ADHD patients did not significantly differ from controls in task performance. MPH relative to placebo had no significant ameliorating effect on task performance within patients or on the differences relative to healthy controls. Nevertheless, MPH relative to placebo had significant upregulation and normalization effects on brain activation. MPH elicited enhanced activation within ADHD patients in right inferior prefrontal and premotor cortices as well as in left cerebellum and inferior and middle temporal lobes. When patients under placebo were compared with controls, they showed reduced activation in right inferior prefrontal cortex reaching into inferior parietal lobe, in left basal ganglia and thalamus, in ventromedial and dorsomedial prefrontal, and in temporal regions. The underactivation in basal ganglia, thalamus, and ventromedial frontal lobe, furthermore, was negatively associated with symptom severity. No brain regions were increased in activation in patients relative to controls. All activation deficit clusters relative to controls remained when patients were under MPH, with the exception of the underactivation clusters in right inferior prefrontal cortex, and the symptom-severity-associated cluster in left basal ganglia/thalamus and ventromedial prefrontal cortex. Furthermore, the region-specific normalization effects were significant, given that the effect sizes of the activation differences in these two activation clusters were significantly larger for the comparison between controls and ADHD under placebo than for the comparison between controls and ADHD under MPH. The findings suggest that a single clinical dose of MPH has region-specific normalization effects on abnormal brain activation in ADHD patients in inferior and ventromedial fronto-striatal networks during interference inhibition.
Right inferior prefrontal cortex as well as the caudate and thalamus form part of a fronto-striatal network of motor and interference inhibition in adults and children (Aron and Poldrack, 2006
; Li et al, 2008
; Christakou et al, 2009a
; Rubia, 2007c
; Rubia et al, 2003
). Furthermore, the underactivation in these brain regions for ADHD patients was specific to the interference condition, as the group differences in these regions seemed to arise from the fact that control boys showed more activation in these areas for the Simon condition, whereas ADHD patients showed more activation in these regions during the Oddball condition. Inferior prefrontal underactivation in the context of tasks of cognitive control is one of the most consistent findings in fMRI studies in patients with ADHD (Dickstein et al, 2006
; Durston et al, 2003
; Konrad et al, 2006
; Rubia et al, 1999
; Vaidya et al, 1998
; for a review see Rubia (2011)
). Inferior prefrontal cortex, as well as caudate and thalamus, have, furthermore, been found to be dysfunctional in ADHD children during other, more generic attention functions such as performance monitoring (Pliszka et al, 2006
; Rubia et al, 2010a
), selective, sustained, and flexible attention tasks (Rubia et al, 2007b
; Smith et al, 2006
). Inferior prefrontal dysfunction, furthermore, appears to be a disorder-specific neurofunctional deficit compared to patients with conduct (Rubia et al, 2008
) and obsessive-compulsive disorder (Rubia et al, 2010a
), whereas striatal underactivation appears to be disorder specific relative to OCD patients (Rubia et al, 2010a
; for a review see Rubia (2010)
). In these data, furthermore, the activation in the basal ganglia cluster correlated with symptom severity, so that the ADHD patients with more severe inattention and hyperactivity symptoms had more reduced activation. MPH therefore appears to modulate an important neuro-functional biomarker of ADHD, a dysfunction in fronto-striatal neural networks that mediate cognitive control.
The findings of upregulation of activation in inferior prefrontal cortex and the basal ganglia under a single dose of MPH extend previous findings of upregulation of these brain regions in the context of other tasks. Thus, lateral prefrontal and caudate activation has previously been shown to be upregulated, but not normalized in ADHD patients with a single clinical dose of MPH during tasks of motor response inhibition (Vaidya et al, 1998
). Furthermore, our findings of a significant specific normalization effect on the activation in left basal ganglia, but not in temporal lobes, is in line with the study of Shafritz et al (2004)
, who also found a region-specific upregulation and normalization effect of MPH on left striatal underactivation, but not on the underactivation of middle temporal lobe. The finding of upregulation and normalization of right inferior prefrontal/premotor cortex with MPH is in line with strikingly similar findings of upregulation and normalization of underfunctioning relative to controls in this region in the same subjects with the same clinical dose of MPH during a sustained attention task (Rubia et al, 2009b
). The upregulation effects in right prefrontal, premotor, and left thalamic brain regions under a single dose of MPH is also in line with evidence for longer-term, chronic upregulation effects. Chronic doses of MPH over 6 weeks lead to a significant upregulation of these areas in adults with ADHD during a different interference inhibition task (Bush et al, 2008
). The findings of upregulation of fronto-striatal brain activation during interference inhibition in ADHD boys in this study, however, are not in line with a recent study of Peterson et al (2009)
, who found that MPH had no effect on fronto-striatal activation during a Stroop interference inhibition task, but enhanced activation in the control condition of the task in the ventral anterior cingulate and posterior cingulate, which was interpreted as suppression of default-mode activity.
