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. E-mail: *helen.cassaday@nottingham.ac.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 Copyright © 2011 SciRes. OJPsych 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].
E. Kantin et al. / Open Journal of Psychiatry 1 (2011) 20-29 Copyright © 2011 SciRes. OJPsych 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 Copyright © 2011 SciRes. OJPsych 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 Copyright © 2011 SciRes. OJPsych 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 Copyright © 2011 SciRes. OJPsych 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 Copyright © 2011 SciRes. OJPsych 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 Copyright © 2011 SciRes. OJPsych 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 Copyright © 2011 SciRes. OJPsych 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. 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