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Gray matter volume and microRNA levels in patients with attention-deficit/hyperactivity disorder

  • Liang-Jen Wang
  • Sung-Chou Li
  • Ho-Chang Kuo
  • Wen-Jiun Chou
  • Min-Jing Lee
  • Miao-Chun Chou
  • Huai-Hsuan Tseng
  • Chia-Fen Hsu
  • Sheng-Yu Lee
  • Wei-Che LinEmail author
Original Paper

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder often characterized by gray matter (GM) volume reductions. MicroRNAs, which participate in regulating gene expression, potentially influence neurodevelopment. This study aimed to explore whether differential GM volume is associated with differential miRNA levels in ADHD patients. We recruited a total of 30 drug-naïve patients with ADHD (mean age 10.6 years) and 25 healthy controls (mean age 10.6 years) that underwent a single session of 3.0-T whole brain structural MRI scanning. RNA samples from the participants’ white blood cells were collected to identify the ΔCt values of three miRNAs (miR-30e-5p, miR-126-5p, and miR-140-3p) using the real-time quantitative reverse transcription polymerase chain reaction. In comparison to the control group, ADHD patients demonstrated a significantly lower GM volume in the cingulate gyrus, left middle temporal gyrus, right middle occipital gyrus, left fusiform gyrus, and significantly higher ΔCt values of miR-30e-5p, miR-126-5p, and miR-140-3p. In the ADHD group, the GM volume of cingulate gyrus and left fusiform gyrus was negatively correlated with the ΔCt values of miR-30e-5p, miR-140-3p. The GM volume of left fusiform gyrus was negatively correlated to ADHD behavioral symptoms. Using structural equation modeling (SEM), we observed that the effect of miR-140-3p on hyperactivity/impulsivity symptoms was mediated by left fusiform gyrus. Our findings support that GM volume reduction and miRNA increases may be biomarkers for ADHD in children and adolescents. Expression levels of miRNAs may affect the development of brain structures and further participate in the pathophysiology of ADHD.

Keywords

ADHD Brain imaging Epigenetic miRNA Cortex 

Notes

Acknowledgements

The authors would like to thank Professor Wei-Tsun Soong for granting us the use of the Chinese version of the K-SADS.

Author contribution

LJW participated in study design, patient recruitment, reviewing references, and drafting the manuscript. SCL participated in study design, executed the miRNA analyses and interpreting the data. HCK, MJL, MCC, and WJC participated in data collection and patient recruitment. SYL drafted and revised the manuscript. HHT and CFH participated in protocol development and brain imaging data analyses. WCL participated in study design, brain imaging data analyses, draft and revised the manuscript. All the authors read and approved the final manuscript and contributed to the drafting and revising of the paper.

Funding

This work was supported by Grant from Chang Gung Memorial Hospital Research Project (CMRPG8E1451) and the Taiwan Ministry of Science and Technology (MOST 104-2314-B-182A-032 and MOST 105-2314-B-182A-054 -MY2 to LJ Wang, and MOST 106-2314-B-182A-031–MY2 to WC Lin).

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest.

Supplementary material

406_2019_1032_MOESM1_ESM.xlsx (30 kb)
Supplementary material 1 (XLSX 30 kb)
406_2019_1032_MOESM2_ESM.doc (78 kb)
Supplementary material 2 (DOC 77 kb)

