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Differential effects of methylphenidate and atomoxetine on intrinsic brain activity in children with attention deficit hyperactivity disorder

  • C. Y. Shang (a1), C. G. Yan (a2) (a3), H. Y. Lin (a1), W. Y. Tseng (a4) (a5), F. X. Castellanos (a2) (a3) and S. S. Gau (a1) (a4)...

Abstract

Background

Methylphenidate and atomoxetine are commonly prescribed for treating attention deficit hyperactivity disorder (ADHD). However, their therapeutic neural mechanisms remain unclear.

Method

After baseline evaluation including cognitive testing of the Cambridge Neuropsychological Test Automated Battery (CANTAB), drug-naive children with ADHD (n = 46), aged 7–17 years, were randomly assigned to a 12-week treatment with methylphenidate (n = 22) or atomoxetine (n = 24). Intrinsic brain activity, including the fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo), was quantified via resting-state functional magnetic resonance imaging at baseline and week 12.

Results

Reductions in inattentive symptoms were related to increased fALFF in the left superior temporal gyrus and left inferior parietal lobule for ADHD children treated with methylphenidate, and in the left lingual gyrus and left inferior occipital gyrus for ADHD children treated with atomoxetine. Hyperactivity/impulsivity symptom reductions were differentially related to increased fALFF in the methylphenidate group and to decreased fALFF in the atomoxetine group in bilateral precentral and postcentral gyri. Prediction analyses in the atomoxetine group revealed negative correlations between pre-treatment CANTAB simple reaction time and fALFF change in the left lingual gyrus and left inferior occipital gyrus, and positive correlations between pre-treatment CANTAB simple movement time and fALFF change in bilateral precentral and postcentral gyri and left precuneus, with a negative correlation between movement time and the fALFF change in the left lingual gyrus and the inferior occipital gyrus.

Conclusions

Our findings suggest differential neurophysiological mechanisms for the treatment effects of methylphenidate and atomoxetine in children with ADHD.

Copyright

Corresponding author

*Address for correspondence: S. S. Gau, M.D., Ph.D., Department of Psychiatry, National Taiwan University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan. (Email: gaushufe@ntu.edu.tw) [S.S.G] (Email: francisco.castellanos@nyumc.org) [F.X.C.]

