Areas of the Brain Modulated by Single-Dose Methylphenidate Treatment in Youth with ADHD During Task-Based fMRI: A Systematic Review

Abstract

Introduction

Attention-Deficit/Hyperactivity Disorder (ADHD) is a psychiatric disorder characterized by age-inappropriate frequency or severity of inattentive and/or hyperactive-impulsive behavior(s).¹ It is a widespread pediatric disorder, with prevalence rates ranging from 3% to 7% for American children and a world-wide prevalence of about 5% for children and adolescents.^1,2 There is now convincing evidence that in a significant number of cases, ADHD persists into late adolescence and adulthood, and that children with ADHD suffer worse social and psychiatric outcomes than normally developing peers.^3–5

A common and effective pharmacological intervention currently in use for ADHD is oral methylphenidate (MPH).⁶ Although MPH has been shown to significantly improve the behavioral symptoms associated with ADHD, the mechanism behind its therapeutic effect and its direct effects on brain function are unknown.⁷ The use of Positron Emission Tomography (PET) imaging in healthy subjects and patients with ADHD has revealed a relationship between MPH and dopamine (DA) transmission: MPH was found to inhibit DA reuptake in the striatum and thus increase extracellular concentrations of DA in this area.^8–11 This finding has led to the concept that the clinical manifestations of ADHD may result from aberrant DA signaling; MPH treatment for ADHD attempts to restore the appropriate DA balance in the brain. Further research has shown that MPH also blocks the norepinephrine transporter and increases the concentration of norepinephrine in the prefrontal cortex.^12,13 The ionizing radiation associated with PET, however, renders it unsuitable for research in children, and since electroencephalography and magnetoencephalography both yield relatively poor spatial resolution, MRI is the preferred imaging modality for children; it is non-invasive and yields high spatial resolution.

Functional MRI (fMRI) is a non-invasive imaging technique that uses changes in blood oxygenation level-dependent (BOLD) signal to discover subjects’ brain “activation”.¹⁴ In task-based fMRI, patients perform a specific task while lying in a MRI system, in order to determine which areas of their brains are activated by the given task. The change in brain activation is deduced from the change in regional BOLD signal between the task of interest and the “resting” state or “baseline” task. The differences in activation patterns between two cohorts (e.g., patients with ADHD and typically developing subjects) can then be contrasted.

Task-based fMRI has already been used extensively to characterize the differences between the activated brain areas of unmedicated patients with ADHD versus typically developing children.^15–24 The majority of these studies found a reduction in the activation of areas of the frontal lobes in patients with ADHD, suggesting dysregulation of circuits involving the prefrontal cortices as a hallmark of this disorder.^25,26 This atypical activation pattern was especially apparent when ADHD patients were asked to perform an inhibitory control task.²⁵ Other brain areas, including the basal ganglia, cerebellum, and portions of the parietal and temporal lobes have also all been found to be hypofunctional in ADHD.^24,25,27

Although many studies have sought to understand the neural underpinnings of ADHD, relatively few have addressed how its treatment with MPH works. To date, available neuroimaging data from task-based fMRI studies that examined the change(s) in brain activation experienced by children with ADHD when they were treated with MPH have not been synthesized. The goal of this systematic review is to compile the results of studies that used task-based fMRI to determine how MPH affects the neurocircuitry of pediatric patients with ADHD using. We are particularly interested in determining which areas of the brain in ADHD patients show change in neuronal activity after a single dose of MPH. In that context, we examine (1) which areas of the brain are modulated by MPH, (2) whether the areas responding to MPH are different based on the type of task being performed in the fMRI and (3) whether the changes in brain activation due to MPH correlate with clinical measures of improvement in ADHD-related symptoms. This information will advance knowledge of MPH’s effect on the brains of ADHD patients.

Methods

Journal articles for this systematic review were identified using the electronic databases PubMed and PsycINFO (1967 to 2011). The databases were searched using the following search terms: ADHD AND (methylphenidate OR MPH OR ritalin) AND (neuroimaging OR MRI OR fMRI OR BOLD OR event related). A manual review of relevant authors and journals, including the bibliographies from identified articles, was also performed.

Included studies met all of the following criteria: (1) publication in a peer-reviewed journal, (2) fMRI analysis (i.e. BOLD signal investigation) was conducted on data from children (under 18 years of age) with ADHD, (3) participants were scanned before and after a single dose of MPH medication, and these scans were directly compared as part of the neuroimaging analysis, and (4) the participants performed the same task in MRI during both on- and off-MPH sessions. Articles were excluded if they were reviews or case reports, if they were not in English, if they focused primarily on ADHD in the setting of other comorbid diseases, or if the studies were on animals or focused exclusively on adult ADHD patients. Studies that were identified by manual search or from bibliographies were subject to the same inclusion and exclusion criteria.

