Functional Magnetic Resonance Imaging of Methylphenidate and Placebo in Attention-Deficit/Hyperactivity Disorder During the Multi-Source Interference Task

Departments of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
Archives of general psychiatry (Impact Factor: 13.75). 01/2008; 65(1):102-14. DOI: 10.1001/archgenpsychiatry.2007.16
Source: PubMed

ABSTRACT Previous studies have reported hypofunction, structural abnormalities, and biochemical abnormalities of the dorsal anterior midcingulate cortex (daMCC) in attention-deficit/hyperactivity disorder (ADHD). Stimulant medications are effective treatments for ADHD, but their neural effects have not been fully characterized.
To determine whether the methylphenidate hydrochloride osmotic-release oral system (OROS) would increase functional magnetic resonance imaging (fMRI) activation, compared with placebo, in the daMCC and other frontoparietal regions subserving attention during the Multi-Source Interference Task (MSIT).
Randomized, placebo-controlled, 6-week, before-after fMRI study.
Academic medical center ambulatory clinic.
Twenty-one adults with ADHD randomized to 6 weeks of treatment with methylphenidate OROS (n = 11) or placebo (n = 10).
Patients underwent fMRI twice while performing the MSIT (scan 1 at baseline and scan 2 at 6 weeks).
Group-averaged, random-effects, repeated-measures, general linear model analyses were used to compare daMCC (and whole-brain) fMRI activation during the MSIT. Individual-based daMCC volume-of-interest confirmatory analyses and behavioral data are also presented.
Performance and baseline fMRI measures in the daMCC and other a priori brain regions did not differ between groups. Group comparisons showed a group x scan interaction and t test confirmation of higher activation in the daMCC at 6 weeks in the methylphenidate OROS group than in the placebo group (P < 1 x 10(-4), cluster corrected for multiple comparisons). Individual daMCC volume-of-interest analyses confirmed group-averaged findings and suggested that daMCC activity might be related to clinical response. Methylphenidate OROS also produced higher activation in the dorsolateral prefrontal cortex and the parietal cortex at 6 weeks.
Methylphenidate OROS increased daMCC activation during the MSIT and may act, in part, by normalizing daMCC hypofunction in ADHD.

