects, it is important that procedures be described in detail sufficientfor replication. Perhaps because cognitive measures are often a secondary focus, adequate detail is often missing, compromising comparison of results across studies and discussion of results in t e r n of known behavioral processes. Our procedural review identifies specific task requirements and points out features of the procedures that may influence sensitivity to drug effects. We also suggest ways of adapting tasks to different levels of functioning. A.

Discrimination-Learning Procedures

Discrimination-learningprocedures offer many advantages for assessing drug effects. The literature on discrimination-teachingprocedures that do not rely on

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verbal instruction is extensive (for reviews, see Lancioni & Smeets, 1986; McIlvane, 1992), suggesting that these procedures can be used with subjects with widely ranging abilities. The size of this literature also attests to the importance that has been placed on discrimination learning in the field of MR. On the other hand, the study of drug effects on discrimination learning or acquisition presents difficulties that, at first glance, necessitate group designs and reliance on statistical rather than experimental control of variability. We will first describe the basic measures (tasks) and the importance of task selection. Then we will discuss general design issues pertinent to the use of learning measures. 1. MEASURES Discrimination procedures come in a variety of permutations. The literature allows general predictions about the relative difficulty of the various tasks. For example, tasks requiring conditional discrimination are generally more difficult than those requiring only simple discrimination. Thus, discrimination leiuning tasks can be tailored to different ability levels. a. Simple Discriminafion.In the prototypical simple discrimination procedure, a reinforcer is delivered for a response to one stimulus (the S+), while responses to one or more other stimuli (the S - 's) do not produce reinforcement.A high proportion of responses in the presence of S + relative to responses in the presence of S- indicates discriminative control by the S+ stimulus. In simultaneous discrimination,the S + and S - 's are presented at the same time. Each presentation of the two stimuli is a trial, which is typically completed by a single response (discrete trials procedure). For example, the task might be to point to one of two pictures. The positions of the S + and S- stimuli change unpredictably across trials (unless position is the discriminative stimulus), and the correct stimulus is not presented in the same position on more than three consecutive trials. These provisions are designed to prevent position from acquiring control over the response (position bias). The usual dependent measure is accuracy (the number of trials in which the correct stimulus is selected divided by the total number of trials). In successive discrimination, only one stimulus is presented at a time. Given equivalent stimuli, successive discrimination is likely to be acquired more slowly than simultaneous (Carter & Eckerman. 1975). Procedures can involve either an S + and an S-, or more than one S+ with no S-. In the latter case, each S + controls a different response. Reading different words presented on flash cards provides an example of the latter in a discrete trials procedure. Sometimes freeoperant successive discrimination procedures are used (i.e., a multiple schedule). In these, components associated with a particular stimulus continue for a specified period of time or until a specified response requirement is met. Thus, these differ from discrete trial procedures in that multiple responses can be made in the presence of the stimuli. Frequently, different reinforcement schedules that produce dif-

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ferent patterns or rates of responding are in effect in the presence of each stimulus. For example, in the presence of one stimulus (the S+), 25 responses may be required for reinforcement (FR 25), and in the presence of another stimulus, responses are never reinforced (extinction).The measure of interest is the proportion of responses made in the presence of S+. Response latency may also be an important measure in discrimination procedures. b. Conditional Discrimination. In a conditional discrimination, the function of a discriminative stimulus change based on the presence of another stimulus. The most familiar conditional discriminationprocedure is matching to sample. For example, in arbitrary matching to sample, the words cat and dog may be presented as choice (comparison) stimuli on every trial. When a picture of a cat is the sample stimulus, the word cat is the S + and the word dog is the S - . The opposite holds when a picture of a dog is the sample. We found few examples of the use of matching to sample or other conditional discriminationprocedures as learning procedures in the M R drug assessment literature. Their potential is worth exploring. Identity matching procedures are used to assess memory, which we will discuss in a later section. c. Chins. Many complex learning problems in the natural environmentand traditional measures of cognitive and learning ability require acquisition of extended sequences of responses or chains of discriminations. For example, assembly tasks,navigation from home to the store, and tests of serial lists of words are chains of behavior. In a chain, a response in the presence of one stimulus produces another stimulus that reinforces the response and sets the occasion for the next response;the final response is followedby a terminal reinforcer (Catania, 1992).The components (links) of a chain may also be conditional discriminations. d. Choice of Task: A Critical Step. An ideal discrimination-learningtask is, in plain language, neither too easy nor too hard. Ceiling or floor effects can render a procedure insensitive. Maximum accuracy can show only performance decrements. Chance level accuracy cannot show performance decrementsand may also make improvement unlikely. For example, a position preference in a two-choice discrimination task that results in a reinforcer on approximately every other trial may persist indefinitely without special remedial training. A difficult task may be made easier by appropriateteaching techniques.The extensive literature on the instructional programming of discrimination performances provides procedures for initial teaching. This suggests two options for avoiding chance level baseline performance. One option is to prepare subjects for the task that they will encounter by teaching it through instructionalprogramming before the study begins. Subjects may then come to learn under less structured teaching procedures (Saunders & Spradlin, 1990.1993), and this learning may become the dependentmeasure in the drug assessment.Another option is to test subjects under carefully structured teaching procedures. If the teaching steps and the criteria to advance through them are carefully specified, the number of trials re-

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quired to advance through the procedures may be taken as the dependent measure. Neither of these options have been explored, so both require study. Extreme interpretational difficulties are imposed by the study of ill-prepared subjects. Methods for avoiding these problems will be essential for future progress in drug assessment. A study by Anderson et al. (1 989) illustrates the sort of difficulty that must be overcome. The study compared a single “therapeutic dose” of haloperidol with placebo using five discrimination tasks. Subjects were 45 children who had from borderline to profound retardation. Although a range of discrimination measures were attempted, only 29 subjects completed all of the tasks, and performance in most tasks was at chance levels with little improvement across sessions. (Only group means and some statistical analyses were reported.) The authors concluded that haloperidol did not have an adverse effect on learning. One cannot show less accurate performance than chance levels in these tasks, however. Thus, a more appropriate conclusion is that the measures were insensitive to potential disruptive effects of haloperidol. Selecting a task that is too easy also produces a difficult-to-interpretoutcome. A controlled case study illustrates the problem of ceiling effects (Taylor et al., 1991 ). The task required learning to put particular objects in one of up to four trays that differed only in their position. Thus, accurate responding required conditional discrimination with positions as the comparison stimuli. When placement became accurate, new objects were added. A single subject with mild h4R received naltrexone twice weekly in an ascending series beginning and ending with placebo. Doses were 0.5, 1.O, and 2.0 mgkg. One training session was conducted before the first placebo phase to acclimate the subject to the task. Subsequently, sessions were conducted once a week on a drug day. Accuracy improved from 80% in the predrug placebo test to nearly 100% in all subsequent tests. The paper noted that “improvement on the learning task was associated with naltrexone administration,” and that “all doses had an equal effect on learning.” Also noted is the preliminary nature of the findings. We recommend even greater caution because an increase in accuracy over sessions would be expected without the drug. In fact, the learning set literature indicates more rapid acquisition of both simple and conditional discrimination as a function of the number of problems learned for even lower functioning individuals (Kaufman & F’rehm, 1966; Saunders & Spradlin, 1990). The rapid acquisition of near perfect performance suggests that the task is too “easy” for individuals with mild retardation and thus is likely to be insensitive to drug effects.

2. DESIGN ISSUES The relative merits of within-subject and between-subject comparisons were discussed earlier. We have also presented general options for choosing a task. In this section, we discuss final considerations for developing procedures.