Data for our review were extracted from the original articles’ texts, tables, and figures. Information was gathered on study design, participants’ characteristics, ADHD diagnosis, timing and dosage of MPH, functional task type and improvement on task performance, neuroimaging methods, BOLD signal changes in response to MPH, and clinical improvement of ADHD symptoms.

Results

The original literature search produced a total of 200 abstracts, 9 of which were ultimately included for review (Figure 1). These abstracts were identified by searching PubMed and PsychINFO (1967 to 2011); 147 represented studies done with children under 18 and were written in English. Out of these 147 abstracts, 19 additional articles were excluded as case reports or reviews, leaving 128 studies that were manually reviewed. One hundred and sixteen studies did not meet all inclusion criteria; most studies were excluded because they did not use a design with on- and off-MPH medication sessions. Of the 12 eligible studies thus identified, 3 more were excluded because they did not directly compare the imaging results of ADHD subjects on- and off-MPH. The final number of studies included for review was 9.

Discussion

The purpose of this systematic review was to determine which areas of the brain are modulated by MPH medication in pediatric ADHD patients during task performance, whether these affected brain areas differ by task, and whether any of these brain areas can be linked to improvement in the clinical symptoms of ADHD.

The results of our review suggest that when patients with ADHD are given a single dose of MPH, an increase in activation primarily occurs within the frontal lobes (especially in the inferior and middle frontal gyri), the basal ganglia, and the cerebellum. Abnormalities in these regions have all been implicated in patients with ADHD. Structurally, the prefrontal cortex (which includes portions of the inferior and middle frontal gyri), the caudate (part of the basal ganglia), and the cerebellum have consistently been found to have a smaller volume in patients with ADHD than in typically developing children.³⁷ Functionally, when assessing unmedicated brain activation of patients with ADHD during task performance, less activation has been found in the frontal lobes^{15,17–22,24}, striatum^15,16,18,20, and cerebellum^24,38 in comparison to brain activation of healthy control subjects. The MPH-responsive areas of the brain in youth with ADHD discussed within this review therefore reflect areas that, both structurally and functionally, have previously been reported as abnormal in ADHD. Of the nine studies included in this review, six found that MPH at least partially normalized the activation of the brains of patients with ADHD to the levels seen in typically developing comparison subjects while performing a task.^28–33 The areas most frequently normalized were those in the basal ganglia (4 studies)^28,29,31,33 followed by the frontal lobes^31–33 and parietal lobes^30,32,33 (both found in 3 studies). Taken together, these findings indicate that MPH may help to return the brain functioning of patients with ADHD to the normal levels seen in typically developing children when performing a cognitive task.

The second goal of our systematic review was to determine if brain areas affected by MPH differed by task. When the reviewed studies were grouped by task, we found that the middle and inferior frontal gyri were the brain areas most often affected by MPH during inhibitory control task performance.^29,32–35 Similarly, the one study that used the time discrimination task found that MPH increased activation in the frontal lobes, specifically within the inferior, orbital, and medial frontal cortices, as well as within the anterior cingulate cortex.³¹ These findings differed from MPH’s effects during selective attention task performance, when the basal ganglia were most often activated.^28,30 Since only two studies used this task, it is difficult to say if these results represent the true frequency with which this area is affected. The single study that used a working memory task did not find any increase in brain activation in response to MPH, but further studies using this task may find a different result.³⁶

