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: 14.48). 01/2008; 65(1):102-14. DOI: 10.1001/archgenpsychiatry.2007.16
Source: PubMed


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.

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Available from: Craig B Surman, Oct 17, 2015
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    • "Our finding is in agreement with findings from Bush et al. (2008) that utilized interference task that requires numbering process as well. Despite a consistently reported increase of striatal activation among patients with ADHD by a single dose methylphenidate treatment (Cubillo et al., 2014b; Rubia et al., 2011), present results lacking of striatal activation changes are not surprising because our results are in agreement with studies addressing effect of weeks of methylphenidate treatment (Bush et al., 2008; Schulz et al., 2012). Similar observations were reported in rodent models following 14-day treatment of methylphenidate. "
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    ABSTRACT: Methylphenidate and atomoxetine are effective in treating attention-deficit/hyperactivity disorder (ADHD) with underlying distinct pharmacological mechanisms. To relate neural mechanisms to clinical response, we conducted a comparative trial to differentiate the changes in brain activation of drug-naïve children with ADHD when performing neuropsychological tasks after 12 weeks of pharmacotherapy. We randomized 50 drug-naïve children with ADHD, aged 7-17, to treatment with methylphenidate (n=25) or atomoxetine (n=25). These children were scanned twice with functional magnetic resonance imaging (fMRI) during the counting Stroop task before and after treatment. Focused attention and impulsivity were assessed twice by using the Conner's Continuous Performance Test (CCPT). The final sample for fMRI analysis comprised 20 in the methylphenidate group and 22 in the atomoxetine group. Atomoxetine decreased activations in the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex, which correlated with improvement in focused attention assessed by the CCPT. In contrast, methylphenidate increased activations in the inferior frontal gyrus, which correlated with the decreasing severity of impulsivity assessed by the CCPT. The current findings suggest that differential therapeutic effects on neuronal changes induced by 12-week treatment atomoxetine and methylphenidate may contribute to behavioral improvement.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2015; DOI:10.1016/j.euroneuro.2015.08.024 · 4.37 Impact Factor
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    • "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. "
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    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 · 2.42 Impact Factor
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    • "The current finding of higher reported impulsivity scores which are associated with white matter alterations in MJ smokers may also be related to the crossing of fibers through the genu, connecting the left and right dorsolateral prefrontal cortex (DLPFC), which has strong interconnections to the anterior cingulate cortex (ACC; Pandya and Seltzer 1982; Park et al. 2008). Both the ACC and DLPFC are components of the cingulo-fronto-parietal cognitive attention network, which is implicated in executive control, inhibition, attention, and feedback-based decision making (Bush et al. 2008). Decreased FA in the genu of MJ smokers relative to control participants may therefore alter this network, resulting in the difficulties observed in MJ smokers with impulse control. "
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    ABSTRACT: Marijuana (MJ) use continues to rise, and as the perceived risk of using MJ approaches an all-time historic low, initiation of MJ use is occurring at even younger ages. As adolescence is a critical period of neuromaturation, teens and emerging adults are at greater risk for experiencing the negative effects of MJ on the brain. In particular, MJ use has been shown to be associated with alterations in frontal white matter microstructure, which may be related to reports of increased levels of impulsivity in this population. The aim of this study was to examine the relationship between age of onset of MJ use, white matter microstructure, and reported impulsivity in chronic, heavy MJ smokers. Twenty-five MJ smokers and 18 healthy controls underwent diffusion tensor imaging and completed the Barratt Impulsiveness Scale. MJ smokers were also divided into early onset (regular use prior to age 16) and late onset (age 16 or later) groups in order to clarify the impact of age of onset of MJ use on these variables. MJ smokers exhibited significantly reduced fractional anisotropy (FA) relative to controls, as well as higher levels of impulsivity. Earlier MJ onset was also associated with lower levels of FA. Interestingly, within the early onset group, higher impulsivity scores were correlated with lower FA, a relationship that was not observed in the late onset smokers. MJ use is associated with white matter development and reported impulsivity, particularly in early onset smokers.
    Psychopharmacology 11/2013; 231(8). DOI:10.1007/s00213-013-3326-z · 3.88 Impact Factor
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