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a. Single-ProblemProcedures. Acquisition is a transitory condition. Moreover, once a subject has learned something, the original conditions are not repeatable. Thus, group-crossoverand single-subject designs might seem incompatible with the study of drug effects on learning. One solution is a simple between-groups comparison involving a drug group and a placebo group, with each group presented the same discriminationproblem for a singlephase (parallel groups design). Given appropriate controls to insure that the composition of the two groups is equivalent in all respects except presence of active drug (i.e., random assignment and adequately large groups), differences in the level of asymptotic performance or in rate of reaching asymptote can be analyzed statistically.This strategy is subject to the previously noted difficulties with group designs. A large amount of variability within groups can be anticipated, compromising the sensitivity of the measure. The strategy also requires multiple groups for dose-effect studies. Some studies have attempted within-subject or group-crossover designs using a single problem presented across conditions.Where learning is of interest (as opposed to memory or attention), this method presents difficulties. One problem is that continued presentation of the same problem across different drug conditions confounds learning issues with maintenance of learned performance.Anderson et al. (1984) used this strategy to study haloperidol.Two groups of nine subjectswith autism and MR were exposed to a free operant successive discrimination procedure across three drug conditions. One group received (A) drug, (€3) placebo, (A) drug; the other received (l3) placebo, (A) drug, (B) placebo. In general, mean accuracy improved within each of the conditions,but decreasedeach time a new condition was presented, as if subjects were relearning the task in each phase. It is unclear how the improved accuracy shown within the second and third phases should be interpreted. Possibly as a result of these procedural difficulties, the study found significant differences (in favor of the haloperidol group) only in the first phase (essentially a parallel-groups design). Single-problemlearning procedures can be used most safety with parallel-groups designs. b. Multiple Problem Procedures. An alternative to presenting a single learning problem is to present new, but similar, problems under each drug condition in either a within-subjector group-crossoverdesign. Two difficulties are presented by this strategy. First, the relative difficulty of the problems, which may vary across subjects,may be unknown.A greater concern is that acquisition will become more rapid as a function of the number of problems learned. These potential confounds require full counterbalancingof problem and drug conditions in a group crossover design. However, the variability introducedby these features will contribute to the nonspecific error terms and reduce the sensitivity of the preparation to drug effects. Methods for reducing problem-to-problem variability and producing steady state repeated acquisition of stimulus control are available for use in within-subject-comparison designs (D. Thompson & Moerschbaecher, 1979).The basic log-

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ic is to train the subject on a series of problems that are equated for difficulty and that differ in a consistent manner. Over successive problems, relatively stable patterns of latencies, rates, and accuracy develop. Drug manipulations are not made until stable patterns are shown, allowing drug manipulations to be made against a reproducible baseline of learning individual problems. Individuals can serve as their own controls, with replication possible to assess the reliability of a drug effect. Furthermore, task difficulty can be adjusted to fit the functional level of the individual subject. It should be noted that results from single-problem procedures and multipleproblem procedures are not directly comparable.The conditions in effect in an initial learning experience, typically the focus in parallel groups designs, cannot be replicated across multiple problems. With increased exposure, subjects acclimate to the setting; emotional responses to the situation change, motor responses become more efficient, and a history with the reinforcement procedures is established. Parallel groups studies that establish the minimal response and a reinforcer delivery routine prior to initial learning of the problem may produce results different from studies that do not. The effects of drugs on learning, and the effects of drugs on uncontrolled variables associated with novel situations must be separated in a mature analysis. c. Repeated Acquisition of Chins. A procedure for studying the repeated acquisition of behavioral chains in nonhuman primates was first described by Boren and colleagues (Boren. 1963; Boren & Devine, 1968). Modified versions have been used to study the effects of pharmacological and nonpharmacologicalvariables on learning in animal and human subjects (Thompson & Moerschbaecher, 1979). The repeated acquisition of chains procedure is the most frequently used discrimination learning procedure in the pharmacology literature as a whole, so we will discuss it in some detail. Aminimum of three response buttons is used, usually arranged horizontally.The correct response sequence is the same for every trial in a session. For example, a sequencemight be the lejl button, then right, then center; then lejl, followed by reward (a four link chain). Each link in the chain is correlated with a different stimulus such as a colored light. These stimuli are presented in the same order in every session, but during each session, a new sequence of button presses is required (i.e., each stimulus must control a different response from the previous session). Each correct response advances the chain to the next link, changing the stimulus. Usually, incorrect responses in any link produce a brief, signaled time out from the opportunity to respond. After the time out, the chain is either resumed in the link in which the error was made or reset to the beginning. Stimulus changes or signals following correct and incorrect responses facilitate acquisition (see Boren & Devine, 1968; Hursh, 1977).Vaughan (1985) and Thompson and Moerschbaecher (1979) described procedures for initial training without verbal instruction. The primary measure of learning is the accuracy or error rate for each sequence,

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but response rates and latency measures may also be informative. Learning is shown when accuracy increases across trials within sessions.The error quarter-life is a method of quantifying this change (discussedby Bickel et al., 1989). Quarterlife of errors is the proportion of the session in which 25% of the errors occur (see Gollub, 1964).Quarter-lifevalues of 25 indicate no change in errors across the session and no learning; values below 25 indicate that most of the errors occur early in the session; and values above 25 indicate that performance worsens through the session. Generally, these measures improve gradually across sessions until a stable rate of acquisition is attained. This repeated acquisitionprocedure allows several parameters to be adjusted for increased or decreased difficulty.The number of links can be manipulated until a desired difficulty is obtained. With normally capable people, 10 or 12 component sequences have been used (Bickel et al., 1989; Perone & Baron, 1982), and with young children and pigeons, four component chains have been used (Thompson, 1975; Vaughan, 1985). Another manipulation that has been shown to increase errors (difficulty) and increase sensitivity to drug effects is removing the external stimulus associated with each component link (tandem schedule, Ferster & Skinner, 1957; Thompson, 1975). Reinforcing sequencesonly occasionallyrather than for each correct sequence may also increase errors and sensitivity to drug effects. The repeated acquisition of behavioral chains is one of the few procedures that has been proven to be similarly sensitive to drug effects in animal and human subjects. The procedures have been used successfully with human subjects with a range of characteristics.For example, Perone and Baron (1982) demonstrateddifferential effects of speeded response requirements on learning in older (>60 yr.) and younger (college students) subjects, and Vaughan (1985) studied the effects of instructional stimuli (prompts) on learning in 3.5-to 5.5-year-old normally capable children. In nonhuman animals, the procedure has been used to study the effects of a wide variety of drugs on learning including neuroleptics, stimulants, and antiepileptic medications (e.g., Picker, Leibold, Endsley. & Poling, 1986; Poling, Cleary, Berens, & Thompson, 1990; D. Thompson, 1980; D. Thompson & Moerschbaecher, 1979). The procedure has recently been used to study the effects of anxiolytics,the anticholinergicdrug atropine, alcohol, and cocaine in normally capable, adult human subjects (e.g., Desjardins, Moerschbaecher, Thompson, & Thomas, 1982; Higgins, Bickel, O’Leary, & Yingling, 1987; Higgins, Woodward, & Henningfield, 1989; Higgins et al., 1992). Despite the demonstrated utility of this procedure for studying pharmacological and nonpharmacological variables on learning, there are no published studies involving persons with MR. This may be due to difficulties teaching the task. As often used (described above) the chain is a type of conditional discrimination. somewhat analogous to arbitrary matching to sample (an important difference is that responses on any link can be controlled by the stimulus associated with the link, the response on the previous link, or both). Conditional discriminationcan be

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quite difficult for individuals with MR, and individuals with more than mild levels of MR are often unsuccessfulunder typical trial-and-error teaching procedures. Only recently have teaching procedures that do not require verbal instruction and are tailored to the task requirements of arbitrary matching appeared in the literature (Saunders & Spradlin. 1989,1990,1993;Zygmont, Lazar, Duk, & Mcllvane, 1992).The adaptation of these procedures to the acquisition of chains is a promising course for future procedural development. d. Repeated Acquisition of Simple Discriminations. In theory, any discrimination task can be used in a repeated acquisition procedure, as long as a fairly stable acquisition rate without ceiling level performance can be generated. For example, simple simultaneousdiscrimination procedures might be adapted for use with individuals functioning at a range of levels. We have varied task difficulty by varying the number of individual discriminations that are presented in one session. For example, six different discriminations (with no stimuli in common) may be presented across the first six trials, with the same discriminations presented in a randomized order in the next six trials, and so on. It is often possible to arrive at a number of discriminations that produce a fairly stable, but less than perfect, acquisition pattern. We used such procedures to evaluate the effects of time since propranolol administration (corresponding to the known time course of drug levels in the blood) on discrimination learning in two subjects. One subject with severe MR was exposed to one simple discrimination per session. The other had mild MR and was exposed to 12 discriminations per session. New problem sets were presented each day. Both made fewer errors when propranolol blood level would be expected to be higher. Propranolol's short half-life allowed us to alternate drug conditions rapidly. Thus, the gradual improvement across sessions shown by the single-discrimination subject did not interfere with the detection of an effect. It should be noted, however, that the single-discrimination subject ultimately showed no difference between the high and low drug conditions, and continued replication was not possible. Pilot work suggests that these procedures may be used to generate different learning rates within subject, providing several baselines against which to assess the effects of drugs. The subject with severe retardation discussed above went on to procedures that presented either one, two, three, or four simple discriminations in a session.Across a number of replications,acquisition occurred rapidly with one or two discriminations;more errors were made with three or four. It remains to be seen, however, how long such performances will remain stable. e. Combining Learning and Performance Measures. Individual subjects may be exposed to both a learning condition, in which a new discrimination or chain is presented each session, and a performance condition, in which the problem is the same from session to session. This is often done in studies using the repeated acquisition of chains procedure (e.g., Bickel et al., 1989). The different conditions are signaled by distinctive stimuli and may be alternated within or across sessions.

