Psychopharmacology

, Volume 194, Issue 2, pp 173–183 | Cite as

Functional MRI of inhibitory processing in abstinent adolescent marijuana users

  • Susan F. Tapert
  • Alecia D. Schweinsburg
  • Sean P. A. Drummond
  • Martin P. Paulus
  • Sandra A. Brown
  • Tony T. Yang
  • Lawrence R. Frank
Original Investigation

Abstract

Background

Marijuana intoxication appears to impair response inhibition, but it is unclear if impaired inhibition and associated brain abnormalities persist after prolonged abstinence among adolescent users. We hypothesized that brain activation during a go/no-go task would show persistent abnormalities in adolescent marijuana users after 28 days of abstinence.

Methods

Adolescents with (n = 16) and without (n = 17) histories of marijuana use were compared on blood oxygen level dependent (BOLD) response to a go/no-go task during functional magnetic resonance imaging (fMRI) after 28 days of monitored abstinence. Participants had no neurological problems or Axis I diagnoses other than cannabis abuse/dependence.

Results

Marijuana users did not differ from non-users on task performance but showed more BOLD response than non-users during inhibition trials in right dorsolateral prefrontal, bilateral medial frontal, bilateral inferior and superior parietal lobules, and right occipital gyri, as well as during “go” trials in right prefrontal, insular, and parietal cortices (p < 0.05, clusters > 943 μl). Differences remained significant even after controlling for lifetime and recent alcohol use.

Conclusions

Adolescent marijuana users relative to non-users showed increased brain processing effort during an inhibition task in the presence of similar task performance, even after 28 days of abstinence. Thus, increased brain processing effort to achieve inhibition may predate the onset of regular use or result from it. Future investigations will need to determine whether increased brain processing effort is associated with risk to use.

Keywords

Marijuana Cannabis Functional magnetic resonance imaging Adolescence Response inhibition Abstinence 

Notes

Acknowledgements

This research was supported by National Institute on Drug Abuse grants R21 DA015228-03 and R01 DA021182-01 to S. F. Tapert, and R37 AA07033-19 to S. A. Brown. Appreciation is expressed to the following people for their assistance with this project: Valerie Barlett, Christina Burke, Lisa Caldwell, Mairav Cohen-Zion, Lawrence Frank, Krista Lisdahl Medina, Tim McQueeny, MJ Meloy, Bonnie Nagel, Ann Park, Claudia Padula, Brian Schweinsburg, Rebecca Theilmann, and Jennifer Winward. We would also like to acknowledge the support and advice of Dr. Robert Fitzgerald and the VA Laboratory Service.

Portions of this research were presented at the Annual Scientific Meeting of the College on Problems of Drug Dependence, June 18-23 2005, Orlando, FL, USA.

