- Email: [email protected]
hyperactivity disorder
European Psychiatry 21 (2006) 544–547 http://france.elsevier.com/direct/EURPSY/
Short communication
Dose-related effect of methylphenidate on stopping and changing in children with attention-deficit/hyperactivity disorder Marijn Lijffijt a,*, J. Leon Kenemans a,b, Annemiek ter Wal a,d, Elise H. Quik a, C. Kemner d, Herman Westenberg c, Marinus N. Verbaten a, Herman van Engeland d a
Department of Psychopharmacology, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands b Department of Psychonomics, Utrecht University, Utrecht, The Netherlands c Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands d Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands Received 1 April 2004; accepted 13 April 2005 Available online 01 July 2005
Abstract Purpose. – The effect of methylphenidate (MPH) on inhibitory control as assessed by the stop task in children with attentiondeficit/hyperactivity disorder (ADHD) could be influenced by task difficulty and may be mediated by attention. Subjects and methods. – Fifteen children with ADHD performed the stop and the change task after placebo, 0.5 and 1.0 mg/kg MPH in a within-subject design. Results. – Linear-trend analysis showed a similar effect of MPH in both tasks and a stronger effect for inhibitory control than for attention. Furthermore, a correlation was found between blood serum metabolites of norepinephrine and dopamine for attentional measures and inhibitory control measures, respectively. Discussion and conclusion. – In children with ADHD MPH could act primarily on inhibitory control, and is not influenced by task difficulty. Also, attention and inhibitory control could have differential pharmacological profiles. © 2005 Elsevier Masson SAS. All rights reserved. Keywords: Attention-deficit/hyperactivity disorder; Methylphenidate; Stop-signal paradigm; Inhibitory control; Attention; Blood serum
1. Introduction Inhibitory control, as assessed in the stop-signal paradigm and quantified as stop-signal reaction time (SSRT) [11], is impaired in children with attention-deficit/hyperactivity disorder (ADHD) [10,13,14], and improved after administrating methylphenidate (MPH) [4,15–17]. Previous studies suggest that high MPH doses (> 0.8 mg/kg) are most efficacious in non-selective stop tasks [15,16], whereas lower doses (0.3– 0.5 mg/kg) are optimal in change and selective varieties [4,17]. Behavioral parameters indicate that choice-responding as well as stopping is more difficult in especially the change task than in the stop task [3], and so the different dose–response curves * Corresponding author. Present address: Department of Psychiatry and Behavioral Sciences, The university of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX 77555-0189, USA. Tel.: +1 409 747 9682; fax: +1 409 747 8351. E-mail address: [email protected] (M. Lijffijt). 0924-9338/$ - see front matter © 2005 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2005.04.003
could reflect a dependency of MPH effects on task difficulty. Here, we tested this hypothesis within a single design. Another unresolved question is whether a decrease in SSRT reflects improved inhibition, or rather a general improvement of attention [4]. If the former is true, shortening of SSRT under MPH should be disproportional to shortening of basic reaction time. Finally, attention and inhibition have been linked to norepinephrine [2] and dopamine [8], respectively, which are both affected by MPH. The present study assessed correlations between measures of attention and inhibition, and blood serum dopamine and norepinephrine metabolite levels (Table 1).