In healthy participants, the performance of inhibitory control tasks has been found to preferentially activate the dorsolateral prefrontal cortex (including the middle frontal gyrus), inferior frontal gyrus, anterior cingulate, and parietal cortex.³⁹ The activation within each of these areas was increased by the use of MPH in youth with ADHD in at least one of the included studies that used an inhibitory control task, but the middle and inferior frontal cortex activation was increased in almost all of these studies (4/5 studies for each). It is therefore possible that in ADHD, MPH influences the activation within the middle and inferior frontal gyri while performing an inhibitory control task. Given these neuroimaging findings, one might expect that children with ADHD would perform better on inhibitory control tasks after they receive MPH than they do without MPH; however this prediction was not borne out by our investigation. Only two of the five studies that used an inhibitory control task reported that MPH improved ADHD patients’ performance on the task (i.e. errors decreased, variability in reaction time decreased, or target discrimination increased). Although it is possible that this improvement on the task was the result of MPH medication, such an improvement could also be due to practice. In one of these two studies, patients with ADHD went through two imaging sessions, whereas healthy participants were scanned only once; thus it is possible that the ADHD patients improved on the task because they performed it more than once. In the other of these two studies, both ADHD patients and healthy participants were given MPH and imaged twice, and both improved on task performance. It is therefore difficult to determine whether or not this improvement was due to practice or medication. Furthermore, neither of these two studies reported that MPH normalized the activation within ADHD patient’s frontal lobes to the levels seen in typically developing children: in one of these 2 studies, medicated ADHD patients’ brain activations were not directly compared to the typically developing control group, and in the other, normalizations of brain activation within the basal ganglia were found. It is therefore possible that MPH’s effects on areas of the frontal lobe are insufficient to improve inhibitory control task performance or that the power of the studies was insufficient to capture improved task performance.

Similar to the inhibitory control task, the time discrimination task has been found to preferentially activate the dorsolateral prefrontal cortex, inferior frontal gyrus, and cerebellum during performance by healthy adults.⁴⁰ In the single included study that used this type of task, activation in the inferior, orbital, and medial frontal gyrus, the anterior cingulate gyrus, and the cerebellum was increased by MPH administration during task performance in patients with ADHD. MPH normalized all these areas of ADHD patients’ brains to the activation levels seen in typically developing children, but patients with ADHD did not commit significantly fewer errors on task when they were treated with MPH. This may indicate that MPH does not have a powerful enough effect to improve time discrimination task performance. It is possible, however, that the number of patients with ADHD included in this single study (12 boys) was too small to capture a statistically significant difference in task performance.

In contrast to inhibitory control and time discrimination tasks — which selectively activate areas mostly in the frontal lobe — selective attention tasks, including visual and auditory attention tasks and the continuous performance task, have been found to activate a wide range of brain regions, including portions of the frontal, parietal, temporal, and occipital lobes, as well as the cerebellum and basal ganglia.^41,42 Although at least one of the two selective attention studies included in this review found that MPH increased brain activation in the frontal, parietal, and occipital lobes, as well as the basal ganglia and cerebellum, neither of these studies found increased activation in the temporal lobes.^28,30 Therefore, MPH may not work in this region during performance of a selective attention task. Both of the included studies reported increased activation in the basal ganglia in response to MPH, but only one study showed normalization to healthy control levels in this area.²⁸ Neither of these studies found that MPH improved how well patients with ADHD performed on the task, which again maybe an issue of insufficient power.

Finally, this review included a single study that assessed working memory; this study found no increase in brain activation in response to MPH. With only a single study to consider, no definite conclusions about the nature of MPH’s effects during working memory task performance can be made.

The last goal of this review was to determine if brain regions affected by MPH could be related to improvement in clinical ADHD symptoms. We found that none of the included studies reported measurements of the severity of ADHD symptoms before and after MPH medication administration. We were therefore unable to compare brain regions of interest between studies that found clinical improvement and those that did not. Previous work has shown, however, that MPH ameliorates the symptoms of ADHD. The landmark Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder revealed that medication management with MPH effectively reduced inattentive and hyperactive symptoms of ADHD.⁴³ In this study, participants received individually-titrated doses of MPH, starting (on average) at ∼12 mg. The doses of MPH reported in this review are comparable to that amount (the lowest dose in the reviewed studies was 10 mg). We therefore speculate that had ADHD symptoms been recorded as part of the reviewed studies, improvement in these symptoms were possible.

Though it was not an explicit goal of this review, we also examined the effect of previous medication status on brain activation in response to MPH. When the included studies were grouped based on whether or not ADHD participants had received stimulant medication prior to the reported study, it became evident that there was a difference in MPH-induced brain activation patterns between the stimulant naïve and non-naïve groups. In response to MPH, studies that used stimulant naïve participants reported an increase in activation –in the inferior frontal cortex, parietal lobes, temporal lobes, occipital lobes, and cerebellum — more often than studies that used non-naïve participants. This result may indicate that these areas of the brain are more responsive to initial MPH treatment but, over time, become less sensitive to the medication’s effects. Alternatively, chronic treatment with MPH may increase baseline activation of these areas such that the difference between signal on- and off-MPH treatment scan sessions is no longer evident. This possibility is supported by a SPECT study that found chronic MPH treatment improved cerebral blood flow to frontal and temporal lobes in patients with ADHD; these changes were still detectable two months after discontinuation of MPH.⁴⁴ It is therefore possible that after a period of treatment with MPH, tonic blood flow to brain areas affected by MPH is increased. This permanently increased blood flow would then translate to increased blood oxygenation levels in these areas, resulting in readings of higher brain activation at baseline, i.e. the pre-MPH (single dose) imaging session. However, results from the only study that has assessed the chronic effects of MPH in pediatric patients with ADHD using fMRI analysis do not corroborate these findings: following one year of MPH treatment, boys with ADHD did not show increased neural activity during the performance of tasks designed to assess executive (inhibitory) control and selective attention compared to the pre-treatment imaging session.⁴⁵