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This allows differential effects on learning and performance (maintenance) to be assessed. Amajor advantageof this strategy is that nonspecific effects, such as motor impairment, can be detected with the performance measure. A highly consistent result of both the animal and human studies is that many drugs selectively interfere with learning new sequencesover performance of well-practiced sequences ( ~ B i c k e lHiggins, , &Hughes, 1991; Thompson & Moerschbaecher, 1979). Furthermore, greater tolerance may occur to the disruptive effects of drugs on performance of well-learned chains than on learning new chains in humans (Bickel et al., 1989) and in animals (Thompson, 1977).

B.

Memory Procedures

The delayed identity matching-to-sample procedure has been widely used to study memory in the basic learning literature and in behavioral pharmacology. Its increased use in the study of drug effects in MR would facilitate comparisons with these literatures.Aman and White (1986) noted the underuse of delayed matching in this literature (although a variant described below was used in a number of early studies). In its most basic form, a delayed matching trial begins with the presentation of a sample stimulus (e.g., a circle). Aresponse to the sample removes it from the display and two or more comparison, or choice, stimuli (e.g., a circle and a triangle) appear after a specified delay. A response to the stimulus that is identical to the sample stimulus (the circle) produces a reinforcer. In a variant of the task. the nonmatching stimulus is correct (oddity matching). (See Mackay, 1991, for an excellent summary and review of matching-to-sample procedures.) Performance can often be readily established in subjects who demonstrate generalized identity matching (i.e., can respond based on the formal similarity of the stimuli). In fact, some higher functioning subjects may show such accurate performance at long delays that the procedure becomes logistically unwieldy. Below we suggestprocedures to vary the difficulty of the task. The literature contains relatively little information on delayed matching in lower functioning individuals, but the existing information suggests the viability of the procedure. Constantine and Sidman (1975) reported accurate matching of pictures with delays of 4 to 12 sec in three of four subjects with severe retardation when the subjects named the sample stimuli. Without naming, accuracy decreased rapidly beginning with delays of 2 to 4 sec. Dalton and colleagues (Dalton, 1992; Dalton & Crapper McLachlan, 1984; Dalton, Crapper. & Schlotterer, 1974) have used delayedmatching procedures to evaluate memory deficits in a range of subjects with MR. Because the procedure has had limited use, however, researchers planning to use it with subjects with severe and profound M R may need to do some preliminary investigation of the task. The difficulty of delayed matching can be adjusted by varying (a) the length of

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the delay, (b) the complexity (or the familiarity) of the stimuli, and (c) across-trial interference (conditional vs. nonconditional matching). 1. VARYING THE LENGTH OF THE DELAY The delay can be varied by randomly mixing various delays across trials within a session, in whole sessions with a single delay, or in a titrating-delay procedure. The titrating-delay procedure is the most frequently used in the pharmacology literature with subjects with MR. In it, the length of the delay increases (e.g., by .5 sec) whenever a specified number of consecutive correct responses occurs. Delay decreases with each error. Under these procedures, delay eventually stabilizes at a particular level. This can be expressed as the longest delay at which a specified number of consecutive correct responses occurs (e.g., usually three or four). The effects of drug administration on the maximum delay achieved can be assessed. Procedures using a variable delay across trials are seldom used to assess drug effects in MR. The classic effect from the animal literature is that accuracy decreases as a function of delay length (Cumming & Berryman, 1965). Few studies have examined the behavior of individual subjects with MR at a range of delays. Dalton and Crapper McLachlan (1984) reported group means for subjects whose IQs ranged from 20 to 54. Apparently, most subjects showed above-chance performance with a O-sec delay (i.e., the comparisons appear immediately upon disappearance of the sample). Large accuracy decreases were shown with 5-sec and higher delays. In our own pilot work with subjects with mild retardation, these procedures generate accuracy ranging from 100% to chance as a function of delay. Thus these procedures have the potential advantage of providing a range of baselines upon which to assess the effects of the drugs. Titrating delay procedures were used by Wysocki, Fuqua, Davis, and Breuning (1 98 1;the National Institutes of Health [NIH] panel that found Breuning guilty of scientificmisconductjudged this study to have been conducted as described). They studied four adults with IQs ranging from 5 1 to 78. Doses of thioridazine were decreased over time, and all subjects showed increases in accuracy over time. Because this outcome might be expected as a function of practice, effects must be judged in terms of the rapidity with which the maximum delay achieved in a given phase consistently exceeded the delay achieved in the previous phase. The longer the previous phase, the more convincing the increase. Using these criteria, the data suggest that thioridazine adversely affects delayed-matching performance. Attempts to replicate these procedures should include comparisons made after dose increases (only one of four subjects received a reversal). Decreases in accuracy that are counter to the expected increase as a function of experience would provide a powerful corroboration of these effects. Aman, Kern, McGhee, and Arnold (1993) used the titrating delayed matchingto-sample procedure to assess the effects of one dose of fenfluramine, methyl-

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phenidate, and placebo in children with MR and attention deficit hyperactivity disorder (ADHD).Each of three groups received the conditions in a different order. IQ ranged from untestable to 78. They reported that 23 of 28 subjects were able to perform the task. The mean longest delay achieved with fenfluramine, 6.23 sec, was higher than that achieved with placebo, 4.98; the effect approached significance (F = 3.05, p = .059, two-tailed). Further study of a range of doses within subjects appears promising. Aman (1991) described the range of subjects in whom delayed matching has been used successfully with minimal pretraining in his laboratory. Across two studies (including the one described above) the majority of subjects with mental ages of at least 3 to 4 years or IQs of at least 40 to 50 performed the task. In total, 38 of 55 subjects performed the task. Increasing the number of successful subjects might be as simple as beginning training with simultaneous and then 0-delay matching rather than with the minimum delay of 1 sec used by Aman and colleagues (see Cumming & Berryman, 1965).This tactic seems especially important in light of the potential that premature exposure to a longer delay level may have established training-resistant error patterns.

2. VARYING THE COMPLEXITY OF THE STIMULI Delayed-matching procedures may be made more difficult by varying the complexity of the stimuli. One method is presenting samples with more than one element. Scott (1971) reported a procedure used to study memory in subjects with mental retardation. The procedure received early use in the study of drug effects in normal children. An array of one or more pictures is presented as a sample. After the samples disappear, a single stimulus is presented as a comparison. If that stimulus was in the sample array, a response to a lever to the left of the screen is reinforced. If it was not, a response to the right-hand lever is reinforced. Mean accuracy in a group of subjects whose IQs ranged from 45 to 74 (mean = 56.2) decreased as a function of the number of picture elements in the sample. In a similar group of subjects, accuracy decreased little as a function of delays of up to 12 sec and the effect of number of stimuli (1-5) was slight. At delays of 24 sec, clear effects of number of stimuli were shown, with accuracy of 95% shown with one stimulus and 64% accuracy shown with 5. It seems likely that less extreme delays would be necessary to produce a range of accuracy levels in lower functioning subjects. Aman and colleagues have used this procedure in a number of studies, apparently with a single delay of 5 sec (Aman, 1991).Aman (1991) summarized the results of 1 1 studies, concluding that only two found significant drug effects on accuracy and that the measure was insensitive.The procedure may merit more study, however, given the sensitivity demonstratedin earlier studies of children with normal IQ (summarized in Aman, 1978). Studies revealing the performance of individual subjects on a range of doses and/or delays may be illuminating. A study not involving drugs by Stromer, McIlvane, Dube, and Mackay (1993)