2. Subjects and methods Fifteen children (Table 1) were recruited from a database from the Department of Child Psychiatry from the Univer-
M. Lijffıjt et al. / European Psychiatry 21 (2006) 544–547 Table 1 Sample Characteristics n (male:female) Age in years, mean (S.D.) Weight in kg, mean (S.D.) Daily dose in mg/kg, mean (S.D.) WISC-R IQ score Total Verbal Performance ADHD subtype (# participants) Inattention Hyperactivity/impulsivity Combined Comorbid diagnosis (# participants) Anxiety ODD Parent–child relation problem None
15 (13:2) 10.74 (1.30) 37.33 (12.23) 22.67 (7.29) 97.60 (14.97) 97.93 (14.39) 97.73 (14.16) 2 2 11 6 5 2 4
sity Medical Center Utrecht consisting of children with ADHD. The study was approved by the national medical ethical committee (CCMO). Parents signed written informed consent and children gave oral consent for participation. All participants had good sight and hearing as reported by the participants and their caretakers. Participants were between 7 and 13 years of age, had an WISC-R IQ score higher than 80, had a diagnosis of ADHD according to DSM-IV criteria [1], which was confirmed by scores above the clinical range on the child behavior checklist (CBCL), the teacher’s report form (TRF), and the Conner parent and teacher rating scales (CPRS and CTRS, respectively). All participants were familiar with the intake of MPH for at least 1 year, which they refrained from taking 24 h prior to testing. Participants performed the stop and the change task 60 min after intake of placebo, 0.5 or 1.0 mg/kg MPH in a doubleblind, randomized, within-subjects, cross-over design, divided across three successive weeks in a test facility at the department of child psychiatry. They were seen on the same day at the same time each week. Although side effects were minimal (a feeling of sleepiness), four participants were too fatigued after placebo or the 1.0 mg/kg dose to continue with the change task after they first completed the stop task. Children were instructed to respond as quickly as possible with either the left or right index finger when they perceived a go-stimulus (squares consisting of thick or thin black and white bars presented for 750 ms at the center of the screen following a 500 ms warning stimulus). Furthermore, they were instructed to try to withhold the response when they heard a tone (400 ms, 80 dB at 1000 Hz, binaurally) (stop task), or to stop and react with both feet as quickly as possible when they heard a tone (change task). They were not allowed to wait for the tone to occur. Go-stimuli were followed by a blank screen (1.0–1.25 s variable inter-stimulus interval). The children started by practicing responding to the visual stimulus (60 trials), followed by a practice block containing stop trials (126 trials, including 50 stop trials). Next, four blocks were presented (each block consisted of 126 trials of which 50 were
545
stop trials). After a 15-min break participants continued with the change task in which the same procedure as in the stop task used. Each task took approximately 30 min to be completed and they were balanced across participants. The interval between the go- and stop stimulus was adjusted by the tracking procedure derived from De Jong et al. [7] in which the go–stop interval was adjusted according to the percentage of successful stops in the previous block. All trials were pseudo-randomized within blocks. There were never more than three succeeding stop trials without being followed by a go trial. Dependent variables for both tasks were stop speed (SSRT), mean RT (MRT), and within-subject standard deviation of the reaction time (SDRT). Because of the small sample size (stop task n = 15; change task n = 11), all data were analyzed using linear and quadratic trend contrasts [12]. The hypothesis for the dose–response relationship for SSRT in the stop and change task was tested for the smallest sample (n = 11). Trend analyses of the other variables were performed for the stop task only, including an additional analysis to directly test the difference between SSRT and MRT. When trends were significant Helmert contrasts were performed to test placebo against the low and high dose and to test the low dose against the high dose. Effects were considered significant when P < 0.05 (two-tailed). To study the association between stop task performance and the influence of MPH on neurotransmitter (norepinephrine, dopamine and serotonin) systems more closely, 45 min after intake of the drug (during rest) blood samples were drawn. Metabolites of these neurotransmitter systems (3methoxy-4-hydroxyphenylglycol [MHPG], homovannilic acid [HVA], and 5-hydroxyindole acetic acid [5-HIAA] levels, respectively) were correlated with SSRT, MRT, and SDRT in the stop task, separately for each dose condition (n = 12).
