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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Available from: Alan Charles Evans, Oct 07, 2015
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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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    • "However there is evidence that stimulants may normalise both brain function (e.g. Rubia et al. 2009) and aspects of WM (Castellanos et al. 2002) and GM (Nakao et al. 2011) macrostructure, including the trajectory of cortical development (Shaw et al. 2009). Many ADHD diffusion studies have included pharmacologically-treated participants although they have varied in the requirement for a washout/withholding period. "
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    ABSTRACT: Traits of autism spectrum disorder (ASD) in children with attention-deficit/hyperactivity disorder (ADHD) have previously been found to index clinical severity. This study examined the association of ASD traits with diffusion parameters in adolescent males with ADHD (n = 17), and also compared WM microstructure relative to controls (n = 17). Significant associations (p < 0.05, corrected) were found between fractional anisotropy/radial diffusivity and ASD trait severity (positive and negative correlations respectively), mostly in the right posterior limb of the internal capsule/corticospinal tract, right cerebellar peduncle and the midbrain. No case-control differences were found for the diffusion parameters investigated. This is the first report of a WM microstructural signature of autistic traits in ADHD. Thus, even in the absence of full disorder, ASD traits may index a distinctive underlying neurobiology in ADHD.
    Journal of Autism and Developmental Disorders 05/2014; 44(11). DOI:10.1007/s10803-014-2131-9 · 3.06 Impact Factor
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    • "Most (clinical) studies are hampered by the fact that they are retrospective in design, and therefore the findings could be caused by other factors on which the groups differed. As pointed out by Shaw and colleagues: ‘….the ideal study design for this question would be a randomized trial comparing cortical growth in children on psychostimulants against an unmedicated comparison group—but this would be both logistically and ethically challenging’ [13]. Notwithstanding this challenge, we have set up three studies (the effects of Psychotropic drugs On the Developing brain ‘ePOD’ project): two randomized controlled trials (RCTs) and a retrospective cohort study, investigating the possibility of the existence of neuronal imprinting in children medicated with these drugs while using several modalities to assess neurocognitive development. "
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    ABSTRACT: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of different approaches to determine whether there are related findings in humans. Animal studies were carried out to investigate age-related effects of psychotropic drugs and to validate new neuroimaging techniques. In addition, we set up two double-blind placebo controlled clinical trials with MPH in 50 boys (10-12 years) and 50 young men (23-40 years) suffering from ADHD (ePOD-MPH) and with FLX in 40 girls (12-14 years) and 40 young women (23-40 years) suffering from depression and anxiety disorders (ePOD-SSRI). Trial registration numbers are: Nederlands Trial Register NTR3103 and NTR2111. A cross-sectional cohort study on age-related effects of these psychotropic medications in patients who have been treated previously with MPH or FLX (ePOD-Pharmo) is also ongoing. The effects of psychotropic drugs on the developing brain are studied using neuroimaging techniques together with neuropsychological and psychiatric assessments of cognition, behavior and emotion. All assessments take place before, during (only in case of MPH) and after chronic treatment. The combined results of these approaches will provide new insight into the modulating effect of MPH and FLX on brain development.
    BMC Psychiatry 02/2014; 14(1):48. DOI:10.1186/1471-244X-14-48 · 2.21 Impact Factor
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