References

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Ahrendts, J, Rusch, N, Wilke, M, Philipsen, A, Eickhoff, SB, Glauche, V, Perlov, E, Ebert, D, Hennig, J, van Elst, LT (2011). Visual cortex abnormalities in adults with ADHD: a structural MRI study. World Journal of Biological Psychiatry 12, 260270.
An, L, Cao, QJ, Sui, MQ, Sun, L, Zou, QH, Zang, YF, Wang, YF (2013 a). Local synchronization and amplitude of the fluctuation of spontaneous brain activity in attention-deficit/hyperactivity disorder: a resting-state fMRI study. Neuroscience Bulletin 29, 603613.
An, L, Cao, XH, Cao, QJ, Sun, L, Yang, L, Zou, QH, Katya, R, Zang, YF, Wang, YF (2013 b). Methylphenidate normalizes resting-state brain dysfunction in boys with attention deficit hyperactivity disorder. Neuropsychopharmacology 38, 12871295.
Biederman, J, Mick, E, Surman, C, Doyle, R, Hammerness, P, Harpold, T, Dunkel, S, Dougherty, M, Aleardi, M, Spencer, T (2006). A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biological Psychiatry 59, 829835.
Biswal, B, Yetkin, FZ, Haughton, VM, Hyde, JS (1995). Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magnetic Resonance in Medicine 34, 537541.
Capotosto, P, Babiloni, C, Romani, GL, Corbetta, M (2009). Frontoparietal cortex controls spatial attention through modulation of anticipatory alpha rhythms. Journal of Neuroscience 29, 58635872.
Castellanos, FX, Proal, E (2012). Large-scale brain systems in ADHD: beyond the prefrontal-striatal model. Trends in Cognitive Sciences 16, 1726.
Cheng, W, Ji, X, Zhang, J, Feng, J (2012). Individual classification of ADHD patients by integrating multiscale neuroimaging markers and advanced pattern recognition techniques. Frontiers in Systems Neuroscience 6, 58.
Cubillo, A, Smith, AB, Barrett, N, Giampietro, V, Brammer, M, Simmons, A, Rubia, K (2014 a). Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory. Psychological Medicine 44, 633646.
Cubillo, A, Smith, AB, Barrett, N, Giampietro, V, Brammer, MJ, Simmons, A, Rubia, K (2014 b). Shared and drug-specific effects of atomoxetine and methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys. Cerebral Cortex 24, 174185.
Del Campo, N, Chamberlain, SR, Sahakian, BJ, Robbins, TW (2011). The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biological Psychiatry 69, e145e157.
Dickstein, SG, Bannon, K, Castellanos, FX, Milham, MP (2006). The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis. Journal of Child Psychology and Psychiatry 47, 10511062.
DuPaul, GJ, Power, TJ, Anastopoulos, AD, Reid, R (1998). ADHD Rating Scale-IV: Checklists, Norms, and Clinical Interpretations. Guilford: New York.
Elliott, GR, Blasey, C, Rekshan, W, Rush, AJ, Palmer, DM, Clarke, S, Kohn, M, Kaplan, C, Gordon, E (2014). Cognitive testing to identify children with ADHD who do and do not respond to methylphenidate. Journal of Attention Disorders. Published online: 13 August 2014. doi:10.1177/1087054714543924.
Faries, DE, Yalcin, I, Harder, D, Heiligenstein, J (2001). Validation of the ADHD Rating Scale as a clinician administered and scored instrument. Journal of Attention Disorders 5, 3947.
Fox, MD, Raichle, ME (2007). Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nature Reviews 8, 700711.
Gamo, NJ, Wang, M, Arnsten, AF (2010). Methylphenidate and atomoxetine enhance prefrontal function through alpha2-adrenergic and dopamine D1 receptors. Journal of the American Academy of Child and Adolescent Psychiatry 49, 10111023.
Gau, SS, Huang, YS, Soong, WT, Chou, MC, Chou, WJ, Shang, CY, Tseng, WL, Allen, AJ, Lee, P (2007). A randomized, double-blind, placebo-controlled clinical trial on once-daily atomoxetine in Taiwanese children and adolescents with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology 17, 447460.
Gau, SS, Shang, CY (2010 a). Executive functions as endophenotypes in ADHD: evidence from the Cambridge Neuropsychological Test Battery (CANTAB). Journal of Child Psychology and Psychiatry 51, 838849.
