Hostname: page-component-7c8c6479df-p566r Total loading time: 0 Render date: 2024-03-27T07:06:37.790Z Has data issue: false hasContentIssue false

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

Published online by Cambridge University Press:  30 August 2016

C. Y. Shang
Affiliation:
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
C. G. Yan
Affiliation:
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA The Center for Neurodevelopmental Disorders at the Child Study Center at NYU Langone Medical Center, New York, NY, USA
H. Y. Lin
Affiliation:
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
W. Y. Tseng
Affiliation:
Graduate Institute of Brain and Mind Sciences, Taipei, Taiwan Center for Optoelectronic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
F. X. Castellanos*
Affiliation:
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA The Center for Neurodevelopmental Disorders at the Child Study Center at NYU Langone Medical Center, New York, NY, USA
S. S. Gau*
Affiliation:
Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan Graduate Institute of Brain and Mind Sciences, Taipei, Taiwan
*
*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.]
*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.]

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.

Type
Original Articles
Copyright
Copyright © Cambridge University Press 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Castellanos, FX, Proal, E (2012). Large-scale brain systems in ADHD: beyond the prefrontal-striatal model. Trends in Cognitive Sciences 16, 1726.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
DuPaul, GJ, Power, TJ, Anastopoulos, AD, Reid, R (1998). ADHD Rating Scale-IV: Checklists, Norms, and Clinical Interpretations. Guilford: New York.Google Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
Fox, MD, Raichle, ME (2007). Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nature Reviews 8, 700711.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Han, DD, Gu, HH (2006). Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacology 6, 6.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Luciana, M, Nelson, CA (1998). The functional emergence of prefrontally-guided working memory systems in four- to eight-year-old children. Neuropsychologia 36, 273293.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Nandam, LS, Hester, R, Bellgrove, MA (2014). Dissociable and common effects of methylphenidate, atomoxetine and citalopram on response inhibition neural networks. Neuropsychologia 56, 263270.CrossRefGoogle ScholarPubMed
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.Google Scholar
Paloyelis, Y, Mehta, MA, Kuntsi, J, Asherson, P (2007). Functional MRI in ADHD: a systematic literature review. Expert Review of Neurotherapeutics 7, 13371356.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Sharma, A, Couture, J (2014). A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Annals of Pharmacotherapy 48, 209225.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Simpson, D, Perry, CM (2003). Atomoxetine. Paediatric Drugs 5, 407415; discussion 416–407.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Yan, CG, Zang, YF (2010). DPARSF: a MATLAB toolbox for ‘pipeline’ data analysis of resting-state fMRI. Frontiers in Systems Neuroscience 4, 13.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Zang, Y, Jiang, T, Lu, Y, He, Y, Tian, L (2004). Regional homogeneity approach to fMRI data analysis. Neuroimage 22, 394400.CrossRefGoogle ScholarPubMed
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.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Supplementary material: Image

Shang supplementary material S1

Supplementary Figure

Download Shang supplementary material S1(Image)
Image 92.7 KB
Supplementary material: Image

Shang supplementary material S2

Supplementary Figure

Download Shang supplementary material S2(Image)
Image 1 MB
Supplementary material: File

Shang supplementary material S3

Supplementary Table

Download Shang supplementary material S3(File)
File 33.3 KB
Supplementary material: File

Shang supplementary material S4

Supplementary Table

Download Shang supplementary material S4(File)
File 29.7 KB