3. Results Trend analysis revealed a significantly linear-trend for Dose (F(1,10) = 8.82, P = 0.014), but no significant Dose * Task (stop vs. change) interaction. In the stop task, linear dose– response curves for SSRT (F(2,13) = 19.63, P < 0.005), MRT (F(2,13) = 7.7, P < 0.05), SDRT (F(2,13) = 36.16, P < 0.005) and error and omissions rate (F(2,13) = 18.09, P < 0.005, and F(2,13) = 6.58, P < 0.05, respectively) were found, indicating a general improvement of inhibitory control and attention after intake of MPH (Table 2). A direct test revealed a significant interaction between Dose (linear trend) and Measure (MRT vs. SSRT) (F(1,96,19.46) = 4.60, P < 0.05), indicating that MPH was more effective in improving SSRT than MRT. Helmert contrasts showed that SSRT after placebo intake was longer than after the intake of MPH (F(1,14) = 16.01, P < 0.005), and longer after the low dose than after the high dose (F(1,14) = 11.16, P < 0.005). For MRT, SDRT, error and omission rate, MPH led to better performance than placebo (F(1,14) = 15.19, P < 0.005,
546
M. Lijffıjt et al. / European Psychiatry 21 (2006) 544–547
Table 2 Descriptives of Stop and Change Task Performance Placebo Measure Mean S.D. Stop task (n = 15) Mean RT 621.13 89.61 SDRT 206.91 61.58 Error rate 22.09 10.99 Omission rate 9.31 7.61 SSRT 350.17 160.60 Change task (n = 11) Mean RT 667.46 139.78 SDRT 213.99 76.97 Error rate 32.01 15.63 Omission rate 9.00 8.17 SSRT 358.74 188.67 Change RT 786.71 146.00
0.5 mg/kg Mean S.D.
1.0 mg/kg Mean S.D.
579.59 161.77 14.90 4.76 251.31
88.41 58.81 6.63 4.18 91.37
566.54 146.01 11.88 4.00 210.67
89.32 60.42 7.55 5.53 92.71
616.38 160.65 17.82 2.79 296.18 778.42
101.87 78.89 11.56 2.96 94.89 163.14
622.89 155.21 15.32 2.33 261.69 785.75
106.33 69.80 8.80 2.44 74.74 190.72
S.D., standard deviation; Mean RT, mean reaction time; SDRT, withinsubject standard deviation of reaction time; SSRT, stop-signal reaction time, stop latency. Mean RT, Change RT SDRT, and SSRT are in ms; error and omission rates are in percentage.
F(1,14) = 31.00, P < 0.005, F(1,14) = 13.50, P < 0.005, and F(1,14) = 6.24, P < 0.05, respectively), but there was no difference between the two doses. Performance did not improve significantly across blocks. Blood serum analysis revealed a significant correlation between SSRT and HVA level (r = –0.68, P = 0.02) and mean RT and SDRT and MHPG level (r = –0.74, P = 0.006 and r = –0.70, P = 0.01, respectively), in the high dose condition only.
4. Discussion It was specifically hypothesized that dose-related effects on SSRT would be linear in the stop task, but that the higher (1.0 mg/kg) dose would be less optimal than the lower one (0.5 mg/kg) in the change task. However, a direct comparison between stopping and changing performance (SSRT) revealed no difference between dose–response curves, suggesting that the efficacy of MPH was not affected by task difficulty, and that previous results could be explained by differences between samples or experimental designs. Furthermore, the hypothesis that MPH affected inhibitory control by influencing attentional processes rather than inhibitory control itself was not confirmed. A direct test for the difference in dose-related effects between MRT and SSRT revealed that MPH affected speed of stopping (SSRT) more than speed of responding (MRT), suggesting a specific additional effect of MPH on inhibitory control, which could not be attributed to its effect on attention. On the other hand, Kramer et al. [9] found that MPH enhanced the rapidity to switch between tasks and to focus attention on the new relevant response set, suggesting that part of the effect of MPH on stopping may still be caused by a positive effect on switching attention. Volkow et al. [18] showed that MPH increased brain dopamine levels, which could increase the level of saliency
of an already salient task. The instruction of the current tasks gave the stop stimulus a more salient load than the go stimulus, because participants had to react to the stopping signal with another response than on most other trials. In accordance with the finding of Volkow et al., we found a significant negative correlation between blood serum dopamine and SSRT. This finding suggests that stopping is more efficient in those children with the higher increases in the levels of dopamine, possibly by increasing in saliency of the tone. Measures of attention and inhibitory control were associated with different neurotransmitter metabolite levels (under 1.0 mg/kg MPH). Attentional measures correlated more with the norepinephrine metabolite, whereas inhibition correlated more with the dopamine system. This could reflect specific relations between attention and norepinephrine and between inhibition and dopamine, which are both affected by MPH. That inhibition is affected more than attention is to our knowledge a pharmacological dissociation between the two executive functions that has not been reported before. The negative correlation between attentional measures and the neurotransmitter systems suggests that when more neurotransmitter is available, performance improves after MPH intake (shorter mean RT and SSRT and smaller SDRT), confirming previous findings of a positive correlation between CSF HVA and the improvement of the level hyperactivity after MPH intake [5,6].
