Psychostimulant Treatment and the Developing Cortex in Attention Deficit Hyperactivity Disorder

Child Psychiatry Branch, Bldg. 10, Center Dr., NIMH, Bethesda, MD 20892, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 10/2008; 166(1):58-63. DOI: 10.1176/appi.ajp.2008.08050781
Source: PubMed


While there has been considerable concern over possible adverse effects of psychostimulants on brain development, this issue has not been examined in a prospective study. The authors sought to determine prospectively whether psychostimulant treatment for attention deficit hyperactivity disorder (ADHD) was associated with differences in the development of the cerebral cortex during adolescence.
Change in cortical thickness was estimated from two neuroanatomic MRI scans in 43 youths with ADHD. The mean age at the first scan was 12.5 years, and at the second scan, 16.4 years. Nineteen patients not treated with psychostimulants between the scans were compared with an age-matched group of 24 patients who were treated with psychostimulants. Further comparison was made against a template derived from 620 scans of 294 typically developing youths without ADHD.
Adolescents taking psychostimulants differed from those not taking psychostimulants in the rate of change of the cortical thickness in the right motor strip, the left middle/inferior frontal gyrus, and the right parieto-occipital region. The group difference was due to more rapid cortical thinning in the group not taking psychostimulants (mean cortical thinning of 0.16 mm/year [SD=0.17], compared with 0.03 mm/year [SD=0.11] in the group taking psychostimulants). Comparison against the typically developing cohort without ADHD showed that cortical thinning in the group not taking psychostimulants was in excess of age-appropriate rates. The treatment groups did not differ in clinical outcome, however.
These findings show no evidence that psychostimulants were associated with slowing of overall growth of the cortical mantle.

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    • "Diffusion MRI (dMRI) is a powerful neuroimaging technique used to examine microstructural brain properties and connections (Basser, Pajevic, Pierpaoli, Duda, & Aldroubi, 2000; O'Donnell & Pasternak, 2014; Weyandt, Swentosky, & Gudmundsdottir, 2013). In ADHD there is evidence for alterations of white matter fiber tracts and structures encompassing inferior and superior longitudinal fasciculus, cingulum bundle, anterior corona radiata, internal capsule, forceps minor, cerebellar tracts, thalamic radiation and isthmus of corpus callosum (Kobel et al., 2010; Konrad et al., 2010; Makris, Biederman, Monuteaux, & Seidman, 2009; Pavuluri et al., 2009; Peterson et al., 2011; Silk, Vance, Rinehart, Bradshaw, & Cunnington, 2009; Weyandt et al., 2013; Zhang & Li, 2010), however, results lack consistency (for reviews, see Cao et al., 2014; van Ewijk, Heslenfeld, Zwiers, Buitelaar, & Oosterlaan, 2012; Weyandt et al., 2013). Region of interest (ROI) studies typically report lower fractional anisotropy (FA; a measure of white matter integrity) in ADHD, while wholebrain studies find the opposite result (Ashtari et al., 2005; Davenport, Karatekin, White, & Lim, 2010; Konrad et al., 2010; Nagel et al., 2011; Zhang & Li, 2010), perhaps because these include a larger set of brain regions containing so-called " crossing fibers " . "
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    ABSTRACT: Prior studies demonstrate altered organisation of functional brain networks in attentiondeficit/hyperactivity disorder (ADHD). However, the structural underpinnings of these functional disturbances are poorly understood. In the current study, we applied a graphtheoretic approach to whole-brain diffusion magnetic resonance imaging data to investigate the organisation of structural brain networks in adults with ADHD and unaffected controls using deterministic fibre tractography. Groups did not differ in terms of global network metrics - small-worldness, global efficiency and clustering coefficient. However, there were widespread ADHD-related effects at the nodal level in relation to local efficiency and clustering. The affected nodes included superior occipital, supramarginal, superior temporal, inferior parietal, angular and inferior frontal gyri, as well as putamen, thalamus and posterior cerebellum. Lower local efficiency of left superior temporal and supramarginal gyri was associated with higher ADHD symptom scores. Also greater local clustering of right putamen and lower local clustering of left supramarginal gyrus correlated with ADHD symptom severity. Overall, the findings indicate preserved global but altered local network organisation in adult ADHD implicating regions underpinning putative ADHD-related neuropsychological deficits.
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    • "These observations were further supported by structural (Shaw et al., 2009) and functional (Pliszka et al., 2006) neuroimaging studies comparing medication-naïve children (Pliszka et al., 2006) and adolescents (Shaw et al., 2009) to their treated counterparts. In a prospective study, Bush et al. (2008) also found increased left IFG activation after treatment with methylphenidate for 6 weeks in adults with ADHD. "
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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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    • "Grey matter volumes are only one among different possible indicators of brain structure, along with cortical thickness, surface area and cortical gyrification (Winkler et al., 2009). One longitudinal study examined change in cortical thickness in medicated and never-medicated adolescents with ADHD when compared to TD adolescents, and found an excessive rate of cortical thinning in the right motor strip, the left middle/inferior frontal gyrus and the right parieto-occipital region in the never-medicated group only (Shaw et al., 2009). In a larger sample encompassing the participants recruited in this study, no significant differences in cortical thickness were detected at study entrance when comparing medicated and never-medicated children with ADHD, except in a small region in the anterior temporal cortex (Shaw et al., 2006). "
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    ABSTRACT: Psychostimulants are the first-line treatment in attention deficit/hyperactivity disorder (ADHD), but their effects on brain development remain poorly understood. In particular, previous structural magnetic resonance imaging (sMRI) studies only investigated treatment effects on grey matter (GM) volumes in selected regions of interest (ROIs). In this study, voxel-based morphometry (VBM) was used to assess medication-related GM volume differences across the entire brain. Automated tracing measurements of selected ROIs were also obtained. Three groups (77 participants aged 7-to-13 year old) underwent MRI scans and were compared: never-medicated children with ADHD (n=33), medicated (methylphenidate) children with ADHD (n=20) and typically developing children (TD; n=24). Optimised VBM was used to investigate regional GM volumes, controlling for age and gender. Automated tracing procedures were also used to assess the average volume of the caudate nucleus, the amygdala and the nucleus accumbens. When compared to both medicated children with ADHD and TD children, never-medicated children with ADHD exhibited decreased GM volume in the insula and in the middle temporal gyrus. When compared to TD children, medicated children with ADHD had decreased GM volume in the middle frontal gyrus and in the precentral gyrus. Finally, ROI analyses revealed a significant association between duration of treatment and GM volume of the left nucleus accumbens in medicated children with ADHD. In conclusion, this study documents potential methylphenidate-related GM volume normalization and deviation in previously unexplored brain structures, and reports a positive association between treatment history and GM volume in the nucleus accumbens, a key region for reward-processing. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 04/2015; 25(8). DOI:10.1016/j.euroneuro.2015.04.015 · 4.37 Impact Factor
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