Skip to main content
SpringerLink
Log in

Dopamine D4 Receptor Gene Associated with the Frontal-Striatal-Cerebellar Loop in Children with ADHD: A Resting-State fMRI Study

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder that has been linked to the dopaminergic system. This study aimed to investigate the effects of regulation of the dopamine D4 receptor (DRD4) on functional brain activity during the resting state in ADHD children using the methods of regional homogeneity (ReHo) and functional connectivity (FC). Resting-state functional magnetic resonance imaging data were analyzed in 49 children with ADHD. All participants were classified as either carriers of the DRD4 4-repeat/4-repeat (4R/4R) allele (n = 30) or the DRD4 2-repeat (2R) allele (n = 19). The results showed that participants with the DRD4 2R allele had decreased ReHo bilaterally in the posterior lobes of the cerebellum, while ReHo was increased in the left angular gyrus. Compared with participants carrying the DRD4 4R/4R allele, those with the DRD4 2R allele showed decreased FC to the left angular gyrus in the left striatum, right inferior frontal gyrus, and bilateral lobes of the cerebellum. The increased FC regions included the left superior frontal gyrus, medial frontal gyrus, and rectus gyrus. These data suggest that the DRD4 polymorphisms are associated with localized brain activity and specific functional connections, including abnormality in the frontal-striatal-cerebellar loop. Our study not only enhances the understanding of the correlation between the cerebellar lobes and ADHD, but also provides an imaging basis for explaining the neural mechanisms underlying ADHD in children.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 2007, 164: 942–948.

    Article  PubMed  Google Scholar 

  2. Ma G, Fan H, Shen C, Wang W. Genetic and neuroimaging features of personality disorders: state of the art. Neurosci Bull 2016, 32: 286–306.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Petronis A, Van Tol HH, Lichter JB, Livak KJ, Kennedy JL. The D4 dopamine receptor gene maps on 11p proximal to HRAS. Genomics 1993, 18: 161–163.

    Article  PubMed  CAS  Google Scholar 

  4. Kotler M, Manor I, Sever Y, Eisenberg J, Cohen H, Ebstein RP, et al. Failure to replicate an excess of the long dopamine D4 exon III repeat polymorphism in ADHD in a family-based study. Am J Med Genet 2000, 96: 278–281.

    Article  PubMed  CAS  Google Scholar 

  5. Ding YC, Chi HC, Grady DL, Morishima A, Kidd JR, Kidd KK, et al. Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proc Natl Acad Sci U S A 2002, 99: 309–314.

    Article  PubMed  CAS  Google Scholar 

  6. Kebir O, Tabbane K, Sengupta S, Joober R. Candidate genes and neuropsychological phenotypes in children with ADHD: review of association studies. J Psychiatry Neurosci 2009, 34: 88–101.

    PubMed  PubMed Central  Google Scholar 

  7. Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 2009, 126: 51–90.

    Article  PubMed  CAS  Google Scholar 

  8. Li D, Sham PC, Owen MJ, He L. Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 2006, 15: 2276–2284.

    Article  PubMed  CAS  Google Scholar 

  9. Laucht M, Becker K, Blomeyer D, Schmidt MH. Novelty seeking involved in mediating the association between the dopamine D4 receptor gene exon III polymorphism and heavy drinking in male adolescents: results from a high-risk community sample. Biol Psychiatry 2007, 61: 87–92.

    Article  PubMed  CAS  Google Scholar 

  10. Chang FM, Kidd JR, Livak KJ, Pakstis AJ, Kidd KK. The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. Hum Genet 1996, 98: 91–101.

    Article  PubMed  CAS  Google Scholar 

  11. Park S, Kim BN, Cho SC, Kim Y, Kim JW, Lee JY, et al. Association between urine phthalate levels and poor attentional performance in children with attention-deficit hyperactivity disorder with evidence of dopamine gene-phthalate interaction. Int J Environ Res Public Health 2014, 11: 6743–6756.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Leung PW, Lee CC, Hung SF, Ho TP, Tang CP, Kwong SL, et al. Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention-deficit/hyperactivity disorder (ADHD): increased prevalence of the 2-repeat allele. Am J Med Genet B Neuropsychiatr Genet 2005, 133B: 54–56.

    Article  PubMed  Google Scholar 

  13. Qian Q, Wang Y, Zhou R, Yang L, Faraone SV. Family-based and case-control association studies of DRD4 and DAT1 polymorphisms in Chinese attention deficit hyperactivity disorder patients suggest long repeats contribute to genetic risk for the disorder. Am J Med Genet B Neuropsychiatr Genet 2004, 128B: 84–89.

    Article  PubMed  Google Scholar 

  14. Manor I, Tyano S, Eisenberg J, Bachner-Melman R, Kotler M, Ebstein RP. The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA). Mol Psychiatry 2002, 7: 790–794.

    Article  PubMed  CAS  Google Scholar 

  15. Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH. Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem 1995, 65: 1157–1165.

    Article  PubMed  CAS  Google Scholar 

  16. Reist C, Ozdemir V, Wang E, Hashemzadeh M, Mee S, Moyzis R. Novelty seeking and the dopamine D4 receptor gene (DRD4) revisited in Asians: haplotype characterization and relevance of the 2-repeat allele. Am J Med Genet B Neuropsychiatr Genet 2007, 144B: 453–457.

    Article  PubMed  CAS  Google Scholar 

  17. Shaw P, Gornick M, Lerch J, Addington A, Seal J, Greenstein D, et al. Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2007, 64: 921–931.

    Article  PubMed  Google Scholar 

  18. Gilsbach S, Neufang S, Scherag S, Vloet TD, Fink GR, Herpertz-Dahlmann B, et al. Effects of the DRD4 genotype on neural networks associated with executive functions in children and adolescents. Dev Cogn Neurosci 2012, 2: 417–427.

    Article  PubMed  Google Scholar 

  19. Henriquez-Henriquez M, Villarroel L, Henriquez H, Zamorano F, Rothhammer F, Aboitiz F. Intratask variability as a correlate for DRD4 and SLC6A3 variants: A pilot study in ADHD. J Atten Disord 2015, 19: 987–996.

    Article  PubMed  Google Scholar 

  20. Zhang K, Zhu Y, Zhu Y, Wu S, Liu H, Zhang W, et al. Molecular, functional, and structural imaging of major depressive disorder. Neurosci Bull 2016, 32: 273–285.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Zang Y, Jiang T, Lu Y, He Y, Tian L. Regional homogeneity approach to fMRI data analysis. Neuroimage 2004, 22: 394–400.

    Article  PubMed  Google Scholar 

  22. Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med 1995, 34: 537–541.

    Article  PubMed  CAS  Google Scholar 

  23. Friston KJ, Frith CD, Liddle PF, Frackowiak RS. Functional connectivity: the principal-component analysis of large (PET) data sets. J Cereb Blood Flow Metab 1993, 13: 5–14.

    Article  PubMed  CAS  Google Scholar 

  24. Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, et al. Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 1997, 36: 980–988.

    Article  PubMed  CAS  Google Scholar 

  25. Smith SM. Fast robust automated brain extraction. Hum Brain Mapp 2002, 17: 143–155.

    Article  PubMed  Google Scholar 

  26. McGeary J. The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review. Pharmacol Biochem Behav 2009, 93: 222–229.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Mulcrone J, Kerwin RW. The regional pattern of D4 gene expression in human brain. Neurosci Lett 1997, 234: 147–150.

    Article  PubMed  CAS  Google Scholar 

  28. Fornari E, Knyazeva MG, Meuli R, Maeder P. Myelination shapes functional activity in the developing brain. Neuroimage 2007, 38: 511–518.

    Article  PubMed  Google Scholar 

  29. Pang GF, Wang SH, Ren YL, Ma L, Chen J, Xing W, et al. Cognitive development of normal school age children: a resting-state fMRI study. Zhonghua Yi Xue Za Zhi 2009, 89: 1313–1317.

    PubMed  Google Scholar 

  30. Rubia K. Neuro-anatomic evidence for the maturational delay hypothesis of ADHD. Proc Natl Acad Sci U S A 2007, 104: 19663–19664.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Rubia K, Overmeyer S, Taylor E, Brammer M, Williams SC, Simmons A, et al. Functional frontalisation with age: mapping neurodevelopmental trajectories with fMRI. Neurosci Biobehav Rev 2000, 24: 13–19.

    Article  PubMed  CAS  Google Scholar 

  32. Xia S, Foxe JJ, Sroubek AE, Branch C, Li X. Topological organization of the “small-world” visual attention network in children with attention deficit/hyperactivity disorder (ADHD). Front Hum Neurosci 2014, 8: 162.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Dickstein SG, Bannon K, Castellanos FX, Milham MP. The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis. J Child Psychol Psychiatry 2006, 47: 1051–1062.