Also, in this study, we did not observe a normalization effect of MPH on the dysfunction in medial frontal activation. Like in this study, the SMA and anterior cingulate have previously been found to be underactivated in ADHD patients during interference inhibition tasks (Bush et al, 1999
; Rubia et al, 2011
). Previous studies, however, unlike this one, found a modulation of either chronic (Bush et al, 2008
) or single doses of MPH (Vaidya et al, 1998
) on this structure during motor and interference inhibition, or on the control condition of the task (Peterson et al, 2009
). Differences in findings may be due to the differences in task design or differences in medication history, as patients were not medication naïve in these previous studies.
We observed, however, normalization in a more ventromedial frontal location. Upregulation and normalization of abnormal activation in this region has been observed in the same patient group during a time discrimination task (Rubia et al, 2009a
). Ventromedial frontal cortex is thought to be important for holding information in representational memory (Schoenbaum et al, 2006
) and has been associated with selective attention and decision making (Christakou et al, 2009b
Posterior thalamic underactivation clusters in patients relative to controls under placebo were also upregulated and normalized with MPH. Posterior thalamic brain regions have been associated both with inhibitory control (Aron and Poldrack, 2006
; Li et al, 2008
), as well as attention to salient stimuli such as oddball, novel, or incongruent targets (Rubia et al, 2007c
; Stevens et al, 2007
; Tamm et al, 2006
). The significant normalization effects in inferior and ventromedial frontal, striatal, and thalamic brain regions therefore suggest that MPH appears to normalize activation of all parts of a fronto-striato-thalamic cognitive control network (Rubia et al, 2007c
). Furthermore, this network cluster was significantly associated with symptom severity in ADHD patients. This suggests that MPH had a normalization effect on brain deficits that are associated with symptom severity, which may be the mechanism of action that underlies behavioral improvement.
The inferior frontal underactivation cluster that was normalized with the single MPH dose in patients, furthermore, reached into inferior parietal lobe in more superior slices. To our knowledge, normalization of inferior parietal activation with MPH has only recently been observed in ADHD patients, in the context of sustained attention (Rubia et al, 2009b
) and another interference inhibition task (Bush et al, 2008
MPH prevents the reuptake of catecholamines from the synaptic cleft by blocking DAT and norepinephrine transporter (NET) (Volkow et al, 1995
). In vitro
studies in animals show that MPH has high affinity for the DAT, lower affinity for the NET, and minimum affinity for the serotonin transporter (Bymaster et al, 2002
; Gatley et al, 1996
). In human kidney cells, MPH has shown to have greater affinity for NET than DAT (Eshleman et al, 1999
). Positron emission tomography (PET) studies show that MPH in healthy adults blocks 60–70% of striatal DAT in a dose-dependent manner and significantly increases levels of extracellular DA in the striatum (Schiffer et al, 2006
; Volkow et al, 1997
), as well as in frontal, thalamic, and temporal brain regions (Montgomery et al, 2007
). The upregulating effects on the caudate activation were therefore likely mediated by effects on the dopaminergic system. In frontal regions, however, studies in rats and mice have shown that MPH upregulates noradrenaline to the same or greater extent than DA (Balcioglu et al, 2009
; Berridge et al, 2006
). This is thought to be mediated by reuptake inhibition of NET, as NET in frontal regions clear up both DA and noradrenaline, given that there are few DATs in these areas (Moron et al, 2002
; Arnsten and Dudley, 2005
; Arnsten, 2006b
; Berridge et al, 2006
; Bymaster et al
, 2002; Staller and Faraone, 2007
). The effects of MPH on the inferior prefrontal activation could therefore have been associated with both DA and noradrenaline upregulation effects (Arnsten, 2006a
). Likewise, the effect on thalamic upregulation may have been mediated by blockage of NETs, as these are densely distributed in the thalamus (Hannestad et al, 2010
). Furthermore, a recent PET study showed that MPH at clinically relevant doses significantly occupies 70–80% of NETs in NET-rich regions, including cortical and thalamic areas, which is larger than the percentage of blockage that has previously been observed on DAT occupancy (Volkow et al, 1998
). As opposed to the significantly high blockage of DAT in striatal regions, however, MPH had little effect on NET in the basal ganglia (Hannestad et al, 2010
). The upregulating effects on frontal and thalamic activation, therefore, may have been mediated by enhanced DA and noradrenaline neurotransmission caused by NET blockage, whereas basal ganglia upregulation effects were more likely caused by DAT-mediated effects on DA neurotransmission.
