Atomoxetine Treatment Strengthens an Anti-Correlated Relationship between Functional Brain Networks in Medication-Naïve Adults with Attention-Deficit Hyperactivity Disorder: A Randomized Double-Blind Placebo-Controlled Clinical Trial

Hsiang-Yuan Lin, Susan Shur-Fen Gau, Hsiang-Yuan Lin, Susan Shur-Fen Gau

Abstract

Background: Although atomoxetine demonstrates efficacy in individuals with attention-deficit hyperactivity disorder, its treatment effects on brain resting-state functional connectivity remain unknown. Therefore, we aimed to investigate major brain functional networks in medication-naïve adults with attention-deficit hyperactivity disorder and the efficacy of atomoxetine treatment on resting-state functional connectivity.

Methods: After collecting baseline resting-state functional MRI scans from 24 adults with attention-deficit hyperactivity disorder (aged 18-52 years) and 24 healthy controls (matched in demographic characteristics), the participants with attention-deficit hyperactivity disorder were randomly assigned to atomoxetine (n=12) and placebo (n=12) arms in an 8-week, double-blind, placebo-controlled trial. The primary outcome was functional connectivity assessed by a resting-state functional MRI. Seed-based functional connectivity was calculated and compared for the affective, attention, default, and cognitive control networks.

Results: At baseline, we found atypical cross talk between the default, cognitive control, and dorsal attention networks and hypoconnectivity within the dorsal attention and default networks in adults with attention-deficit hyperactivity disorder. Our first-ever placebo-controlled clinical trial incorporating resting-state functional MRI showed that treatment with atomoxetine strengthened an anticorrelated relationship between the default and task-positive networks and modulated all major brain networks. The strengthened anticorrelations were associated with improving clinical symptoms in the atomoxetine-treated adults.

Conclusions: Our results support the idea that atypical default mode network task-positive network interaction plays an important role in the pathophysiology of adult attention-deficit hyperactivity disorder. Strengthening this atypical relationship following atomoxetine treatment suggests an important pathway to treat attention-deficit hyperactivity disorder.

Trial registration: ClinicalTrials.gov NCT00917371.

Keywords: adult; atomoxetine; attention-deficit hyperactivity disorder; randomized double-blind placebo-controlled clinical trial; resting-state fMRI.

© The Author 2015. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
Flow diagram of the procedure of the clinical trial.
Figure 2.
Figure 2.
Differences in resting state functional connectivity of the major neural networks between controls and adults with attention-deficit hyperactivity disorder (ADHD) at baseline. Comparisons of the 2 groups demonstrated the controls had stronger positive connectivity in the (A) dorsal attention network between the left frontal eye field (FEF) and right fusiform/inferior temporal gyrus (ITG) and between the right FEF and right dorsolateral prefrontal cortex (DLPFC), and in the (B) default mode network (DMN) between the left precuneus (PRE) and right middle temporal gyrus (MTG). The control group also had greater negative connections in the (C) cognitive control network between the left DLPFC and PRE and between the right DLPFC and medial prefrontal cortex (mPFC). Adults with ADHD had stronger anticorrelations in the (D) dorsal attention network from the right FEF to left DLPFC and left MTG/angular gyrus. Statistical height threshold P<.01, FWE cluster-level corrected P<.05. The green dots represent the seed regions and the red dots indicate the regions showing atypical functional connectivity (peak coordinates). L, left; R, right.
Figure 3.
Figure 3.
Connections demonstrating treatment × time interactions in the clinical trial. A mixed model for repeated measures revealed atomoxetine treatment modulated resting state functional connectivity across all the major neural networks investigated. Statistical height threshold P<.01, FWE cluster-level corrected P<.05. The green dots represent the seed regions and the red dots indicate the regions showing treatment × time interactions in the clinical trial (peak coordinates). The color (yellow areas with red edges) in the brain map displayed only the spatial extents of the clusters, but did not represent statistical values (see Table 4 for statistical values and functional connection strength). DLPFC,dorsolateral prefrontal cortex; FEF,frontal eye field; ITG,inferior temporal gyrus; L,left; MOG,middle occipital gyrus; mPFC,medial prefrontal cortex; MTG,middle temporal gyrus; OFC,orbitofrontal cortex; PCC,posterior cingulate cortex; PRE,precuneus; R,right; SubgeACC,subgenual anterior cingulate cortex; TPJ,temporoparietal junction.
Figure 4.
Figure 4.
Functional connectivity changes with improvement in clinical symptoms and neuropsychological performances. Regions that showed significant (statistical height threshold P<.01, FWE cluster-level corrected P<.05) alterations in functional connectivity as symptoms and performances of Rapid Visual Information Processing (RVP) improved, in (A) ventral attention network, (B) cognitive control network, (C) dorsal attention network, and (D) default mode network (DMN). Yellow maps corresponded to positive associations, whereas blue maps represented negative associations. DLPFC,dorsolateral prefrontal cortex; FEF,frontal eye field; PCC,posterior cingulate cortex; PRE,precuneus; TPJ,temporo-parietal junction; VFC,ventral frontal cortex.

