Open Journal of Psychiatry, 2011, 1, 20-29 OJPsych
doi:10.4236/ojpsych.2011.12004 Published Online July 2011 (http://www.SciRP.org/journal/OJPsych/).
Published Onl ine July 2011 in SciRes. http://www.scirp.org/journal/OJPsych
Associative learning in ADHD: improved expression under
methylphenidate
Ebrahim Kantini1, Helen Joan Cassaday1*, Martin Joseph Batty2, Chris Hollis2, Ge or gin a Margaret
Jackson2
1School of Psychology, University of Nottingham University, Nottingham, UK;
2 Division of Psychiatry, University of Nottingham, Nottingham, UK.
Received 12 May 2011; revised 7 June 2011; accepted 15 June 2011.
ABSTRACT
Attention Deficit/Hyperactivity Disorder (ADHD) is
characterised by developmentally inappropriate le-
vels of inattention, impulsivity and hyperactivity. As
might be expected of a disorder in which inhibitory
deficits form part of the diagnostic criteria, deficits in
response inhibition in ADHD have been evidenced in
a number of studies. To date, the tasks used in such
studies have required participants to inhibit the
learned stimulus-response associations that result in
unwanted behavior. However, no research has ex-
amined the inhibition of stimulus-stimulus associa-
tions, formally ‘conditioned inhibition’. The present
study used video game style conditioned inhibition
procedures, developed for children and adolescents
with a clinical diagnosis of ADHD and suitable for
typically developing matched controls. Two comput-
er-based tasks (‘Mission to Mars’ and ‘Weapon-X’)
required participants to predict the occurrence of an
outcome based on the stimuli presented. We selected
12 male participants with ADHD on medication (me-
thylphenidate), but without comorbid Tourette Syn-
drome, pervasive developmental disorder, learning
disability or psychosis. This group showed overall
normal inhibition of stimulus-stimulus associations,
measured repeatedly over trials and with two task
variants. There was no correlation between inhibitory
learning and symptom severity ratings. However,
participants with ADHD on higher dosages of me-
thylphenidate, or longer duration of treatment with
methylphenidate, showed improved ability to antic-
ipate outcomes following the different stimulus pres-
entations on non-inhibited versus inhibited trials.
This effect was most clearly demonstrated on the
Weapon-X task. Thus, methylphenidate
dose-relatedly improved the expression of associative
learning. This action may contribute to its therapeu-
tic effects in improving cognitive function in ADHD.
Keywords: ADHD; Associative Learning; Conditioned
Inhibition; Methylphenidate.
1. INTRODUCTION
Attention Deficit/Hyperactivity Disorder (ADHD) is a
pervasive neurodevelopmental disorder characterised by
developmentally inappropriate levels of inattention and
hyperactivity/impulsivity [1-3]. The prevalence of ADHD
has been variably estimated as high as 10% - 18% [4,3],
but is generally considered to be around 3 - 5% [1].
As might be expected, a variety of experimental tasks,
principally the ‘stop signal’ and ‘Go/No-Go’ task, have
demonstrated deficits in response inhibition in children
with ADHD [5-10]. From a learning theory perspective,
these procedural tasks have the common feature that
successful performance requires inhibition of prepotent
stimulus-response (S-R) associations.
There have been few studies of stimulus-stimulus
(S-S) learning in ADHD. Since the neural circuitries ne-
cessary for S-R and S-S associations are not equivalent,
we cannot assume that the latter will also be abnormal in
ADHD. In a study of blocking, Oades and Müller [11]
found that the establishment of a prior S-S association
was no bar to learning about an additional (redundant)
stimulus in children with ADHD compared to matched
controls. However, although the demonstration of block-
ing is based on S-S associations, the effect is not gener-
ally considered to be mediated by inhibition from the
earlier association [12-14]. To our knowledge, no re-
search has examined the inhibition of S-S associations
(formally ‘conditioned inhibition’) in ADHD. In condi-
tioned inhibition procedures, a conditione d stimulus (CS)
is presented immediately prior to an unconditioned sti-
mulus (UCS), except on those occasions when it is pre-
ceded by the conditioned inhibitor (CI). Thus, the CI

E. Kantin et al. / Open Journal of Psychiatry 1 (2011) 20-29
21
comes to inhibit the CS-UCS association [15]. We have
developed video game style conditioning procedures that
demonstrate reliable conditioned inhibition and are suit-
able for younger participants [16,17]. In both tasks,
summation tests measure the generalisation of the inhi-
bitory properties of the CI to additional stimuli: a novel
stimulus that does not appear at all in the training phase
but is sufficiently similar to produce generalised res-
ponding (Sg); and a transfer stimulus (CSt) that does not
appear with the CI in the training phase. In both summa-
tion test variants, conditioned inhibition is demonstrated
by a significant difference in the direction of UCS rein-
forced stimuli receiving higher expectancy ratings than
non-reinforced stimuli presented with the pre-tr a ined CI.