5. Limitations Unfortunately, the current sample was small, reducing statistical power, especially for the results in the change task. Despite the lack of power, results are still in accordance with previous studies. Another limitation in this study is that neurotransmitter metabolites were taken from blood serum, which are less reliable than neurotransmitter levels derived from for example CSF, and which are not a direct reflection of cerebral activity.
References [1]
[2] [3]
[4]
[5]
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. Aston-Jones G, Rajkowski J, Cohen J. Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 1999;46:1309–20. Band GP, van Boxtel GJ. Inhibitory motor control in stop paradigms: review and reinterpretation of neural mechanisms. Acta Psychol (Amst) 1999;101:179–211. Bedard AC, Ickowicz A, Logan GD, Hogg-Johnson S, Schachar R, Tannock R. Selective inhibition in children with attention-deficit hyperactivity disorder off and on stimulant medication. J Abnorm Child Psychol 2003;31:315–27. Castellanos FX, Elia J, Kruesi MJP, Gulotta CS, Mefford IN, Potter WZ, et al. Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder. Psychiatry Res 1994;52:305– 16.
M. Lijffıjt et al. / European Psychiatry 21 (2006) 544–547 [6]
Castellanos FX, Elia J, Kruesi MJP, Marsh WL, Gulotta CS, Potter WZ, et al. Cerebrospinal fluid homovannilic acid predicts behavioral response to stimulants in 45 boys with attention deficit/ hyperactivity disorder. Neuropsychopharmacol 1996;14:125–37. [7] De Jong R, Coles MG, Logan GD. Strategies and mechanisms in nonselective and selective inhibitory motor control. J Exp Psychol Hum Percept Perform 1995;21:498–511. [8] Gorelova N, Seamans JK, Yang CR. Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex. J Neurophysiol 2002;88:3150–66. [9] Kramer AF, Cepeda NJ, Cepeda ML. Methylphenidate effects on task-switching performance in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2001;40:1277–84. [10] Lijffijt M, Kenemans JL, Verbaten MN, van Engeland MA. A metaanalytic review of stopping performance in attention-deficit/ hyperactivity desorder: deficient inhibitory motor control? J Abnorm Psychol 2005;114:216–22. [11] Logan GD. On the ability to inhibit thought and action: a users’ guide to the stop-signal paradigm. In: Dagenbach D, Carr TH, editors. Inhibitory processes in attention, memory, and language. San Diego: Academic Press; 1994. p. 189–239.
547
[12] Maxwell SE, Delaney HD. Designing experiments and analyzing data: a model comparison perspective. Mahwah, NJ: Lawrence Erlbaum Associates; 2000. [13] Nigg JT. Is ADHD a disinhibitory disorder? Psychol Bull 2001;127: 571–98. [14] Sergeant JA, Geurts H, Oosterlaan J. How specific is a deficit of executive functioning for attention-deficit/hyperactivity disorder? Behav Brain Res 2002;130:3–28. [15] Scheres A, Oosterlaan J, Swanson J, Morein-Zamir S, Meiran N, Schut H, et al. The effect of methylphenidate on three forms of response inhibition in boys with AD/HD. J Abnorm Child Psychol 2003;31:105–20. [16] Tannock R, Schachar RJ, Carr RP, Chajczyk D, Logan GD. Effects of methylphenidate on inhibitory motor control in hyperactive children. J Abnorm Child Psychol 1989;17:473–91. [17] Tannock R, Schachar R, Logan G. Methylphenidate and cognitive flexibility: dissociated dose effect in hyperactive children. J Abnorm Child Psychol 1995;23:235–66. [18] Volkow ND, Wang G, Fowler JS, Telang F, Maynard L, Logan J, et al. Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am J Psychiatry 2004;161:1173–80.