References

  1. Achenbach TM, Rescorla LA (2001) Manual for the ASEBA school-age forms & profiles. University of Vermont, Research Center for Children, Youth, and Families, Burlington, VTGoogle Scholar
  2. Adleman NE, Menon V, Blasey CM, White CD, Warsofsky IS, Glover GH, Reiss AL (2002) A developmental fMRI study of the Stroop color-word task. Neuroimage 16(1):61–75PubMedCrossRefGoogle Scholar
  3. Anderson KG, Schweinsburg AD, Paulus MP, Brown SA, Tapert SF (2005). Examining personality and alcohol expectancies using fMRI with adolescents. J Stud Alcohol 66(3):323–331PubMedGoogle Scholar
  4. APA (1994) Diagnostic and statistical manual of mental disorders (4th edn). American Psychiatric Association, Washington, DC, USAGoogle Scholar
  5. Bandettini PA, Jesmanowicz A, Wong EC, Hyde JS (1993) Processing strategies for time-course data sets in functional MRI of the human brain. Magn Reson Med 30:161–173PubMedCrossRefGoogle Scholar
  6. Beck AT (1978) Beck depression inventory (BDI). Psychological Corporation, San Antonio, TX, USAGoogle Scholar
  7. Block RI, O’Leary DS, Hichwa RD, Augustinack JC, Ponto LL, Ghoneim MM, Arndt S, Ehrhardt JC, Hurtig RR, Watkins GL, Hall JA, Nathan PE, Andreasen NC (2000). Cerebellar hypoactivity in frequent marijuana users. NeuroReport 11(4):749–753PubMedCrossRefGoogle Scholar
  8. Bolla KI, Brown K, Eldreth D, Tate K, Cadet JL (2002) Dose related neurocognitive effects of marijuana use. Neurology 59(9):1337–1343PubMedGoogle Scholar
  9. Boynton GM, Engel SA, Glover GH, Heeger DJ (1996) Linear systems analysis of functional magnetic resonance imaging in human V1. J Neurosci 16(13):4207–4221PubMedGoogle Scholar
  10. Brown GG, Eyler Zorrilla LT, Georgy B, Kindermann SS, Wong EC, Buxton RB (2003). BOLD and perfusion response to finger-thumb apposition after acetazolamide administration: Differential relationship to global perfusion. J Cereb Blood Flow Metab 23:829–837PubMedCrossRefGoogle Scholar
  11. Brown SA, Myers MG, Lippke L, Tapert SF, Stewart DG, Vik PW (1998) Psychometric evaluation of the customary drinking and drug use record (CDDR): a measure of adolescent alcohol and drug involvement. J Stud Alcohol 59:427–438PubMedGoogle Scholar
  12. Caldwell LC, Schweinsburg AD, Nagel BJ, Barlett VC, Brown SA, Tapert SF (2005) Gender and adolescent alcohol use disorders on BOLD (blood oxygen level dependent) response to spatial working memory. Alcohol Alcohol 40:194–200PubMedGoogle Scholar
  13. Chang L, Yakupov R, Cloak C, Ernst T (2006) Marijuana use is associated with a reorganized visual-attention network and cerebellar hypoactivation. Brain 129(Pt 5):1096–1112PubMedCrossRefGoogle Scholar
  14. Chen AC, Porjesz B, Rangaswamy M, Kamarajan C, Tang Y, Jones KA, Chorlian DB, Stimus AT, Begleiter H (2007). Reduced frontal lobe activity in subjects with high impulsivity and alcoholism. Alcohol Clin Exp Res 31(1):156–165PubMedCrossRefGoogle Scholar
  15. Costa PTJ, McCrae RR (1992) Professional manual: revised NEO personality inventory (NEO PI-R) and NEO five-factor inventory (NEO-FFI). Psychological Assessment Resources, Lutz, FL, USAGoogle Scholar
  16. Cox RW (1996) AFNI: Software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 29:162–173PubMedCrossRefGoogle Scholar
  17. Cox RW, Jesmanowicz A (1999) Real-time 3D image registration for functional MRI. Magn Reson Med 42:1014–1018PubMedCrossRefGoogle Scholar
  18. Delis D, Kaplan E (2001) Manual for the Delis–Kaplan executive function system. Psychological Corporation, San AntonioGoogle Scholar
  19. Drummond SPA, Bischoff-Grethe A, Dinges DF, Ayalon L, Mednick CM, Meloy MJ (2005) The neural basis of the psychomotor vigilance task. Sleep 28:1059–1068PubMedGoogle Scholar