In the present study, these procedures were used to test
children and adolescents with a clinical diagnosis of
ADHD (corresponding to ICD-10 hyperkinetic disorder)
and typically developing age and sex matched controls.
Medication for ADHD has traditionally been with indi-
rect dopamine agonists, of which methylphenidate is the
most commonly used drug [18,19]. The participants with
ADHD tested in the present study were all medicated
with methylphenidate. In animal studies, conditioned
inhibition is enhanced by treatment with amphetamine
[20]. Thus, in addition to examining the prediction that
conditioned inhibition would be impaired in ADHD, we
examined the effect of dose and duration of treatment
with methylphenidate.
2. METHODS
2.1. Participants
This study fully conformed to international guidelines on
the ethical conduct of experimental work with human
participants, as implemented in the UK. Ethical approval
was obtained from the local research ethics committee
and the R&D Departments of the Nottinghamshire and
Lincolnshire Partnership NHS Trusts (Derbyshire REC,
08/H0401/34, approved April 2008). After a complete
description of the study, written informed consent and
verbal assent was obtained from parents and children
respectively.
2.1.1. ADHD Group
12 Children and adolescents with a clinical diagnosis of
ADHD (12 males: mean age = 13 years 11 months; range
= 11 years 9 months – 16 years 9 months) were recruited
for the current study. The sample was part of a larger
separate study, reported elsewhere [21,22]. Briefly, par-
ents of children and adolescents with a diagnosis of
ADHD were asked to attend an assessment session in
which a battery of measures including the Development
and Well Being Assessment (DAWBA; [23]), Strengths
and Difficulties Questionnaire (SDQ; [24,25]), Conners’
long form (CPRS-R: L; [26]) and Social and Communi-
cations Questionnaire (SCQ; [27]) were administered.
Teacher completed versions of the DAWBA, SDQ and
the CPRS-R: L were also available for each child. This,
along with a review of medical records formed the basis
for a clinical consensus diagnostic meeting, in which
diagnosis was confirmed or overturned. Only children
with an established po sitive response to methylphenidate
and combined type ADHD were included. Any children
with Tourette Syndrome (TS), pervasive developmental
disorder, learning disability (defined as a full-scale intel-
ligence quotient (FSIQ < 70), or psychosis were ex-
cluded. The demographic characteristics, details of me-
dication with methylphenidate, and the symptom scores
(CPRS-R: L) of the ADHD participants tested are sum-
marised in Table 1.
2.1.2. Control Group
Of the 35 controls tested, 11 were matched for age ( ± 6
months) and sex with the ADHD participants and in-
cluded in the study (11 males: mean age = 13 years 11
months; range = 11 years 7 months - 17 years 1 month).
The control participants were screened for probable at-
tentional problems using the Strengths and Difficulties
Que s tio nnaire [24], and asked whether they had any
family member s who had ADHD (althou gh there was no
formal assessment for psychiatric conditions) prior to
testing. The matched control participants selected for
inclusion in the study did not report difficulties indicative
of any undiagnosed illness; similarly, none reported tak-
ing psychotropic medication for ADHD, or any other
condition.
IQ scores were not available for all control partici-
pants. The IQ range of the participants with ADHD (n =
12) was 75 - 108 and 102 - 107 in the age-matched con-
trols for whom IQ scores were available (n = 5). All of
the participants with ADHD were on medication (Con-
certa – an extended-release preparation of methylpheni-
date) at the point of testing. Participant details are sum-
marised in Table 1.
2.2. Materia ls
The task programmes were produced using E-prime
(Psychology Software Tools Inc., Pittsburgh, USA) run-
ning on personal computers with 17” monitors, or on a
15” laptop computer when travel to the participant was
required for testing. Participants’ responses were made
using a mouse.
2.3. Proce dure
Behavioural procedures were identical to those used to
test young participants with TS [16].

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22
Table 1. Demographics, details of medication with methylphenidate, and symptom scores for the ADHD participants.