Gau, SS, Shang, CY (2010 b). Improvement of executive functions in boys with attention deficit hyperactivity disorder: an open-label follow-up study with once-daily atomoxetine. International Journal of Neuropsychopharmacology 13, 243256.
Gilbert, DL, Isaacs, KM, Augusta, M, Macneil, LK, Mostofsky, SH (2011). Motor cortex inhibition: a marker of ADHD behavior and motor development in children. Neurology 76, 615621.
Han, DD, Gu, HH (2006). Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacology 6, 6.
Hannestad, J, Gallezot, JD, Planeta-Wilson, B, Lin, SF, Williams, WA, van Dyck, CH, Malison, RT, Carson, RE, Ding, YS (2010). Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo . Biological Psychiatry 68, 854860.
Jenkinson, M, Bannister, P, Brady, M, Smith, S (2002). Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 17, 825841.
Kratochvil, CJ, Heiligenstein, JH, Dittmann, R, Spencer, TJ, Biederman, J, Wernicke, J, Newcorn, JH, Casat, C, Milton, D, Michelson, D (2002). Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. Journal of the American Academy of Child and Adolescent Psychiatry 41, 776784.
Luciana, M, Nelson, CA (1998). The functional emergence of prefrontally-guided working memory systems in four- to eight-year-old children. Neuropsychologia 36, 273293.
Marquand, AF, De Simoni, S, O'Daly, OG, Williams, SC, Mourao-Miranda, J, Mehta, MA (2011). Pattern classification of working memory networks reveals differential effects of methylphenidate, atomoxetine, and placebo in healthy volunteers. Neuropsychopharmacology 36, 12371247.
Marquand, AF, O'Daly, OG, De Simoni, S, Alsop, DC, Maguire, RP, Williams, SC, Zelaya, FO, Mehta, MA (2012). Dissociable effects of methylphenidate, atomoxetine and placebo on regional cerebral blood flow in healthy volunteers at rest: a multi-class pattern recognition approach. Neuroimage 60, 10151024.
Montoya, A, Hervas, A, Cardo, E, Artigas, J, Mardomingo, MJ, Alda, JA, Gastaminza, X, Garcia-Polavieja, MJ, Gilaberte, I, Escobar, R (2009). Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naive children and adolescents with attention deficit/hyperactivity disorder. Current Medical Research and Opinion 25, 27452754.
Mostofsky, SH, Rimrodt, SL, Schafer, JG, Boyce, A, Goldberg, MC, Pekar, JJ, Denckla, MB (2006). Atypical motor and sensory cortex activation in attention-deficit/hyperactivity disorder: a functional magnetic resonance imaging study of simple sequential finger tapping. Biological Psychiatry 59, 4856.
Mulas, F, Capilla, A, Fernandez, S, Etchepareborda, MC, Campo, P, Maestu, F, Fernandez, A, Castellanos, FX, Ortiz, T (2006). Shifting-related brain magnetic activity in attention-deficit/hyperactivity disorder. Biological Psychiatry 59, 373379.
Nandam, LS, Hester, R, Bellgrove, MA (2014). Dissociable and common effects of methylphenidate, atomoxetine and citalopram on response inhibition neural networks. Neuropsychologia 56, 263270.
Ni, H-C, Lin, Y-J, Gau, SS-F, Huang, H-C, Yang, L-K (2013). An open-label, randomized trial of methylphenidate and atomoxetine treatment in adults with ADHD. Journal of Attention Disorders. Published online: 8 March 2013. doi:10.1177/1087054713476549.
Paloyelis, Y, Mehta, MA, Kuntsi, J, Asherson, P (2007). Functional MRI in ADHD: a systematic literature review. Expert Review of Neurotherapeutics 7, 13371356.
Rubia, K, Halari, R, Cubillo, A, Mohammad, AM, Brammer, M, Taylor, E (2009). Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naive children with ADHD during a rewarded continuous performance task. Neuropharmacology 57, 640652.
Rubia, K, Halari, R, Cubillo, A, Smith, AB, Mohammad, AM, Brammer, M, Taylor, E (2011). Methylphenidate normalizes fronto-striatal underactivation during interference inhibition in medication-naive boys with attention-deficit hyperactivity disorder. Neuropsychopharmacology 36, 15751586.
Schulz, KP, Fan, J, Bedard, AC, Clerkin, SM, Ivanov, I, Tang, CY, Halperin, JM, Newcorn, JH (2012). Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder. Archives of General Psychiatry 69, 952961.