  20. Drummond SPA, Paulus MP, Tapert SF (2006) Effects of 2 nights sleep deprivation and 2 nights recovery sleep on response inhibition. J Sleep Res 15:261–265PubMedCrossRefGoogle Scholar
  21. Eggan SM, Lewis DA (2007) Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate neocortex: a regional and laminar analysis. Cereb Cortex 17:175–191PubMedCrossRefGoogle Scholar
  22. Fletcher JM, Page JB, Francis DJ, Copeland K, Naus MJ, Davis CM, Morris R, Krauskopf D, Satz P (1996) Cognitive correlates of long-term cannabis use in Costa Rican men. Arch Gen Psychiatry 53(11):1051–1057PubMedGoogle Scholar
  23. Forman SD, Cohen JD, Fitzgerald M, Eddy WF, Mintun MA, Noll DC (1995) Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold. Magn Reson Med 33(5):636–647PubMedCrossRefGoogle Scholar
  24. Fraser AD, Coffin L, Worth, D (2002) Drug and chemical metabolites in clinical toxicology investigations: the importance of ethylene glycol, methanol and cannabinoid metabolite analyses. Clin Biochem 35(7):501–511PubMedCrossRefGoogle Scholar
  25. Fruyt FD, Mervielde I, Hoekstra HA, Rolland J-P (2000) Assessing adolescents’ personality with the NEO-PI-R. Assessment 7:329–345PubMedCrossRefGoogle Scholar
  26. Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, Nugent TF 3rd, Herman DH, Clasen LS, Toga AW, Rapoport JL, Thompson PM (2004) Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA 101(21):8174–8179PubMedCrossRefGoogle Scholar
  27. Gruber SA, Yurgelun-Todd DA (2005) Neuroimaging of marijuana smokers during inhibitory processing: a pilot investigation. Brain Res Cogn Brain Res 23(1):107–118PubMedCrossRefGoogle Scholar
  28. Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO (1991) The Fagerstrom test for nicotine dependence: a revision of the Fagerstrom tolerance questionnaire. Br J Addict 86(9):1119–1127PubMedCrossRefGoogle Scholar
  29. Herning RI, Better WE, Tate K, Cadet JL (2005) Cerebrovascular perfusion in marijuana users during a month of monitored abstinence. Neurology 64(3):488–493PubMedGoogle Scholar
  30. Huestis MA, Cone EJ (1998) Differentiating new marijuana use from residual drug excretion in occasional marijuana users. J Anal Toxicol 22(6):445–454PubMedGoogle Scholar
  31. Jacobsen LK, Mencl WE, Westerveld M, Pugh KR (2004) Impact of cannabis use on brain function in adolescents. Ann NY Acad Sci 1021:384–390PubMedCrossRefGoogle Scholar
  32. Jacobsen LK, Pugh KR, Constable RT, Westerveld M, Mencl WE (2007) Functional correlates of verbal memory deficits emerging during nicotine withdrawal in abstinent adolescent cannabis users. Biol Psychiatry 61:31–40PubMedCrossRefGoogle Scholar
  33. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE (2005) Monitoring the future national results on adolescent drug use 1975–2004: vol 1, secondary school students (NIH Publication No. 05-5727). National Institute on Drug Abuse, Bethesda, MD, USAGoogle Scholar
  34. Kamarajan C, Porjesz B, Jones K, Chorlian D, Padmanabhapillai A, Rangaswamy M, Stimus A, Begleiter H (2006) Event-related oscillations in offspring of alcoholics: neurocognitive disinhibition as a risk for alcoholism. Biol Psychiatry 59(7):625–634PubMedCrossRefGoogle Scholar
  35. Kanayama G, Rogowska J, Pope HG, Gruber SA, Yurgelun Todd DA (2004) Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study. Psychopharmacology (Berl) 176(3–4):239–247CrossRefGoogle Scholar
  36. Kirisci L, Tarter RE, Reynolds M, Vanyukov M (2006) Individual differences in childhood neurobehavior disinhibition predict decision to desist substance use during adolescence and substance use disorder in young adulthood: a prospective study. Addict Behav 31(4):686–696PubMedCrossRefGoogle Scholar