Short communication
Dose-related effect of methylphenidate on stopping and changing in children with attention-deficit/hyperactivity disorder Marijn Lijffijt a,*, J. Leon Kenemans a,b, Annemiek ter Wal a,d, Elise H. Quik a, C. Kemner d, Herman Westenberg c, Marinus N. Verbaten a, Herman van Engeland d a
Department of Psychopharmacology, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands b Department of Psychonomics, Utrecht University, Utrecht, The Netherlands c Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands d Department of Child and Adolescent Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands Received 1 April 2004; accepted 13 April 2005 Available online 01 July 2005
Abstract Purpose. – The effect of methylphenidate (MPH) on inhibitory control as assessed by the stop task in children with attentiondeficit/hyperactivity disorder (ADHD) could be influenced by task difficulty and may be mediated by attention. Subjects and methods. – Fifteen children with ADHD performed the stop and the change task after placebo, 0.5 and 1.0 mg/kg MPH in a within-subject design. Results. – Linear-trend analysis showed a similar effect of MPH in both tasks and a stronger effect for inhibitory control than for attention. Furthermore, a correlation was found between blood serum metabolites of norepinephrine and dopamine for attentional measures and inhibitory control measures, respectively. Discussion and conclusion. – In children with ADHD MPH could act primarily on inhibitory control, and is not influenced by task difficulty. Also, attention and inhibitory control could have differential pharmacological profiles. © 2005 Elsevier Masson SAS. All rights reserved. Keywords: Attention-deficit/hyperactivity disorder; Methylphenidate; Stop-signal paradigm; Inhibitory control; Attention; Blood serum
1. Introduction Inhibitory control, as assessed in the stop-signal paradigm and quantified as stop-signal reaction time (SSRT) [11], is impaired in children with attention-deficit/hyperactivity disorder (ADHD) [10,13,14], and improved after administrating methylphenidate (MPH) [4,15–17]. Previous studies suggest that high MPH doses (> 0.8 mg/kg) are most efficacious in non-selective stop tasks [15,16], whereas lower doses (0.3– 0.5 mg/kg) are optimal in change and selective varieties [4,17]. Behavioral parameters indicate that choice-responding as well as stopping is more difficult in especially the change task than in the stop task [3], and so the different dose–response curves * Corresponding author. Present address: Department of Psychiatry and Behavioral Sciences, The university of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX 77555-0189, USA. Tel.: +1 409 747 9682; fax: +1 409 747 8351. E-mail address: [email protected] (M. Lijffijt). 0924-9338/$ - see front matter © 2005 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2005.04.003
could reflect a dependency of MPH effects on task difficulty. Here, we tested this hypothesis within a single design. Another unresolved question is whether a decrease in SSRT reflects improved inhibition, or rather a general improvement of attention [4]. If the former is true, shortening of SSRT under MPH should be disproportional to shortening of basic reaction time. Finally, attention and inhibition have been linked to norepinephrine [2] and dopamine [8], respectively, which are both affected by MPH. The present study assessed correlations between measures of attention and inhibition, and blood serum dopamine and norepinephrine metabolite levels (Table 1).
