Ketamine pp 15-31 | Cite as

Brain Imaging of Ketamine Abusers

  • Yanhui Liao
  • Wei Hao


In this chapter, we highlight the role of brain imaging techniques (e.g., magnetic resonance imaging [MRI]) in studying ketamine abuse. In the past two to three decades, brain imaging studies demonstrated deficits in brain circuits related to drug addiction and drug abuse. This chapter begins with a brief introduction of structural and functional brain imaging techniques such as computed tomography (CT) and electroencephalogram (EEG). Then, we give a brief introduction of ketamine abuse in mainland China before introducing structural MRI and functional MRI and reviewing the application of structural MRI study for ketamine abusers (including reduction of gray matter volume and disruption of white matter integrity) and functional MRI study for ketamine abusers (including alternation of regional homogeneity (ReHo) of resting-state brain activity, functional connectivity by resting-state fMRI, task-based fMRI). Finally, we discuss the implication for medical use of ketamine by brain imaging study, especially its rapid-acting glutamatergic antidepressant effects and the “ketamine model” of psychosis.


Brain imaging Magnetic resonance imaging Structural MRI Functional MRI Chronic ketamine use Ketamine abusers 


  1. Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ (2012) Ketamine for depression: where do we go from here? Biol Psychiatry 72:537–547CrossRefGoogle Scholar
  2. Abdallah CG, Averill LA, Collins KA, Geha P, Schwartz J, Averill C, DeWilde KE, Wong E, Anticevic A, Tang CY (2017) Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology 42:1210PubMedCrossRefPubMedCentralGoogle Scholar
  3. Belliveau JW, Rosen BR, Kantor HL, Rzedzian RR, Kennedy DN, McKinstry RC, Vevea JM, Cohen MS, Pykett IL, Brady TJ (1990) Functional cerebral imaging by susceptibility-contrast NMR. Magn Reson Med 14:538–546PubMedCrossRefPubMedCentralGoogle Scholar
  4. Biswal B, Zerrin Yetkin F, Haughton VM, Hyde JS (1995) Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med 34:537–541PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bonnet U (2015) Long-term ketamine self-injections in major depressive disorder: focus on tolerance in ketamine’s antidepressant response and the development of ketamine addiction. J Psychoactive Drugs 47:276–285PubMedCrossRefPubMedCentralGoogle Scholar
  6. Bush G, Frazier JA, Rauch SL, Seidman LJ, Whalen PJ, Jenike MA, Rosen BR, Biederman J (1999) Anterior cingulate cortex dysfunction in attention-deficit/hyperactivity disorder revealed by fMRI and the Counting Stroop. Biol Psychiatry 45:1542–1552PubMedCrossRefPubMedCentralGoogle Scholar
  7. Canu E, Agosta F, Filippi M (2015) A selective review of structural connectivity abnormalities of schizophrenic patients at different stages of the disease. Schizophr Res 161:19–28PubMedCrossRefPubMedCentralGoogle Scholar
  8. Cartwright P, Pingel S (1984) Midazolam and diazepam in ketamine anaesthesia. Anaesthesia 39:439–442PubMedCrossRefPubMedCentralGoogle Scholar
  9. Casey BJ, Tottenham N, Liston C, Durston S (2005) Imaging the developing brain: what have we learned about cognitive development? Trends Cogn Sci 9:104–110PubMedCrossRefPubMedCentralGoogle Scholar
  10. Chan KW, Lee TM, Siu AM, Wong DP, Kam C-M, Tsang SK, Chan CC (2013) Effects of chronic ketamine use on frontal and medial temporal cognition. Addict Behav 38:2128–2132PubMedCrossRefPubMedCentralGoogle Scholar
  11. Clarke K, Hall L (1990) A survey of anaesthesia in small animal practice: AVA/BSAVA report. J Assoc Vet Anaesth Great Britain Ireland 17:4–10CrossRefGoogle Scholar
  12. Deakin JW, Lees J, McKie S, Hallak JE, Williams SR, Dursun SM (2008) Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco–magnetic resonance imaging study. Arch Gen Psychiatry 65:154–164PubMedCrossRefPubMedCentralGoogle Scholar
  13. Elia N, Tramèr MR (2005) Ketamine and postoperative pain—a quantitative systematic review of randomised trials. Pain 113:61–70PubMedCrossRefPubMedCentralGoogle Scholar
  14. Ezquerra-Romano II, Lawn W, Krupitsky E, Morgan C (2018) Ketamine for the treatment of addiction: evidence and potential mechanisms. Neuropharmacology 142:72–82CrossRefGoogle Scholar
  15. Fang YX, Wang YB, Shi J, Liu ZM, Lu L (2006) Recent trends in drug abuse in China. Acta Pharmacol Sin 27:140–144PubMedCrossRefPubMedCentralGoogle Scholar
  16. Fedota JR, Stein EA (2015) Resting-state functional connectivity and nicotine addiction: prospects for biomarker development. Ann N Y Acad Sci 1349:64PubMedPubMedCentralCrossRefGoogle Scholar
  17. Fleisher AS, Sherzai A, Taylor C, Langbaum JB, Chen K, Buxton RB (2009) Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer’s disease risk groups. Neuroimage 47:1678–1690PubMedPubMedCentralCrossRefGoogle Scholar
  18. Fouche J-P, Du Plessis S, Hattingh C, Roos A, Lochner C, Soriano-Mas C, Sato JR, Nakamae T, Nishida S, Kwon JS (2017) Cortical thickness in obsessive–compulsive disorder: multisite mega-analysis of 780 brain scans from six centres. Br J Psychiatry 210:67–74PubMedCrossRefPubMedCentralGoogle Scholar
  19. Goldstein RZ, Volkow ND (2011) Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 12:652PubMedPubMedCentralCrossRefGoogle Scholar
  20. Green SM, Johnson NE (1990) Ketamine sedation for pediatric procedures: part 2, review and implications. Ann Emerg Med 19:1033–1046PubMedCrossRefPubMedCentralGoogle Scholar
  21. Hibar D, Westlye LT, van Erp TG, Rasmussen J, Leonardo CD, Faskowitz J, Haukvik UK, Hartberg CB, Doan NT, Agartz I (2016) Subcortical volumetric abnormalities in bipolar disorder. Mol Psychiatry 21:1710PubMedPubMedCentralCrossRefGoogle Scholar
  22. Hirsch GV, Bauer CM, Merabet LB (2015) Using structural and functional brain imaging to uncover how the brain adapts to blindness. Ann Neurosci Psychol 2:5PubMedPubMedCentralGoogle Scholar
  23. Hoge RD, Atkinson J, Gill B, Crelier GR, Marrett S, Pike GB (1999) Investigation of BOLD signal dependence on cerebral blood flow and oxygen consumption: the deoxyhemoglobin dilution model. Magn Reson Med 42:849–863PubMedCrossRefPubMedCentralGoogle Scholar
  24. Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500PubMedPubMedCentralCrossRefGoogle Scholar
  25. Honey G, Bullmore E (2004) Human pharmacological MRI. Trends Pharmacol Sci 25:366–374PubMedCrossRefPubMedCentralGoogle Scholar
  26. Honey GD, Corlett PR, Absalom AR, Lee M, Pomarol-Clotet E, Murray GK, McKenna PJ, Bullmore ET, Menon DK, Fletcher PC (2008) Individual differences in psychotic effects of ketamine are predicted by brain function measured under placebo. J Neurosci 28:6295–6303PubMedPubMedCentralCrossRefGoogle Scholar
  27. Hong S-B, Zalesky A, Cocchi L, Fornito A, Choi E-J, Kim H-H, Suh J-E, Kim C-D, Kim J-W, Yi S-H (2013) Decreased functional brain connectivity in adolescents with internet addiction. PLoS One 8:e57831PubMedPubMedCentralCrossRefGoogle Scholar
  28. Jenike MA, Breiter HC, Baer L, Kennedy DN, Savage CR, Olivares MJ, O’Sullivan RL, Shera DM, Rauch SL, Keuthen N (1996) Cerebral structural abnormalities in obsessive-compulsive disorder: a quantitative morphometric magnetic resonance imaging study. Arch Gen Psychiatry 53:625–632PubMedCrossRefPubMedCentralGoogle Scholar
  29. Katalinic N, Lai R, Somogyi A, Mitchell PB, Glue P, Loo CK (2013) Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Aust N Z J Psychiatry 47:710–727PubMedCrossRefPubMedCentralGoogle Scholar
  30. Kokkinou M, Ashok AH, Howes OD (2017) The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry 23:59PubMedPubMedCentralCrossRefGoogle Scholar
  31. Krystal JH, Sanacora G, Duman RS (2013) Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 73:1133–1141PubMedPubMedCentralCrossRefGoogle Scholar
  32. Kwong KK, Belliveau JW, Chesler DA, Goldberg IE, Weisskoff RM, Poncelet BP, Kennedy DN, Hoppel BE, Cohen MS, Turner R (1992) Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc Natl Acad Sci 89:5675–5679PubMedCrossRefPubMedCentralGoogle Scholar
  33. Laruelle M, Kegeles LS, Abi-Dargham A (2003) Glutamate, dopamine, and schizophrenia. Ann N Y Acad Sci 1003:138–158PubMedCrossRefPubMedCentralGoogle Scholar
  34. Lauterbur PC (1973) Image formation by induced local interactions: examples employing nuclear magnetic resonance. Nature 242:190–191CrossRefGoogle Scholar
  35. Li C-SR, Zhang S, Hung C-C, Chen C-M, Duann J-R, Lin C-P, Lee TS-H (2017a) Depression in chronic ketamine users: sex differences and neural bases. Psychiatry Res Neuroimaging 269:1–8PubMedCrossRefPubMedCentralGoogle Scholar
  36. Li Q, Shi L, Lu G, Yu H-L, Yeung F-K, Wong N-K, Sun L, Liu K, Yew D, Pan F (2017b) Chronic ketamine exposure causes white matter microstructural abnormalities in adolescent cynomolgus monkeys. Front Neurosci 11:285PubMedPubMedCentralCrossRefGoogle Scholar
  37. Liao Y, Tang J, Ma M, Wu Z, Yang M, Wang X, Liu T, Chen X, Fletcher PC, Hao W (2010) Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. Brain 133:2115–2122PubMedCrossRefGoogle Scholar
  38. Liao Y, Tang J, Corlett PR, Wang X, Yang M, Chen H, Liu T, Chen X, Hao W, Fletcher PC (2011) Reduced dorsal prefrontal gray matter after chronic ketamine use. Biol Psychiatry 69:42–48PubMedCrossRefGoogle Scholar
  39. Liao Y, Tang J, Fornito A, Liu T, Chen X, Chen H, Xiang X, Wang X, Hao W (2012) Alterations in regional homogeneity of resting-state brain activity in ketamine addicts. Neurosci Lett 522:36–40PubMedCrossRefPubMedCentralGoogle Scholar
  40. Liao Y, Qi C, Wu Q, Tang J (2016a) Psychiatric symptoms in individuals who use ketamine versus methamphetamine—implications for glutamatergic and dopaminergic model for schizophrenia: a cohort study. Lancet 388:S67CrossRefGoogle Scholar
  41. Liao Y, Tang J, Liu J, Xie A, Yang M, Johnson M, Wang X, Deng Q, Chen H, Xiang X (2016b) Decreased thalamocortical connectivity in chronic ketamine users. PLoS One 11:e0167381PubMedPubMedCentralCrossRefGoogle Scholar
  42. Liao Y, Tang Y-l, Hao W (2017) Ketamine and international regulations. Am J Drug Alcohol Abuse 43:495–504PubMedCrossRefPubMedCentralGoogle Scholar
  43. Liao Y, Johnson M, Qi C, Wu Q, Xie A, Liu J, Yang M, Huang M, Zhang Y, Liu T (2018) Cue-induced brain activation in chronic ketamine-dependent subjects, cigarette smokers, and healthy controls: a task functional magnetic resonance imaging study. Front Psych 9:88CrossRefGoogle Scholar
  44. Liu Y, Lin D, Wu B, Zhou W (2016) Ketamine abuse potential and use disorder. Brain Res Bull 126:68–73PubMedCrossRefPubMedCentralGoogle Scholar
  45. Mansfield P, Maudsley AA (1977) Medical imaging by NMR. Br J Radiol 50:188–194PubMedCrossRefPubMedCentralGoogle Scholar
  46. Michels II, Fang Y-x, Zhao D, Zhao L-y, Lu L (2007) Comparison of drug abuse in Germany and China. Acta Pharmacol Sin 28:1505PubMedCrossRefPubMedCentralGoogle Scholar
  47. Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–2927PubMedPubMedCentralCrossRefGoogle Scholar
  48. Morgan CJ, Curran HV (2006) Acute and chronic effects of ketamine upon human memory: a review. Psychopharmacology (Berl) 188:408–424CrossRefGoogle Scholar
  49. Morgan CJ, Monaghan L, Curran HV (2004a) Beyond the K-hole: a 3-year longitudinal investigation of the cognitive and subjective effects of ketamine in recreational users who have substantially reduced their use of the drug. Addiction 99:1450–1461PubMedCrossRefPubMedCentralGoogle Scholar
  50. Morgan CJ, Riccelli M, Maitland CH, Curran HV (2004b) Long-term effects of ketamine: evidence for a persisting impairment of source memory in recreational users. Drug Alcohol Depend 75:301–308PubMedCrossRefPubMedCentralGoogle Scholar
  51. Morgan CJ, Curran HV, Drugs ISC o (2012) Ketamine use: a review. Addiction 107:27–38PubMedCrossRefPubMedCentralGoogle Scholar
  52. Narendran R, Frankle WG, Keefe R, Gil R, Martinez D, Slifstein M, Kegeles LS, Talbot PS, Huang Y, Hwang D-R (2005) Altered prefrontal dopaminergic function in chronic recreational ketamine users. Am J Psychiatry 162:2352–2359PubMedCrossRefPubMedCentralGoogle Scholar
  53. Ogawa S, Lee TM, Kay AR, Tank DW (1990) Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A 87:9868–9872PubMedPubMedCentralCrossRefGoogle Scholar
  54. Parvaz MA, Alia-Klein N, Woicik PA, Volkow ND, Goldstein RZ (2011) Neuroimaging for drug addiction and related behaviors. Rev Neurosci 22:609–624PubMedPubMedCentralCrossRefGoogle Scholar
  55. Roberts RE, Curran HV, Friston KJ, Morgan CJ (2014) Abnormalities in white matter microstructure associated with chronic ketamine use. Neuropsychopharmacology 39:329CrossRefGoogle Scholar
  56. Rosen BR, Belliveau JW, Vevea JM, Brady TJ (1990) Perfusion imaging with NMR contrast agents. Magn Reson Med 14:249–265PubMedCrossRefPubMedCentralGoogle Scholar
  57. Rosenblat JD, Carvalho AF, Li M, Lee Y, Subramanieapillai M, McIntyre RS (2019) Oral ketamine for depression: a systematic review. J Clin Psychiatry 80:18r12475PubMedCrossRefPubMedCentralGoogle Scholar
  58. Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E, Barrow R, Yeo R, Lauriello J, Brooks WM (2005) Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry 162:394–396PubMedCrossRefPubMedCentralGoogle Scholar
  59. Rowland LM, Beason-Held L, Tamminga CA, Holcomb HH (2010) The interactive effects of ketamine and nicotine on human cerebral blood flow. Psychopharmacology (Berl) 208:575–584CrossRefGoogle Scholar
  60. Sassano-Higgins S, Baron D, Juarez G, Esmaili N, Gold M (2016) A review of ketamine abuse and diversion. Depress Anxiety 33:718–727PubMedCrossRefPubMedCentralGoogle Scholar
  61. Schmaal L, Hibar D, Sämann P, Hall G, Baune B, Jahanshad N, Cheung J, Van Erp T, Bos D, Ikram M (2017) Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA major depressive disorder working group. Mol Psychiatry 22:900PubMedCrossRefPubMedCentralGoogle Scholar
  62. Seidman LJ, Valera EM, Makris N (2005) Structural brain imaging of attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1263–1272PubMedCrossRefPubMedCentralGoogle Scholar
  63. Sparks B, Friedman S, Shaw D, Aylward EH, Echelard D, Artru A, Maravilla K, Giedd J, Munson J, Dawson G (2002) Brain structural abnormalities in young children with autism spectrum disorder. Neurology 59:184–192PubMedCrossRefPubMedCentralGoogle Scholar
  64. Stoeckel LE, Garrison KA, Ghosh SS, Wighton P, Hanlon CA, Gilman JM, Greer S, Turk-Browne NB, deBettencourt MT, Scheinost D (2014) Optimizing real time fMRI neurofeedback for therapeutic discovery and development. NeuroImage Clin 5:245–255PubMedPubMedCentralCrossRefGoogle Scholar
  65. Strakowski SM, DelBello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM, Larson ER (1999) Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry 56:254–260PubMedCrossRefPubMedCentralGoogle Scholar
  66. Sun L, Li Q, Li Q, Zhang Y, Liu D, Jiang H, Pan F, Yew DT (2014) Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys. Addict Biol 19:185–194PubMedCrossRefPubMedCentralGoogle Scholar
  67. Sutherland MT, McHugh MJ, Pariyadath V, Stein EA (2012) Resting state functional connectivity in addiction: lessons learned and a road ahead. Neuroimage 62:2281–2295PubMedPubMedCentralCrossRefGoogle Scholar
  68. Symms M, Jäger H, Schmierer K, Yousry T (2004) A review of structural magnetic resonance neuroimaging. J Neurol Neurosurg Psychiatry 75:1235–1244PubMedPubMedCentralCrossRefGoogle Scholar
  69. Tang W, Liang H, Lau C, Tang A, Ungvari GS (2013) Relationship between cognitive impairment and depressive symptoms in current ketamine users. J Stud Alcohol Drugs 74:460–468PubMedCrossRefPubMedCentralGoogle Scholar
  70. Tang J, Liao Y, He H, Deng Q, Zhang G, Qi C, Cui H, Jiao B, Yang M, Feng Z (2015a) Sleeping problems in Chinese illicit drug dependent subjects. BMC Psychiatry 15:28PubMedPubMedCentralCrossRefGoogle Scholar
  71. Tang J, Morgan HL, Liao Y, Corlett PR, Wang D, Li H, Tang Y, Chen J, Liu T, Hao W (2015b) Chronic administration of ketamine mimics the perturbed sense of body ownership associated with schizophrenia. Psychopharmacology (Berl) 232:1515–1526CrossRefGoogle Scholar
  72. Tsai TH, Cha TL, Lin CM, Tsao CW, Tang SH, Chuang FP, Wu ST, Sun GH, Yu DS, Chang SY (2009) Ketamine-associated bladder dysfunction. Int J Urol 16:826–829PubMedCrossRefPubMedCentralGoogle Scholar
  73. Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, Krystal JH, Sanacora G (2011) The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [1H]-MRS. Psychiatry Res Neuroimaging 191:122–127CrossRefGoogle Scholar
  74. Van Erp TG, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC, Pearlson GD, Yao N, Fukunaga M, Hashimoto R (2018) Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro imaging genetics through meta analysis (ENIGMA) consortium. Biol Psychiatry 84:644–654PubMedPubMedCentralCrossRefGoogle Scholar
  75. Volkow ND, Wang G-J, Fowler JS, Tomasi D, Baler R (2014) Neuroimaging of addiction. In: Imaging of the human brain in health and disease. Elsevier, Amsterdam, pp 1–26Google Scholar
  76. Wang C, Zheng D, Xu J, Lam W, Yew D (2013) Brain damages in ketamine addicts as revealed by magnetic resonance imaging. Front Neuroanat 7:23PubMedPubMedCentralCrossRefGoogle Scholar
  77. Wood R, Bassett K, Foerster T, Spry C, Tong L (2012) 1.5 tesla magnetic resonance imaging scanners compared with 3.0 tesla magnetic resonance imaging scanners: systematic review of clinical effectiveness. CADTH Technol Overviews 2:e2201Google Scholar
  78. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H (2018) Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554:317CrossRefGoogle Scholar
  79. Yeung L, Wai MS, Fan M, Mak Y, Lam W, Li Z, Lu G, Yew DT (2010) Hyperphosphorylated tau in the brains of mice and monkeys with long-term administration of ketamine. Toxicol Lett 193:189–193PubMedCrossRefPubMedCentralGoogle Scholar
  80. Young LE, Bartram D, Diamond MJ, Gregg AS, Jones R (1993) Clinical evaluation of an infusion of xylazine, guaifenesin and ketamine for maintenance of anaesthesia in horses. Equine Vet J 25:115–119PubMedCrossRefPubMedCentralGoogle Scholar
  81. Yu H, Li Q, Wang D, Shi L, Lu G, Sun L, Wang L, Zhu W, Mak YT, Wong N (2012) Mapping the central effects of chronic ketamine administration in an adolescent primate model by functional magnetic resonance imaging (fMRI). Neurotoxicology 33:70–77PubMedCrossRefPubMedCentralGoogle Scholar
  82. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:481PubMedPubMedCentralCrossRefGoogle Scholar
  83. Zou X, Patterson TA, Sadovova N, Twaddle NC, Doerge DR, Zhang X, Fu X, Hanig JP, Paule MG, Slikker W (2009) Potential neurotoxicity of ketamine in the developing rat brain. Toxicol Sci 108:149–158PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Yanhui Liao
    • 1
    • 2
    • 3
    • 4
  • Wei Hao
    • 3
    • 4
  1. 1.Department of PsychiatrySir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityHangzhouChina
  2. 2.Key Laboratory of Medical Neurobiology of Zhejiang ProvinceHangzhouChina
  3. 3.Department of PsychiatryThe Second Xiangya Hospital, Central South UniversityChangshaChina
  4. 4.National Clinical Research Center on Mental DisordersChangshaChina

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