This review has focused exclusively on pediatric neuroimaging, but there is considerable interest in the effects of MPH on adult ADHD patients’ brain activity, given that ADHD persists into adulthood in 15 – 65% of childhood cases, depending on diagnostic criteria.³ In one of the studies included in this review, MPH’s effects were reported on both child and adult groups of child-parent dyads diagnosed with ADHD.³⁴ This study used an inhibitory control task, and found that although areas of the frontal lobes, striatum, and cerebellum showed increased activity in the children in response to MPH, only the striatum (specifically the caudate) showed increased activation in the adults. By contrast, a study that examined the activation of the dorsal anterior midcingulate cortex (part of the frontal lobe) in adults while performing an inhibitory control task (the multi-source interference task) found that after six weeks of treatment with MPH, activation in this area increased, in comparison to the placebo-treated group.⁴⁶ This study also found that MPH treatment increased activation in the dorsolateral prefrontal and pre-motor cortex (portions of the superior, middle, and inferior frontal gyri), parietal cortex, striatum (specifically the caudate), cerebellum, and thalamus, compared to placebo. With only two studies to consider, it is difficult to state whether adults with ADHD exhibit similar brain activation responses to MPH as children with ADHD. However, both of these studies with adult participants agree that MPH increases the brain activation during inhibitory control task performance within the striatum, specifically within the caudate.

The major limitation of this systematic review is the small number of studies it included. To date, only nine studies have examined how a single-dose of MPH affects the brain response during task performance in youth with ADHD. These nine studies employed only four types of task, which limits the applicability of this review to other types of tasks. Another limitation of this systematic review is the fact that four of our included studies^30–33 were published by the same first author; insofar as those studies included overlapping patient populations, they would not represent independent contributions to the review. In addition, this review reported the general anatomical brain areas, rather than Brodmann Areas or Talairach Coordinates. Although all included papers described the anatomical locations of BOLD signal changes, only some reported Brodmann Areas or Talairach Coordinates, making it difficult to universally compare these more specific regions of interest. Finally, many of the included studies were not specific about the multiple comparison corrections applied in their analysis, which may affect the validity of the findings.

The results of this systematic review point to several areas of future research. As none of the included studies examined the relationship between ADHD symptom improvement and BOLD brain activation in response to MPH, this component would be an important one to include in future studies. Another avenue for future research may lie in investigating MPH’s effect on functional connectivity, either during task performance or the resting state. The current studies reveal the effects of MPH on functional brain activation, while a connectivity analysis would lead to a better understanding regarding the underlying neural networks. The nine studies included in this review focused mostly on the MPH-induced functional activation differences in the brains of youth with ADHD. One of these studies, however, also examined the changes in brain functional connectivity during selective attention task performance. That study found that MPH normalized all intercorrelation differences between children with ADHD and healthy control children, providing more insight into the possible effects of MPH administration on brain networks. Future studies that also examine these functional connectivity responses to MPH may help expand understanding of this drug’s effects.

In conclusion, children with ADHD showed changes in brain activation due to a single-dose of MPH especially within frontal lobes, basal ganglia, and cerebellum. MPH appears to more frequently affect regions of the frontal lobes during inhibitory control tasks compared to those assessing selective attention. By contrast, during selective attention tasks, MPH results in an increase in activation in a wider range of areas, including parts of the parietal and occipital lobes, as well as the cerebellum and basal ganglia. These regions correspond to those that exhibit typical activation patterns during task performance by typically developing participants and may provide evidence that MPH facilitates the return of brain function in ADHD patients to, or close to, a “typically” functioning state. As it stands, the existing literature supports the notion that MPH helps normalize brain activation, specifically within the frontal lobes, basal ganglia, and cerebellum, but whether or not the activation of these areas correlates with ADHD symptom improvement has yet to be demonstrated.

Acknowledgments

Footnotes

References