References

    1. Beckmann M, Johansen-Berg H, Rushworth MF. (2009) Connectivity-based parcellation of human cingulate cortex and its relation to functional specialization. J Neurosci 29:1175–1190.
    1. Behzadi Y, Restom K, Liau J, Liu TT. (2007) A component based noise correction method (CompCor) for BOLD and perfusion based fMRI. NeuroImage 37:90–101.
    1. Biederman J, Monuteaux MC, Mick E, Spencer T, Wilens TE, Silva JM, Snyder LE, Faraone SV. (2006) Young adult outcome of attention deficit hyperactivity disorder: a controlled 10-year follow-up study. Psychol Med 36:167–179.
    1. Birn RM, Molloy EK, Patriat R, Parker T, Meier TB, Kirk GR, Nair VA, Meyerand ME, Prabhakaran V. (2013) The effect of scan length on the reliability of resting-state fMRI connectivity estimates. NeuroImage 83:550–558.
    1. Bostan AC, Dum RP, Strick PL. (2013) Cerebellar networks with the cerebral cortex and basal ganglia. Trends Cogn Sci 17:241–254.
    1. Bush G, Holmes J, Shin LM, Surman C, Makris N, Mick E, Seidman LJ, Biederman J. (2013) Atomoxetine increases fronto-parietal functional MRI activation in attention-deficit/hyperactivity disorder: a pilot study. Psychiatry Res 211:88–91.
    1. Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW. (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27:699–711.
    1. Cao Q, Zang Y, Sun L, Sui M, Long X, Zou Q, Wang Y. (2006) Abnormal neural activity in children with attention deficit hyperactivity disorder: a resting-state functional magnetic resonance imaging study. Neuroreport 17:1033–1036.
    1. Castellanos FX, Sonuga-Barke EJ, Milham MP, Tannock R. (2006) Characterizing cognition in ADHD: beyond executive dysfunction. Trends Cogn Sci 10:117–123.
    1. Castellanos FX, Margulies DS, Kelly C, Uddin LQ, Ghaffari M, Kirsch A, Shaw D, Shehzad Z, Di Martino A, Biswal B, Sonuga-Barke EJ, Rotrosen J, Adler LA, Milham MP. (2008) Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder. Biol Psychiatry 63:332–337.
    1. Castellanos FX, Di Martino A, Craddock RC, Mehta AD, Milham MP. (2013) Clinical applications of the functional connectome. NeuroImage 80:527–540.
    1. Chai XJ, Castanon AN, Ongur D, Whitfield-Gabrieli S. (2012) Anticorrelations in resting state networks without global signal regression. NeuroImage 59:1420–1428.
    1. Conners CK, Erhardt D, Sparrow E. (1999) Conners’ adult ADHD rating scales (CAARS). New York: MHS.
    1. Cortese S, Kelly C, Chabernaud C, Proal E, Di Martino A, Milham MP, Castellanos FX. (2012) Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies. Am J Psychiatry 169:1038–1055.
    1. Cubillo A, Smith AB, Barrett N, Giampietro V, Brammer M, Simmons A, Rubia K (2014a) Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory. Psychol Med 44:633–646.
    1. Cubillo A, Smith AB, Barrett N, Giampietro V, Brammer MJ, Simmons A, Rubia K (2014b) Shared and drug-specific effects of atomoxetine and methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys. Cereb Cortex 24:174–185.
    1. Depue BE, Burgess GC, Willcutt EG, Ruzic L, Banich MT. (2010) Inhibitory control of memory retrieval and motor processing associated with the right lateral prefrontal cortex: evidence from deficits in individuals with ADHD. Neuropsychologia 48:3909–3917.
    1. Ding YS, Naganawa M, Gallezot JD, Nabulsi N, Lin SF, Ropchan J, Weinzimmer D, McCarthy TJ, Carson RE, Huang Y, Laruelle M. (2014) Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: implications on treatment of depression and ADHD. NeuroImage 86:164–171.