2. Subjects and methods Fifteen children (Table 1) were recruited from a database from the Department of Child Psychiatry from the Univer-
M. Lijffıjt et al. / European Psychiatry 21 (2006) 544–547 Table 1 Sample Characteristics n (male:female) Age in years, mean (S.D.) Weight in kg, mean (S.D.) Daily dose in mg/kg, mean (S.D.) WISC-R IQ score Total Verbal Performance ADHD subtype (# participants) Inattention Hyperactivity/impulsivity Combined Comorbid diagnosis (# participants) Anxiety ODD Parent–child relation problem None
15 (13:2) 10.74 (1.30) 37.33 (12.23) 22.67 (7.29) 97.60 (14.97) 97.93 (14.39) 97.73 (14.16) 2 2 11 6 5 2 4
sity Medical Center Utrecht consisting of children with ADHD. The study was approved by the national medical ethical committee (CCMO). Parents signed written informed consent and children gave oral consent for participation. All participants had good sight and hearing as reported by the participants and their caretakers. Participants were between 7 and 13 years of age, had an WISC-R IQ score higher than 80, had a diagnosis of ADHD according to DSM-IV criteria [1], which was confirmed by scores above the clinical range on the child behavior checklist (CBCL), the teacher’s report form (TRF), and the Conner parent and teacher rating scales (CPRS and CTRS, respectively). All participants were familiar with the intake of MPH for at least 1 year, which they refrained from taking 24 h prior to testing. Participants performed the stop and the change task 60 min after intake of placebo, 0.5 or 1.0 mg/kg MPH in a doubleblind, randomized, within-subjects, cross-over design, divided across three successive weeks in a test facility at the department of child psychiatry. They were seen on the same day at the same time each week. Although side effects were minimal (a feeling of sleepiness), four participants were too fatigued after placebo or the 1.0 mg/kg dose to continue with the change task after they first completed the stop task. Children were instructed to respond as quickly as possible with either the left or right index finger when they perceived a go-stimulus (squares consisting of thick or thin black and white bars presented for 750 ms at the center of the screen following a 500 ms warning stimulus). Furthermore, they were instructed to try to withhold the response when they heard a tone (400 ms, 80 dB at 1000 Hz, binaurally) (stop task), or to stop and react with both feet as quickly as possible when they heard a tone (change task). They were not allowed to wait for the tone to occur. Go-stimuli were followed by a blank screen (1.0–1.25 s variable inter-stimulus interval). The children started by practicing responding to the visual stimulus (60 trials), followed by a practice block containing stop trials (126 trials, including 50 stop trials). Next, four blocks were presented (each block consisted of 126 trials of which 50 were
545
stop trials). After a 15-min break participants continued with the change task in which the same procedure as in the stop task used. Each task took approximately 30 min to be completed and they were balanced across participants. The interval between the go- and stop stimulus was adjusted by the tracking procedure derived from De Jong et al. [7] in which the go–stop interval was adjusted according to the percentage of successful stops in the previous block. All trials were pseudo-randomized within blocks. There were never more than three succeeding stop trials without being followed by a go trial. Dependent variables for both tasks were stop speed (SSRT), mean RT (MRT), and within-subject standard deviation of the reaction time (SDRT). Because of the small sample size (stop task n = 15; change task n = 11), all data were analyzed using linear and quadratic trend contrasts [12]. The hypothesis for the dose–response relationship for SSRT in the stop and change task was tested for the smallest sample (n = 11). Trend analyses of the other variables were performed for the stop task only, including an additional analysis to directly test the difference between SSRT and MRT. When trends were significant Helmert contrasts were performed to test placebo against the low and high dose and to test the low dose against the high dose. Effects were considered significant when P < 0.05 (two-tailed). To study the association between stop task performance and the influence of MPH on neurotransmitter (norepinephrine, dopamine and serotonin) systems more closely, 45 min after intake of the drug (during rest) blood samples were drawn. Metabolites of these neurotransmitter systems (3methoxy-4-hydroxyphenylglycol [MHPG], homovannilic acid [HVA], and 5-hydroxyindole acetic acid [5-HIAA] levels, respectively) were correlated with SSRT, MRT, and SDRT in the stop task, separately for each dose condition (n = 12).