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illustrates a potentially useful variation of these procedures. Their matching task presented complex samples of two nonsense stimuli. Rather than the yes-no response required by Scott (1971). their procedure presented two comparison stimuli, one of which was one of the sample elements. Subjects whose mental ages ranged from 3 years 8 months to 7 years 7 months consistently showed lower accuracy on a delayed matching task (either 0 or 1-sec delay) with complex samples than on a simultaneous task with complex samples or a delayed task with singleelement samples. Accuracy typically ranged from 75 to 90% on the complex sample, delayed task. Stromer et al. (1993) interpreted their results in terms of attention rather than memory. The procedure’s possibilities as a memory task could be further explored by evaluating performance at a range of delays. It seems likely that a range of accuracies would be observed within subjects. The one subject who was exposed to two different delay values showed high accuracy at 0-delay and intermediate accuracy at 1-sec delay. This procedure is potentially valuable for assessing the effects of drugs because it produces intermediate accuracy at very brief delays. In contrast, the Wysocki et al. (198 1) study discussed earlier, in which single-element color samples were used, involved delays ranging from 5 to 75 sec. Briefer delays present fewer logistical problems. Another promising feature of the procedure used by Stromer et al. is that performance was fairly stable over a number of sessions. 3. CONDITIONALVERSUS NONCONDITIONALMATCHING In a typical conditional identity matching task, the same two-choice stimuli are presented across trials and two different sample stimuli alternate randomly across trials. Thus, a stimulus serves as both S and S - across trials. In a nonconditional identity task,each trial presents a different sample stimulus and sample stimuli are never presented as incorrect comparisons (see Dube, McIlvane, & Green, 1992). Because it does not require conditional discrimination, eliminating the across-trial interference that can occur with conditional procedures, this task may be easier for some subjects (Dube, Iennaco, & McIlvane, 1993). Given these two extremes, one might vary difficulty by increasing the number of sample stimuli that are presented in a session, but retaining the conditional aspect of the task (i.e., all stimuli serve both S + and S - functions). This would decrease the recency with which a stimulus had been presented with the opposite function, a variable that has been shown to affect accuracy (Mackay & Gould, 1992).We have used three variations of the matching procedure in subjects with mild retardation: (a) a nonconditional procedure, (b) a 6- or 12-sample conditional procedure, and (c) a 2-sample conditional procedure. In cases in which individual subjects have been exposed to more than one of these procedures, more accurate performance has typically been found in the nonconditional task as compared to the conditional task, and accuracy with 12 samples is higher than accuracy with 2 samples in the conditional tasks.

+

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C. Attention Procedures Attention has been a major construct in the study of MR. Deficits in learning and remembering have been attributed to deficiencies of attention (Zeaman & House, 1963). Becauseof the potential role of attentionalprocesses in a wide range of basic cognitive skills related to adaptive functioning,a large literature compares attentional functioning of persons with MR with that of normally capable persons (see Memll, 1990 Warm & Berch, 1985; Zeaman & House, 1963, for reviews). This literature is almost entirely composed of procedures that employ instructed performance and motivation, short (one session) participation, and persons with mild to moderate MR. Attention procedures involve the maintenance, rather than the acquisition, of stimulus control (usually successive discrimination). Fuo variations are shortterm attention tasks and sustained attention tasks.These are important distinctions that are not always drawn in the literature on drugs and MR. 1. SUSTAINEDATIWVI”T0NTASKS

Sustained attention refers to the ability to maintain attentional focus on relevant stimuli with repeated presentation over extended periods. Vigilance tasks are the prototypic procedure used for measuring sustainedattention. Vigilance procedures vary in form but generally have several features in common. A stimulus (the signal or target) that controls some response is presented aperiodically and infrequently relative to background stimulus conditions (“noise”). The background stimulus conditions may be constant, such as white noise. or composed of discrete presentations of nontarget or distracter stimuli that are usually similar to the target (e.g.. different spoken words or visual letters). Discriminative stimuli or signals may be of short duration or otherwise difficult to discriminate from background conditions, but above-discriminationthresholds and reliably responded to under nonvigilance conditions. The task is continuous over a prolonged session (usually 1-2 hr) and responding does not affect the probability of stimulus presentations. Measures of stimulus control can be accuracy (percentage of stimulus presentations that produce responses) and/or reaction timdatency to respond to the “target” stimulus. In addition, the number of responses made in the absence of the stimulus is measured. The robust result of vigilance studies is a reliable decrement in the proportion of stimuli that produce reporting responses and/or in the speed of responding to S+ as a function of time in the session. The magnitude and rapidity of these decrements are said to measure the capacity to sustain focused attention, or “attention span.” The decrementhas been demonstrated to occur sooner as a function of neuropsychiatric impairment, aging, and MR (e.g., Warm & Berch, 1985). Procedural variables also determine the course of sustained attention. Factors that increase the rapidity and magnitude of the decrement are a difficult target-

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noise discrimination, a conditional versus a simple discrimination, high-fiequency distracters and targets (e.g., 40 vs. 12 stimuli per min), and rare target events. Extreme values of these parameters can produce significant decreases in stimulus control within the first 5 min of the session, even after extended practice (Parasuraman & Giambra. 1991). Various vigilance tasks have been used to assess cognitive side effects of psychotropic and antiepileptic medications in clinical and normal populations of adults and children of normal IQ (see reviews by Novelly et al., 1986; Rapport & Kelly, 1991; Wittenborn, 1978).Aman (1991) noted that these are the most extensively used procedures in pediatric psychopharmacology. The task typically used is the continuous performance task (CPT). Two general versions of this task have been used, one requiring simple successive discrimination and the other adding a requirement for conditional control. In the former, the subjects must respond to a single S + that is presented less frequently than one or more S-’s. For example, the letter X is the target with other letters as distracters. In the conditional version, the target stimulus functions as an S only if it has been preceded by a specified stimulus. For example, the letter X is the S +, but only if preceded by the letter A; otherwise, X is an S -. The literature contains little information on vigilance tasks in general in subjects functioning below the mild level of MR (see Warm & Berch, 1985, for a review). Moreover, we found no study of subjects with MR on the effects of drugs on sustained attention, per se. Although the CPT has been used, the studies have used short duration sessions and have not focused on performance decrements across the session. Short duration sessions are likely to reduce the sensitivity of the procedure to drug effects. Studies using the CPT in short duration sessions do give some indication of the range of subjects who can perform the task with little training (usually with instruction).In a procedural review, Aman (1991) noted that few subjects with IQs below 40 or 50 could perform the task. Because continuous attention tasks have been widely used in the drug literatureon normally capable subjects, it seems wise to fully develop their use in studies of subjects with MR. The range of possible subjects can be increased by using training procedures that do not rely on verbal instructions. Procedures for training successive discrimination, such as stimulus fading, are applicable (for options, see Lancioni & Smeets, 1986; Spradlin, Locke, & Fulton, 1969; Stoddard & McIlvane, 1989; Terrace, 1963). In addition, explicit reinforcement procedures will be necessary to maintain responding over long duration sessions in people who are not responsive to instructions (Baron & Galizio, 1983). For example, Perryman, Halcomb, and Landers (198 l), studied subjects with mild MR in a 68-min simple-discrimination CPT.Responsecontingent reinforcement completely eliminated the across-session performancedecrement shown under no-feedback conditions.This raises important issues about the use of these procedures. The effects of reinforcement,

+

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feedback, and repeated practice on sustaining attention in people with MR are largely unexplored. Further development of these tasks with subjects functioning across a range of mental ages is required before these procedures can be used as drug baselines. 2. SHORT-TERMATENTION PROCEDURES In contrast to sustained attention tasks, short-term attention tasks involve the maintenance of a (usually more complex) discrimination over shorter time periods. There are two types: focused attention and breadth of attention tasks. Focused attention involves maintaining stimulus control in the face of distraction. Distracters may compete for control due to physical similarity to the target, their relevance on other trials (as in conditional discriminations),or other features of history. The CPT and other vigilance procedures used to measure sustained attention can serve as focused attention tasks. In fact, the limited use of the CPT in the MR drug literature has been in relatively brief sessions. Complex matching-to-sampletasks have been used to address attention in the drug literature. For example, the matching familiar figures task (MFFT) is frequently used in the ADHD literature. However, summarizing a number of studies conducted in his laboratory,Aman (1991)judged the procedure not very sensitive. Because it is one of a few attention procedures that has been used in the MR drug literature, we mention it for completeness.In the MFFT, the sample is a line drawing. The subject must select the comparison stimulus that is identical to the sample from among severalhighly similar choices. Because the distracters share many elements with the sample, selecting the correct comparison requires careful observation of all stimuli. Aman (1991) summarized the performance of approximately 60 subjects (includedinAman, 1991, a n d m et al., 1993). Subjects with MAS below 3 or 4 years (along with some with higher MAS) were unsuccessful. The task could be made easier by reducing the complexity of the stimuli and/or the number of comparisons. Moreover, given improvements in training identity matching (Dube et al., 1993). more reliable acquisition seems possible. The sensitivity of the procedure in this population is unknown. A similar attention task was described by Aman (1991). In it, samples that varied on four dimensions(i.e.. square or triangle; red or blue; thick or thin; circle or star affixed). Sixteen comparison stimuli (all possible permutations) were presented on each trial. This task has the advantage of allowing precise specification of the overlapping stimulus components. A second type of task involves breadth of attention. Recent work focuses on the costs of dividing attention across multiple stimuli compared to attending to a single stimulus. Procedures that involve complex samples in a matching-to-sample format have been used to address this issue. Examples of such procedures were discussed in the section on delayed matching to sample (i.e., the multiple element sample tasks used by Scott, 1971, and Stromer et al., 1993).Because comparison