    Article  PubMed  Google Scholar 

  34. Tamm L, Menon V, Reiss AL. Parietal attentional system aberrations during target detection in adolescents with attention deficit hyperactivity disorder: event-related fMRI evidence. Am J Psychiatry 2006, 163: 1033–1043.

    Article  PubMed  Google Scholar 

  35. Andrews-Hanna JR, Smallwood J, Spreng RN. The default network and self-generated thought: component processes, dynamic control, and clinical relevance. Ann N Y Acad Sci 2014, 1316: 29–52.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chen Q, Weidner R, Vossel S, Weiss PH, Fink GR. Neural mechanisms of attentional reorienting in three-dimensional space. J Neurosci 2012, 32: 13352–13362.

    Article  PubMed  CAS  Google Scholar 

  37. Seghier ML. The angular gyrus: multiple functions and multiple subdivisions. Neuroscientist 2013, 19: 43–61.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hirnstein M, Bayer U, Ellison A, Hausmann M. TMS over the left angular gyrus impairs the ability to discriminate left from right. Neuropsychologia 2011, 49: 29–33.

    Article  PubMed  Google Scholar 

  39. Li F, He N, Li Y, Chen L, Huang X, Lui S, et al. Intrinsic brain abnormalities in attention deficit hyperactivity disorder: a resting-state functional MR imaging study. Radiology 2014, 272: 514–523.

    Article  PubMed  Google Scholar 

  40. Zang YF, He Y, Zhu CZ, Cao QJ, Sui MQ, Liang M, et al. Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI. Brain Dev 2007, 29: 83–91.

    Article  PubMed  Google Scholar 

  41. Durston S, Tottenham NT, Thomas KM, Davidson MC, Eigsti IM, Yang Y, et al. Differential patterns of striatal activation in young children with and without ADHD. Biol Psychiatry 2003, 53: 871–878.

    Article  PubMed  Google Scholar 

  42. Booth JR, Burman DD, Meyer JR, Lei Z, Trommer BL, Davenport ND, et al. Larger deficits in brain networks for response inhibition than for visual selective attention in attention deficit hyperactivity disorder (ADHD). J Child Psychol Psychiatry 2005, 46: 94–111.

    Article  PubMed  Google Scholar 

  43. Shafritz KM, Marchione KE, Gore JC, Shaywitz SE, Shaywitz BA. The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder. Am J Psychiatry 2004, 161: 1990–1997.

    Article  PubMed  Google Scholar 

  44. Castellanos FX, Proal E. Large-scale brain systems in ADHD: beyond the prefrontal-striatal model. Trends Cogn Sci 2012, 16: 17–26.

    Article  PubMed  Google Scholar 

  45. Liston C, Malter Cohen M, Teslovich T, Levenson D, Casey BJ. Atypical prefrontal connectivity in attention-deficit/hyperactivity disorder: pathway to disease or pathological end point? Biol Psychiatry 2011, 69: 1168–1177.

    Article  PubMed  Google Scholar 

  46. Halperin JM, Schulz KP. Revisiting the role of the prefrontal cortex in the pathophysiology of attention-deficit/hyperactivity disorder. Psychol Bull 2006, 132: 560–581.

    Article  PubMed  Google Scholar 

  47. Middleton FA, Strick PL. Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain Res Brain Res Rev 2000, 31: 236–250.

    Article  PubMed  CAS  Google Scholar 

  48. Konrad K, Eickhoff SB. Is the ADHD brain wired differently? A review on structural and functional connectivity in attention deficit hyperactivity disorder. Hum Brain Mapp 2010, 31: 904–916.

    Article  PubMed  Google Scholar 

  49. Valera EM, Faraone SV, Murray KE, Seidman LJ. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biol Psychiatry 2007, 61: 1361–1369.

    Article  PubMed  Google Scholar 

  50. Mulder MJ, Baeyens D, Davidson MC, Casey BJ, van den Ban E, van Engeland H, et al. Familial vulnerability to ADHD affects activity in the cerebellum in addition to the prefrontal systems. J Am Acad Child Adolesc Psychiatry 2008, 47: 68–75.