Participants 1 2 3 4 5 6 7 8 9 10 11 12
Medication
Age (months) 201 190 161 141 144 167 169 190 145 142 153 194
IQ (WASI) 75 87 77 108 79 98 77 103 94 105 104 85
Dosage (mg/k g) 0.85 1.08 1.93 1.03 0.82 0.89 0.77 0.57 1.33 0.83 1.23 1.42
Medication duration (months) 63 41 51 5 19 22 18 92 11 54 59 27
Medication duration corrected for age 0.31 0.22 0.32 0.04 0.13 0.13 0. 11 0.48 0.08 0.38 0.39 0.14
CPRS-R: L
Oppositional 80 84 90 87 85 90 89 54 83 85 75 90
Cognitive Problems 62 74 74 59 78 75 77 57 63 74 78 77
Hyperactivity 85 57 85 87 90 90 90 80 85 90 80 90
Anxious 54 44 61 45 79 90 47 51 63 45 63 68
Perfectionism 65 43 49 69 77 77 55 50 58 41 69 52
Social Problems 72 60 73 69 65 90 81 90 45 90 77 80
Psychosomatic 61 61 42 63 88 90 90 90 58 48 83 58
ADHD Index 70 77 77 73 77 83 79 60 75 82 76 75
Global Restless Score 63 70 86 77 82 90 86 70 80 86 75 81
Emotional Lability 90 73 83 78 72 90 83 61 72 72 83 79
Global Total 72 72 88 80 81 90 88 69 80 84 80 83
DSM Inattentive 69 76 77 65 80 81 71 58 65 80 77 78
DSM Hyperactive 86 63 81 87 90 90 87 81 81 90 81 90
DSM Total 78 73 81 77 88 90 80 69 74 90 81 89
DSM Inattentive Count 8 9 9 7 9 8 8 2 6 9 9 9
DSM Hyperactivity Count 6 2 7 9 9 9 9 6 7 9 8 8
Legend: ADHD = Attention Deficit/Hyperactivity Disorder; mg/kg = milligrams medication per kilogram body weight dosage per day; CPRS-R : L = Conners’
Parent Rat ing Scal e—Revised: Long; WASI: Wechsler Abbr eviated Scal e of Intel ligence. With the exception of the bottom two rows, which are counts (in the
range 0-9), the CPRS-R: L ratings are T scores (mean = 50, SD = 10).
2.3.1 Conditioned Inhibition Task 1: ‘Mission to
Mars’
The task scenario was based on a hypothetical mission to
Mars and has been described in full elsewhere
[16,17].Participants were informed that they were to play
the role of a commander of a fleet of starships travelling
on an exploratory mission to Mars. However, trouble
arises as, during the course of this mission, spaceships in
the fleet ke e p myst e riously exploding.
The training phase consisted of 45 learning trials of
the types shown in Table 2. During the training phase
there were no explicit learning instructions; participants
were simply asked to carefully count the number of sur-
viving r oc ke t s .
There were 9 presentations of 5 trial types, which used
different CSs presented with or without the CI: CSa+, [CI,
CSa] –, CSb+, [CI, CSb] –, an d CS t+, where “+” signified
reinforcement (i.e. rocket UCS presentation), and “–”
signified non-reinforcement (i.e. no rocket UCS presen-
tation, represented as an exploded rocket). The 5 trial
types were presented in a random order. As the masking
task, participants were required to keep track of the
number of surviving spaceships, so that the associations
to be learned were less obvious. On non -reinfor ced trials,
a 1-second grey frame surrounding a blue screen was
presented. This was the CI. On excitatory trials, there
was a 1-second presentation of an empty blue screen (at
the equivalent point in the stimulus sequence). Next, the
CS (a large planet) was followed b y 3 distractors (small-
er planets) appearing and disappearing on the same
screen for a combined total of 4 seconds, then the UCS
(i.e. rocket presentation) on reinforced trials, or the ab-
sence of the UCS (i.e. exploded rocket presentation) on
non-reinforced trials. The purpose of the distractor sti-
muli was to mask the absence of the CI cue and to con-
trol for external inhibition. The distractors were also in-
tended to reduce the likelihood of direct associations
between the inhibitor and the absence of the US, as this
was represented as an alternative outcome. Participants
were required to press any button on the mouse to con-
tinue on to the next p re s e nt a tion.
The testing phase immediately followed on from the

E. Kantin et al. / Open Journal of Psychiatry 1 (2011) 20-29
23
Tabl e 2. The stimulus combinations presented during the train-
ing and testing phase of the two tasks.
