Frontal Lobe Disinhibition in Attention Deficit Disorder

Transcription

1 Frontal Lobe Disinhibition in Attention Deficit Disorder Gordon J. Chelune, Ph.D. Cleveland Clinic Foundation William Ferguson, Ph.D. St. Joseph Hospital Richard Koon, M.D. West Virginia University Medical Center T. O. Dickey, M.D. Shawnee Hills MH/MR Center ABSTRACT: Comparison of the neuropsychological performances of ADD children and matched controls revealed a relatively circumscribed pattern of deficits on tests presumed to measure frontal lobe inhibitory control. Age trends were noted on several variables, suggesting a possible maturational lag in frontal lobe functioning among the ADD subjects. Physician ratings of medication response and fit with DSM-III criteria for ADD, along with Parent and Teacher Conners' ratings, were also related to the ADD children's neuropsychological test scores. The results are discussed in terms of the potential overlap of hyperactivity with disorders of disinhibition such as conduct disorder. Attention Deficit Disorder (ADD) has replaced the old "hyperkinetic reaction of childhood" disorder in the current DSM-III nosology, and is used to describe a group of school-age children who manifest signs of developmentally inappropriate inattention, impulsivity, and hyperactivity relative to their mental and chronological age. While there is evidence that clinicians are in general agreement as to the key behavioral elements of ADD, 1 the underlying neuroanatomical and/or neurophysiological mechanisms of the disorder remain uncleary Early studies focusing on the hyperkinetic aspect of ADD posited an underlying defect in CNS arousal systems. Laufer, Denhoff, and Solomons 3 suggested that hyperactivity resulted from cortical "overarousal" due to a diencephalic (thalamic and/or hypothalamic) deficit, Address Correspondence To: Gordon J. Chelune, Ph.D. Department of Psychiatry, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio Child Psychiatry and Human Development, Vol. 16(4), Summer Human Sciences Press 221

2 222 Child Psychiatry and Human Development whereas Wender 4 and Satterfield ~ proposed that the high levels of motor activity observed clinically were secondary to lower levels of RAS excitation. This latter hypothesis was especially attractive since it appeared to account for the paradoxical calming effect of amphetamine on the behavior of ADD children; that is, a calming effect would be expected since amphetamine acted to increase cortical arousal to a more optimal level. However, more recent studies by Rapoport and her colleagues 6,7 indicate that there is no particular response selectivity among ADD children as stimulants have a similar effect on normal children. With the recent shift in emphasis from the hyperkinetic to attentional component of ADD, the role of higher cortical inhibitory mechanisms have become of interest. Early on, Conners, Eisenberg, and Sharpe s observed that ADD children appeared to lack inhibitory capacity over their internal drives and responses to external stimuli. Dykman, Ackerman, Clements and Peters 9 also suggested that a defect in a hypothesized forebrain inhibitory system would account for ADD on the basis of deficient inhibition of reticular and diencephalic structures through its descending pathways. In reviewing the clinical and experimental literature on frontal lobe lesions, Mattes 1~ has drawn a striking parallel between frontal lobe dysfunction and the symptoms of ADD. While deficient frontal lobe functioning may not account for all forms of ADD or hyperactivity, the frontal lobe hypothesis does offer a parsimonous model for explaining many of the findings associated with ADD. The prefrontal regions of the frontal lobes have a rich network of reciprocal pathways with the reticular formation and diencephalic structures, 11 which regulate arousaw and the ability to suppress responses to task-irrelevant stimulij 3 Lesions of the prefrontal regions result in a breakdown of the regulation of goal-directed activity and modulation of impulsive responding. ~'14 Patients with such lesions have difficulty suppressing ongoing activities despite environmental feedback that they are no longer appropriate (perseveration) and demonstrate increased reactivity to extraneous stimuli (distractibility and impulsivity), which results in deficient goal-directed behavior. 1~,16,17,~s,~9 Hyperactivity/hyperreactivity is also often among the behavioral sequelae associated with frontal lobe lesionsj ~ Hyperactivity is thought to be the result of disturbed higher levels of cortical inhibition in the form of a failure of inhibition of inappropriate responses, disinhibition of inhibitory cortical reflexes, or an absence of inhibition of orienting responses that therefore become strongerj ~ Given the apparent similarity in the behavioral manifestations of