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stimuli are presented after the sample is removed, the subject must attend to all elements of the sample to obtain maximum reinforcement. As the number of elements in the sample is increased, a greater burden is placed on attentional capacity. The less the attentional capacity, the greater the performance decrement with an increased number of sample stimulus elements (Kinchla, 1992; Memll, 1990; Shriffren, 1988). Decreasing accuracy (and, when measured, increased reaction time) with increased complexity of the sample has been shown in normally capable subjects.As compared to normal controls, subjects with mild MR show greater decrements with complex samples (Memll, 1990). Older (>60yr.) normally capable subjects show greater decrements than do college students (see Baron, Myerson, & Hale, 1988). Sprague, Barnes, and Werry (1970) used the Scott procedure (1971; see section on delayed matching) with 12 hyperactive children. An equal number of one-, two-, or three-element sample trials were intermixed in sessions. Correct responses produced a small piece of candy. After two practice sessions, subjects were exposed to one session at each of two doses of methylphenidate(.25 and .35 mgkg), one session at each of two doses of thioridazine (.75 mgkg and 1.O mg/kg), and two placebo sessions in counterbalanced order. No practice effect on accuracy or RT was shown-an important aspect of a procedure that is to be used for multiple sessions. Accuracy was significantly greater and RT was significantly faster with methylphenidate as compared to placebo or thioridazine. The larger the number of sample elements, the greater the effect. That is, the number of sample elements affected the sensitivity of the procedure. This procedure (or a variant) appears promising for the assessment of drug effects in individuals with MR. Data from Aman et al. (1991) might seem discouraging, however. Of 27 subjects,only 10 successfullyperformed the task. The study used either three or nine sample elements and only one delay value (5 sec). The task can be made less difficult by varying the number of sample elements and decreasing the delay (Scott, 1971).In addition, pretraining with simultaneousmatching and shorter delays can be given. Finally, the task can be modified to a twochoice procedure (as in Stromer et al., 1993), which may be easier to teach than the yes-no response of the Scott task. These changes are likely to greatly increase the number of successful subjects. IV.

SUMMARY AND CONCLUSIONS

Many persons with mental retardation receive some form of psychoactive medication. Unfortunately, virtually nothing is known about the effects of psychoactive drugs on learning, memory, and attention in this population. Research progress has been limited by profound methodological difficulties. We suggest modifications in strategy that can make progress more rapid. First, the procedures and find-

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ings of behavioral pharmacology should be used. The experimental situation should be arranged to exert experimental control over variability rather than relying on statistical control. Group designs involving widely varying performances are inherently insensitive. Drug effects are the result of a complex interaction of dose, specific task, level of performance, and the events maintaining the performance. Taking this complexity into account in the design of experiments will enhance the potential for interpretable results. Increased use of single-subject research designs will avoid the lack of procedural sensitivity that results from the known complexity of drug-behavior-environment interactions. Exerting experimentalcontrol over the behavior of interest will be a critical element of this enhanced experimental control. At present, most studies simply accept whatever level of performanceis achieved after a brief pretrainingperiod. The development of more effective procedures will require prior analyses of behavior under these tasks, especially in subjects with severe and profound mental retardation. Much important information is available in the rapidly developing stimulus control literature, an important component of which uses subjects who function at less than the mild level of mental retardation. From this literature comes basic knowledge of the processes involved in the performances of interest as well as procedures for establishing baseline performances without instructions. ACKNOWLEDGMENTS This work was supported by National Institute of Child Health and Development (NICHD) grants 5-POlHD26927, l-POlHD18955, and 5-P30HD02528. We thank Mark Egli, Jessica Hellings, Bill McIlvane, Matt Reese, Dave Schaal, Steve Schroeder, Joe Spradlin. and Rick Tessel for their comments; Pat White for editorial assistance; and Linda Lee Stahlman for library assistance.

REFERENCES Aman, M. G. (1978). Drugs, learning, and the psychotherapies. In J. S. Weny (Ed.), Pediatric psychopharmacology: The use of behavior modifying drugs in children (pp. 79-108). New York Brunnerhlazel. Aman, M. G. (1984). Drugs and learning in mentally retardedpersons. In G. D. Burrows & J. S. Werry (Eds.),Advances in human psychopharmacology (Vol. 3, pp. 121-163). Greenwich, CT JAI press. Aman, M. G. (1991).Applicationsof computerized cognitive-motormeasures to the assessmentof psychoactive drugs. In W. E. Dodson, M. Kinsboume, & B. Hiltbrunner (Eds.),The assessment of cognitiveficnction in epilepsy (pp. 69-96). New York: Demos Publications. Aman, M.G., & Kem, R. A. (1989).Review of fenfluraminein the treatment ofthe developmental disabilities.Journal of the American Academy of Child and Adolescent Psychiatry, 28.549-565. Aman, M. G., Kern. R.A., McGhee, D. E., &Amold, L. E.(1993). Fentluramine and methylphenidate in children with mental retardation and attention deficit hyperactivity disorder: Laboratory effects. Journal ofAutism and Developmental Disorders, 23, 1-16.

DRUGS AND COGNITION

179

A m a M. ~ G., & Singh, N. N. (1980).The usefulnessof thioridazinefor treating childhood d i s o r d e w Fact or folklore? American Journal of Mental Deficiency. 84,331-338. Aman, M.G., & Singh N. H. (1988). Patterns of drug use, methodological considerations, measurement techniques, and future trends. In M.G. Aman & N. N. Singh (Eds.), Psychophamcology of the developmental di s (pp. 1-28). New York Springer-Verlag. Aman, M.G., & White, A. J. Measures of drug change in mental retardation. In K. D.Gadow (Ed.), Advances in learning and behavioral disabilities. (Vol. 5, pp. 157-202). Greenwich, CT: JAI Press. Anderson, L.T., Campbell, M.,Grega D.M.,Perry, R., Small, A. M., & Green, W. H. (1984). Haloperido1 in the treatment of infantile autism: Effects on learning and behavioral symptoms. American Journal of Psychiatry, 141,1195-1202. Anderson, L. T., Campbell, M.,Adams, P., Small, A. M.,Perry, R., & Shell, J. (1989). The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children. Journal of Autism and Development Disorders, 19, 227-239. Baldessarini, R. J. (1990). Drugs and the treatment of psychiatric disorders. In A. G . Gilman et al. (Eds.),Goodman and Cilmunk the pharmacological basis of therapeutics(8th ed., pp. 383-435). New York: Pergamon. Baldessarini, R. J., & Frankenburg, F. R. (1993). Clozapine: A novel antipsychotic agent. In J. Yesavage (Ed.), Clozapine:A compendium of selected readings (2nd ed., pp. 3-16). Stanford,CA: Sandoz Pharmaceuticals Corp. Barlow, D. H., & Hersen, M. (1984). Single case experimental designs. New York Pergamon Press. Baron. A.. & Galizio, M.(1983). Instructional control of human operant behavior. The Psychological Record, 33,495-520. Baron, A., Myerson, J., & Hale, S. (1988). An integrated analysis of the structure and function of behavior: Aging and the cost of dividing attention. In G. Davey & C. Cullen (Eds.),Human operant conditioning and behuvior modification (pp. 139-166). New York: John Wiley & Sons. Barrett, J. E. (1976). Effects of alcohol, chlordiazepoxide, cocaine and pentobarbital on responding maintained under fixed-intervalschedules of food or shock presentation.Journal of Pharmucology and Experimental 'Therapeutics, 196,605-61 5 . Baumeister, A. A., & Sevin, J. A. (1990). Pharmacologic control of aberrant behavior in the mentally retarded: Toward a more rational approach. Neuroscience & Biobehuvioral Reviews, 14, 253-262. Baumeister, A. A., Todd, M.E.. & Sevin, J. A. (1993). Efficacy and specificityof pharmacologicaltherapies for behavioral disorders in persons with mental retardation. Clinical Neurophurmucology, 16,271-294. Bickel, W. K., Higgim, S. T.. & Griffiths, R. R. (1989). Repeated diazepam administration:Effects on the acquisition and performance of response chains in humans. Journal of the Experimental Analysis of Behavior, 52.47-56. Bickel, W. K., Higgim, S. T., & Hughes, J. R. (1991). The effects of diazepam and triazolam on repeated acquisition and performance of response sequences with an observing response. Journal of the Experimental Analysis of Behavior, 56,217-231. Boren, J. J. (1963).The repeated acquisition of new behavioral chains. American Psychologist, 18,421. (Abstract) Boren, J. 1.. & Devine, D.D.(1 968). The repeated acqu on of behavioral chains. Journal of the Experimental Analysis of Behuvior, II,651-660. Branch, M. N. (1984). Rate, dependency, behavioral mechanisms,and behavioral pharmacology. Journal of the Experimenial Analysis of Behavior, 42.51 1-522. Branch, M.N. (1991). Behavioral pharmacology. In I. H. Iversen & K. A. L a d (Eds.), Experimenial analysis of behavior. Par? 2 (pp. 21-77). New York: Elsevier.

180

D. C. Williams and K. J. Saunders

BustiUo, J. R., Kirkpatrick, B., & Buchanan, R. W. (1995). Neuroleptic treatment and negative symp toms in deficit and nondeficit schizophrenia. Biological Psychiarry, 38.64-67. Campbell. D. T.,& Stanley, J. C. (1963). Experimental and quasi-experimental designsfor research. Chicago, IL: Rand McNally. Campbell, M., Anderson, L. T.,Small, A. M., Locascio, J. J., Lynch, N. S., & Choroco. M. C. (1990). Naltrexone in autistic children: A double-blind and placebo-controlled study. Psychopharmacology Bulletin, 26,130-135. Campbell, M., Anderson, L. T.. Small, A. M., Perry, R., Green, W. H., & Caplan, R. (1982). The effects of haloperidol on learning and behavior in autistic children. Journal of Autism and Developmental Disonlers. 12. 167-175. Can,E. G.,& Durand V. M. (1985). Reducing behavior problems through functional communication training. Journal of Applied Behavior Analysis, 18,111-126. Carter, D. E., & Eckennan, D. A. (1975). Symbolic matching by pigeons: Rate of learning complex discriminations predicted from simple discriminations.Science, 187.662-664. Calania, C. A. (1992). karning (3rd 4.). Englewood Cliffs, NJ: Prentice-Hall. Cohen, S. A., & Underwood, M. T. (1994). The use of clozapine in a mentally retarded and aggressive population. Journal of Clinical Psychiarry, 55,440-444. Constantine,B., & Sidman,M. (1975). Role of naming in delayed matching-to-sample.American JourM I of Mental Deficiency, 79,680-689. Cumming, W. W., & Berryman, R. (1965). The complex discriminated operant: Studies of matchingto-sample and related problems. In D. 1. Mostofsky (Ed.), Stimulus generalization(pp. 284-330). Stanford, CA: Stanford University Press. Dalton, A. J. (1992). Dementia in Down syndrome: Methods of evaluation. In L. Nadel & C. Epstein (Eds.),Down syndrome and Alzheimer disease. (pp. 51-76) New York:Wiley-Liss. Dalton, A. J., & Crapper McLachlan, D. R. (1984). Incidence of memory deterioration in aging persons with Down’s syndrome. In J. M. Berg (Ed.), Perspectives and progress in menral reraniarion, Vol. II: Biomedical aspects (pp. 55-62). Baltimore, MD: University Park Press. Dalton, A. J., Crapper McLachlan. D. R..& Schlotterer,G. R. (1974).Alzheimer’s disease in Down’s Syndrome: Visual retention deficits. Conex, 10.36377. Desjardins, P. J., Moerschbaecher,J. M.. Thompson, D. M., &Thomas, J. R. (1982). Intravenous diazepam in humans: Effects on acquisition and performance of response chains. Pharmacology Biochemistry and Behavior, 17, 1055-1059. D e t t e m , D. K., Mayer, J. D., Caruso. D. R., Legree, P. J., Conners. F. A., & Taylor, R. (1992). Assessment of basic cognitive abilities in relation to cognitive defects, American Journal on Mental Retardation, 97,251-286. Dews, P. B. (1958). Studies on behavior. N.Stimulant action of methamphetamine. The Journal of Pharmacology and Experimental Therapeutics,122, 137-147. Dews, P. B. (1981). History and present status of rate-dependencyinvestigations.Advances in Behavioral Pharmacology,3, I1 1-1 18. Dube, W. V., Iennco, F. M., & Mcllvane, W. J. (1993). Generalizedidentity matching to sample of twodimensional forms in individuals with intellectual disabilities.Research in Developmental DisDube, W. V., McIlvane, W. J., & Green, G. (1992). An analysis of generalized identity matching-tosample test procedures. The Psychological Record, 42, 17-28. Durwen, H.F., Hufnagel,A,, & Elger, C. E. (1992). Anticonvulsantdrugs affect particular steps of verbal memory processing-An evaluation of 13 patients with intractable complex partial seizures of left temporal lobe origin. Neuropsychologia.30,623-631. T. J. (1993). Pharmacotherapy:I. JournalofDevelopmenral and Evenden, J. L. (1988). Issues in behavioral pharmacology implications for developmental disorders.

DRUGS AND COGNITION

181

In M.G. Aman & N. N. Singh (Eds.),Psychophannacology of the developmental disabilities (pp. 216-238). New York: Springer-Verlag. Ferster, C. B., & Skinner. B. F. (1957). Schedules of reinforcement. Englewood Cliffs, NJ: PrenticeHall. Files, E J., Blanch, M.N., & Clody, D. (1989). Effects of methylphenidate on responding under extinction in the presence and absence of conditioned reinforcement. Behavioral Pharmacology, 1 , 1 13-12 1. Gadow, K. D. (1986). Children on medication, Vol. I : Hyperactivity, learning disabilities, and mental retardation. Boston, MA: Little, Brown and Company. Gadow, K. D., & Poling, A. D. (1988). Pharmacotherapy and mental retardation. Boston, MA: College Hill Press. Galizio, M.,& AUen, A. R. (1991). Variable-ratio schedules of time out from avoidance: Effects of d-amphetamine and morphine. Journal of the Experimental Analysis of Behavior, 56, 193-203. Goldman. R.S., Tandon, R.,Liberzon, I.. Goodson, J., & Greden, J. F. (1991). Stability of .positive and . negative symptom constructs during neuroleptic treatment in schizophrenia. Psychopathology, 24,247-252. Gollub, L. R.(1964).The relations among measures of performance on fixed-intervalschedules. Journal of the Experimental Analysis of Behavior, 7. 337-343. Gualtieri, C. T. (1991). Neuropsychiatry and behavioral pharmacology. New York: Springer-Verlag. Hammock, R.,Schroeder, S. R.,& Levine, W. A. (1995). Clozapine for self-injurious behavior. Journal of Autism and Developmental Disorders, 25,611627. Hartlage, L. C . (1965). Effect of chlorpromazine on learning. Psychological Bulletin, 4, 235-245. Herman. B. H. (1991). Effects of opioid receptor antagonists in the treatment of autism and self-injurious behavior. In J. J. Ratey (Ed.), Mental retardation: Developing pharmacotherapies (pp. 107-137). Washington, DC: American Psychiatric Press. Hersen, M.,& Barlow, D. H. (1976). Single case experimental designs: Strategiesfor studying behavior change. New York: Pergamon Press. Higgins, S. T.,Bickel, W. K.. O’Leary. D. K., & Ymgling J. (1987). Acute effects of ethanol and diazepam on the acquisition and performance of response sequences in humans. Journal of Pharmacology and Experimental Therapeutics,243, 1-8. Higgins, S. T., Rush, C. R.,Hughes, J. R.,Bickel, W. K., Lynn, M., & Capeless, M. A. (1992). Effects of cocaine and alcohol, alone and in combination, on human learning and performance. Journal of the Experimental Analysis of Behavior. 58,87-105. Higgins, S . T., Woodward, B. M., & Henningfield, J. E. (1989). Effects of atropine on the repeated acquisition and performance of response sequences in humans. Journal of the Experimental Analysis of Behavior, 51,5-15. Hursh, S. R. (1977). The conditioned reinforcement of repeated acquisition. Journal ofthe Experimental Analysis of Behavior, 27. 315-326. Johnston, J. M.. & Pennypacker, H. S. (1980). Strategies and racrics of human behavioral research. Hillsdale, NJ: Lawrence Erlbaum. Katz, J. L. (1982). Effects of drugs on stimulus control of behavior. I. Independent assessment of effects on response rates and stimulus control. Journal of Pharmacology and Experimental Therapeutics, 223.61 7-623. Katz, J. L. (1983). Effects of drugs on stimulus control of behavior. 11. Degree of stimulus control .a a determinant of effect. Journal of Pharmacology and Experimental Therapeutics, 226, 756763. Kaufman, M. E., & Prehm, H. J. (1966). A review of research on learning sets and transfer of training in mental defectives. In N. R. Ellis (Ed.),International review of research in mental retardation (Vol. 2, pp. 123-149). New York: Academic Press. Kelleher, R.T., & Morse, W. H. (1968). Determinants of the specificity of the behavioral effects of