3. Results Trend analysis revealed a significantly linear-trend for Dose (F(1,10) = 8.82, P = 0.014), but no significant Dose * Task (stop vs. change) interaction. In the stop task, linear dose– response curves for SSRT (F(2,13) = 19.63, P < 0.005), MRT (F(2,13) = 7.7, P < 0.05), SDRT (F(2,13) = 36.16, P < 0.005) and error and omissions rate (F(2,13) = 18.09, P < 0.005, and F(2,13) = 6.58, P < 0.05, respectively) were found, indicating a general improvement of inhibitory control and attention after intake of MPH (Table 2). A direct test revealed a significant interaction between Dose (linear trend) and Measure (MRT vs. SSRT) (F(1,96,19.46) = 4.60, P < 0.05), indicating that MPH was more effective in improving SSRT than MRT. Helmert contrasts showed that SSRT after placebo intake was longer than after the intake of MPH (F(1,14) = 16.01, P < 0.005), and longer after the low dose than after the high dose (F(1,14) = 11.16, P < 0.005). For MRT, SDRT, error and omission rate, MPH led to better performance than placebo (F(1,14) = 15.19, P < 0.005,
546
M. Lijffıjt et al. / European Psychiatry 21 (2006) 544–547
Table 2 Descriptives of Stop and Change Task Performance Placebo Measure Mean S.D. Stop task (n = 15) Mean RT 621.13 89.61 SDRT 206.91 61.58 Error rate 22.09 10.99 Omission rate 9.31 7.61 SSRT 350.17 160.60 Change task (n = 11) Mean RT 667.46 139.78 SDRT 213.99 76.97 Error rate 32.01 15.63 Omission rate 9.00 8.17 SSRT 358.74 188.67 Change RT 786.71 146.00
0.5 mg/kg Mean S.D.
1.0 mg/kg Mean S.D.
579.59 161.77 14.90 4.76 251.31
88.41 58.81 6.63 4.18 91.37
566.54 146.01 11.88 4.00 210.67
89.32 60.42 7.55 5.53 92.71
616.38 160.65 17.82 2.79 296.18 778.42
101.87 78.89 11.56 2.96 94.89 163.14
622.89 155.21 15.32 2.33 261.69 785.75
106.33 69.80 8.80 2.44 74.74 190.72
S.D., standard deviation; Mean RT, mean reaction time; SDRT, withinsubject standard deviation of reaction time; SSRT, stop-signal reaction time, stop latency. Mean RT, Change RT SDRT, and SSRT are in ms; error and omission rates are in percentage.
F(1,14) = 31.00, P < 0.005, F(1,14) = 13.50, P < 0.005, and F(1,14) = 6.24, P < 0.05, respectively), but there was no difference between the two doses. Performance did not improve significantly across blocks. Blood serum analysis revealed a significant correlation between SSRT and HVA level (r = –0.68, P = 0.02) and mean RT and SDRT and MHPG level (r = –0.74, P = 0.006 and r = –0.70, P = 0.01, respectively), in the high dose condition only.
4. Discussion It was specifically hypothesized that dose-related effects on SSRT would be linear in the stop task, but that the higher (1.0 mg/kg) dose would be less optimal than the lower one (0.5 mg/kg) in the change task. However, a direct comparison between stopping and changing performance (SSRT) revealed no difference between dose–response curves, suggesting that the efficacy of MPH was not affected by task difficulty, and that previous results could be explained by differences between samples or experimental designs. Furthermore, the hypothesis that MPH affected inhibitory control by influencing attentional processes rather than inhibitory control itself was not confirmed. A direct test for the difference in dose-related effects between MRT and SSRT revealed that MPH affected speed of stopping (SSRT) more than speed of responding (MRT), suggesting a specific additional effect of MPH on inhibitory control, which could not be attributed to its effect on attention. On the other hand, Kramer et al. [9] found that MPH enhanced the rapidity to switch between tasks and to focus attention on the new relevant response set, suggesting that part of the effect of MPH on stopping may still be caused by a positive effect on switching attention. Volkow et al. [18] showed that MPH increased brain dopamine levels, which could increase the level of saliency
of an already salient task. The instruction of the current tasks gave the stop stimulus a more salient load than the go stimulus, because participants had to react to the stopping signal with another response than on most other trials. In accordance with the finding of Volkow et al., we found a significant negative correlation between blood serum dopamine and SSRT. This finding suggests that stopping is more efficient in those children with the higher increases in the levels of dopamine, possibly by increasing in saliency of the tone. Measures of attention and inhibitory control were associated with different neurotransmitter metabolite levels (under 1.0 mg/kg MPH). Attentional measures correlated more with the norepinephrine metabolite, whereas inhibition correlated more with the dopamine system. This could reflect specific relations between attention and norepinephrine and between inhibition and dopamine, which are both affected by MPH. That inhibition is affected more than attention is to our knowledge a pharmacological dissociation between the two executive functions that has not been reported before. The negative correlation between attentional measures and the neurotransmitter systems suggests that when more neurotransmitter is available, performance improves after MPH intake (shorter mean RT and SSRT and smaller SDRT), confirming previous findings of a positive correlation between CSF HVA and the improvement of the level hyperactivity after MPH intake [5,6].