Training Phase Testing Phase
CSa CSt+
[CI, CSa] – [CI, CSt] –
CSb+ Sg+
[CI, CSb] – [CI, Sg] –
CSt+
Legend: A ‘+’ indicates the present ation of th e UCS (i.e. an intact rocket for
the Mission to Mars and a picture of Wolverine for the Weapon X task). A
‘–’ indicates the absence of th e UCS (i.e. an exploded rocket for the Mission
to Mars and a pi cture of Fer al Logan for the Weapon X task).
training phase and consisted of 20 further trials. There
were 5 presentations of 4 trial types: Sg+, [CI, Sg]–, CSt+,
and [CI, CSt]–, in which Sg was a generalised stimulus
not previously introduced during the training phase (de-
scribed above). The 4 trial types were pre- sented in a
random order. The procedure for test trials was identical
to that used in training, except that prior to the presenta-
tion of the US (or its absence), participants were pre-
sented with an on-screen rating, scaled 1 - 9. At this point,
participants were required to estimate the likelihood of
the spaceship surviving, with a rating of 9 to represent
the highest likelihood of survival, and a rating of 1 to
represent the lowest likelihood of survival. An interme-
diate rating of 5 represented uncertainty. Ratings were
made by selecting the appropriate on screen box using
the mouse. Figure 1 shows the stimuli used in the train-
ing and test phases of the experiment.
This was a summation test of conditioned inhibition.
Participants’ ratings provided a measure of the inhibitory
properties of the CI using two kinds of test stimuli: (1) Sg
(a stimulus that was from the same category but had not
been explicitly pre-trained); and (2) CSt (a stimulus fa-
miliar from training, but that had not previously been
preceded by the CI).
2.3.2. Conditioned Inhibition Task 2: ‘Weapon-X’
This task presented a scenario based on the Weapon-X
comic book story and has been described in full else-
where [16]. Participants were informed that they were to
play the role of Professor Thorton, Director of the Wea-
pon-X project, with the job to create the ultimate living
weapon, using metallurgic skeletal bonding to convert
Logan into Wolverine. Failure results in the feral muta-
tion of Logan. Participants were further informed that in
order to learn Thorton’s secret, they were to carefully
observe his work in order to work out the causes of suc-
cess (Wolverine) versus failure (the feral mutation). Thus,
they were explicitly instructed to try to discover the
cause of the outcome.
As for the previous task, the training phase consisted
of 45 learning trials, presented as 9 presentations of the 5
Figure 1. The screen shots used during the Mission to Mars
task. Upper panel shows the blank screen presented in the ab-
sence of the inhibitor followed by the unconditioned stimulus
(US) presentation and the alternative framed screen with a grey
border used on inhibited trials followed by the absence of the
desired US, depicted as an exploded rocket. The middle panel
shows the alternative conditioned stimuli (CSs) including the
inhibited transfer stimulus (CSt) and the generalised stimulus
(Sg). The bottom panel shows the distractor stimuli used to
control for external inhibition.
Figure 2. The screen shots used during the Weapon-X task.
Upper panel shows alternative syringe stimuli shown in the
absence of the inhibitor followed by the unconditioned stimulus
(US) presentation and the syringe presented on inhibited trials
followed by the absence of the desired US, depicted as the un-
successful transformation. The middle panel shows the alterna-
tive conditioned stimuli (CSs) including the inhibited transfer
stimulus (CSt) and the generalised stimulus (Sg). The bottom
panel shows the distractor stimuli used to control for external
inhibition.
trial types shown in Table 2. The stimuli were different
in that in this task variant, participants were asked to
observe a computer simulation of the Weapon-X trans-
formation. This consisted of 3 stimuli appearing simul-
taneously: the CI (r epresented by a yellow syringe) or its
absence (when instead one of three alternative syringes

E. Kantini et al. / Open Journal of Psychiatry 1 (2011) 20-29
24
was presented, see Figure 2 upper panel), the CS (a
block of a certain fictitious alloy), and one of the five
distractors (various types of radiation, see Figure 2 low-
er panel), for a total of 4 seconds on screen. The purpose
of the alternative syringe stimuli was to mask the other-
wise notable absence of the CI cue and to control for
external inhibition (as above). The radiation distractors
were to further reduce the likelihood of direct associa-
tions between the inhibitor and the absence of the US, as
this was represented as an alternative outcome. These
images were followed by a 1 second presentation of an
image of Logan in the midst of the attempted transfor-
mation, then the presentation of the US (or its absence).
The success or failure of the metallurgical bonding was
represented by an image of Wolverine as the UCS, or a
picture of feral Logan representing the absence of the
UCS.
Participants were required to press any button on the
mouse to continue. As above, the testing phase consisted
of 20 further trials (as per Table 2) with the key genera-
lised (Sg) and transfer stimuli (CSt) for the summation
test of conditioned inhibition. The procedure for test tri-
als was identical to that used in training, except that prior
to the presentation of the US or its absence, participants
were presented with an onscreen rating on the scale 1-9,
with 9 representing the highest likelihoo d of success. All
choices were made by selecting the appropriate box on
screen using the mouse. Fi gu re 2 shows the stimuli used
in the training and test phases of the experiment.
All participants were tested on both task variants, in a
counterbalanced order, so practice effects could not ac-
count for any difference in performance on the two tasks.
2.3.3. Design and Analysis
Analysis of variance (ANOVA) was run in a mixed de-
sign with up to four within-subjects factors to assess
conditioned inhibition by participants’ summation test
performance: inhibition (the presence or absence of the
CI); task (Mission to Mars versus Weapon-X); stimulus
type (summation test with Sg versus CSt); test phase
presentation (of which there were five levels). To im-
prove focus, analyses were subsequently collapsed by
stimulus type and test phase presentation where these
factors did not interact with inhibition [28]. Diagnosis
was the between subjects factor.
In order to investigate any possible effects of medica-
tion, median split analyses were conducted with respect
to duration of medication (with correction for participant
age) and the dosage of medication (mg/kg). These were
distinct parameters in that duration and dose of medica-
tion were not correlated (see below). Median split analy-
sis was also used to examine the effect of symptom se-
verity (measured using the CPRS-R: L) on the expres-
sion of conditioned inhibition. The dependent variable to
assess the expression of associative learning was the par-
ticipants’ expectancy score (for appearances of an intact
rocket in task 1 or the successful transformation of Lo-
gan into Wolverine in task 2). Planned comparisons
(two-tailed t-tests) were conducted to examine effects of
a priori interest. In addition, effect sizes of likely interest
are reported (Cohen’s d).
A conditioned inhibition ratio was calculated by di-
viding the average expectancy score for non-inhibited
stimulus presentations by the average expectancy score
for inhibited stimulus presentations. Thus, conditioned
inhibition is indicated by a r atio greater than one and the
absence of conditioned inhibition by a ratio less than or
equal to one. The interrelationship between the level of
conditioned inhibition summarised by the ratio and
symptom severity scores (measured by the CPRS-R: L)
was explored by Pearson’s r correlation, 2-tailed. Where
data were available (for all ADHD participants and 5
matched controls), the same analyses were repeated to
examine summation test performance on each of the
tasks in relation to IQ. Similarly, the effect of medication
was further examined by correlational analysis, using
duration of medication, duration of medication adjusted
for age (months on medication divided by the age of the
participant) and medication dosage (mg/kg).
3. RESULTS
Analysis with respect to the diagnostic groups (ADHD
and matched controls), confirmed that there was a sig-
nificant main effect of inhibition (F1,21 = 24.782, p <
0.001). However, there was no significant interaction
between diagnostic group and inhibition (F1,21 = 0.763).
Neither was there any interaction between task, inhibi-
tion and diagnostic group (F1,21 = 0.029). Both the
matched controls (t11 = 3.624, p < 0.005, d = 2.16) and
the ADHD group (t11 = 3.374, p < 0.01, d = 1.94) dem-
onstrated an overall effect of inhibition at the summation
test (Figure 3). There were no significant interactions
between inhibition or diagnostic group with respect to
either stimulus, and/or pres entation (max F1, 21 = 1.906, p
= 0.182). However, there was a marginal task by inhibi-
tion interaction (F1,21 = 4.11, p = 0.055) reflecting better
performance in the Weapon-X than in the Mission to
Mars task.
The analysis of effects by medication was confined to
the ADHD group alone. As expected, the effect of inhibi-
tion remained signif icant (F1,11 = 11.384, p < 0.01). Since
there were again no significant interactions between in-
hibition and stimulus or presentation (max F1,21 = 1.388),
all further analyses were collapsed across the factors of
stimulus and presentation. However, analyses were con

E. Kantin et al. / Open Journal of Psychiatry 1 (2011) 20-29
25
Figure 3. The overall effect of inhibition in the ADHD and
matched control group. Mean Response refers to the partici-
pants’ expectancy ratings (scaled 1 - 9) with a rating of 9 to
represent the highest likelihood of the outcome (see text for
further details). ** = p < 0.01.