    1. Fair DA, Posner J, Nagel BJ, Bathula D, Dias TG, Mills KL, Blythe MS, Giwa A, Schmitt CF, Nigg JT. (2010) Atypical default network connectivity in youth with attention-deficit/hyperactivity disorder. Biol Psychiatry 68:1084–1091.
    1. Fayyad J, De Graaf R, Kessler R, Alonso J, Angermeyer M, Demyttenaere K, De Girolamo G, Haro JM, Karam EG, Lara C, Lepine JP, Ormel J, Posada-Villa J, Zaslavsky AM, Jin R. (2007) Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry 190:402–409.
    1. Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. (2005) The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A 102:9673–9678.
    1. Fox MD, Zhang D, Snyder AZ, Raichle ME. (2009) The global signal and observed anticorrelated resting state brain networks. J Neurophysiol 101:3270–3283.
    1. Frank DW, Dewitt M, Hudgens-Haney M, Schaeffer DJ, Ball BH, Schwarz NF, Hussein AA, Smart LM, Sabatinelli D. (2014) Emotion regulation: quantitative meta-analysis of functional activation and deactivation. Neurosci Biobehav Rev 45:202–211.
    1. Friston K. (2012) Ten ironic rules for non-statistical reviewers. NeuroImage 61:1300–1310.
    1. Fusar-Poli P, Placentino A, Carletti F, Landi P, Allen P, Surguladze S, Benedetti F, Abbamonte M, Gasparotti R, Barale F, Perez J, McGuire P, Politi P. (2009) Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies. J Psychiatry Neurosci 34:418–432.
    1. Gallezot JD, Weinzimmer D, Nabulsi N, Lin SF, Fowles K, Sandiego C, McCarthy TJ, Maguire RP, Carson RE, Ding YS. (2011) Evaluation of [(11)C]MRB for assessment of occupancy of norepinephrine transporters: studies with atomoxetine in non-human primates. Neuroimage 56:268–279.
    1. Gau SS, Huang WL. (2014) Rapid visual information processing as a cognitive endophenotype of attention deficit hyperactivity disorder. Psychol Med 44:435–446.
    1. Hahn A, Wadsak W, Windischberger C, Baldinger P, Hoflich AS, Losak J, Nics L, Philippe C, Kranz GS, Kraus C, Mitterhauser M, Karanikas G, Kasper S, Lanzenberger R. (2012) Differential modulation of the default mode network via serotonin-1A receptors. Proc Natl Acad Sci U S A 109:2619–2624.
    1. Hayasaka S, Nichols TE. (2003) Validating cluster size inference: random field and permutation methods. NeuroImage 20:2343–2356.
    1. Hayasaka S, Phan KL, Liberzon I, Worsley KJ, Nichols TE. (2004) Nonstationary cluster-size inference with random field and permutation methods. NeuroImage 22:676–687.
    1. Hoekzema E, Carmona S, Ramos-Quiroga JA, Richarte Fernandez V, Bosch R, Soliva JC, Rovira M, Bulbena A, Tobena A, Casas M, Vilarroya O. (2014) An independent components and functional connectivity analysis of resting state fMRI data points to neural network dysregulation in adult ADHD. Hum Brain Mapp 35:1261–1272.
    1. Kelly AM, Uddin LQ, Biswal BB, Castellanos FX, Milham MP. (2008) Competition between functional brain networks mediates behavioral variability. NeuroImage 39:527–537.
    1. Kucyi A, Hove MJ, Biederman J, Van Dijk KR, Valera EM. (2015) Disrupted functional connectivity of cerebellar default network areas in attention-deficit/hyperactivity disorder. Hum Brain Mapp 36:3373–3386.
    1. Kundu P, Brenowitz ND, Voon V, Worbe Y, Vertes PE, Inati SJ, Saad ZS, Bandettini PA, Bullmore ET. (2013) Integrated strategy for improving functional connectivity mapping using multiecho fMRI. Proc Natl Acad Sci U S A 110:16187–16192.