Schweren, LJ, de Zeeuw, P, Durston, S (2013). MR imaging of the effects of methylphenidate on brain structure and function in attention-deficit/hyperactivity disorder. European Neuropsychopharmacology 23, 11511164.
Shang, CY, Pan, YL, Lin, HY, Huang, LW, Gau, SS (2015). An open-label, randomized trial of methylphenidate and atomoxetine treatment in children with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology 25, 566573.
Sharma, A, Couture, J (2014). A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Annals of Pharmacotherapy 48, 209225.
Shaw, P, Sharp, WS, Morrison, M, Eckstrand, K, Greenstein, DK, Clasen, LS, Evans, AC, Rapoport, JL (2009). Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder. The American Journal of Psychiatry 166, 5863.
Shulman, GL, Astafiev, SV, Franke, D, Pope, DL, Snyder, AZ, McAvoy, MP, Corbetta, M (2009). Interaction of stimulus-driven reorienting and expectation in ventral and dorsal frontoparietal and basal ganglia-cortical networks. Journal of Neuroscience 29, 43924407.
Simpson, D, Perry, CM (2003). Atomoxetine. Paediatric Drugs 5, 407415; discussion 416–407.
Swanson, CJ, Perry, KW, Koch-Krueger, S, Katner, J, Svensson, KA, Bymaster, FP (2006). Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat. Neuropharmacology 50, 755760.
Valera, EM, Spencer, RM, Zeffiro, TA, Makris, N, Spencer, TJ, Faraone, SV, Biederman, J, Seidman, LJ (2010). Neural substrates of impaired sensorimotor timing in adult attention-deficit/hyperactivity disorder. Biological Psychiatry 68, 359367.
Wang, L, Zhu, C, He, Y, Zang, Y, Cao, Q, Zhang, H, Zhong, Q, Wang, Y (2009). Altered small-world brain functional networks in children with attention-deficit/hyperactivity disorder. Human Brain Mapping 30, 638649.
Wu, SY, Gau, SS (2013). Correlates for academic performance and school functioning among youths with and without persistent attention-deficit/hyperactivity disorder. Research in Developmental Disabilities 34, 505515.
Yan, CG, Cheung, B, Kelly, C, Colcombe, S, Craddock, RC, Di Martino, A, Li, Q, Zuo, XN, Castellanos, FX, Milham, MP (2013). A comprehensive assessment of regional variation in the impact of head micromovements on functional connectomics. Neuroimage 76, 183201.
Yan, CG, Zang, YF (2010). DPARSF: a MATLAB toolbox for ‘pipeline’ data analysis of resting-state fMRI. Frontiers in Systems Neuroscience 4, 13.
Yang, H, Wu, QZ, Guo, LT, Li, QQ, Long, XY, Huang, XQ, Chan, RC, Gong, QY (2011). Abnormal spontaneous brain activity in medication-naive ADHD children: a resting state fMRI study. Neuroscience Letters 502, 8993.
Yang, HN, Tai, YM, Yang, LK, Gau, SS (2013). Prediction of childhood ADHD symptoms to quality of life in young adults: adult ADHD and anxiety/depression as mediators. Research in Developmental Disabilities 34, 31683181.
Zang, Y, Jiang, T, Lu, Y, He, Y, Tian, L (2004). Regional homogeneity approach to fMRI data analysis. Neuroimage 22, 394400.
Zang, YF, He, Y, Zhu, CZ, Cao, QJ, Sui, MQ, Liang, M, Tian, LX, Jiang, TZ, Wang, YF (2007). Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI. Brain & Development 29, 8391.
Zhu, Y, Gao, B, Hua, J, Liu, W, Deng, Y, Zhang, L, Jiang, B, Zang, Y (2013). Effects of methylphenidate on resting-state brain activity in normal adults: an fMRI study. Neuroscience Bulletin 29, 1627.
Zou, QH, Zhu, CZ, Yang, Y, Zuo, XN, Long, XY, Cao, QJ, Wang, YF, Zang, YF (2008). An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: fractional ALFF. Journal of Neuroscience Methods 172, 137141.
Zuo, XN, Di Martino, A, Kelly, C, Shehzad, ZE, Gee, DG, Klein, DF, Castellanos, FX, Biswal, BB, Milham, MP (2010). The oscillating brain: complex and reliable. Neuroimage 49, 14321445.

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Differential effects of methylphenidate and atomoxetine on intrinsic brain activity in children with attention deficit hyperactivity disorder

  • C. Y. Shang (a1), C. G. Yan (a2) (a3), H. Y. Lin (a1), W. Y. Tseng (a4) (a5), F. X. Castellanos (a2) (a3) and S. S. Gau (a1) (a4)...

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