ducted separately by task because of the difference by
task identified above. Figure 4 shows that participants
who were below or equal to the median for medication
dose, or duration of medication (with or without adjust-
ment for age) did not show significant conditioned inhi-
bition in either task variant (max t5 = 1.955, d = 0.99).In
contrast, significant summation test discrimination was
demonstrated in the Weapon-X task variant by partici-
pants above the median dose (t5 = 5.167, p < 0.01, d =
4.5), or above the median duration of m edication (with or
without adjustment for age, t5 = 3.042, p < 0.05, d =
2.62). Figure 4 shows that, in the Weapon-X task,
non-inhibited and inhibited ratings were respectively
higher and lower above the median medication parame-
ters. However, the only significant change was for the
non-inhibited ratings in relation to dose (t10 = 2.237, p <
0.05, d = 1.41). No other differences between the inhi-
bited and non-inhibited ratings reached significance
(max t10 = 1.341, d = 0.85).
Although somewhat increased in those participants
with longer duration of treatment, the improvements in
summation test discrimination demonstrated above the
median medication parameters were not significant in the
Mission to Mars task variant (max t5 = 1.671, d = 1.4).
Again within the ADHD group, there was no interaction
between symptom level (median split on the CPRS-R: L
ratings) and inhibition or inhibition by task (max F =
0.666). Thus, high and low symptom participants showed
equivalent summation test discrimination. Nevertheless,
participants may have shown individual variation on the
task in relation to symptom sev erity. To address the like-
ly confound between medication status and ADHD
symptom severity, ANCOVA was applied to the median
split analyses for the ADHD group, using the ADHD
index of the CPRS-R: L as covariate.
(a)
(b)
(c)
Figure 4. The effects of medication on summation test dis-
crimination within the ADHD group. (a) ADHD group: differ-
ences by medication dosage; (b) ADHD group: differences by
duration of medication; (c ) ADHD group: differences by dura-
tion of medication adjusted for age. Effects of medication
shown separately for the two task variants, with respect to
(panel A) below or equal versus above median dosage [mg/kg],
(panel B) below or equal versus above median duration of me-
dication and (panel C) below or equal versus above median
duration of medication adjusted for age (* = p < 0.05, ** = p <
0.01, *** = p < 0.001). Mean Response refers to the partici-
pants’ expectancy ratings (scaled 1 - 9) with a rating of 9 to
represent the highest likelihood of the outcome (see text for
further details).

E. Kantini et al. / Open Journal of Psychiatry 1 (2011) 20-29
26
There were no significant interactions between dose
and inhibition (max F1, 9 = 1.629) . However, a significant
interaction between duration of medication and inhibi-
tion was fo und (F1,9 = 5.748, p < 0.05). Inspection of the
adjusted means shows that when symptom severity was
taken into account, overall summation test discrimi-
nation was more pronounced in participants above the
median duration of medication (mean inhibited ratings =
3.37, s.e.m. = 0.526; mean non-inhibited ratings = 7.519,
s.e.m. = 0.405) compared with summation test discrimi-
nation seen in participants below the median time on
medication (mean inhibited ratings = 4.747, s.e.m. =
0.526, mean non-inhibited ratings = 5.922, s.e.m. =
0.405). Repeating the analysis with duration of medica-
tion adjusted for age yielded the same outcome. No other
interactions were significant (max F < 1).
Due to the design of the two tasks, no data were col-
lected during the training phase of the procedure. How-
ever, in order to analyse whether participants demon-
strated equivalent levels of learning at the end of the
training phase, the ratings from the first presentation of
the non-inhibited transfer stimulus during the test phase
were analysed. Univariate ANOVA of the first presenta-
tion ratings demonstrated no significant difference be-
tween the ADHD group and the matched controls overall,
for the Weapon-X task (F = 0.271), the Mission to Mars
task (F 1, 21 = 2.248), or over both tasks combined (F =
0.266).
Moreover, in order to test whether learning under me-
thylphenidate had affected baseline excitatory learning,
the analysis was repeated with medication dosage (me-
dian split) and duration of medication (median split) as
the between subject variables.
Univariate ANOVA of the first presentation ratings
demonstrated no significant difference between the two
medication dosage groups for the Weapon-X task (F =
0.156), the Mission to Mars task (F = 0.015), or over
both tasks combined (F = 0.084). Likewise, there were
no significant differences between the duration (high vs.
low) of medication groups for the Weapon-X task (F1,10 =
1.607), the Mission to Mars task (F = 0.015), or over
both tasks combined (F = 0.236).
3.1. Correlational Analyses
Within the ADHD sample, there was no significant
correlation between dose or duration of medication and
performance on either task as summarised by the condi-
tioned inhibition ratios (max r12 = –0.408). Dose and
duration were distinct medication parameters in that
there was no correlation between medication dosage and
participants’ time on medication (r12 = –0.168). In addi-
tion, there was no correlation between medication dosage
and participants’ time on medication adjusted by age (r12
= –0.115), or between symptom severity measured by the
CPRS-R: L (either overall or by its subscales; max r12 =
–0.511), or between IQ and the su mmary sco r es pr ovided
by the conditioned inhibition ratios for either task (max
r12 = –0.549). Similarly, the overall correlation between
conditioned inhibition and IQ across both the ADHD and
matched controls for whom IQ scores were available was
also non-significant for both task variants (max r17 =
–0.426).
4. DISCUSSION
Two variants of the summation test showed that inhibi-
tion was transferred to a CS that had not been previously
presented with the CI during training (CSt) as well as to a
novel stimulus from the same category to which excita-
tory responding was generalised (Sg) [14]. Moreover,
conditioned inhibition was tested using two task variants.
The first (Mission to Mars) was a modified version of an
established task, which used serial presentation of the CI
followed by CSt or Sg [17]. The second (Weapon-X) was
a novel task, similarly designed to be engaging for
younger participants, which used simultaneous presenta-
tion of the CI together with CSt or Sg. Since the original-
ly developed task tested learning implicitly, the novel
task variant used explicit learning instructions, to further
confirm the generality of observed effects.
Conditioned inhibition was successfully demonstrated
in all participants in the present study. Thus, young males
with ADHD can successfully suppress S-S associations.
However, there was variation within the ADHD group, in
that participants on either a higher dosage or longer du-
ration of treatment with methylphenidate showed im-
proved performance and, consistent with some overall
difference in inhibition by task, this effect was most
clearly demonstrated in the Weapon-X variant. The dif-
ference took the form of improved summation test dis-
crimination, but the improvement was not solely attri-
butable to lower ratings given on inhibited stimulus
presentations.
Summation test performance reflects the expression of
prior learning. The course of acquisition was not directly
assessed in the training phases of the tasks due to the
implicit nature of the Mission to Mars task and the need
to keep the tasks formally equivalent as far as possible.
Analysis of first test trial responding to CSt, which was
used as the best estimate of (effects on) excitatory learn-
ing did not show any effect of diagnostic group or medi-
cation status. Although the profile of action on the sum-
mation test is consistent with generally improved asso-
ciative learning under methylphenidate, the present re-
sults only allow the conclusion that the expression of
prior learning was improved under methylphenidate.
Moreover, there were differences by task in that the ac-

E. Kantin et al. / Open Journal of Psychiatry 1 (2011) 20-29
27
centuated summation test performance only reached sig-
nificance in the Weapon-X variant (see also below).
4.1. Effects of Symptom Severity and IQ
There was no detectable correlation between the CPRS-R:
L scores of the ADHD participants (either overall or by
its subscales) and the level of inhibition demonstrated in
either task variant. This lack of correlation between
symptom severity and conditioned inhibition could be
due to a ceiling effect, given the relatively restricted
range of scores in the patient sample who all met diag-
nostic criteria for A DHD, and/or the limited sample size.
However, there was some indication in the data that the
effect of medication was more than would be expected
on the basis of symptom severity: when symptom sever-
ity was taken into account statistically (by analysis of
covariance), there was an interaction between duration
(but not dose) of medication and inhibition - in this case
overall rather than separately by task. This result shows
that, when symptom severity was taken into account, the
summation test discrimination was improved overall in
participants treated with methylphenidate over a longer
time frame.
While a number of the participants with ADHD had a
lower than average IQ, there was no correlation between
IQ and the level of inhibition demonstrated, either within
the ADHD sample, or including the matched controls
where data were available. Conventional tests of inhibi-
tion used with ADHD participants (the stop signal, the
Go/No-Go and a modified version of the Stroop task),
similarly showed a deficit in relation to ADHD, but no
association with IQ [29]. In the present study, it was not
possible to match controls on the basis of IQ, as IQ
scores were not available for all participants. However,
there are arguments against matching on the basis of IQ
in that disorders such as ADHD are a likely cause of de-
pressed IQ: the matching fallacy whereby participants
may be ‘overmatched’ on variables which are not inde-
pendent of the disor der in ques t ion [8].