  37. Lafolie P, Beck O, Blennow G, Boreus L, Borg S, Elwin CE, Karlsson L, Odelius G, Hjemdahl P (1991) Importance of creatinine analyses of urine when screening for abused drugs. Clin Chem 37(11):1927–1931PubMedGoogle Scholar
  38. Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, Kochunov PV, Nickerson D, Mikiten SA, Fox PT (2000) Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 10(3):120–131PubMedCrossRefGoogle Scholar
  39. Liu X, Banich MT, Jacobson BL, Tanabe JL (2004) Common and distinct neural substrates of attentional control in an integrated Simon and spatial Stroop task as assessed by event-related fMRI. Neuroimage 22(3):1097–1106PubMedCrossRefGoogle Scholar
  40. Lucas CP, Zhang H, Fisher PW, Shaffer D, Regier DA, Narrow WE, Bourdon K, Dulcan MK, Canino G, Rubio Stipec M, Lahey BB, Friman P (2001) The DISC predictive scales (DPS): efficiently screening for diagnoses. J Am Acad Child Adolesc Psychiatry 40(4):443–449PubMedCrossRefGoogle Scholar
  41. Luna B, Thulborn KR, Munoz DP, Merriam EP, Garver KE, Minshew NJ, Keshavan MS, Genovese CR, Eddy WF, Sweeney JA (2001) Maturation of widely distributed brain function subserves cognitive development. Neuroimage 13(5):786–793PubMedCrossRefGoogle Scholar
  42. Lundqvist T, Jonsson S, Warkentin S (2001) Frontal lobe dysfunction in long-term cannabis users. Neurotoxicol Teratol 23(5):437–443PubMedCrossRefGoogle Scholar
  43. Mathew RJ, Wilson WH, Turkington TG, Hawk TC, Coleman RE, DeGrado TR, Provenzale J (2002) Time course of tetrahydrocannabinol induced changes in regional cerebral blood flow measured with positron emission tomography. Psychiatry Res 116(3):173–185PubMedCrossRefGoogle Scholar
  44. Medina KL, Nagel BJ, Park A, McQueeny T, Tapert SF (2007a) Depressive symptoms in adolescents: Associations with white matter volume and marijuana use. J Child Psychol Psychiatry 48:592–600Google Scholar
  45. Medina KL, Schweinsburg AD, Cohen-Zion M, Nagel BJ, Tapert SF (2007b) Effects of alcohol and combined marijuana and alcohol use during adolescence on hippocampal volume and asymmetry. Neurotoxicol Teratol 29:141–152PubMedCrossRefGoogle Scholar
  46. Millsaps CL, Azrin RL, Mittenberg W (1994) Neuropsychological effects of chronic cannabis use on the memory and intelligence of adolescents. J Child Adolesc Subst Abuse 3(1):47–55CrossRefGoogle Scholar
  47. Nagel B, Medina K, Yoshii J, Schweinsburg A, Moadab I, Tapert S (2006) Age-related changes in prefrontal white matter volume across adolescence. NeuroReport 17:1427–1431PubMedCrossRefGoogle Scholar
  48. O’Leary DS, Block RI, Koeppel JA, Flaum M, Schultz SK, Andreasen NC, Ponto LB, Watkins GL, Hurtig RR, Hichwa RD (2002) Effects of smoking marijuana on brain perfusion and cognition. Neuropsychopharmacology 26(6):802–816PubMedCrossRefGoogle Scholar
  49. Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun Todd D (2001) Neuropsychological performance in long term cannabis users. Arch Gen Psychiatry 58(10):909–915PubMedCrossRefGoogle Scholar
  50. Pope HGJ, Yurgelun Todd D (1996) The residual cognitive effects of heavy marijuana use in college students. JAMA 275(7):521–527PubMedCrossRefGoogle Scholar
  51. Rajah MN, D’Esposito M (2005) Region-specific changes in prefrontal function with age: a review of PET and fMRI studies on working and episodic memory. Brain 128(Pt 9):1964–1983PubMedCrossRefGoogle Scholar
  52. Rice JP, Reich T, Bucholz KK, Neuman RJ, Fishman R, Rochberg N, Hesselbrock VM, Nurnberger JI Jr, Schuckit MA, Begleiter H (1995) Comparison of direct interview and family history diagnoses of alcohol dependence. Alcohol Clin Exp Res 19(4):1018–1023PubMedCrossRefGoogle Scholar
  53. SAMHSA (2003) Results from the 2002 national survey on drug use and health: national findings (No. DHHS Publication No. SMA 03-3836). Office of Applied Studies, Rockville, MD, USAGoogle Scholar
  54. Schulz KP, Fan J, Tang CY, Newcorn JH, Buchsbaum MS, Cheung AM, Halperin JM (2004) Response inhibition in adolescents diagnosed with attention deficit hyperactivity disorder during childhood: an event related FMRI study. Am J Psychiatry 161(9):1650–1657PubMedCrossRefGoogle Scholar
  55. Schwartz RH, Gruenewald PJ, Klitzner M, Fedio P (1989) Short-term memory impairment in cannabis-dependent adolescents. Am J Dis Child 143(10):1214–1219PubMedGoogle Scholar
  56. Schweinsburg AD, Nagel BJ, Barlett VC, Killeen LA, Caldwell LC, Pulido CP, Brown SA, Paulus MP, Tapert SF (2004a) fMRI of response inhibition across adolescent development. Paper presented at the Annual Meeting of the International Neuropsychological Society, Baltimore, MD, USAGoogle Scholar
  57. Schweinsburg AD, Paulus MP, Barlett VC, Killeen LA, Caldwell LC, Pulido CP, Brown SA, Tapert SF (2004b) An fMRI study of response inhibition in youths with a family history of alcoholism. Ann NY Acad Sci 1021:391–394PubMedCrossRefGoogle Scholar
  58. Schweinsburg AD, Nagel BJ, Tapert SF (2005a) fMRI reveals alteration of spatial working memory networks across adolescence. J Int Neuropsychol Soc 11(5):631–644PubMedCrossRefGoogle Scholar
  59. Schweinsburg AD, Schweinsburg BC, Cheung EH, Brown GG, Brown SA, Tapert SF (2005b) fMRI response to spatial working memory in adolescents with comorbid marijuana and alcohol use disorders. Drug Alcohol Depend 79(2):201–210PubMedCrossRefGoogle Scholar
  60. Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME (2000) NIMH diagnostic interview schedule for children version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. J Am Acad Child Adolesc Psych 39(1):28–38CrossRefGoogle Scholar
  61. Sneider JT, Pope HG Jr, Silveri MM, Simpson NS, Gruber SA, Yurgelun-Todd DA (2006). Altered regional blood volume in chronic cannabis smokers. Exp Clin Psychopharmacol 14(4):422–428PubMedCrossRefGoogle Scholar
  62. Sobell LC, Sobell MB (1992) Timeline follow-back: a technique for assessing self-reported alcohol consumption. In: Litten RZ, Allen JP (eds) Measuring alcohol consumption: psychosocial and biochemical methods. Humana Press, Totowa, NJ, US, pp 41–72Google Scholar
  63. Solowij N, Michie PT, Fox AM (1991) Effects of long-term cannabis use on selective attention: an event-related potential study. Pharmacol Biochem Behav 40(3):683–688PubMedCrossRefGoogle Scholar
  64. Solowij N, Michie PT, Fox AM (1995) Differential impairments of selective attention due to frequency and duration of cannabis use. Biol Psychiatry 37(10):731–739PubMedCrossRefGoogle Scholar
  65. Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, Christiansen K, McRee B, Vendetti J (2002) Cognitive functioning of long term heavy cannabis users seeking treatment. JAMA 287(9):1123–1131PubMedCrossRefGoogle Scholar
  66. Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW (2003) Mapping cortical change across the human life span. Nat Neurosci 6:309–315PubMedCrossRefGoogle Scholar
  67. Sowell ER, Trauner DA, Gamst A, Jernigan TL (2002) Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study. Dev Med Child Neurol 44(1):4–16PubMedCrossRefGoogle Scholar
  68. Spielberger CD, Gorsuch RL, Lushene RE (1970) Manual for the state-trait anxiety inventory. Consulting Psychologists Press, Palo Alto, CA, USAGoogle Scholar
  69. Stewart DG, Brown SA (1995) Withdrawal and dependency symptoms among adolescent alcohol and drug abusers. Addiction 90:627–635PubMedCrossRefGoogle Scholar
  70. Struve FA, Patrick G, Straumanis JJ, Fitz-Gerald MJ, Manno J (1998) Possible EEG sequelae of very long duration marihuana use: pilot findings from topographic quantitative EEG analyses of subjects with 15 to 24 years of cumulative daily exposure to THC. Clin Electroencephalogr 29(1):31–36PubMedGoogle Scholar
  71. Tabachnick BG, Fidell LS (2007) Using multivariate statistics (5th edn). Pearson, BostonGoogle Scholar
  72. Talairach J, Tournoux P (1988) Coplanar stereotaxic atlas of the human brain. Three-dimensional proportional system: an approach to cerebral imaging. Thieme, New YorkGoogle Scholar
  73. Tamm L, Menon V, Reiss AL (2002) Maturation of brain function associated with response inhibition. J Am Acad Child Adolesc Psych 41(10):1231–1238CrossRefGoogle Scholar
  74. Tapert SF, Brown GG, Kindermann S, Cheung EH, Frank LR, Brown SA (2001) fMRI measurement of brain dysfunction in alcohol-dependent young women. Alcohol Clin Exp Res 25:236–245PubMedCrossRefGoogle Scholar
  75. Tapert SF, Baratta MV, Abrantes AM, Brown SA (2002a) Attention dysfunction predicts substance involvement in community youths. J Am Acad Child Adolesc Psych 41(6):680–686CrossRefGoogle Scholar
  76. Tapert SF, Granholm E, Leedy NG, Brown SA (2002b) Substance use and withdrawal: Neuropsychological functioning over 8 years in youth. J Int Neuropsychol Soc 8(7):873–883PubMedCrossRefGoogle Scholar
  77. Tapert SF, Schweinsburg AD, Barlett VC, Brown SA, Frank LR, Brown GG, Meloy MJ (2004) Blood oxygen level dependent response and spatial working memory in adolescents with alcohol use disorders. Alcohol Clin Exp Res 28(10):1577–1586PubMedCrossRefGoogle Scholar
  78. Verdejo-Garcia A, Bechara A, Recknor EC, Perez-Garcia M (2006) Executive dysfunction in substance dependent individuals during drug use and abstinence: an examination of the behavioral, cognitive and emotional correlates of addiction. J Int Neuropsychol Soc 12(3):405–415PubMedGoogle Scholar
  79. Ward BD (1997) Simultaneous inference for FMRI data. Biophysics Research Institute, Medical College of Wisconsin, Milwaukee, WI, USAGoogle Scholar
  80. Ward BD (2002) Deconvolution analysis of FMRI time series data. Biophysics Research Institute, Medical College of Wisconsin, Milwaukee, WI, USAGoogle Scholar
  81. Wechsler D (1999) Manual for the Wechsler abbreviated scale of intelligence. Psychological Corporation, San Antonio, TX, USAGoogle Scholar
  82. Wilkinson GS (1993) The wide range achievement test-3 administration manual. Jastak Associates, Wilmington, DE, USAGoogle Scholar
  83. Wong EC, Luh WM, Buxton RB, Frank LR (2000) Single slab high resolution 3D whole brain imaging using spiral FSE. Proc Int Soc Magn Reson Med 8:683Google Scholar
  84. Yurgelun-Todd D, Gruber AJ, Hanson RA, Baird AA, Renshaw PF, Pope HG Jr (1998). Residual effects of marijuana use: an fMRI study. In: Harris LS (ed) Problems of drug dependence 1998: proceedings of the 60th annual scientific meeting, the college on problems of drug dependence. NIDA Research Monograph 179, National Institute on Drug Abuse, Bethesda, MD, USA, pp 78Google Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Susan F. Tapert
    • 1
    • 2
  • Alecia D. Schweinsburg
    • 3
  • Sean P. A. Drummond
    • 1
    • 2
  • Martin P. Paulus
    • 1
    • 2
  • Sandra A. Brown
    • 1
    • 2
    • 3
  • Tony T. Yang
    • 2
  • Lawrence R. Frank
    • 1
    • 4
  1. 1.VA San Diego Healthcare SystemSan DiegoUSA
  2. 2.Department of PsychiatryUniversity of California San DiegoSan DiegoUSA
  3. 3.Department of PsychologyUniversity of California San DiegoSan DiegoUSA
  4. 4.Department of RadiologyUniversity of California San DiegoSan DiegoUSA

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