    1. Lancaster JL, Tordesillas-Gutierrez D, Martinez M, Salinas F, Evans A, Zilles K, Mazziotta JC, Fox PT. (2007) Bias between MNI and Talairach coordinates analyzed using the ICBM-152 brain template. Hum Brain Mapp 28:1194–1205.
    1. Li AN, Xiao-Hua CA, Qing-Jiu CA, Li SU, Li YA, Qi-Hong ZO, Rubia KA, Yu-Feng ZA, Yu-Feng WA. (2013) Methylphenidate normalizes resting-state brain dysfunction in boys with attention deficit hyperactivity disorder. Neuropsychopharmacology 38:1287–95.
    1. 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 60:1015–1024.
    1. Mattfeld AT, Gabrieli JD, Biederman J, Spencer T, Brown A, Kotte A, Kagan E, Whitfield-Gabrieli S. (2014) Brain differences between persistent and remitted attention deficit hyperactivity disorder. Brain 137:2423–2428.
    1. McCarthy H, Skokauskas N, Mulligan A, Donohoe G, Mullins D, Kelly J, Johnson K, Fagan A, Gill M, Meaney J, Frodl T. (2013) Attention network hypoconnectivity with default and affective network hyperconnectivity in adults diagnosed with attention-deficit/hyperactivity disorder in childhood. JAMA Psychiatry 70:1329–1337.
    1. Meadows M-E. (2011) Calcarine cortex. In: Encyclopedia of clinical neuropsychology (Kreutzer J, DeLuca J, Caplan B, eds), pp 472–472. New York: Springer.
    1. Miller GA, Chapman JP. (2001) Misunderstanding analysis of covariance. J Abnormal Psych 110:40–48.
    1. Nandam LS, Hester R, Bellgrove MA. (2014) Dissociable and common effects of methylphenidate, atomoxetine and citalopram on response inhibition neural networks. Neuropsychologia 56:263–270.
    1. Newcorn JH, Sutton VK, Weiss MD, Sumner CR. (2009) Clinical responses to atomoxetine in attention-deficit/hyperactivity disorder: the Integrated Data Exploratory Analysis (IDEA) study. J Am Acad Child Adolesc Psychiatry 48:511–518.
    1. Ni HC, Lin YJ, Gau SS, Huang HC, Yang LK. (2013. a) An open-label, randomized trial of methylphenidate and atomoxetine treatment in adults With ADHD. J Atten Disord.
    1. Ni HC, Shang CY, Gau SS, Lin YJ, Huang HC, Yang LK. (2013. b) A head-to-head randomized clinical trial of methylphenidate and atomoxetine treatment for executive function in adults with attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol 16:1959–1973.
    1. Patriat R, Molloy EK, Meier TB, Kirk GR, Nair VA, Meyerand ME, Prabhakaran V, Birn RM. (2013) The effect of resting condition on resting-state fMRI reliability and consistency: a comparison between resting with eyes open, closed, and fixated. Neuroimage 78:463–473.
    1. Posner J, Park C, Wang Z. (2014) Connecting the dots: a review of resting connectivity MRI studies in attention-deficit/hyperactivity disorder. Neuropsychol Rev 24:3–15.
    1. Proal E, Reiss PT, Klein RG, Mannuzza S, Gotimer K, Ramos-Olazagasti MA, Lerch JP, He Y, Zijdenbos A, Kelly C, Milham MP, Castellanos FX. (2011) Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood. Arch Gen Psychiatry 68:1122–1134.
    1. Qi R, Zhang LJ, Lu GM. (2014) Emphasize the effect of methylphenidate on brain function in attention-deficit/hyperactivity disorder research. JAMA Psychiatry 71:210.
    1. Retz W, Stieglitz RD, Corbisiero S, Retz-Junginger P, Rosler M. (2012) Emotional dysregulation in adult ADHD: What is the empirical evidence? Expert Rev Neurother 12:1241–1251.
    1. Sarpal DK, Robinson DG, Lencz T, Argyelan M, Ikuta T, Karlsgodt K, Gallego JA, Kane JM, Szeszko PR, Malhotra AK. (2015) Antipsychotic treatment and functional connectivity of the striatum in first-episode schizophrenia. JAMA Psychiatry 72:5–13.