3 Gordon J. Chelune, et al. 223 ADD and adult patients with frontal lobe disorders, it is tempting to infer, by analogy, a common CNS origin. However, Fletcher and Taylor 22 astutely note that "similarity of behavior in the absence of independent assessment does not provide sufficient evidence of common origins" in children and adults (p. 46). Since clear CNS deviations have not been established in ADD, a different approach to "independent assessment" must be taken. One such approach is to examine the cognitive/behavioral correlates of the manifest disorder. 22 Although numerous studies using various psychological tests have established the presence of information processing deficits among ADD children despite normal performance of many standard psychometric tests} 3 Mattes 1~ notes that these studies have "generally not been interpreted from a neuropsychological perspective" (p. 365). Evaluation of the frontal lobe hypothesis of ADD from a neuropsychological perspective has been hindered in part by controversy as to when the behaviors attributed to frontal lobe functioning reach functional maturity. Luria 12 has suggested that the prefrontal regions do not begin to become prepared for action until the child is between the ages of 4 and 7, whereas Golden 24 has suggested the frontal regions do not become functionally mature until adolescence. Recent empirical studies 2~,~6 demonstrate that those behaviors, presumed to be dependent on frontal lobe functioning, develop rapidly from the age of 6 years and essentially reach adult levels of mastery between the ages of 10 and 12. The issue of developmental change is particularly relevant for understanding the nature of ADD since it is essentially defined as a disorder of maturation; that is, the cognitive and behavioral abilities of the ADD child are not seen as deviant, but rather as developmentally inappropriate for the child's chronological and mental age. The present study was designed to examine the similarities and differences in neuropsychological performance between a group of children diagnosed as ADD and a group of carefully matched controls. Of particular interest was whether the ADD children would differ from the controls in general or specifically on tests such as the Wisconsin Card Sorting Test, ~7 which has been extensively used in the evaluation of adult patients with frontal lobe lesions. Subjects Method The subjects (n = 48) consisted of 24 children diagnosed as ADD and 24 matched controls. The ADD subjects all met minimal DSM-III criteria for ADD

4 224 Child Psychiatry and Human Development as determined by their treating physicians. Parent and/or Teacher Conners' Rating Scales were available on 19 of the ADD children (16 having both), and the respective means were (range 12-28) and (range 15-30). These subjects were yoked with normal controls from the Chelune and Baer ~5 study such that both groups had identical mean ages of months and consisted of 17 males and 7 females. The two groups were also matched for both maternal and paternal educational backgrounds. All but one child was right-handed. Tests and Procedure All of the ADD children were medication free for at least 16 hours prior to testing, and all subjects were individually administered the following tests: 1. The Peabody Picture Vocabulary Test (PPVT) is a measure of receptive vocabulary designed to provide a global estimate of intelligence The Number Recall, Word Order, Gestalt Closure and Triangles subtests from the Kaufman Assessment Battery for Children (K.ABC) were administered to obtain estimates of the children's sequential and simultaneous processing abilities." The Kaufmans' speculate that tasks such as Number Recall and Word Order require sequential processing dependent on the anterior regions of the brain, whereas visual-perceptual tasks such as Gestalt Closure and Triangles require simultanous processing involving the posterior regions of the brain. To assess potential differences in processing styles, the sum of the two simultaneous tasks was subtracted from the sum of the two sequential tasks to yield a difference score. 3. The Wisconsin Card Sorting Test (WCST) is a measure of perseverative thinking and concept formation, and has been found to be especially useful in discriminating between frontal and nonfrontal brain lesions in adults. 27 The WCST uses stimulus and response cards that display figures varying in form, color, and number. The subject is instructed to sort a deck of response cards to match the stimulus cards, and is told whether s/he is correct or incorrect after each response. Although the subject is never told how to sort the cards, the object is to sort 10 cards to color, 10 to form, and 10 to number. To count as a success, the 10 cards must be sorted consecutively to the correct category, an interruption in the sequence results in a return to the criterion of 10 consecutive correct responses. Four basic scores can be derived: Total percent (%) Correct; number of correct Categories Achieved; number of Perseverative Errors, defined as a response that would have been correct during the previous category, and Failures to Maintain Set, defined as an interruption of the correct sorting strategy after either three consecutive correct unambiguous responses or after any five consecutive correct responses. 4. Progressive Figures and Color Forms 3~ are timed tasks requiring cognitive flexibility in a manner similar to the adult Trail Making Tests. Time and error are recorded for both tests. Physician Ratings To further assess the sensitivity of the neuropsychological tests to other relevant aspects of ADD, two psychiatrists independently reviewed the ADD children's charts and made ratings on 5-point scales for: 1) how well each child's