182

D. C, Williams and K. J. Saunders

drugs. Ergebnisse der Physiologie Biologischen Chemie und Experimen rellen Pharmaknlogie. 60.1-56. Kinchla, R. A. (1992). Attention. In M. R. Rosenzweig & L. W. Porter (Eds.),Annual review of psychology (Vol. 43, pp. 711-742). Palo Alto, CA: Annual Reviews. Lancioni. G. E.. & Smeets, P. M. (1986). Procedures and parametem of enorless discrimination training with developmentallyimpaired individuals. h N. R. Ellis & N. W. Bray (Eds.),International review of research in mental reradarion (Vol. 14, pp. 135-164). New York: Academic Ress. Lander, J. D. (1981).Rate-dependenceand the effects of phenothiazine antipsychoticsin pigeons. Advances in Behavioral Pharmacology, 3.21-37. Louttit, R. T. (1965). Chemical facilitation of intelligenceamong the mentallyretarded.American Journal of Mental Deficiency, 69,495-501. Mackay, H. A. (1991). Conditional stimulus control.In I. H. Iversen & K. A. Lattal (Eds.), Experimental analysis of behavior: Part I (pp. 301-350). New York: Elsevier. Mackay, H. A., & Gould, D. D. (1992). Relative sample recency and proactive interference in adults with mental retardation. Experimenral Analysis of Human Behavior Bulletin, 10. 1-5. Mcllvane, W. J. (1992). Stimulus control analysis and nonverbal instructional methods for people with intellectual disabilities. In N. W. Bray (Ed.), Inrernarional review of research in menral reradarion (Vol. 18, pp. 55-109). New York Academic Press. McKeamey, J. W. (1981). Rate dependency: Scope and limitations in the explanation and analysis of the behavioral effects of drugs. Advances in Behavioral Pharmacology, 3,91-109. Meltzer, H. Y.,Lee, M. A., & Ranjan, R. (1994). Recent advances in the pharmacotherapy of schizophrenia. Acra Psychiarrica Scandinavica, 384.95-101. Merrill, E. C. (1990).Attentional resource allocation and mental retardation. In N. W. Bray (Ed.), Inrernarional review of research in menral retardation (Vol. 16, pp. 51-88). San Diego: Academic Press. Moller, H. -J. (1993). Neuroleptic treatment of negative symptoms in schizophrenicpatients. Efficacy problems and methodologicaldifficulties.European Neuropsychopharmacology.3, 1-1 1. Moller, H. -J., Miiller, H., Borison, R. L., Schooler. N. R., & Chouinard, G. (1995). A path-analytical approach to differentiate between direct and indirect drug effects on negative symptomsin schizophrenic patients: A re-evaluation of the North American risperidone study. European Archives of Psychiaty Clinical Neuroscience, 245.45-49. Novelly, R. A., Schwartz,M. M., Mattson, R. H.. & Cramer, J. A. (1986). Behavioral toxicity associated with antiepileptic drugs: Concepts and methods of assessment. Epilepsia. 27,331-340. Overton, D. A. (1971). Discriminative control of behavior by drug states. In T. Thompson & R. Pickens @Is.), Srimulusproperfies of drugs (pp. 87-1 10). New York: Appleton-Century-Crofts. Parasuraman. R., & Giambra, L. (1991). Skill development in vigilance: Effects of event rate and age. Psychology and Aging, 6,155-169. Perone, M. (1991). Experimental design in the analysis of free-operant behavior. In I. H. Iversen & K. A. Lanai (Eds.),Experimental analysis of behavior: Part I (pp. 135-171). New York: Elsevier. Perone, M., & Baron, A. (1982). Age-related effects of pacing on acquisition and performance of response sequences: An operant analysis. Journal of Gerontology, 37,443-449. Perryman, R. E., Halcomb. C. R., & Landers, W. F.(1981). Operant conditioningof mental retardates' visual monitoring. Perceprual and Moror Skills, 53,507-512. Picker, M.,Leibold L., Endsley, B., & Poling, A. (1986). Effects of clonazepam and ethosuximideon the responding of pigeons under a fmed-consecutive-numberschedule with and without an external discriminative stimulus. Psychopharmacology, 88.325-330. Poling, A., & Cleary, J. (1986). Within-subject designs. In K. D. Gadow &A. Poling (Eds.),Advances in learning and behavioral disab s, Suppl. I Methodological issues in human psychopharmacology (pp. 115-136). Greenwich, CT:JAI Press.

DRUGS AND COGNITION

183

Poling, A., Cleary, J., Berens, K., & Thompson, T. (1990). Neuroleptics and learning: Effects of haloperidol. molindone. mesoridazine and thioridazine on the behavior of pigeons under a repeated acquisition procedure.Journal of Pharmacology and Experimental Therapeutics, 255, 1240-1245.

Poling, A., Gadow, K. D., & Cleary, J. (1991). Drug therapy f o r behavior disorders: An introduction. New York: Pergamon Press. Poling,A., Henningfield.J. E., & Wysocki, T. (1986). Behavioral pharmacologyand principles of drug action. In K. D. Gadow & A. Poling (Eds.), Advances in learning and behavioral disab Suppl. I Methodological issues in human psychopharmacology (pp. 1-39). Greenwich, C T JAI Press. Poling, A., & Picker, M. (1987). Behavioral effects of anticonvulsant drugs. In T. Thompson, P. 9. Dews, & J. E. Barrett (Eds.), Neurobehavioral pharmacology (pp. 157-192). Hillsdale, N J Lawrence Erlbaum. Rapport, M. D., DuPaul, G. J., & Smith, N. F. (1985). Rate-dependency and hyperactivity: Methylphenidate effects on operant responding. Pharmacology Biochemistry & Behavior, 23, 77-83. Rapport,M.D., & Kelly, K. L.(1991). Psychostimulant effects on learning and cognitive function: Findings and implications for children with attention deficit hyperactivity disorder. Clinical Psychology Review, I I , 61-92. Ratey. J. J., & Gualtieri, C. T. (1991). Neuropsychiatry and mental retardation. In J. J. Ratey (Ed.), Mental retardation: Developingpharmacotherapies(pp. 1-17). Washington,DC: American Psychiatric Press. Saunders, K.J., & Spradlin, J. E. (1989). Conditional discrimination in mentally retarded adults:The effect of training the component simple discriminations. Journal of the Experimental Analysis of Behavior. 52, 1-12. Saunders, K.J., & Spradlin, J. E. (1990). Conditional discrimination in mentally retarded adults: The development of generalized skills. Journal of the Experimental Analysis of Behavior, 54. 239-250. Saunders, K.J., & Spradlin, J. E. (1 993). Conditionaldiscrimination in mentally retarded subjects: Programming acquisition and learning set. Journal of the Experimental Analysis of Behavior, 60, 571-585. Schaal, D. W., & Hackenberg, T. (1994). Toward a functional analysis of drug treatment for behavior problems in people with developmental disabilities.American Journal on Mental Retardation, 99,123-140. Schroeder.S. R. (1988). Neuroleptic medications for persons with developmental disab Aman & N. N. Singh (Eds.),Psychopharmacologyof thedevelopmental disabilities (pp. 82-100). New York: Springer-Verlag. Scott, K. G. (1971). Recognition memory: A research strategy and a summary of initial findings. In N.R. Ellis (Ed.), International review of research in mental retardation (Vol. 5 , pp. 83-1 11). New Yo& Academic Press. Share, J. B. (1976). Review ofdrug treatment for Down's syndromepersons.American Journal ofhfental Deficiency. 80,388-393. Shriffrin, R. M. (1988).Attention. In R. C. Atkinson, R. J. Hemstein, G. Lindzey, & R. D. Luce (Eds.), Stevens' handbook of experimental psychology (2nd. ed.) Vol. 2: Learning and cognition (pp. 739-811). New Yo&: John Wiley & Sons. Sidman, M.(1960). Tactics of scientific research: Evaluating experimental data in psychology. New York: Basic Books. Singh, N. N.. Singh, Y.N., & Ellis, C. R. (1992). Psychopharmacologyof self-injury. In J. K.Luiselli. J. L. Matson, & N. N. Singh (Eds.),Self-injurious behavior: Analysis, assessment, and treatmenf (pp. 307-351). New York: Springer-Verlag.

