GUALTIERI EFFICIENT ALLOCATION 1 EFFICIENT ALLOCATION OF ATTENTIONAL RESOURCES IN PATIENTS WITH ADHD: MATURATIONAL CHANGES FROM AGE 10 TO 29 C Thomas Gualtieri MD

BACKGROUND: It is has been proposed that the neurocognitive basis of Attention DeficitHyperactivity Disorder (ADHD) resides in the executive control functions (ECF). One aspect of the study of ECF in ADHD individuals that has received little attention, however, is the evolution of ECF with maturation. METHOD: A naturalistic, cross-sectional study of ADHD patients compared to normal controls on a computerized neurocognitive test battery, CNS Vital Signs. SUBJECTS: 175 patients with ADHD, medication free, age 10-29, evaluated at the North Carolina Neuropsychiatry Clinics, compared to 175 age-matched normal controls, RESULTS: ADHD patients were impaired, relative to normal controls, in measures of psychomotor speed, reaction time, cognitive flexibility and attention. Test score improvement was correlated with age in normals in all of the tests in the neurocognitive battery. The same was true in ADHD patients for most tests, but not for tests of ECF, the Stroop test and the shifting attention test. In the shifting attention test, performance of normals and ADHD patients improved with age. Normals, however, improved their performance with shorter reaction times. ADHD patients improved their performance, but by adopting a less efficient strategy: their reaction times increased with age. CONCLUSIONS: These data support ECF as a “core deficit” in ADHD. In the Stroop and the shifting attention tests, ADHD patients proved to be inefficient in allocating their attentional resources. BACKGROUND: It has been proposed that Attention Deficit-Hyperactivity Disorder (ADHD) is an executive control disorder. Little is known, however, about the maturation of executive control in ADHD. METHOD: A cross-sectional study of ADHD patients compared to normal controls tested on a computerized neurocognitive test battery. SUBJECTS: 175 patients with ADHD, age 10-29, compared to 175 age-matched normal controls, RESULTS: In every age group, ADHD patients were impaired in measures of psychomotor speed, reaction time, cognitive flexibility and attention. Subjects in both groups improved with age. In tests of executive control, normals improved their performance with shorter reaction times. ADHD patients improved their performance, but by adopting a less efficient strategy: their reaction times increased with age. CONCLUSIONS: These data support executive control as a “core deficit” in ADHD. In the Stroop and the shifting attention tests, ADHD patients proved to be inefficient in allocating their attentional resources. GUALTIERI EFFICIENT ALLOCATION 3 ACKNOWLEDGEMENTS, DISCLOSURES Drs Gualtieri and Johnson are two of the developers of the CNS Vital Signs screening battery, and are shareholders in CNS Vital Signs LLC. Dr Gualtieri has conducted clinical trials on behalf of Astra-Zeneca, Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Glaxo-Smith-Kline, Medeva, Organon, Shire, Wyeth-Ayerst, and UCB. He has been a speaker for and/or consultant to Eli Lilly, GSK, Pfizer, Shire and Wyeth. This research was supported by North Carolina Neuropsychiatry, PA, in Chapel Hill and Charlotte. No external support was sought or received on behalf of this research. EFFICIENT ALLOCATION OF ATTENTIONAL RESOURCES IN PATIENTS WITH ADHD: MATURATIONAL CHANGES FROM AGE 10 TO 29 It is reasonable to assume that the pathology of Attention Deficit/Hyperactivity Disorder (ADHD) is related to an underlying neuropsychological deficit, and this assumption has driven a great deal of productive research in recent years. One assumes, as well, that understanding the nature of such deficits will help clinicians to understand patients who have the disorder. At one time, problems with sustained attention were thought to be central to ADHD. That belief is not only implied by the name, but also operationalized in the commercial popularity of tests for the disorder, like the TOVA and the Continuous Performance Test (CPT), that measure sustained attention. The primacy of sustained attention, however, has been gradually supplanted by a broader conception of the disorder: that the neurocognitive basis of ADHD is more diffuse, and resides in the broader domains of attentional and executive control functions (ECF). The limitations of a unitary attentional model of ADHD are manifest. Impairment of sustained attention is not limited to ADHD. It seems to be common to all of the psychiatric disorders of childhood and adolescence, including anxiety and depression (Swaab-Barneveld et al., 2000). Patients with ADHD actually do better than normals in certain types of attention tasks (Koschack, Kunert, Derichs, Weniger, & Irle, 2003), and different subgroups of ADHD children are characterized by different attention profiles (Zalsman et al., 2003). In ADHD, various components of attention may be impaired, including the ability to focus upon or to “engage” a stimulus, the ability to encode stimulus properties, and the ability to disengage from a stimulus and shift one’s focus in an appropriate manner (Seidman, Biederman, Monuteaux, Doyle, & Faraone, 2001; Stearns, Dunham, McIntosh, & Dean, 2004). These particular components of the attentional system are closely integrated with the broader cognitive domain of executive control. GUALTIERI EFFICIENT ALLOCATION 4 Executive control functions (ECF) refer to the capacity for autonomous behavior beyond the structure of external guidance. In clinical terms, this refers to initiative, motivation, spontaneity, planning, judgment, insight, goal-directed behavior, the ability to operate in favor of a remote or an abstract reward, the capacity for self-monitoring and the flexibility required for selfcorrection. The executive functions are activity-related behaviors that are necessary for appropriate, socially responsible and self-serving adult conduct. In the clinical literature concerned with deficits in executive behavior, lesions of the frontal lobes are most commonly implicated, although other cortical and subcortical structures may also be involved (Lezak, 1983; Gualtieri, 2002). As it happens, frontal lobe patients also have significant deficits in sustained attention. They are easily distracted by irrelevant stimuli, or they may be distracted by an immediate stimulus from the more important requirements of a remote goal. Deficits in sustained attention, however, are only one component of the frontal lobe syndrome. ECF’s are measured by special tests. The Stroop test, for example, is a test of cognitive flexibility, where appropriate responding entails the inhibition of an habitual response and the activation of an unaccustomed response. The Wisconsin Card Sort test and Halstead Categories measure “set-shifting,” or one’s ability to change cognitive sets quickly and accurately. ADHD patients, like patients with frontal lobe lesions, perform poorly on these tests (Homack & Riccio, 2004; Bedard, Ickowicz, & Tannock, 2002; Romine et al., 2004). “Dual task" or “shifting attention” tests are also difficult for ADHD patients, just as they are for patients with frontal lobe lesions (Mehta, Goodyer, & Sahakian, 2004; McLean et al., 2004). Shifting attention tests require the patient to respond to different stimuli with different response patterns. They test the patient’s ability to allocate their attentional resources efficiently in response to changing demands. Perseveration and distractibility are two symptoms of the failure to focus one’s attention appropriately in response to environmental demands. If a shifting attention test is administered by computer, it is possible to record patients’ reaction time. A slower reaction time indicates difficulty with shifting sets. Brain injury patients have slower reaction times on such tasks (Gualtieri & Johnson, 2004); and, as we shall see, so do patients with ADHD. Barkley has proposed that the “core deficit” of ADHD is in one particular aspect of selfregulation, inhibitory control. According to this view, people with ADHD are impaired in (1) their ability to inhibit a “prepotent” response to an event; (2) their ability to interrupt an ongoing response; and (3) their ability to withstand disruptions from competing events (Barkley, 1997b). In order to perform at a comparable level to normal people, the ADHD patient has to trigger inhibitory processes earlier and more strongly than controls (Smith, Johnstone, & Barry, 2004). Others have emphasized the regulation of response execution processes, and have suggested that ADHD cannot be fully explained by an inhibition-specific deficit (Banaschewski et al., 2004; Scheres et al., 2004). In fact, the supposition of a “core deficit” in ADHD is arguable. There are many components of attention and executive function, and it is possible that impairments in one, or several, of the components may be impaired in individuals with ADHD. This would account for the well-known heterogeneity of the syndrome. Factor analysis of neurocognitive test performance in a large group of young children with ADHD has suggested multiple early-appearing neurodevelopmental bases for ADHD (Sonuga-Barke, 2003). Whether or not inhibitory control is the “core deficit” in ADHD, the evidence in support of ECF as central to the condition has had broad support. Studies using different measures of ECF have indicated executive dysfunction in the family members of ADHD children (Crosbie & Schachar, 2001; Sonuga-Barke, 2003). ECF deficits are associated with poor outcome in patients with ADHD, including academic failure (Biederman et al., 2004) and drug use in adolescence ((Aytaclar, Tarter, Kirisci, & Lu, 1999)). Although functional neuroimaging studies have been somewhat variable in their findings, there is consistency in their demonstration of abnormalities (or at least, slight deviations from normal) in the prefrontal cortex and the striatum, consistent with the primacy given to the broad domains of attention and executive function (Castellanos, 1997; Schulz et al., 2004). Functional MRI studies, for example, have indicated abnormal frontal-striatal activation in ADHD children on GUALTIERI EFFICIENT ALLOCATION 5 tests of cognitive inhibition (Vaidya et al., 1998). Underactivation in frontal regions during shifting attention tests suggest a core deficit in ADHD (Tamm, Menon, Ringel, & Reiss, 2004). One aspect of the study of ECF in ADHD individuals has received little attention, however. That is the evolution of ECF with maturation. Patients’ performance on neuropsychological tests like the Stroop test and tests of shifting attention are not static. They change as individuals mature, and then they change again as they age. For virtually every measure of ECF, performance improves dramatically from childhood through adolescence, and achieves an optimal level in early adult life (see below). In order to develop this point, we took advantage of a large database of cognitive data in children, adolescents and young adults with ADHD. The cognitive data included a wide range of cognitive domains, but our particular interest was performance on tests of ECF, the Stroop test and the shifting attention test. The specific question was how ECF’s change with maturation. If meaningful changes do occur (and we believe we have demonstrated that they do), how does that affect our understanding of the condition, and, more important, how does it improve our appreciation of the problems ADHD individuals face as they grow up? MATERIALS & METHODS This was a naturalistic, cross-sectional study of 175 ADHD patients compared to 175 normal controls who were tested with a computerized neurocognitive assessment battery. SUBJECTS The patients were 175 people with ADHD, age 10-29, evaluated at the North Carolina Neuropsychiatry Clinics. The diagnoses were conferred by experienced clinicians, according to DSM-IVr criteria, and reviewed by a senior psychiatrist. For all the subjects, ADHD was the primary diagnosis. Patients with comorbid disorders were excluded. As part of their diagnostic evaluation, the patients were administered a computerized battery of tests, CNS Vital Signs. All of the patients were drug-free at the time of evaluation. Patients’ performance was compared to that of 175 age-matched normal controls who had also taken the CNS Vital Signs battery. The normal controls had participated in standardizing the normative database for the computerized battery. The patients and the normal controls were all in good health, and taking no concomitant medications. To illustrate the point that performance on the Shifting Attention Test changes with aging, we have drawn from data on normal individuals in the CNS Vital Signs Database, N = 556, age 889. “Normals” are people who are free of current or past neurological, developmental or psychiatric disorders, and who are taking no centrally-active medications. COGNITIVE EVALUATION Patient’s neurocognitive performance was measured on a computerized battery of tests, “CNS Vital Signs” (CNSVS). CNSVS is a PC-based neurocognitive screening battery, comprised of seven familiar neuropsychological tests: verbal and visual memory (VBM, VIM), finger tapping (FTT), symbol-digit coding (SDC), the Stroop test (ST), the shifting attention test (SAT) and the continuous performance test (CPT). The test battery is self-administered in the clinic on an ordinary PC, and takes about 30 minutes. The tests in the “Vital Signs” battery are highly reliable (test-retest, r = 0.63-0.88) (Gualtieri, Johnson, & Benedict, 2004b). Normative data from 556 normal subjects, age 8-89, indicates typical performance differences by age and gender (Gualtieri, Johnson, & Benedict, 2004a). Concurrent validity was established in studies comparing the Vital Signs battery to conventional neuropsychological tests (Gualtieri, Johnson, & Bendict, 2004; Benedict & Benson, 2004). GUALTIERI EFFICIENT ALLOCATION 6 THE VITAL SIGNS SHIFTING ATTENTION TEST (SAT) The special focus of this report is the SAT, a test of the subject’s ability to shift sets quickly and accurately. Three figures appear on the screen, one on top and two on the bottom. The top figure is either a square or a circle. The bottom figures are a square and a circle. The figures are either red or blue; the colors are mixed randomly. The subject is asked to match one of the bottom figures to the top figure. But the rules change at random. For one presentation, the subject has to match the figures by shape; for another, by color. This goes on for 90 seconds. Scoring is correct responses, errors and average reaction time for all responses. “Number correct” is how many stimuli the subject was able to match correctly in 90 seconds. “Errors” are incorrect matches. Reaction time is measured for correct responses. The SAT has been standardized in 500 normal subjects age 8-89. The test was proven reliable in a test-retest study of 107 subjects: SAT correct responses, r = 0.73, errors = 0.63, reaction time, r = 0.80. GUALTIERI EFFICIENT ALLOCATION 7