    1. 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. Arch Gen Psychiatry 69:952–961.
    1. Seixas M, Weiss M, Muller U. (2012) Systematic review of national and international guidelines on attention-deficit hyperactivity disorder. J Psychopharmacol 26:753–765.
    1. Seneca N, Gulyas B, Varrone A, Schou M, Airaksinen A, Tauscher J, Vandenhende F, Kielbasa W, Farde L, Innis RB, Halldin C. (2006) Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2. Psychopharmacology (Berl) 188:119–127.
    1. 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. J Neurosci 29:4392–4407.
    1. Silk TJ, Vance A, Rinehart N, Bradshaw JL, Cunnington R. (2009) White-matter abnormalities in attention deficit hyperactivity disorder: a diffusion tensor imaging study. Hum Brain Mapp 30:2757–2765.
    1. Song XW, Dong ZY, Long XY, Li SF, Zuo XN, Zhu CZ, He Y, Yan CG, Zang YF. (2011) REST: a toolkit for resting-state functional magnetic resonance imaging data processing. PLoS One 6:e25031.
    1. Sonuga-Barke EJ, Castellanos FX. (2007) Spontaneous attentional fluctuations in impaired states and pathological conditions: a neurobiological hypothesis. Neurosci Biobehav Rev 31:977–986.
    1. Sripada C, Kessler D, Fang Y, Welsh RC, Prem Kumar K, Angstadt M. (2014) Disrupted network architecture of the resting brain in attention-deficit/hyperactivity disorder. Hum Brain Mapp 35:4693–4705.
    1. Suckling J. (2011) Correlated covariates in ANCOVA cannot adjust for pre-existing differences between groups. Schizophr Res 126:310–311.
    1. Tagliazucchi E, Laufs H. (2014) Decoding wakefulness levels from typical fMRI resting-state data reveals reliable drifts between wakefulness and sleep. Neuron 82:695–708.
    1. Tomasi D, Volkow ND. (2012) Abnormal functional connectivity in children with attention-deficit/hyperactivity disorder. Biol Psychiatry 71:443–450.
    1. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M. (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 15:273–289.
    1. Van Dijk KR, Hedden T, Venkataraman A, Evans KC, Lazar SW, Buckner RL. (2010) Intrinsic functional connectivity as a tool for human connectomics: theory, properties, and optimization. J Neurophysiol 103:297–321.
    1. Whitfield-Gabrieli S, Nieto-Castanon A. (2012) Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect 2:125–141.
    1. Woo CW, Krishnan A, Wager TD. (2014) Cluster-extent based thresholding in fMRI analyses: pitfalls and recommendations. NeuroImage 91:412–419.
    1. Xia M, Wang J, He Y. (2013) BrainNet Viewer: a network visualization tool for human brain connectomics. PLoS One 8:e68910.
    1. Xia S, Foxe JJ, Sroubek AE, Branch C, Li X. (2014) Topological organization of the “small-world” visual attention network in children with attention deficit/hyperactivity disorder (ADHD). Front Hum Neurosci 8:162.
    1. Yan CG, Zhang YF. (2010) DPARSF: a MATLAB toolbox for “pipeline” data analysis of resting-state fMRI. Front Syst Neurosci 4:13.
    1. 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 76:183–201.
    1. Yarkoni T, Poldrack RA, Nichols TE, Van Essen DC, Wager TD. (2011) Large-scale automated synthesis of human functional neuroimaging data. Nat Meth 8:665–670.
    1. Yeh CB, Gau SS, Kessler RC, Wu YY. (2008) Psychometric properties of the Chinese version of the adult ADHD Self-report Scale. Int J Methods Psychiatr Res 17:45–54.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir