Journal of Attention Disorders Medications Do Not Necessarily Normalize Cognition in ADHD Patients
Lynda G. JohnsonNorth Carolina Neuropsychiatry Clinics, Chapel Hill and CharlotteObjective: Although ADHD medications are effective for the behavioral components of the disorder, little information exists concerning their effects on cognition, especially in community samples. Method: A cross-sectional study of ADHD patients treated with three different ADHD drugs was conducted. Patients’ performance on a computerized neurocognitive screening battery was compared to untreated ADHD patients and normal controls (NML). A total of 177 ADHD patients aged 10–18, achieved a favorable response to one of the following medications: Adderall XR (AMP), atomoxetine (ATMX), and Concerta (MPH-OROS) compared to 95 untreated ADHD patients and 101 NML. Results: Significant differences were detected between normals and untreated ADHD patients. Treated patients performed better than untreated patients but remained significantly impaired compared to normal subjects. Conclusion: Even with optimal treatment, based on parents’ and teachers’ opinions, subtle and not-so-subtle neurocognitive impairments persisted in the ADHD patients. Some ADHD patients may require additional educational assistance, even in the face of successful medication treatment. (J. of Att. Dis. 2007; XX(X) XX-XX) Keywords: ADHD; cognition; amphetamine; methylphenidate; atomoxetine
Psychostimulant drugs affect diverse cognitive func-
It has been suggested that neurocognitive testing has
tions, including executive function, reaction time,
predictive value in determining individual differences in
fine motor coordination, and various aspects of attention.
drug response (Mehta, Goodyer, & Sahakian, 2004),
Neuropsychological studies of ADHD children and
although studies have also shown that cognition may
adults indicate impairments in many cognitive areas:
improve in ADHD patients, excluding behavioral
selective attention (Brodeur & Pond, 2001); memory
improvement (Gimpel et al., 2005; Vance, Maruff, &
(Muir-Broaddus, Rosenstein, Medina, & Soderberg,
Barnett, 2003). Conversely, behavior may improve absent
2002; Roth et al., 2004); reaction time (Leth-Steensen,
detectable changes in cognition (Everett, Thomas, Cote,
Elbaz, & Douglas, 2000) and information processing
Levesque, & Michaud, 1991; Lufi, Parish-Plass, & Gai,
speed (Weiler, Bernstein, Bellinger, & Waber, 2000);
1997). Computerized tests of attention and vigilance
motor speed (Mitchell, Chavez, Baker, Guzman, &Azen, 1990) and visuomotor ability (Kalff et al., 2002);
Authors’ Note: Drs Gualtieri and Johnson are two of the developers
and executive control functions, such as set-shifting
of the CNS Vital Signs screening battery. Dr Gualtieri has conducted
(Cepeda, Cepeda, & Kramer, 2000), inhibitory control
clinical trials on behalf of Astra-Zeneca, Bristol-Myers Squibb,
(Schachar et al., 2002), and working memory (Barnett
Celltech, Cephalon, Eli Lilly, Glaxo-Smith-Kline, Medeva, Organon,
et al., 2001). It has never been established, however, that
Shire, Wyeth-Ayerst, and UCB. He has been a speaker for and/or con-
the cognitive effects of stimulant drugs are central to
sultant to Eli Lilly, GSK, Pfizer, Shire, and Wyeth. This research was
their therapeutic utility. In ADHD treatment, cognitive
supported by North Carolina Neuropsychiatry, PA, in Chapel Hill andCharlotte. No external support was sought or received on behalf of
and behavioral improvement are not necessarily dissoci-
this research. Address correspondence to Dr C. Thomas Gualtieri, NC
ated, but neither are they closely correlated (Konrad,
Neuropsychiatry, 400 Franklin Square, 1829 East Franklin Street,
Gunther, Hanisch, & Herpertz-Dahlmann, 2004).
Chapel Hill, NC 27514; e-mail: [email protected].
(Continuous Performance Tests [CPTs]), widely used in
examining the clinical status of all the ADHD patients in
the evaluation and treatment of ADHD, have been criti-
a particular locus at a point in time. The question we
cized for their low specificity and sensitivity (Lovejoy &
posed is, how effective are stimulant (and related) drugs
Rasmussen, 1990; Trommer, Hoeppner, Lorber, &
as they are used by practitioners in the real world, at least
Armstrong, 1988), and the correspondence between
impulsive errors on CPTs and behavioral impulsivity hasnot been established (Abikoff & Klein, 1992). When
Methods and Materials
used for assessment of medication efficacy, the applica-bility of results to the patient’s natural environment is
This was a cross-sectional descriptive study of clinic
unproven (Aman & Turbott, 1991; Cohen, Kelly, &
attendees, children, and adolescents to evaluate their
Atkinson, 1989) or even absent (Elia, Borcherding,
neurocognitive performance with respect to medication
Rapoport, & Keysor, 1991). CPTs are not consistently
treatment. The subjects had responded satisfactorily to
sensitive to stimulant effects (Fischer & Newby, 1998).
one of the three most frequently prescribed medications
When ADHD studies address the issue of cognition,
for ADHD in the United States: Adderall XR (AMP, four
the methods employed tend to demonstrate that treated
salts of d- and 1-amphetamine in an extended release
patients perform better than untreated patients on neu-
preparation), atomoxetine (ATMX), and Concerta
ropsychological tests or that patients improve on neu-
(MPH-OROS, methylphenidate isomers in an osmotic
ropsychological measures after they are treated
release capsule) compared to NML and to untreated
(Aggarwal & Lillystone, 2000; Gimpel et al., 2005). Few
studies, however, evaluate posttreatment performance inADHD patients relative to normal controls (NML). In1991, Everett et al. compared untreated ADHD children
Subjects
to NML on two tests of executive function, the Stroop
All of the ADHD patients at two neuropsychiatry clin-
Test (ST) and the Wisconsin Cart Sort. At baseline, the
ics (in Chapel Hill and Charlotte, NC) are administered
ADHD group was significantly impaired compared to
a computerized screening battery of cognitive tests as
normals. After a year of treatment, they improved on the
part of their initial evaluation and at appropriate intervals
Wisconsin but remained impaired on the ST (Everett
during follow-up. They are requested to allow the clinics
et al., 1991). In 1993, Risser and Bowers compared 10
to store their data in a central research database after it is
ADHD children on stimulant medication to normal
appropriately deidentified. The database includes basic
children on a number of cognitive measures, including
demographic data, diagnoses, medication status, and test
the Wechsler Developmental Index, the Bender Visual-
motor Gestalt Test, and the Benton Visual Retention Test.
The subjects of this investigation were children and
In spite of treatment, the ADHD children had persistent
adolescents with all types of ADHD. Initial diagnoses
neuropsychological deficits (Risser & Bowers, 1993). In
were made by treating clinicians on the basis of DSM-IV-
another study, stimulant treatment in ADHD children led
TR criteria, parent and teacher rating scales. Diagnoses
to improvement in simple but not choice reaction time
were reviewed by a second senior psychiatrist (T.G.) or
neuropsychologist (L.J.) prior to inclusion in the data-
We have only found one study that generated contrary
base and then again prior to inclusion in this study.
results. Barnett et al., using a computerized test (CogState),
Subjects were outpatients who had been treated with one
reported that 21 stimulant-treated ADHD children per-
of the three medications listed above, and the dose had
formed as well as NML on a spatial working memory
been titrated to an optimal clinical response. The Ss
task, whereas 27 untreated ADHD children performed
selected for this investigation had been on a stable dose
significantly worse (Barnett et al., 2001). The CogState
battery, however, captures data on several other cognitive
The patients were not randomly assigned to one drug
functions, and these were not reported in the article.
or another; rather, they themselves chose which medica-
The question we address here is not whether cognitive
tion to use. As a rule, newly diagnosed ADHD patients
and behavioral changes are correlated when ADHD
are given two prescriptions, one for AMP and one for
patients are treated with psychostimulant medications; it
MPH-OROS. Patients are instructed to take one drug for
is fairly well established that they are not. The question
2 weeks and to titrate to optimal dose, and then to try the
we pose is whether, in a community-treated sample of
other. The titration schedule for AMP would be 20 or 40
patients, successful treatment normalizes neurocognitive
mg qam and for MPH-OROS 18–36–54–72 mg qam.
performance. We employed a cross-sectional approach,
After 4 weeks, the patients return to the clinic and a
Gualtieri, Johnson / Medications Do Not Necessarily Normalize Cognition
and validity of the CNSVS battery have been published
Demographic Characteristics of the Five Groups
elsewhere (Gualtieri & Johnson, 2006d).
Verbal memory (VBM) and visual memory (VIM) are
adaptations of the Rey Auditory Verbal Learning Test
and the Rey Visual Design Learning Test (Rey, 1964;
Taylor, 1959). VBM and VIM are recognition tests, how-
ever, not tests of recall. Correct responses from VBM
and VIM are summed to generate a composite memory
The Finger Tapping Test (FTT) is one of the core tests
of the Halstead-Reitan Battery, but similar tests were
used by 19th century psychologists like Wundt, Galton,
and Cattell. Symbol digit coding (SDC) is based on the
Symbol Digit Modalities Test (SDMT) (Smith, 1982),
which is a variant of the Wechsler digit symbol substitu-
tion test (DSST). The total of right and left taps from the
FTT and total correct responses on the SDC generates a
composite score for psychomotor speed.
The ST in CNSVS has three parts that generate simple
Note: NML = normal controls; MPH-OROS = Concerta; ATMX =
and complex reaction times. Averaging the two complex
reaction time scores from the ST generates a domainscore for reaction time. It might be more precise to refer
decision is made on clinical grounds to continue on one
to this domain as information processing speed.
drug or another. After another month, they return to the
The Shifting Attention Test (SAT) measures the
clinic and are tested on what they (and their parents) con-
subject’s ability to shift from one instruction set to
sider to be the optimal dose of the preferred drug. This
another quickly and accurately. Other computerized bat-
method accounted for the 81 subjects on AMP and the 51
teries, such as the Neurobehavioral Evaluation System 2
(NES2), CogState, and CANTAB®, have SATs. Color-
A group of patients on stable and clinically effective
shape tests such as the SAT have been used in cognitive
doses of the nonstimulant ADHD drug, ATMX, were
imaging studies (Le, Pardo, & Hu, 1998; Nagahama et al.,
chosen as a comparison group. The 45 patients on
1998). A domain score for cognitive flexibility is gener-
ATMX were children and adolescents who were taking
ated by taking the number of correct responses on the
ATMX because they had experienced side effects on
SAT and subtracting the number of errors on the SAT
NML (N = 101) were children and adolescents with no
The CPT is a measure of vigilance or sustained atten-
active psychiatric, neurological, or medical conditions nor
tion (Rosvold & Delgado, 1956). A domain score for
any history of participating in a normative study for the
complex attention is generated by adding the number of
CNS Vital Signs (CNSVS) database. ADHD controls (N =
errors committed in the CPT, the SAT, and the Stroop.
95) were newly diagnosed patients who had not yet begun
The domain score for vigilance attention is the sum of
to take any medications. Demographic data on the five
A composite score, the Neurocognition Index (NCI),
is computed as the average of the z scores of fivedomains (memory, psychomotor speed, reaction time,
Cognitive Evaluation
complex attention, and cognitive flexibility).
Patients’ neurocognitive performance was measured
The CNSVS battery has been normed in 1,069 normal
on a computerized battery of tests. The CNSVS battery
volunteers who were in good health without past or pre-
contains seven tests that are widely used by neuropsy-
sent psychiatric or neurological disorders, head injury,
chologists and known to be reliable and valid. The tests
learning disabilities, and so on, and free of any centrally
embrace an appropriate span of cognitive domains and
acting medications. The subjects ranged in age from 7 to
are known to be sensitive to most of the causes of mild
90. Peak performance on the tests is achieved during the
cognitive dysfunction. Data establishing the reliability
third decade of life and declines gradually thereafter. Clinical Data for Five Groups. Test Scores and Significance
Note: NML = normal controls; MPH-OROS = Concerta; ATMX = atomoxetine; AMP = Adderall XR; MANOVA = multivariate analysis of thevariance.
Test-retest (TRT) reliability of the CNSVS battery
and bipolar disorder (Gualtieri & Johnson, 2006a); and
was established in a study of 99 Ss, 40 normal volun-
malingering (Gualtieri & Johnson, 2006d).
teers, and 59 psychiatric patients who took the entirebattery on two separate occasions, separated on average
by 62 days. The TRT interval ranged from 1 to 282 days,with a median interval of 27 days. Reliability coeffi-
The CNSVS database contains records from more
cients ranged from .65 (Attention) to .87 (Psychomotor
than 4,000 patients with neurological and/or psychiatric
Speed). The TRT of the CNSVS battery is comparable to
disorders. The database was scanned for patients who
those reported for similar, traditional tests and to similar
met the following criteria: (a) primary diagnosis ADHD;
tests in other computerized test batteries (Gualtieri &
(b) age, 10–18 years; (c) no comorbid neurological con-
ditions, cognitive disorders (e.g., learning disabilities,
The concurrent validity of the CNSVS battery was
brain injury), or psychiatric disorders (e.g., anxiety,
established in a series of studies comparing the perfor-
depression, autism); (d) treatment with AMP, ATMX, or
mance of subjects on CNSVS to their performance on
MPH-OROS, stable doses maintained for at least 4
conventional neuropsychological tests and on another
weeks; (e) no concurrent medications.
computerized neurocognitive test, the NES2 (Baker
This process identified four groups: Three groups
et al., 1985). The conventional tests were the Rey
were children and adolescents treated with MPH-OROS,
Auditory Verbal Learning Test, Logical Memory and
ATMX, or AMP. The charts were reexamined by the
Facial Recognition from the Wechsler Memory Test, a
authors to establish that parents and treating clinicians
mechanical finger tapper, the ST, Trails B, and the Verbal
agreed that the patient was a positive responder to the
Fluency Test. From the NES2, the comparison tests were
medication and that no further treatment recommenda-
Finger Tapping, Switching Attention, and the CPT.
tions were contemplated. The fourth group was untreated
CNSVS tests were moderately well correlated with tests
and newly diagnosed ADHD patients. These were the
of psychomotor speed (finger tapping [.41–.52] and cod-
ing [.6–.79]) and executive function on the NES2
The NML were selected from the CNSVS normative
(.51–.55). Correlations between the CPT in CNSVS and
database. These were individuals with no present or past
the NES2 were low (.26–.47). The concurrent validity of
psychiatric, developmental, or neurological disorder, in
the CNSVS battery is comparable to similar conven-
good health, in good standing in school, and taking no
current medications. All of the patients had been tested
The discriminant validity of the CNSVS battery has
within a 14-month period (July 2003–August 2004).
been established in studies of patients with mild cogni-tive impairment (MCI) and early dementia (Gualtieri &Johnson, 2006c); Post-Concussion Syndrome (PCS) and
severe traumatic brain injury (Gualtieri & Johnson,2005, 2006b); ADHD (Gualtieri & Johnson, 2006a);
Subject data, test scores, and results of the multivariate
depression (Gualtieri & Johnson, 2006e); schizophrenia
analysis are presented in Table 2. There were no significant
Gualtieri, Johnson / Medications Do Not Necessarily Normalize Cognition
Three-Group Comparison
Note: MANOVA = multivariate analysis of variance.
differences among the groups in terms of race, but there
neuropsychiatric disorders, does not necessarily nor-
were for age and gender; therefore, the multivariate analy-
malize the cognitive performance of ADHD children
sis of the variance (MANOVA) incorporate age and gen-
and adolescents. Taking the NCI as a benchmark,
untreated ADHD patients perform 15% lower than nor-
The results in Table 2 indicate highly significant
mals. However, treated ADHD patients perform 10%
group differences among the five groups, in all six cog-
nitive domains and in the summary score, NCI. The next
Three alternative conclusions might be drawn from
step was to determine the source of the differences.
these data. First, it is possible that the treatment was sub-
It did not reside in the between-drug comparisons
optimal. Perhaps better practitioners might have achieved
(Pillai’s trace, F = 1.053, p > .40). In light of that, the
better results. Second, because ADHD is a behavioral dis-
results of the three drug groups were combined, and
order, cognitive performance is irrelevant to treatment. We
analysis was performed comparing three groups, NML,
do not accept either of these. We believe that the third pos-
medicated ADHD patients, and unmedicated ADHD
sible conclusion is the right one: That even with optimal
controls. As expected, group differences, controlling for
treatment by experienced clinicians, children, and adoles-
age and gender, were significantly different for the NCI
cents with ADHD, as a group, have persistent cognitive
disabilities. Drug treatment may ameliorate the cognitive
The data in Table 4 indicate where the significant
difficulties of ADHD patients, but it does not necessarily
group differences reside. Analysis of variance (ANOVA)
normalize cognition. Medication treatment may be neces-
with Bonferroni correction measured the significance of
sary, therefore, for children and adolescents with ADHD,
differences, and effect sizes were measured by Cohen’s
d. The most impressive differences were, as expected,
This conclusion would be more convincing if we had
between NML and untreated ADHD; significant differ-
systematic behavioral data to present. The premise on
ences and moderate-to-strong effect sizes were observed
which the study is based, after all, is that the treated
in every domain, save memory, and in the NCI. The
subjects were positive responders on clinical grounds. If
NML were also significantly superior to treated ADHD
we had objective data, from behavioral observations, or
patients in every domain, except reaction time and psy-
even subjective data from rating scales, which would
chomotor speed. Medicated patients differed from
lend strength to the assertion that all the subjects were in
untreated patients in the domains of reaction time, cog-
fact responders. We regret that no such data were avail-
nitive flexibility, and vigilance attention, although the
able. On the other hand, in the neuropsychiatry clinics,
medication response in ADHD children and adolescents
The data are presented graphically in Figure 1.
is assessed on the basis of interviews with parents andpatients, reports from teachers and improvement in
Discussion
grades, and by comparing different drugs and differentdoses. This is, in fact, the way response is measured in
ADHD treatment, conducted by experienced practi-
clinical practice, and the point of this study is simply
tioners in a clinic specializing in ADHD and other
this: Under the usual circumstances of good clinical care,
Group Differences by ANOVA With Bonferroni Correction and Effects Size by Cohen’s d Normals, Medicated Patients, and Untreated Patients
Notes, Figure 1. NML = normal controls. MED = ADHD patients on medication. ADHD = unmedicated ADHD patients. NCI = neurocognition index. MEM = memory domain score. PMS = psychomotor speed. RT = reaction time. CF = cognitive flexibility. ATT = complex attention. AV = vigilance attention.
medication treatment does not necessarily resolve all of
testing. The degree to which neuropsychological tests
the cognitive problems that ADHD patients have.
correlate with real-world performance has been the
The patients in this study were treated with medica-
subject of a good deal of research and controversy.
tion because they were doing poorly in school. With
Overall, the research suggests that many neuropsycho-
treatment, their performance in school improved. We
logical tests have a moderate level of ecological validity
regret that we do not have grades to analyze and report,
when predicting everyday cognitive functioning. The
and to correlate with improvement in cognition on the
strongest relationships are noted when the outcome mea-
computerized neurocognitive test battery. That would be
sure corresponds to the cognitive domain assessed by the
the appropriate subject for a prospective study, and
neuropsychological tests (Chaytor & Schmitter-
would address the ecological validity of the cognitive
Gualtieri, Johnson / Medications Do Not Necessarily Normalize Cognition
The relevance of neuropsychological tests to ADHD
30 words is presented. The 15 target words are mixed
diagnosis and to treatment assessment has also been the
randomly among 15 new words. When the subject rec-
subject of some concern. The results of psychological
ognizes a word from the original list, he or she presses
tests, for example, the freedom from distractibility factor
the space bar. After this trial of 30 stimuli, the subject
of the Wechsler Intelligence Scale for Children (WISC-
goes on to do the next six tests. At the end of the battery,
III) is not found to be “a reliable or a valid index of atten-
about 20 min later, the 15 target words appear again,
tion or a diagnostic screening measure for identifying
children with ADHD” (Reinecke, Beebe, & Stein, 1999,
The VIM Test is based on the Rey Visual Design
p. 322). The correlation between performance on the
Learning Test; the latter is in turn, a parallel to the Rey
CPT and parent or teacher rating scales is modest at best
Auditory Verbal Learning Test, using geometric figures
(Forbes, 1998; McGee, Clark, & Symons, 2000; Raggio
rather than words, and requiring the subject to draw the
& Pierce, 1999; Rielly, Cunningham, Richards, Elbard,
figures from memory. In CNSVS, the VIM Test is just
& Mahoney, 1999), and computerized CPTs like the tests
like the VBM Test. In the VIM Test 15 geometric figures
of variables of attention (TOVA) generate unacceptably
are presented; the subject has to identify those figures
high false positive rates (30%) in NML and children with
nested among 15 new figures. Then, after five more tests,
other psychiatric disorders (28%) (Forbes, 1998; Schatz,
there is a delayed recognition trial.
The VBM draws from a reservoir of 120 words selected
If a child’s behavior, then, is improved when he or she
from word-frequency tables. The VIM draws from a reser-
has been treated with an ADHD medication, and if
voir of 120 simple geometric designs. The scoring is cor-
grades improve as well, then why should it matter if per-
rect hits and correct passes, immediate and delayed.
formance on a battery of neuropsychological tests is 10%
Correct responses from VBM and VIM are summed to
lower than normal? We believe that this is more than a
generate a composite memory or memory domain score.
trivial result, and that it does have clinical relevance.
The highest score one can attain is 120, the lowest is 60.
Even with successful treatment, ADHD children and
Scores below 60 suggest willful exaggeration.
adolescents have subtle but clearly demonstrable cogni-tive deficits. Some of these patients may need more than
Finger Tapping Test (FTT)
just medication. Furthermore, it is possible that theinsufficiency of ADHD treatment is responsible for the
The FTT is one of the most commonly used tests in
relatively low adherence rates over time. Recent reports
neuropsychology, because of its simplicity and reliabil-
indicate that one third of ADHD children are no longer
ity, and also generates relevant data about fine motor
taking medication after 2 years (Bussing et al., 2005) and
control, which is based on motor speed as well as kines-
that only about one in five take medication over a longer
thetic and visual-motor ability (Mitrushina, Boone, &
period (Miller, Lalonde, & McGrail, 2004).
D’Elia, 1999). It was one of the core tests of theHalstead-Reitan Battery, which dates to the 1940s, butsimilar tests were used by 19th century psychologists
Appendix
like Wundt, Galton, and Cattell. The FTT is believed tobe one of the most sensitive neuropsychological tests for
The CNS Vital Signs (CNSVS) Battery
determining brain impairment (Mitrushina et al., 1999). Verbal Memory (VBM) Test and Visual
In CNSVS, the FTT is a very simple test. Subjects are
asked to press the space bar with their right index finger
Memory (VIM) Test
as many times as they can in 10 s. They do this once forpractice, and then there are three test trials. The test is
Vital Signs includes parallel tests of verbal memory
repeated with the left hand. The score is the average
(word list learning) and visual memory (figure learning).
The tests are virtually identical, but one uses words asstimuli, the other geometric shapes. Symbol digit coding (SDC)
The VBM test is an adaptation of the Rey Auditory
Verbal Learning Test (Rey, 1964; Taylor, 1959). It is a
The Symbol Digit Modalities Test (SDMT) (Smith,
recognition test, however, not a test of recall. In the
1982) is a variant of the Wechsler DSST, but the position
CNSVS version, 15 words are presented, one-by-one, on
of symbols and digits is reversed. The clinical and psy-
the screen. A new word is presented every 2 s. The
chometric properties of the SDMT are similar to those of
subject is asked to remember these words. Then a list of
the DSST. Although the SDMT may be a harder test, and
thus more sensitive to neurotoxicity, performance on the
generated in part two of the test (range, 78–188 ms) (the
SDMT and the DSST are highly correlated (Lezak,
Stroop effect). Part three also generates an error score.
1994). Smith maintained that the SDMT was “usually
Averaging the two complex reaction time scores from
the most sensitive (test) to the presence of acute or
the ST generates a domain score for reaction time. It
chronic ‘organic’ cerebral dysfunction” (Smith, 1982).
might be more precise to refer to this domain as infor-
In the CNSVS SDC, the subject is given a training
session to learn how to link numbers to digits. The testitself consists of serial presentations of screens, each of
The Shifting Attention Test (SAT)
which contains a bank of eight symbols above and eightempty boxes below. The subject types in the number that
The SAT measures the subject’s ability to shift from
corresponds to the symbol that is highlighted. Only the
one instruction set to another quickly and accurately. In
digits from 2 through 9 are used; this is to avoid confu-
the SAT, subjects are instructed to match geometric
sion between “1” and “I” on the keyboard. The test lasts
objects either by shape or by color. Three figures appear
for 120 s. The goal is to type in as many correct numbers
on the screen, one on top and two on the bottom. The top
figure is either a square or a circle. The bottom figures
Neither the SDMT nor the DSST are suitable for
are a square and a circle. The figures are either red or
repeated administration, because subjects are able to
blue; the colors are mixed randomly. The subject is asked
remember the code and thus accelerate their perfor-
to match one of the bottom figures to the top figure. The
mance (Hindmarch, 1980). Modifications in the test are
rules change at random. For one presentation, the rule is
necessary if it is to be used repeatedly; for example,
to match the figures by shape, for another, by color. This
changing the code in a random way on successive admin-
goes on for 90 s. The goal is to make as many correct
istrations. The SDC in CNSVS draws from a reservoir of
matches as one can in the time allotted. The scores gen-
32 symbols. Each time the test is administered, the pro-
erated by the SAT are: correct matches, errors, and
gram randomly chooses eight new symbols to match to
response time (ms). A domain score for cognitive flexi-
bility is generated by taking the number of correct
Scoring is the number of correct responses generated
responses on the SAT and subtracting the number of
in 2 min. The total of right and left taps from the FTT
and total correct responses on the SDC generates a com-
There is not a precise parallel to the SAT in the com-
pendium of conventional neuropsychological tests,although Trails B and the Wisconsin Cart Sort are some-
The Stroop Test (ST)
times considered to be tests of shifting attention. Computerized tests, however, such as the NES2,
There have been several versions of the ST over the
CogState, and CANTAB, have SATs that are not dissim-
years. The modification adopted for CNSVS uses only
ilar to the SAT, and color-shape tests like the SAT have
four colors/color words (red, green, yellow, blue), and
been used in cognitive imaging studies (Le et al., 1998;
only one key is in play, the space bar. The test has three
parts. In the first, the words RED, YELLOW, BLUE, andGREEN (printed in black) appear at random on the screen,
The Continuous Performance Test (CPT)
and the subject presses the space bar as soon as he or shesees the word. This generates a simple reaction time score.
The CPT is a measure of vigilance or sustained atten-
In the second part, the words RED, YELLOW, BLUE,
tion or attention over time (Rosvold & Delgado, 1956).
and GREEN appear on the screen, printed in color. The
It has been a popular test because of its robust relation-
subject is asked to press the space bar when the color of
ship to psychiatric disorders. Poor performance on the
the word matches what the word says. This generates a
CPT has been reported in ADHD (Epstein, Johnson,
Varia, & Conners, 2001; Sykes, Douglas, Weiss, &
In the third part, the words RED, YELLOW, BLUE,
Minde, 1971), learning disabilities (Lindsay, Tomazic,
and GREEN appear on the screen, printed in color. The
Levine, & Accardo, 2001; McGee et al., 2000), patients
subject is asked to press the space bar when the color of
with epilepsy (Mirksy & van Buren, 1965), and schizo-
the word does not match what the word says. This part
phrenics (Vadhan, Serper, Harvey, Chou, & Cancro,
also generates a complex reaction time score, called the
2001; Wohlberg & Kornetsky, 1973). It is sensitive to
color-word reaction time. The color-word reaction time is
CNS dysfunction in general, and is not specific to any
on average 120 ms longer than the complex reaction time
particular condition (Riccio & Reynolds, 2001).
Gualtieri, Johnson / Medications Do Not Necessarily Normalize Cognition
The CPT is also sensitive, for better or worse, to the
Benedict, K. B., & Benson, J. (2004). The use of CNSVS in college
effects of various drugs. In ADHD children, performance
students with primary attention and/or learning disorders. 16th Annual
on the CPT is reliably improved by stimulant medica-
Postsecondary Disability Training Institute (PTI), Mount Snow, VT.
Bird, C. M., Papadopoulou, K., Ricciardelli, P., Rossor, M. N., &
tions (Barkley, 1977; Riccio, Waldrop, Reynolds, &
Cipolotti, L. (2003). Test-retest reliability, practice effects and
Lowe, 2001). Alcohol consumption (Dougherty, Marsh,
reliable change indices for the recognition memory test. British
Moeller, Chokshi, & Rosen, 2000) adversely affects per-
Journal of Clinical Psychology, 42, 407-425.
formance on the CPT, but nicotine tends to improve per-
Bornstein, R. A., Miller, H. B., & Van Schoor, J. T. (1989).
formance on the test (Levin, Conners, Silva, Canu, &
Neuropsychological deficit and emotional disturbance in head-injured patients. Journal of Neurosurgery, 70, 509-513.
March, 2001). Certain anticonvulsant medications impair
Brodeur, D. A., & Pond, M. (2001). The development of selective
performance on the CPT (Hutt, Jackson, Belsham, &
attention in children with attention deficit hyperactivity disorder. Journal of Abnormal Child Psychology, 29, 229-239.
The CPT in Vital Signs is a conventional version of
Bussing, R., Zima, B., Mason, D., Hou, W., Garvan, C., & Forness, S.
the test, although it is shorter than some other versions.
(2005). Use and persistence of pharmacotherapy for elementary
In the Vital Signs CPT, the subject is asked to respond to
school students with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 15, 78-87.
target stimulus “B” but not to any other letter. In 5 min,
Cepeda, N. J., Cepeda, M. L., & Kramer, A. F. (2000). Task switch-
the test presents 200 letters; 40 of the stimuli are targets
ing and attention deficit hyperactivity disorder. Journal of
(the letter “B”) and 160 are nontargets (other letters). Abnormal Child Psychology, 28, 213-226.
The stimuli are presented at random, although the target
Chaytor, N., & Schmitter-Edgecombe, M. (2003). The ecological
stimulus is blocked so it appears 8 times during each
validity of neuropsychological tests: A review of the literature oneveryday cognitive skills. Neuropsychology Review, 13, 181-197.
Cohen, M. L., Kelly, P. C., & Atkinson, A. W. (1989). Parent, teacher,
Scoring is correct responses, commission errors
child. A trilateral approach to attention deficit disorder. American
(impulsive responding), and omission errors (inatten-
Journal of Diseases of Children, 143, 1229-1233.
tion). The CPT also reports subjects’ choice reaction
Collie, A., Maruff, P., Darby, D. G., & McStephen, M. (2003). The
time for each variable. A domain score for complex
effects of practice on the cognitive test performance of neurologi-
attention is generated by adding the number of errors
cally normal individuals assessed at brief test-retest intervals. Journal of the International Neuropsychological Society, 9, 419-428.
committed in the CPT, the SAT, and the Stroop.
Coughlan, A. K., & Hollows, S. E. (1984). Use of memory tests in
differentiating organic disorder from depression. British JournalReferences
Dikmen, S. S., Heaton, R. K., Grant, I., & Temkin, N. R. (1999). Test-
Abikoff, H., & Klein, R. G. (1992). Attention-deficit hyperactivity
retest reliability and practice effects of expanded Halstead-Reitan
and conduct disorder: Comorbidity and implications for treatment.
Neuropsychological Test Battery. Journal of InternationalJournal of Consulting and Clinical Psychology, 60, 881-892. Neuropsychological Society, 5, 346-356.
Adams, W. (1982). Effect of methylphenidate on thought processing
Dikmen, S. S., Temkin, N. R., Miller, B., Machamer, J., & Winn, H. R.
time in children. Journal of Developmental & Behavioral
(1991). Neurobehavioral effects of phenytoin prophylaxis of post-
traumatic seizures. Journal of the American Medical Association,
Aggarwal, A., & Lillystone, D. (2000). A follow-up pilot study of
objective measures in children with attention deficit hyperactivity
Dodrill, C. B., & Troupin, A. S. (1975). Effects of repeated adminis-
disorder. Journal of Paediatrics and Child Health, 36, 134-138.
trations of a comprehensive neuropsychological battery among
Aman, M. G., & Turbott, S. H. (1991). Prediction of clinical response
chronic epileptics. The Journal of Nervous and Mental Disease,
in children taking methylphenidate. Journal of Autism andDevelopmental Disorders, 21, 211-228.
Dougherty, D. M., Marsh, D. M., Moeller, F. G., Chokshi, R. V., &
Baker, E. L., Letz, R. E., Fidler, A. T., Shalat, S., Plantamura, D., &
Rosen, V. C. (2000). Effects of moderate and high doses of alco-
Lyndon, M. (1985). A computer-based neurobehavioral evaluation
hol on attention, impulsivity, discriminability, and response bias in
system for occupational and environmental epidemiology:
immediate and delayed memory task performance. Alcohol and
Methodology and validation studies. Neurobehavioral ToxicologyClinical Experimental Research, 24, 1702-1711. & Teratology, 7, 369-377.
Dulcan, M., & Popper, C. (1991). Concise Guide to Child and
Barkley, R. A. (1977). A review of stimulant drug research with
Adolescent Psychiatry. Washington, DC.
hyperactive children. Journal of Child Psychology and Psychiatry,
Elia, J., Borcherding, B. G., Rapoport, J. L., & Keysor, C. S. (1991).
Methylphenidate and dextroamphetamine treatments of hyperactiv-
Barnett, R., Maruff, P., Vance, A., Luk, E. S., Costin, J., Wood, C., et al.
ity: Are there true nonresponders? Psychiatry Research, 36, 141-155.
(2001). Abnormal executive function in attention deficit hyperac-
Elwood, R. W. (2001). MicroCog: Assessment of cognitive function-
tivity disorder: The effect of stimulant medication and age on
ing. Neuropsychology Review, 11, 89-100.
spatial working memory. Psychological Medicine, 31, 1107-1115.
Epstein, J. N., Johnson, D. E., Varia, I. M., & Conners, C. K. (2001).
Barr, W. B. (2003). Neuropsychological testing of high school ath-
Neuropsychological assessment of response inhibition in adults
letes. Preliminary norms and test-retest indices. Archives of
with ADHD. Journal of Clinical & Experimental Neuropsychology,Clinical Neuropsychology, 18, 91-101.
Erlanger, D., Feldman, D., Kutner, K., Kaushik, T., Kroger, H., Festa, J.,
Hindmarch, I. (1980). Psychomotor function and psychoactive drugs.
et al. (2003). Development and validation of a web-based neuro-
British Journal of Clinical Pharmacology, 10, 189-209.
psychological test protocol for sports-related return-to-play
Hutt, S. J., Jackson, P. M., Belsham, A., & Higgins, G. (1968).
decision-making. Archives of Clinical Neuropsychology, 18, 316.
Perceptual-motor behaviour in relation to blood phenobarbitone
Everett, J., Thomas, J., Cote, F., Levesque, J., & Michaud, D. (1991).
level: A preliminary report. Developmental Medicine and Child
Cognitive effects of psychostimulant medication in hyperactive
children. Child Psychiatry and Human Development, 22, 79-87.
Kalff, A. C., Hendriksen, J. G., Kroes, M., Vles, J. S., Steyaert, J.,
Fischer, M., & Newby, R. F. (1998). Use of the restricted academic
Feron, F. J., et al. (2002). Neurocognitive performance of 5-
task in ADHD dose-response relationships. Journal of Learning
and 6-year-old children who met criteria for attention deficit/
hyperactivity disorder at 18 months follow-up: Results from a
Forbes, G. B. (1998). Clinical utility of the Test of Variables of
prospective population study. Journal of Abnormal Child
Attention (TOVA) in the diagnosis of attention-deficit/hyperactiv-
ity disorder. Journal of Clinical Psychology, 54, 461-476.
Konrad, K., Gunther, T., Hanisch, C., & Herpertz-Dahlmann, B.
Franzen, M. D., Tishelman, A. C., Sharp, B. H., & Friedman, A. G.
(2004). Differential effects of methylphenidate on attentional
(1987). An investigation of the test-retest reliability of the Stroop
functions in children with attention-deficit/hyperactivity disorder.
Color-Word Test across two intervals. Archives of ClinicalJournal of the American Academy of Child and Adolescent Psychiatry,
Gill, D. M., Reddon, J. R., Stefanyk, W. O., & Hans, H. S. (1986).
Le, T. H., Pardo, J. V., & Hu, X. (1998). 4 T-fMRI study of nonspa-
Finger tapping: Effects of trials and sessions. Perceptual and
tial shifting of selective attention: Cerebellar and parietal contri-
butions. Journal of Neurophysiology, 79, 1535-1548.
Gimpel, G., Collett, B., Veeder, M., Gifford, J., Sneddon, P.,
Leth-Steensen, C., Elbaz, Z. K., & Douglas, V. I. (2000). Mean
Bushman, B., et al. (2005). Effects of stimulant medication on
response times, variability, and skew in the responding of ADHD
cognitive performance of children with ADHD. Clinical
children: A response time distributional approach. ActaPediatrics (Phila), 44, 405-411. Psychologica (Amsterdam), 104, 167-190.
Golden, C. J. (1978). Stroop Color and Word Test: A manual for clin-
Levin, E. D., Conners, C. K., Silva, D., Canu, W., & March, J. (2001). ical and experimental uses. Chicago: Stoelting Company.
Effects of chronic nicotine and methylphenidate in adults with
Goldstein, G., & Watson, J. (1989). Test-retest reliability of the
attention deficit/hyperactivity disorder. Experimental and Clinical
Halstead-Reitan Battery and the WAIS in a neuropsychiatric pop-
Psychopharmacology, 9, 83-90.
ulation. Clinical Neuropsychologist, 3, 265-272.
Lezak, M. D. (1994). Domains of behavior from a neuropsycho-
Gonzalez, H., Mungas, D., & Haan, M. (2002). A verbal learning and
logical perspective: The whole story. Nebraska Symposium on
memory test for English- and Spanish-speaking older Mexican-
American adults. Clinical Neuropsychology, 16, 439-451.
Lindsay, R. L., Tomazic, T., Levine, M. D., & Accardo, P. J. (2001).
Green, R. C., Green, J., Harrison, J. M., & Kutner, M. H. (1994).
Attentional function as measured by a continuous performance
Screening for cognitive impairment in older individuals. Validation
task in children with dyscalculia. Journal of Developmental &
study of a computer-based test. Archives of Neurology, 51, 779-786. Behavioral Pediatrics, 22, 287-292.
Gualtieri, C., & Johnson, L. (2005). Allocation of attentional
Lovejoy, M. C., & Rasmussen, N. H. (1990). The validity of vigilance tasks
resources in patients with ADHD: Maturational changes from age
in differential diagnosis of children referred for attention and learning
10 to 29. Journal of Attention Disorders, 9, 534-542.
problems. Journal of Abnormal Child Psychology, 18, 671-681.
Gualtieri, C. T., & Johnson, L. G. (2006a). A computerized neu-
Lufi, D., Parish-Plass, J., & Gai, E. (1997). The effect of methylphenidate
rocogntive test battery for studies of schizophrenic and bipolar
on the cognitive and personality functioning of ADHD children. The Israel Journal of Psychiatry and Related Sciences, 34, 200-209.
Schizophrenia Research, Davos, Switzerland, 2006. Schizophrenia
McGee, R. A., Clark, S. E., & Symons, D. K. (2000). Does the
Conners’ Continuous Performance Test aid in ADHD diagnosis?
Gualtieri, C. T., & Johnson, L. G. (2006b). A computerized test sen-Journal of Abnormal Child Psychology, 28, 415-424. sitive to mild and severe brain injury. Manuscript submitted for
Mehta, M. A., Goodyer, I. M., & Sahakian, B. J. (2004).
Methylphenidate improves working memory and set-shifting in
Gualtieri, C. T., & Johnson, L. G. (2006c). Neurocognitive testing
AD/HD: Relationships to baseline memory capacity. Journal of
supports a broader concept of mild cognitive impairment. JournalChild Psychology and Psychiatry, 45, 293-305. of Alzheimers Related Dementia, 20, 359-366.
Miller, A., Lalonde, C., & McGrail, K. (2004). Children’s persistence
Gualtieri, C. T., & Johnson, L. G. (2006d). Reliability and validity of
with methylphenidate therapy: A population based study.
a computerized neurocognitive test battery, CNS Vital Signs. Canadian Journal of Psychiatry, 49, 761-768. Archives of Clinical Neuropsychology, 21, 623-643.
Mirksy, A. F., & van Buren, J. M. (1965). On the nature of the
Gualtieri, C. T., & Johnson, L. G. (2006e, June). Reliability and valid-
“absence” in centrencephalic epilepsy: A study of some behavioral,
ity of a computerized neurocognitive test for research in schizo-
electroencephalographic and autonomic factors. Electroencephalo-phrenia and bipolar disorder. Presentation at the New Clinical
graphy and Clinical Neurophysiology, 18, 348.
Drug Evaluation Unit (NCDEU), Boca Raton, Florida.
Mitchell, W. G., Chavez, J. M., Baker, S. A., Guzman, B. L., & Azen,
Gualtieri, C. T., Johnson, L. G., & Benedict, K. B. (2004a). A com-
S. P. (1990). Reaction time, impulsivity, and attention in hyperac-
puterized cognitive screening battery for psychiatrists. APA
tive children and controls: A video game technique. Journal of
Gualtieri, C. T., Johnson, L. G., & Benedict, K. B. (2004b).
Mitrushina, M., Boone, K. B., & D’Elia, L. F. (1999). Handbook ofReliability and validity of a brief computerized neurocognitivenormative data for neuropsychological assessment. New York:
screening battery. INS Annual Meeting, Baltimore.
Gualtieri, Johnson / Medications Do Not Necessarily Normalize Cognition
Muir-Broaddus, J. E., Rosenstein, L. D., Medina, D. E., & Soderberg,
Schachar, R., Jadad, A. R., Gauld, M., Boyle, M., Booker, L., Snider, A.,
C. (2002). Neuropsychological test performance of children with
et al. (2002). Attention-deficit hyperactivity disorder: Critical
ADHD relative to test norms and parent behavioral ratings.
appraisal of extended treatment studies. Canadian Journal ofArchives of Clinical Neuropsychology, 17, 671-689.
Nagahama, Y., Sadato, N., Yamauchi, H., Katsumi, Y., Hayashi, T.,
Schatz, A. M., Ballantyne, A. O., & Trauner, D. A. (2001). Sensitivity
Fukuyama, H., et al. (1998). Neural activity during attention shifts
and specificity of a computerized test of attention in the diagnosis
between object features. Neuroreport, 9, 2633-2638.
of Attention-Deficit/Hyperactivity Disorder. Assessment, 8, 357-365.
Raggio, D. J., & Pierce, J. (1999). Use of the school Performance
Smith, A. (1982). Symbol digit modalities test (SDMT) manual
Rating Scale with children treated for attention deficit hyperactiv-
(revised). Los Angeles: Western Psychological Services.
ity disorder. Perceptual and Motor Skills, 88, 957-960.
Sykes, D. H., Douglas, V. I., Weiss, G., & Minde, K. K. (1971).
Reinecke, M. A., Beebe, D. W., & Stein, M. A. (1999). The third
Attention in hyperactive children and the effect of methylphenidate
factor of the WISC-III: It’s (probably) not freedom from dis-
(ritalin). Journal of Child Psychology and Psychiatry, 12, 129-139.
tractibility. Journal of the American Academy of Child and
Taylor, E. M. (1959). The appraisal of children with cerebral deficits.Adolescent Psychiatry, 38, 322-328.
Cambridge, MA: Harvard University Press.
Rey, A. (1964). L’examen clinique en psychologie. Paris: Presses
Trommer, B. L., Hoeppner, J. B., Lorber, R., & Armstrong, K. (1988).
Pitfalls in the use of a continuous performance test as a diagnos-
Riccio, C. A., & Reynolds, C. R. (2001). Continuous performance
tic tool in attention deficit disorder. Journal of Developmental &
tests are sensitive to ADHD in adults but lack specificity. A review
Behavioral Pediatrics, 9, 339-345.
and critique for differential diagnosis. Annals of the New York
Vadhan, N. P., Serper, M. R., Harvey, P. D., Chou, J. C., & Cancro, R. Academy of Science, 931, 113-139.
(2001). Convergent validity and neuropsychological correlates of
Riccio, C. A., Waldrop, J. J., Reynolds, C. R., & Lowe, P. (2001).
the schedule for the assessment of negative symptoms (SANS)
Effects of stimulants on the continuous performance test (CPT):
attention subscale. Journal of Nervous and Mental Disease, 189,
Implications for CPT use and interpretation. Journal ofNeuropsychiatry and Clinical Neuroscience, 13, 326-335.
Vance, A. L., Maruff, P., & Barnett, R. (2003). Attention deficit
Rielly, N. E., Cunningham, C. E., Richards, J. E., Elbard, H. J., &
hyperactivity disorder, combined type: Better executive function
Mahoney, W. J. (1999). Detecting Attention Deficit Hyperactivity
performance with longer-term psychostimulant medication.
Disorder in a communications clinic: Diagnostic utility of the
Australian and New Zealand Journal of Psychiatry, 37, 570-576.
Gordon Diagnostic System. Journal of Clinical and Experimental
Weiler, M. D., Bernstein, J. H., Bellinger, D. C., & Waber, D. P. (2000). Neuropsychology, 21, 685-700.
Processing speed in children with attention deficit/hyperactivity
Risser, M. G., & Bowers, T. G. (1993). Cognitive and neuropsycho-
disorder, inattentive type. Child Neuropsychology (Neuropsychology,
logical characteristics of attention deficit hyperactivity disorder
Development and Cognition: Section C), 6, 218-234.
children receiving stimulant medications. Perceptual and Motor
Wohlberg, G. W., & Kornetsky, C. (1973). Sustained attention in
remitted schizophrenics. Archives in General Psychiatry, 28, 533-537.
Rosvold, H. E., & Delgado, J. M. (1956). The effect on delayed-
alternation test performance of stimulating or destroying elec-
C. Thomas Gualtieri, MD, is medical director at the North
trically structures within the frontal lobes of the monkey’s
Carolina Neuropsychiatry Clinics, Chapel Hill and Charlotte.
brain. Journal of Comparative & Physiological Psychology, 49,365-372.
Roth, R. M., Wishart, H. A., Flashman, L. A., Riordan, H. J., Huey, L.,
Lynda G. Johnson, PhD, is director of neuropsychology at
& Saykin, A. J. (2004). Contribution of organizational strategy
the North Carolina Neuropsychiatry Clinics. Drs Gualtieri and
to verbal learning and memory in adults with attention-deficit/
Johnson are two of the developers of the CNS Vital Signs
hyperactivity disorder. Neuropsychology, 18, 78-84.
Lungentransplantation Mein Name ist Eva Kunzmann. Ich bin 33 Jahre alt und komme aus Esslingen am Neckar. Als CF-Patientin wurde ich im August 2006 an der Medizinischen Hochschule Hannover(MHH) lungentransplantiert. Dass ich mich zu gegebener Zeit transplantieren lassen wollte, stand für mich schon sehrfrüh fest, der richtige Moment dafür allerdings noch lange nicht. Im Jahr 1996 habe ich m
Students investigated how well antibacterial mouthwashes worked. They tested four different mouthwashes, P , Q , R and S . They spread bacteria on nutrient jelly in a Petri dish. They soaked identical discs of filter paper in mouthwashes P , Q , R or S . They placed the discs on the growing bacteria as shown in Diagram 1 . They incubated the Petri dish for two days. The