4.2. Differences by Task
Although conditioned inhibition was overall demon-
strated in both task variants, performance was generally
better on the Weapon-X variant. This difference may
arise because the storyline of the latter task was intrinsi-
cally more engaging for the young males tested in the
present study, or because the use of explicit learning in-
structions influences task solution [30,31]. Alternatively,
some advantage on the Weapon-X task may have been
conferred by the simultaneous rather than serial presen-
tation. Serial or ‘occasion setting’ versions of condi-
tioned inhibition tasks provide a more direct analogue of
response learning tasks, where the required association is
qualified by discriminative stimuli (e.g., Go/No-Go).
However, they may be generally more difficult. Animal
studies have similarly indicated that the effectiveness of
a stimulus as an inhibitor can depend on its temporal
positioning with respect to potential excitors, and sp ecif-
ically that simultaneous rather than serial training more
reliably results in conditioned inhibition as measured by
summation test [32,33].
4.3. Differences by Medication
In participants with TS, medication with clonidine was
found to impair the expression of conditioned inhibition,
measured using identical procedures [16]. In the current
study, the entire sample of ADHD participants was me-
dicated. Moreover, the level of conditioned inhibition
was not equivalent across the two tasks, and the ADHD
group did not show significant conditioned inhibition on
the Mission to Mars task. Accordingly, within the ADHD
sample, the effects of medication were examined sepa-
rately by task. Correlation al analyses did not suggest any
linear relationship betwe en the level of conditioned inh i-
bition and medication dose or duration in either task va-
riant. However, median split analyses to divide the
ADHD group into low v. high dose and short v. long du-
ration of treatment showed that (according to either of
these medication parameters) treatment with methyl-
phenidate tended to improve expression of the condi-
tioned inhibition discrimination measured at the summa-
tion test, significantly so for the Weapon-X task. This
difference by conditioned inhibition variant appears re-
lated to task difficulty, in that the Weapon-X task sup-
ported a stronger conditioned inhibition effect (presuma-
bly in consequence of its explicit learning instructions
and simultaneous rather than serial presentation of the CI
in relation to CSt and Sg). The Weapon-X task also sup-
ported better performance in the unmedicated controls.
In animal studies too, methylphenidate has been found
to increase simple associative learning [34,35]. The
neural substrates of specifically inhibitory learning have
been little investigated to date, but the effect of amphe-
tamine is to enhance conditioned inhibition [20]. This
finding is similarly consistent with the possibility of dif-
ferences in relation to ADHD and its medication with
indirect dopamine agonists.
4.4. Conclusions
The participants with ADHD tested in the present study
were all medicated with methylphenidate; treatment was
thus confounded with diagnosis. Moreover, differences
may have been masked by ceiling effects, since partici-
pants were selected on the basis of high scores on the
CPRS-R: L scale. Thus, the relationship between symp-

E. Kantini et al. / Open Journal of Psychiatry 1 (2011) 20-29
28
tom severity and performance in the conditioned inhibi-
tion tasks should be further investig ated in a larger, more
heterogeneous sample. Relatedly, our procedures were
not suitable for repeat testing with the same task and the
effects of medication point to the need to test the hypo-
thesis that the inhibition of S-S associations should be
impaired in ADHD when medication is withdrawn.
However, effects on the expression of associative learn-
ing in relation to medication in ADHD are nonetheless of
interest. Participants below the median dose or duration
of treatment with methylphenidate showed no discrimi-
nation on the summation test, whereas the summation
test discrimination was significant above these medians
with a small to medium effect size (ds of 4.5 and 2.62,
respectively).
Methylphenidate has previously been reported to im-
prove the capacity to inhibit ongoing and prepotent res-
ponses in conventional tests of response inhibition, in-
cluding the Stroop [36] and variants of the stop signal
task [37]. Although the present study demonstrated im-
proved performance of the key summation test discrimi-
nation in a conditioned inhibition procedure, this result
cannot be taken to reflect enhanced inhibition of S-S
associations under methylphenidate because the im-
provement in discrimination performance had two com-
ponents. Moreover, only the change in non-inhibited
ratings reached significance (for the Weapon-X task,
when the sample was split on the dosage parameter).
Thus, although there was no evidence of drug effects on
excitatory learning, as measured by trial 1 responding to
the CSt, neither was there any evidence that the improved
summation test discrimination arose because of a change
in inhibitory as distinct from excitatory learning. We
therefore conclude that methylphenidate improved the
expression of associative learning in general, and suggest
that this action may contribute to its therapeutic effects in
improving cognitive function in ADHD.
5. ACK NOWLEDGEMENTS
Ebrahim Kantini was supported by an Overseas Research Student
Award, held at the School o f Psychology. We thank Jan e Fowlie for h er
help with data collection.
Declaration of competing interests: The authors declare that they
have no competing interests.
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