    Article  PubMed  Google Scholar 

  51. Williams RW, Herrup K. The control of neuron number. Annu Rev Neurosci 1988, 11: 423–453.

    Article  PubMed  CAS  Google Scholar 

  52. Durston S, Fossella JA, Casey BJ, Hulshoff Pol HE, Galvan A, Schnack HG, et al. Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls. Mol Psychiatry 2005, 10: 678–685.

    Article  PubMed  CAS  Google Scholar 

  53. Zhong P, Liu W, Yan Z. Aberrant regulation of synchronous network activity by the attention deficit/hyperactivity disorder-associated human dopamine D4 receptor variant D4.7 in the prefrontal cortex. J Physiol 2016, 594(1): 135–47.

    Article  PubMed  CAS  Google Scholar 

  54. Castellanos FX, Sonuga-Barke EJ, Milham MP, Tannock R. Characterizing cognition in ADHD: beyond executive dysfunction. Trends Cogn Sci 2006, 10: 117–123.

    Article  PubMed  Google Scholar 

  55. Mulligan RC, Kristjansson SD, Reiersen AM, Parra AS, Anokhin AP. Neural correlates of inhibitory control and functional genetic variation in the dopamine D4 receptor gene. Neuropsychologia 2014, 62: 306–318.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Szekely E, Sudre GP, Sharp W, Leibenluft E, Shaw P. Defining the neural substrate of the adult outcome of childhood ADHD: A multimodal neuroimaging study of response inhibition. Am J Psychiatry 2017, 174: 867–876.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Ha RY, Namkoong K, Kang JI, Kim YT, Kim SJ. Interaction between serotonin transporter promoter and dopamine receptor D4 polymorphisms on decision making. Prog Neuropsychopharmacol Biol Psychiatry 2009, 33: 1217–1222.

    Article  PubMed  CAS  Google Scholar 

  58. Lee JS, Kim BN, Kang E, Lee DS, Kim YK, Chung JK, et al. Regional cerebral blood flow in children with attention deficit hyperactivity disorder: comparison before and after methylphenidate treatment. Hum Brain Mapp 2005, 24: 157–164.

    Article  PubMed  Google Scholar 

  59. Schweitzer JB, Lee DO, Hanford RB, Tagamets MA, Hoffman JM, Grafton ST, et al. A positron emission tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predicting treatment response. Neuropsychopharmacology 2003, 28: 967–973.

    Article  PubMed  CAS  Google Scholar 

  60. O’Gorman RL, Mehta MA, Asherson P, Zelaya FO, Brookes KJ, Toone BK, et al. Increased cerebral perfusion in adult attention deficit hyperactivity disorder is normalised by stimulant treatment: a non-invasive MRI pilot study. Neuroimage 2008, 42: 36–41.

    Article  PubMed  Google Scholar 

  61. Lee JS, Kim BN, Kang EJ, Lee DS, Kim YK, Chung JK, et al. Regional cerebral blood flow in children with attention deficit hyperactivity disorder: Comparison before and after methylphenidate treatment. Hum Brain Mapp 2005, 24: 157–164.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Natural Science Foundation of Zhejiang Province, China (No. LY14H180006, LQ18H090009) and the Natural Science Foundation of Jiangsu Province (BK20160142). We thank all the volunteers for their participations.

Author information

Author notes

  1. Andan Qian and Xin Wang have contributed equally to this work

Authors and Affiliations

  1. Department of Radiology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

    Andan Qian, Huiru Liu, Jiejie Tao, Jiejie Zhou, Qiong Ye, Jiance Li & Meihao Wang

  2. Department of Psychiatry, Wenzhou Medical University, Wenzhou, 325000, China

    Ke Zhao

  3. Department of Mental Health, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

    Chuang Yang

  4. Department of Radiology, Yancheng First People’s Hospital, Yancheng, 224000, China

    Xin Wang

  5. Department of Radiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China

    Jingliang Cheng

Authors
  1. Andan Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huiru Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiejie Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiejie Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qiong Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jiance Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chuang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jingliang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ke Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Meihao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ke Zhao or Meihao Wang.

Ethics declarations

Conflict of interest

All authors claim that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qian, A., Wang, X., Liu, H. et al. Dopamine D4 Receptor Gene Associated with the Frontal-Striatal-Cerebellar Loop in Children with ADHD: A Resting-State fMRI Study. Neurosci. Bull. 34, 497–506 (2018). https://doi.org/10.1007/s12264-018-0217-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-018-0217-7

Keywords

Search

Navigation