184

D. C. Williams and K. J. Saunders

Singh, N. N., & Winton, A. S. W. (1984). Behavioral monitoring of pharmacological interventions for self-injury.Applied Research in Mental Retardation, 5, 161-170. Singh. Y.N., Ricketts, R. W., Ellis, C. R., & Singh, N. N. (1993). Opioid antagonists. I: Pharmacology and rationale for use in treating self-injury. Journal of Developmental and Physical Disabilities, 5.5-16. Sokol, M. S.. & Campbell, M. (1988). Novel psychoactive agents in the treatment of developmental disorders. In M. G. Aman & N. N. Singh (Eds.),Psychopharmacology of the developmental disabilities (pp. 146-167). New York Springer-Verlag. Sovner, R. (1991). Use of anticonvulsant agents for treatment of neuropsychiatric disorders in the developmentallydisabled. In J. J. Ratey (Ed.). Mental retardation: Developing pharmucotherapies (pp. 83-106). Washington, D C American Psychiatric Press. Spradlin, J. E.,Locke, B. J., & Fulton. R. T. (1969). Conditioning and audiological assessment. In R. T. Fulton & L. L. Lloyd (Eds.),Audiometry for the retarded with implications for the difficultto-tesi (pp. 125-163). Baltimore, MD: The Williams & Wilkins Company. Sprague, R. L., Barnes, K.R., & Weny, J. S. (1970). Methylphenidateand thioridazine: Learning, reaction time, activity, and classroom behavior in disturbed children. American Journal of Orthopsychiatry, 40.6 15-628. Sprague, R. L., & Weny, J. S. (1971). Methodology of psychopharmacological studies with the retarded. In N. R. Ellis (Ed.), International review of research in mental retardation (pp. 147-219). New Yok Academic Press. Stoddard,L. T., & McIlvane,W. J. (1989). Establishingcontrol by spoken words with profoundly mentally retarded individuals. Research in Developmental Disabilities, 10, 141-151. Stmmer, R., Mcllvane, W. J., Dube, W. V., & Mackay, H. A. (1993). Assessing control by elements of complex stimuli in delayed matching to sample. Journal of the Experimental Analysis of Behavior, 59,83-102. Taylor, D. V., Hetrick, W. P., Neri, C. L., Touchette, P.. Barron, J. L.. & Sandman, C. A. (1991). Effect of naltrexone upon self-injurious behavior, learning and activity: A case study. Pharmucology Biochemistry & Behavior, 40, 79-82. Terrace, H.S. (1963). Discrimination learning with and without “errors.” Journal of the Experimental Analysis of Behavior, 6, 1-27. Terrace, H. S. (1970). Errorless discrimination learning in the pigeon: Effects of chlorpromazineand imipramine. In T. Thompson, R. Pickens, & R. A. Meisch (Eds.), Readings in behavioral pharmacology (pp. 112-1 15). New York Appleton-Century-Crofts. Thomas, J. R. (1970). Differential effects of two phenothiazines on chain and tandem schedule performance. In T. Thompson, R. Pickens, & R. A. Meisch (Eds.),Readings in Behavioral Phurmucology (pp. 432-441). New York Appleton-Century-Crofts. Thompson, D. M. (1975). Repeat es: Stimulus control and drugs. Journal of the Experimental Thompson, D. M. (1977). Developmentaltolerance to the disruptive effects of cocaine on repeated acquisition and performance of response sequences. Journal of Pharmacology and Experimental Therapeutics,203, 294-302. Thompson, D. M. (1980). Selective antagonism of the rate-decreasing effect of d-amphetamine by chlorpromazinein a repeated-acquisitiontask. Journal of the Experimental Analysis of Behavior, 34,87-92. Thompson, D. M.. & Moerschbaecher,J. M. (1979).Drug effects on repeated acqu son & P. B. Dews (Eds.),Advances in behavioralpharmacology(Vol. 2, pp. 229-255). New York Academic Press. ThompsonT., Hackenberg,T.,& Schaal, D. W. (1991).Pharmacological treatmentsfor behaviorprob1em.s in developmental disabilities. (Publication No. 91-2410, pp. 343-439). Washington, D C National Institute of Child Health and Human Development.

DRUGS AND COGNITION

185

Thompson,T. (1982). Foreword. In S. E. Breuning & A. D. Poling (Eds.), Drugs and menral retanlation (pp. vii-x). Springfield k Charles C. Thomas. Vanden Boore, R., Vermote, R., Buttiens, M., Thiry. P., Dierick, G., Geutjens, J., Sieben, G., & Heylen, S. (1993). Risperidone as add-on therapy in behavioural disturbances in mental retardation: A double-blind placebo-controlled cross-over study. Acra Psychiarrica Scandinuvica, 87, 167- 171. Vaughan, M. E. (1985). Repeated acquisition in the analysis of rule-governed behavior. Journal of the Experimenral Analysis of Behavior, 44, 175-1 84. Warm, J. S., & Berch, D. B. (1985). Sustained attention in the mentally retarded The vigilance paradigm.In N. R. Ellis & N. W. Bray (Eds.),Internarional review ofresearch in menral refardotion (Vol. 13, pp. 1-41). New York Academic Press. Waters,J. M.. Hardy, P. M., & Cohen, M. S. (1987). Interactions of medication and programming: A clinical approach. In J. A. Mulick & R. F. Antonak (Eds.), Transitions in rnenral refardorion Vol. 2: Issues in therapeuric inrervenrion (pp. 211-234). Norwood. NJ: Ablex Publishing. Weny, J. S. (1978). Measures in pediatric psychopharmacology. In J. S. Weny (Ed.), Pediarricpsyc h o p h m c o l o g y : The use of behavior modifying drugs in children (pp. 29-36). New York: B~~erMazel. Weny, J. S. (1988). Conclusions. In M. G. Aman & N. N. Singh (Eds.),Psychophannucology of the developmenial disabilities (pp. 239-245). New York: Springer-Verlag. Weny. J. S., & Sprague, R. L. (1972). Psychopharmacology. In J. Wortis (Ed.),Mental retardation, (Vol. 4, pp. 63-79). New York: Grune & Saatton. Whalen, C. K.,& Henker, B. (1986). Group designs in applied psychopharmacology.In K. D. Gadow & A. Poling (Eds.),Advances in learning and behavioral disab s, Suppl. I Methodological issues in humon psychopharmacology (pp. 137-222). Greenwich, CT: JAI Press. Wittenborn, J. R. (1978). Behavioral toxicity in normal humans as a model for assessing behavioral toxicity in patients. In M. A. Lipton, A. DiMascio, & K. F. Killam (Eds.).Psychophannucology: A generarion of progress (pp. 791-796). New York: Raven Press. Wolfensberger, W., & Menolascino, F. (1968). Basic considerationsin evaluating ability of drugs to stimulate cognitive development in retardates. American Journal of Menral Deficiency, 73, 414-423. Wysocki, T., Fuqua, W., Davis, V. J.. & Breuning, S. E. (1981). Effects of thioridazine (Mellaril) on tihating delayed matching-to-sample performance of mentally retarded adults. American Journal of Menral Deficiency, 85,539-547. Zeaman, D., & House, B. J. (1963). The role of attention in retardate discrimination leaming. In N. R. Ellis (Ed.), Handbook of mental deficiency: Psychological rheory and research (pp. 159-223). New York: McGraw-Hill. Zygmont, D. M., Lazar, R. M., Dube, W. V., & McIlvane, W. J. (1992). Teaching arbitrary matching via sample stimulus-control shaping to young children and mentally retarded individuals: A methodological note. Journal of rhe Experimenral Analysis of Behavior, 57, 109-1 17.