5. Limitations Unfortunately, the current sample was small, reducing statistical power, especially for the results in the change task. Despite the lack of power, results are still in accordance with previous studies. Another limitation in this study is that neurotransmitter metabolites were taken from blood serum, which are less reliable than neurotransmitter levels derived from for example CSF, and which are not a direct reflection of cerebral activity.
References [1]
[2] [3]
[4]
[5]
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. Aston-Jones G, Rajkowski J, Cohen J. Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 1999;46:1309–20. Band GP, van Boxtel GJ. Inhibitory motor control in stop paradigms: review and reinterpretation of neural mechanisms. Acta Psychol (Amst) 1999;101:179–211. Bedard AC, Ickowicz A, Logan GD, Hogg-Johnson S, Schachar R, Tannock R. Selective inhibition in children with attention-deficit hyperactivity disorder off and on stimulant medication. J Abnorm Child Psychol 2003;31:315–27. Castellanos FX, Elia J, Kruesi MJP, Gulotta CS, Mefford IN, Potter WZ, et al. Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder. Psychiatry Res 1994;52:305– 16.
M. Lijffıjt et al. / European Psychiatry 21 (2006) 544–547 [6]
Castellanos FX, Elia J, Kruesi MJP, Marsh WL, Gulotta CS, Potter WZ, et al. Cerebrospinal fluid homovannilic acid predicts behavioral response to stimulants in 45 boys with attention deficit/ hyperactivity disorder. Neuropsychopharmacol 1996;14:125–37. [7] De Jong R, Coles MG, Logan GD. Strategies and mechanisms in nonselective and selective inhibitory motor control. J Exp Psychol Hum Percept Perform 1995;21:498–511. [8] Gorelova N, Seamans JK, Yang CR. Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex. J Neurophysiol 2002;88:3150–66. [9] Kramer AF, Cepeda NJ, Cepeda ML. Methylphenidate effects on task-switching performance in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2001;40:1277–84. [10] Lijffijt M, Kenemans JL, Verbaten MN, van Engeland MA. A metaanalytic review of stopping performance in attention-deficit/ hyperactivity desorder: deficient inhibitory motor control? J Abnorm Psychol 2005;114:216–22. [11] Logan GD. On the ability to inhibit thought and action: a users’ guide to the stop-signal paradigm. In: Dagenbach D, Carr TH, editors. Inhibitory processes in attention, memory, and language. San Diego: Academic Press; 1994. p. 189–239.
547
[12] Maxwell SE, Delaney HD. Designing experiments and analyzing data: a model comparison perspective. Mahwah, NJ: Lawrence Erlbaum Associates; 2000. [13] Nigg JT. Is ADHD a disinhibitory disorder? Psychol Bull 2001;127: 571–98. [14] Sergeant JA, Geurts H, Oosterlaan J. How specific is a deficit of executive functioning for attention-deficit/hyperactivity disorder? Behav Brain Res 2002;130:3–28. [15] Scheres A, Oosterlaan J, Swanson J, Morein-Zamir S, Meiran N, Schut H, et al. The effect of methylphenidate on three forms of response inhibition in boys with AD/HD. J Abnorm Child Psychol 2003;31:105–20. [16] Tannock R, Schachar RJ, Carr RP, Chajczyk D, Logan GD. Effects of methylphenidate on inhibitory motor control in hyperactive children. J Abnorm Child Psychol 1989;17:473–91. [17] Tannock R, Schachar R, Logan G. Methylphenidate and cognitive flexibility: dissociated dose effect in hyperactive children. J Abnorm Child Psychol 1995;23:235–66. [18] Volkow ND, Wang G, Fowler JS, Telang F, Maynard L, Logan J, et al. Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am J Psychiatry 2004;161:1173–80.