  • Source
    • "However, the degree to which the brain 0 s response curve follows the plasma concentration curve is entirely unknown. We chose 75 min because this is when the slope of the plasma concentration curve begins to flatten out, and because most prior studies of behavior and/or neuroimaging have used between 60 and 90 min from dosage to testing as the delay period (Barry et al., 2009; Chamberlain et al., 2009; Dodds et al., 2008; Peterson et al., 2009; Rubia et al., 2009a, 2009b; Wienbruch et al., 2005; Wilson et al., 2012; for an exception, see Bush et al. (2008)). Thus, 75 min was near the middle of the " standard " window. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The ability to attend to particular stimuli while ignoring others is crucial in goal-directed activities and has been linked with prefrontal cortical regions, including the dorsolateral prefrontal cortex (DLPFC). Both hyper- and hypo-activation in the DLPFC has been reported in patients with attention-deficit/hyperactivity disorder (ADHD) during many different cognitive tasks, but the network-level effects of such aberrant activity remain largely unknown. Using magnetoencephalography (MEG), we examined functional connectivity between regions of the DLPFC and the modality-specific auditory cortices during an auditory attention task in medicated and un-medicated adults with ADHD, and those without ADHD. Participants completed an attention task in two separate sessions (medicated/un-medicated), and each session consisted of two blocks (attend and no-attend). All MEG data were coregistered to structural MRI, corrected for head motion, and projected into source space. Subsequently, we computed the phase coherence (i.e., functional connectivity) between DLPFC regions and the auditory cortices. We found that un-medicated adults with ADHD exhibited greater phase coherence in the beta (14–30 Hz) and gamma frequency (30–56 Hz) range in attend and no-attend conditions compared to controls. Stimulant medication attenuated these differences, but did not fully eliminate them. These results suggest that aberrant bottom-up processing may engulf executive resources in ADHD.
    Psychiatry Research Neuroimaging 03/2014; 221(3). DOI:10.1016/j.pscychresns.2014.01.002 · 2.83 Impact Factor
  • Source
    • "Stoy et al. (2011) examined the effect of MPH treatment during childhood on differences in brain activation during reward processing using a monetary incentive delay task in adult ADHD. With OROS-MPH, although treatment for 6 weeks has been found to increase activity in brain regions related to attention (Bush et al., 2008), the effect of relatively long treatment periods on neural processes for reward has not been investigated yet. Here, we examined whether a 3-month OROS-MPH treatment is associated with stable changes in neural activity related to reward sensitivity in ADHD children and adolescents using a longitudinal evaluation encompassing the pre-to post-treatment period, with a concurrent comparison to normally developing children and adolescents. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is neurobehavioral disorder characterized by inattention, hyperactivity/impulsivity and impaired reward system function, such as delay aversion and low reward sensitivity. The pharmacological treatment for ADHD includes methylphenidate (MPH), or osmotic release oral system-MPH (OROS-MPH), which increases extrasynaptic dopamine and noradrenaline levels by blocking their reuptake. Although previous functional magnetic resonance imaging (fMRI) studies revealed that acute treatment with MPH alters activation of the nucleus accumbens during delay aversion in children and adolescents with ADHD, the effects a relatively long period of OROS-MPH treatment on delay aversion as well as reward sensitivity remain unclear. Thus, we evaluated brain activation with fMRI during a reward sensitivity paradigm that consists of high monetary reward and low monetary reward conditions before and after a 3-month treatment with OROS-MPH in 17 children and adolescents with ADHD (mean age, 13.3 ± 2.2) and 17 age- and sex-matched healthy controls (mean age, 13.0 ± 1.9). We found that before treatment there was decreased activation of the nucleus accumbens and thalamus in patients with ADHD during only the low monetary reward condition, which was improved to same level as those of the healthy controls after the treatment. The observed change in brain activity was associated with improved ADHD symptom scores, which were derived from Japanese versions of the ADHD rating scale-IV. These results suggest that treatment with OROS-MPH for a relatively long period is effective in controlling reward sensitivity in children and adolescents with ADHD.
    03/2013; 2:366-76. DOI:10.1016/j.nicl.2013.03.004
  • Source
    • "MPH acts by blocking the DAT, which prevents the reuptake of DA by the presynaptic neuron and thus increases DA concentration in the synaptic cleft. Oral MPH challenges have been used in fMRI investigations involving both healthy and ADHD populations (Shafritz et al., 2004; Bush et al., 2008; Schlosser et al., 2009; Rubia et al., 2009), but not dAMPH users. MPH normalized brain responses in ADHD patients on inhibitory tasks (Vaidya et al., 1998; Liddle et al., 2011) as well as reward-related tasks (Wilkison et al., 1995; Rubia et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Dopamine (DA) is involved in systems governing motor actions, motivational processes and cognitive functions. Preclinical studies have shown that even relatively low doses of d-amphetamine (dAMPH) (equivalent to doses used in clinical Practice) can lead to DA neurotoxicity in rodents and non-human primates (Ricaurte et al., 2005). METHODS: Therefore, we investigated the DAergic function in eight male recreational users of dAMPH and eight male healthy controls using functional magnetic resonance imaging (fMRI). We compared brain activation between both groups during a monetary incentive delay task (Knutson et al., 2001) with and without an oral methylphenidate (MPH) challenge. All subjects were abstinent for at least 2 weeks during the baseline scan. The second scan was performed on the same day 1.5h after receiving an oral dose of 35mg MPH (approximately 0.5mg/kg) when peak MPH binding was assumed. RESULTS: When anticipating reward, dAMPH users showed lower striatal activation in comparison to control subjects. In addition, MPH induced a reduction in the striatal activation during reward anticipation in healthy controls, whereas no such effect was observed in dAMPH users. CONCULSION: The combination of these findings provides further evidence for frontostriatal DAergic dysfunction in recreational dAMPH users and is consistent with preclinical data suggesting neurotoxic effects of chronic dAMPH use. The findings of this explorative study could have important implications for humans in need for treatment with dAMPH, such as patients suffering from ADHD and therefore this study needs replication in a larger sample.
    Drug and alcohol dependence 11/2012; 130(1-3). DOI:10.1016/j.drugalcdep.2012.10.010 · 3.28 Impact Factor
Show more


Available from