Patients compared with controls showed no performance deficits. Evidence for performance deficits in tasks of interference inhibition is controversial in the ADHD literature (Mullane et al, 2009
; Rubia et al, 2007a
; van Mourik et al, 2005
). The negative findings may also be due to the relatively low statistical power for neuropsychological data and the use of an older adolescent age group compared with the childhood age groups previously shown to have performance deficits. The finding of no significant effects of the clinical dose of MPH on performance on the Simon task is in line with previous negative findings of an effect of MPH in the related Stroop interference inhibition task (Solanto et al, 2009
). The findings of brain dysfunctions in patients relative to controls and their upregulation and normalization in boys with ADHD under the clinical dose of MPH despite no observable performance changes show that brain activation is more sensitive than performance to detect both abnormalities and pharmacological effects. We have previously shown that adolescents with ADHD show marked brain dysfunctions despite no task impairment in this and similar inhibition tasks (Rubia et al, 1999
) and brain activation has consistently been shown to be more sensitive than behavior to show pharmacological effects of MPH in ADHD patients (Bush et al, 2008
; Konrad et al, 2006
; Peterson et al, 2009
; Rubia et al, 2009a
; Shafritz et al, 2004
A limitation of the study is the relatively small sample size. Minimum numbers of 15–20 participants have been suggested for fMRI studies (Thirion et al, 2007
). Repeated measures designs, however, are statistically more powerful than independent data sets, which makes the within-subject ANOVA more robust. It cannot be excluded, however, that with larger sample sizes upregulation or normalization effects of MPH could be found for other brain regions. The findings of region-specific normalization effects of MPH on the activation in inferior frontal lobes and the basal ganglia, therefore, need to be considered with caution until replicated in larger datasets.
Another limitation of the study is that patients were tested twice, whereas controls were only scanned once, for ethical and financial reasons. Practice effects, however, were overcome by the counterbalanced design.
Also, this experimental study investigated the effects of one single clinical dose of MPH on brain activation in medication-nïive boys with ADHD. Effects of a single acute dose of MPH are not comparable to long-term MPH treatment effects, where medication is typically titrated and given over longer periods of time. Studies of acute dosage only provide a unique probe of brief changes in catecholamine modulation that can provide insights into the effects of these brief changes on underlying brain function. The findings of this study can therefore not be transferred to elucidate underlying mechanisms of long-term clinical treatment and are hence limited in their applicability to clinical reality.
Furthermore, only male youth were included in the study to increase sample homogeneity. ADHD is more prevalent in boys (Merikangas et al, 2010
) and gender differences exist in clinical manifestation, cognitive deficits, and brain dysfunctions (Gershon, 2002
; Mahone and Wodka, 2008
; Valera et al, 2010
). The findings may therefore not generalize to the female youth population.
The task design did not include an absolute rest condition, so that the active task condition (Simon condition) was contrasted with lower-level baseline conditions (ie, oddball; congruent trials). We found that the activation differences were due to stronger activation in controls relative to ADHD patients during the active task (incongruent trials) relative to the lower-level baseline conditions. The contrast of the active task condition with an absolute baseline, such as a rest condition, could have provided additional information that might have further clarified the interaction findings. ADHD children, however, are known to differ from controls in their brain activation during the resting state (Konrad and Eickhoff, 2010
) and a resting condition may therefore not necessarily be more disambiguating than a lower-level baseline condition.
In conclusion, to our knowledge, this is the first study to show that a single clinical dose of MPH in medication-naïve youth with ADHD has a region-specific effect of significantly normalizing symptom-associated fronto-striatal underfunctioning during interference inhibition.