5 Gordon J. Chelune, et al. 225 clinical presentation fit with DSM-III criteria; and 2) response to medication. Ratings for DSM-III fit ranged from (1) child superficially meets DSM-III criteria for ADD but there are complicating circumstances--chaotic family environment, medical history, or other psychiatric disorders, to (5) child's clinical presentation is classic manifestation of ADD and there are no extenuating circumstances. Ratings of medication response went from (1) behavior and/or attention slightly worse, to (5) great improvment (behavior improved and problems eliminated). For the purpose of data analysis, the physicians' ratings were pooled, and reliability ~1 for the pooled DSM-III ratings was.71 and that for the medication response ratings was.75. Group Comparisons Results The means and standard deviations for the ADD and control groups are presented in Table 1. To determine the potential effects of group and age differences on our measures of cognitive functioning, the subjects were divided into three groups: 6-7 year olds (n = 14); 8-9 year olds (n = 16); and year olds (n = 18). Separate Group X Age ANOVAs were then computed for each test variable. Of the six measures of general intelligence and mental processing (PPVT and K.ABC), only the Number Recall subtest of the K.ABC revealed a significant Group effect, F(1,42) = 8.78, p <.005, and no Age or Group by Age effects were noted. For the Progressive Figures and Color Forms tests, significant Age effects were observed for both Time components; F(2,42) = 3.72, p<.04 and F(2,42)= 4.07, p<.03, respectively. However, the only significant Group effect was for Color Forms Errors, F(1,42) = 5.12, p <.03. No interactions were significant. In contrast to the above tests, significant Group and Age main effects were found for three of the four WCST variables: Categories Achieved, Perseverative Errors, and %Correct. The Group by Age means for these variables are depicted in Figure 1. Across all age levels, controls had more Categories Achieved (p <.025), fewer Perseverative Errors (p <.01), and had a higher %Correct (p <.008), than the ADD children. Also, for all subjects, performance increased with Age on Categories Achieved (p <.008), Perseverative Errors (p <.004), and %Correct (p <.009). However, no Group X Age interactions were significant, indicating that while there were group differences in level of performance, both ADD and normal children became more proficient in meeting the task demands of the WCST with age. It is interesting to

6 226 Child Psychiatry and Human Development Table 1 Means and Standard Deviations for the ADD and Control Groups Test ADD Controls M SD M SD Measure.... PPVT IQ KABC-- Number Recall Word order i Triangles 10, , Gestalt Closure Sequential-Simultaneous Progressive Figures-- Time Errors Color Forms -- Time Errors , WCST-- %Correct ,12 -- Categories Achieved 3, Perseverative Errors Failures to Maintain Set note that the performance levels of the older ADD groups tend to parallel those of the control groups two years their junior; that is, the performance of the 8-9 and year old ADD groups are comparable to the 6-7 and 8-9 year old control groups. Although we had attempted to represent both sexes as equally as possible in our ADD sample, boys outnumbered girls nearly 3:1. Still, we were interested in whether there were any sex differences in cognitive functioning between the ADD and control groups, and separate Group X Sex ANOVAs were computed for each test variable. These analyses yielded no significant main effects for Sex or Group X Sex interactions. Thus, all further analyses were collapsed across sex.

7 Gordon J. Chelune, et al t~ 0 > LM ADULT ~/0 5O C O ~ j o ~n- 40 e~ (~ 9 Controls 0 ADD t t g,i 80 7O on MJ 0 3 W k- 2 s w t > t V- 6,~ 9 Controls =~ 0 ADD 3O t t i t I 10 CONTROLS I I I 1 I I I I I O o 6O I,- Z I,M O ~ I I' I I I / I d 9 Controls 0 ADD AGE GROUPS AGE GROUPS AGE GROUPS Figure 1. Mean Wisconsin Card Sorting Test scores for the ADD and Control subjects across three age levels. Discriminant Function Analysis Our preliminary analyses demonstrate that there are some group differences between ADD and matched control children in terms of their cognitive functioning, most notably on the WCST, with the ADD children performing less well than the controls. To further evaluate these differences, a stepwise discriminant function analysis was computed. The resulting analysis used six test variables, and yielded a cannonical correlation of.62 with an equivalent F(6,41)= 4.30, p<.002. The final order of variables in this multivariate linear equation were: WCST Persevarative Errors and Failures to Maintain Set, Color Forms Time and Errors, and K.ABC Number Recall and Gestalt Closure. Examination of the classification table reveals that 21/24 controls and 20/24 ADD subjects were correcly classified, resulting in an overall correct classification rate of 85.4%. DSM-III and Medication Response Ratings The results of the discriminant analysis indicate that a multivariate discriminant function equation (DFEQ) composed of select neuropsychological variables can discriminate ADD children from normal con-

8 228 Child Psychiatry and Human Development trols with a reasonably high degree of accuracy. The next question we addressed was whether the scores produced by this DFEQ could be used to predict the physicians' ratings of the ADD children's fit with DSM-III criteria and their response to medication, which were found to be essentially unrelated to one another (r =.13). Modest correlations were observed between ratings of DSM-III fit and Age (r= -.41), the PPVT (r= -.30), Progressive Figures Time (r = -.31), and K.ABC Word Order (r =-.37); however, the ADD children's DFEQ scores were basically unrelated to DSM-III fit (r =.12). In contrast, the medication response ratings were modestly correlated with DFEQ scores (r =.32), and had moderate loadings on the WCST %Correct (r =.53), Perseverative Errors (r = -.62), Categories Achieved (r =.52) scores, and Color Forms Time (r = -.53). It is interesting to note that the direction of these correlations indicate that those ADD children who performed most like normal controls while off medication were the same ones who were rated as having the best responses to stimulant medication. Parent and Teacher Conners" Ratings Parent and Teacher Conners' ratings were unrelated in the present sample of ADD children (r =.03), and had very different patterns of association with the physicians' ratings and neuropsychological test scores. While Parent Conners' ratings were modestly correlated with Age (r = -.31), they had little association with neuropsychological test performance. However, the Parent ratings were positively correlated with the medication response ratings (r =.45), suggesting that those children perceived as most disruptive by their parents were apt to be rated as having the best responses to medication by the physicians. In contrast, Teacher ratings were inversely correlated with the medication response ratings (r ), the DFEQ scores (r = -.42), and performance on the WCST measures (range -.41 to -.56). Children with poor conceptual and inhibitory skills and perseverative tendencies were rated as being most disruptive by their teachers. These children were also rated as being least apt to manifest a positive response to stimulant medication. It is clear from these data that parents and teachers were either using different criteria in making their Conners' ratings and/or that the children's behavior was quite different in the home and school environments. In any event, the teachers' ratings appear to have been made on the basis of observed behaviors similar to

9 Gordon J. Chelune, et al. 229 those assessed by the WCST, which are also inversely related to perceived benefit from stimulant medication. Discussion The results of the present study provide partial support for the frontal lobe dysfunction hypothesis of ADD, and also raise some interesting questions regarding the specificity of ADD as a diagnostic entity. Consistent with the thesis put forth by Mattes, TM the ADD children in this study revealed a relatively distinct and circumscribed pattern of cognitive/behavioral deficits. Compared to their age-matched controls, the ADD children did not differ on most measures of general intelligence or mental processing, but were impaired relative to the controls on tasks requiring sustained attention, cognitive flexibility and regulation of goal-directed activity through the use of environmental feedback. Particularly notable were the ADD children's perseverativeness and apparent decreased responsivity to reinforcement in guiding their problem solving behaviors on the WCST, behaviors thought to be mediated, in part, by the frontal lobes, 1~ When taken in linear combination, these variables were able to corectly classify 85.4% of the children, and suggests that ADD children may, in fact, have an underlying dysfunction of the inhibitory forebrain system controlling attentional processes in response to situational demands22 Although it had also been hypothesized that the ADD children would show a significant discrepancy between their sequential and simultaneous processing skills on the K.ABC as a function of their presumed frontal lobe dysfunction, the results revealed no differences compared to the controls. This negative result may be interpreted as failing to support the frontal lobe hypothesis of ADD. Alternately, it m~y be argued that the K.ABC does not adequately assess the sequential and simultaneous processing dimensions originally proposed by Das and his colleagues. 33 In fact, in reviewing the literature on the K.ABC, Das 34 has recently commented that "it [the K.ABC] does not measure sequential processes adequately, and its test items for simultaneous and sequential processes can be also characterized respectively as nonverbal and verbal" (p. 229). Thus, ADD children may show diminished sequential versus simultaneous cognitive competencies, but the K.ABC may not provide an adequate test of this discrepancy.

10 230 Child Psychiatry and Human Development The data from the present study also bear on the question of whether the cognitive deficits associated with ADD are primary impairments or related to a maturational lag. Although not unchallenged, 35 ADD is generally viewed as a maturational lag. This hypothesis is derived from the clinical observations that ADD children appear to behave younger than their peers and that some aspects of the disorder diminish or disappear with increasing age. ~ Satterfield and Braley 36 have Gffered electrophysiological data supporting the view that arousal levels in ADD children with hyperactivity tend to become normalized with age. Similarly, Rapoport and Ferguson 37 note that "at the complex level of cortical evoked potentials, the difference between hyperactive and normal children looks as though it could be attributable to variations in maturational rate" (p. 673). The data from the WCST in the present study lend further evidence of a cognitive nature to the view of ADD as a maturational lag. While there were significant group differences between the ADD and control children, both groups showed age-related changes. Inspection of the data suggests that ADD children make appropriate maturational gains on the WCST, but at a level approximately two years behind their age-matched cohorts. Additional research across a broader age range is needed to strengthen this observation and to determine whether ADD children eventually "catch-up" and achieve normal adult levels of performance on the WCST. Examination of the relationships between the neuropsychological test scores and the physicians' ratings of the ADD children's fit with DSM-III criteria and their response to medication revealed some unexpected findings. Perceived fit with DSM-III criteria for ADD was essentially unrelated to the children's neuropsychological functioning. On the other hand, the physicians' ratings of response to medication were signficantly correlated with the children's cognitive functioning, particularly on the WCST, with the relative absence of Perseverative Errors on the WCST being the single best predictor (r = -.62) of a positive medication response. Scores from the multivariate discriminant function equation (DFEQ) that maximally separated the ADD children from controls also were positively related to medication response, indicating that those ADD children with the least amount of cognitive impairment (i.e., most like the controls) were the ones most apt to have a good response to medication. This relationship is inconsistent with the findings of Millichap and Johnson 3s who reported a positive relationship between drug response and neurological signs and activity levels in both hyperactive children and animals with surgicallyinduced prefrontal lesions.

11 Gordon J. Chelune, et al. 231 Analysis of the Parent and Teacher Conners' Rating scales also produced some surprising results. Parental ratings of hyperactivity were unrelated to test performance, but positively correlated with the physicians' ratings of medication response (r =.45). However, an opposite pattern of relationships emerged from an analysis of the teachers' ratings. Teacher ratings of hyperactivity were inversely related to medication response (r ) and the cognitive dimension (DFEQ) that separated the ADD children from controls (r = -.42). That is, those ADD children who were seen as most disruptive by their teachers were the ones least likely to be perceived as having a good medication response and were most apt to show cognitive impairment on the neuropsychological tests, especially the WCST. While it is clear that the parents and teachers must have used different criteria in making their respective Conners' Ratings, the nature and meaning of this difference within the context of our data is not easy to discern. It could be argued that teachers have a restricted view of a child's behavior within a specific situation, whereas parents know how their child behaves across a broader range of situations. Thus, differences in Conners' Ratings may reflect differences between situational and pervasive hyperactivity29 However, this argument breaks down when one considers that it is the pervasively hyperactive child that typically show the greatest amount of cognitive impairment and neurological immaturity. 4~ If the parents were more sensitive to the pervasive aspects of their children's behavior, their ratings, rather than those of the teachers, should have correlated with neuropsychological test performance. A better possible explanation of the observed data emerges if one considers the underlying factor structure of the Connors' scales. Although these scales were originally devised as measures of hyperactivity, they correlate highly with both hyperactivity and conduct disorder. 41 Furthermore, they have been criticized as relatively poor measures of attention as defined by DSM-III. 42 Since disorders of social conduct in both children ~3 and adults 17 have been conceptualized as manifestations of disinhibition related to frontal lobe dysfunction~ it may be that the WCST is actually assessing disinhibition rather than hyperactivity or attentional deficits. If this is the case, then one would expect a better medication response among children with purely hyperkinetic/attention problems ~8,~ than the hyperkinetic/attention deficit child with problems of disinhibition. 2,",~8 Symptoms of disinhibition (perseverativeness) would also be expected to be most salient in situations with high cognitive demands, such as the academic

12 232 Child Psychiatry and Human Development environment. Thus, the Conners' Ratings of teachers would be more sensitive than those of parents to symptoms of disinhibition, a behavioral dimension that would not be expected to be responsive to stimulant medication. In order to directly test the potential confounding effect of disinhibition among children diagnosed as ADD, these findings need to be replicated among groups of ADD children with and without histories of significant behavior problems. In summary, the results of the present study provide partial support for the frontal lobe dysfunction thesis of ADD. Children diagnosed as ADD were found to have a relatively circumscribed pattern of neuropsychological deficits on tests presumed to measure frontal lobe functioning, and a multivariate weighing of these tests yielded an 85.4% correct discrimination rate between ADD children and age-matched controls. The ADD children's discriminant scores were not correlated with the physicians' ratings of degree of fit with DSM-III criteria, but they were positively associated with medication response ratings; that is, positive medication responses were correlated with the absence of neuropsychological deficit. The relative absence of perseverative tendencies on a card sorting task was the single best predictor of a good medication response ( -.62) among the ADD children. The nature of this apparent "frontal lobe deficit" is not entirely clear, however. Parent Conners' ratings were positively correlated (.45) with medication response but not with neuropsychological performance, whereas Teacher Conners' ratings were inversely related to medication response ( -.64) and neuropsychological functioning ( -.42). These data suggest that the cognitive/behavioral dimension assessed by the neuropsychological tests is nonresponsive to medication, and probably reflects disinhibition rather than hyperactivity or attentional problems. Thus, the neuropsychological tests may be assessing a cognitive/behavioral dimension that is different from, but coexisting with ADD symptomology, namely conduct disorder. To the degree that ADD overlaps with conduct disorder, the results of the present study suggest that greater emphasis be placed on identifying symptoms of disinhibition as well as those of hyperactivity and attentional deficits when assessing the likelihood of a child having a positive response to stimulant medication. References 1. Ullman DG, Egan D, Fielder N, et al.: The many faces of hyperactivity: Similarities and differences in politics. J Consult Clin Psycho149: , 1981.

13 Gordon J. Chelune, et al Trites RL, Laprade L: Evidence for an independent syndrome of hyperactivity. J Child Psychol Psychiat 24: , Laufer MW, Denhoff EH, Solomons GT: Hyperkinetic impulse disorder in children's behavior problems. Psychosom Med 19: 38-49, Wender PH: MinimalBrainDysfunction in Children. New York, Wiley-Interscience, Satterfield JH: Neurophysiologic studies with hyperactive children, in The Hyperactive Child, Cantwell DP (Ed.). New York, Spectrum, Rapoport JL, Buchsbaum MS, Weingartner H, et al.: Dextroamphetamine: Cognitive and behavioral effects in normal and hyperactive boys and normal men. Arch Gen Psychiatry 37: , Rapoport JL, Buchsbaum MS, Zahn TP, et al.: Dextroamphetamine: Cognitive and behavioral effects in normal and prepubertal boys. Science 199: , Conners CK, Eisenberg L, Sharpe L: Effects of methylphenidate (Ritalin) on pairedassociate learning and Porteus Maze performance in emotionally disturbed children. J ConsultPsycho128: 14-22, Dykman RA, Ackerman PT, Clements SD, et al.: Specific learning difficulties: An attentional deficit syndrome, in Progress in Learning Disabilities (Vol. 2), Myklebust HR (Ed.). New York, Grune & Stratton, Mattes JA: The role of frontal lobe dysfunction in childhood hyperkinesis. Compr Psychiatry 21: , Fuster JM: The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal Lobe. New York, Raven, Luria AR: The Working Brain. New York, Basic Books, Grueninger W, Grueninger J: The primate frontal cortex and allassostasis, in Psychophysiology of the Frontal Lobe, Pribram KH and Luria AR (Eds). New York, Academic Press, Numan R: Cortical-limbic mechanisms and response control: A theoretical review. Physiol Psychol 6: , Benson DF, Stuss DT: Motor abilities after frontal leukotomy. Neurology 32: , Drewe EA: Go-no go learning after frontal lobe lesions in humans. Cortex 11: 8-16, Gorenstein EE: Frontal lobe functions in psychopaths. J Abnorm Psychol 91: , Milner B: Effects of different brain lesions on card sorting. Arch Neurol 9: , Petrides M, Milner B: Deficits on subject-ordered tasks after frontal and temporal lobe lesions in man. Neuropsychologia 20: , Hecaen H, Albert ML: Human Neuropsychology. New York, Wiley. 21. Konorski J: Integrative Activity of the Brain: An Interdisciplinary Approach. Chicago, University of Chicago Press, Fletcher JM, Taylor HG: Neuropsychological approaches to children: Towards a developmental neuropsychology. J Clin Neuropsychol 6: 39-56, Rosenthal RH, Allen TW: An examination of attention, arousal, and learning dysfunction of hyperkinetic children. Psychol Bull 85: , Golden, CJ: The Luria-Nebraska Children's Battery: Theory and formulation, in Neuropsychological Assessment of the School Aged Child, Hynd GW and Obrzut JE (Eds.). New York, Grune & Stratton, Chelune GJ, Baer RA: Developmental norms for the Wisconsin Card Sorting Test. J Clin Exp Neuropsychol, in press. 26. Passler MA, Isaac W, Hynd GW: Neuropsychological development of behavior attributed to frontal lobe functioning in children. Dev Neuropsychol, 1, , Heaton RK: The Wisconsin Card Sorting Test Manual. Odessa, FL, Psychological Assessment Resources, 1981.

14 234 Child Psychiatry and Human Development 28. Dunn LM, Dunn LM: Peabody Picture Vocabulary Test-Revised Manual. Circle Pines, MN, American Guidance Service, Kaufman AS, Kaufman NL: Kaufman Assessment Battery for Children Interpretative Manual. Circle Pines, MN, American Guidance Service, Reitan RM, Davison LA: Clinical Neuropsychology: Current Status and Applications. New York, Wiley, Horowitz LM, Inouye D, Siegleman EY: On averaging judges' ratings to increase their correlation with an external criterion. J Consult Clin Psychol 47: , Alabiso F: Inhibitory functions of attention in reducing hyperactive behavior. AmJ Ment Defic 77: Das JP, Kirby J, Jarman RF: Simultaneous and successive syntheses: An alternative model for cognitive abilities. Psychol Bull 82: , Das JP: Simultaneous and successive processes and K-ABC. J Special Educ 18: , Calloway E, Halliday R, Naylor H: Hyperactive children's event-related potentials fail to support underarousal and maturational-lag theories. Arch Gen Psychiatry 40: , Satterfield JH, Braley BW: Evoked potentials and brain maturation in hyperactive and normal children. Electroencephalogr Clin Neurophysio143: 43-51, Rapoport JL, Ferguson HB: Biological validation of the hyperkinetic syndrome. Dev Med Child Neuro123: , Millichap JG, Johnson FH: Methylphenidate in hyperkinetic behavior: Relation of response to degree of activity and brain damage. Exerpta Medica 313: , Schachar R, Rutter M, Smith A: The characteristics of situationally and pervasively hyperactive children: Implications for syndrome definition. J Child Psychol Psychiat 22: , Cohn NJ, Minde K: The 'hyperactive syndrome' in kindergarten children: Comparison of children with pervasive and situational symptoms. J Child Psychol Psychiat 24: , Loney J, Milich RS: Hyperactivity, inattention, and aggression in clinical practice, in Advances in Behavioral Pediatrics (Vol. 2), Wolraich M and Routh DK (Eds.). Greenwich, CT, JAI Press, Ross DM, Ross SA: Hyperativity: Current Issues, Research, and Theory. New York, Wiley, Ponitus AA, Ruttigier, KF: Frontal lobe system maturational lag in juvenile delinquents shown in Narratives Test. Adolescence 44: , Dykman RA, Ackerman PT, McCray DS: Effects of methylphenidate on selective and sustained attention in hyperactive, reading disabled, and presumably attentiondisordered boys. J Nerv Ment Dis 168: , Loney J, Kramer J, Milich R: The hyperactive child grows up: Predictors of symptoms, delinquency, and achievement at follow-up, in Psychosocial Aspects of Drug Treatment for Hyperactivity, Gadow KD and Loney J (Eds.). Boulder, CO, Westview Press, McGee R, Williams S, Silva PA: Behavioral and developmental characteristics of aggressive, hyperactive, and aggressive-hyperactive boys. J Am Acad Child Psychiatry 23: , 1984.