References

  1. 1.
    Thapar A, Cooper M (2016) Attention deficit hyperactivity disorder. Lancet 387(10024):1240–1250PubMedCrossRefGoogle Scholar
  2. 2.
    Polanczyk GV, Willcutt EG, Salum GA, Kieling C, Rohde LA (2014) ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. Int J Epidemiol 43(2):434–442PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Gau SS, Chong MY, Chen TH, Cheng AT (2005) A 3-year panel study of mental disorders among adolescents in Taiwan. Am J Psychiatry 162(7):1344–1350PubMedCrossRefGoogle Scholar
  4. 4.
    Chen YL, Chen WJ, Lin KC, Shen LJ, Gau SS (2019) Prevalence of DSM-5 mental disorders in a nationally representative sample of children in Taiwan: methodology and main findings. Epidemiol Psychiatr Sci 30:1–9CrossRefGoogle Scholar
  5. 5.
    Castellanos FX, Lee PP, Sharp W, Jeffries NO, Greenstein DK, Clasen LS, Blumenthal JD, James RS, Ebens CL, Walter JM, Zijdenbos A, Evans AC, Giedd JN, Rapoport JL (2002) Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA 288(14):1740–1748PubMedCrossRefGoogle Scholar
  6. 6.
    Shaw P, Eckstrand K, Sharp W, Blumenthal J, Lerch JP, Greenstein D, Clasen L, Evans A, Giedd J, Rapoport JL (2007) Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci USA 104(49):19649–19654PubMedCrossRefGoogle Scholar
  7. 7.
    Shaw P, Gilliam M, Liverpool M, Weddle C, Malek M, Sharp W, Greenstein D, Evans A, Rapoport J, Giedd J (2011) Cortical development in typically developing children with symptoms of hyperactivity and impulsivity: support for a dimensional view of attention deficit hyperactivity disorder. Am J Psychiatry 168(2):143–151PubMedCrossRefGoogle Scholar
  8. 8.
    Seidman LJ, Valera EM, Makris N (2005) Structural brain imaging of attention-deficit/hyperactivity disorder. Biol Psychiatry 57(11):1263–1272PubMedCrossRefGoogle Scholar
  9. 9.
    Cao M, Shu N, Cao Q, Wang Y, He Y (2014) Imaging functional and structural brain connectomics in attention-deficit/hyperactivity disorder. Mol Neurobiol 50(3):1111–1123PubMedCrossRefGoogle Scholar
  10. 10.
    von Rhein D, Mennes M, van Ewijk H, Groenman AP, Zwiers MP, Oosterlaan J, Heslenfeld D, Franke B, Hoekstra PJ, Faraone SV, Hartman C, Buitelaar J (2015) The NeuroIMAGE study: a prospective phenotypic, cognitive, genetic and MRI study in children with attention-deficit/hyperactivity disorder. Design and descriptives. Eur Child Adolesc Psychiatry 24(3):265–281CrossRefGoogle Scholar
  11. 11.
    Giedd JN, Raznahan A, Alexander-Bloch A, Schmitt E, Gogtay N, Rapoport JL (2015) Child psychiatry branch of the National Institute of Mental Health longitudinal structural magnetic resonance imaging study of human brain development. Neuropsychopharmacology 40(1):43–49PubMedCrossRefGoogle Scholar
  12. 12.
    Ko CH, Yen JY, Yen CF, Chen CS, Lin WC, Wang PW, Liu GC (2013) Brain activation deficit in increased-load working memory tasks among adults with ADHD using fMRI. Eur Arch Psychiatry Clin Neurosci 263(7):561–573PubMedCrossRefGoogle Scholar
  13. 13.
    Chen CY, Yen JY, Yen CF, Chen CS, Liu GC, Liang CY, Ko CH (2015) Aberrant brain activation of error processing among adults with attention deficit and hyperactivity disorder. Kaohsiung J Med Sci 31(4):179–187PubMedCrossRefGoogle Scholar
  14. 14.
    Villemonteix T, De Brito SA, Kavec M, Baleriaux D, Metens T, Slama H, Baijot S, Mary A, Peigneux P, Massat I (2015) Grey matter volumes in treatment naive vs. chronically treated children with attention deficit/hyperactivity disorder: a combined approach. Eur Neuropsychopharmacol 25(8):1118–1127PubMedCrossRefGoogle Scholar
  15. 15.
    Rogers JC, De Brito SA (2016) Cortical and subcortical gray matter volume in youths with conduct problems: a meta-analysis. JAMA Psychiatry 73(1):64–72PubMedCrossRefGoogle Scholar
  16. 16.
    Thapar A, Cooper M, Eyre O, Langley K (2013) What have we learnt about the causes of ADHD? J Child Psychol Psychiatry 54(1):3–16PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Gallo EF, Posner J (2016) Moving towards causality in attention-deficit hyperactivity disorder: overview of neural and genetic mechanisms. Lancet Psychiatry 3(6):555–567PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Mill J, Petronis A (2008) Pre- and peri-natal environmental risks for attention-deficit hyperactivity disorder (ADHD): the potential role of epigenetic processes in mediating susceptibility. J Child Psychol Psychiatry 49(10):1020–1030PubMedCrossRefGoogle Scholar
  19. 19.
    Schuch V, Utsumi DA, Costa TV, Kulikowski LD, Muszkat M (2015) Attention deficit hyperactivity disorder in the light of the epigenetic paradigm. Front Psychiatry 6:126PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Shukla GC, Singh J, Barik S (2011) MicroRNAs: processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol 3(3):83–92PubMedPubMedCentralGoogle Scholar
  21. 21.
    Kosik KS (2006) The neuronal microRNA system. Nat Rev Neurosci 7(12):911–920PubMedCrossRefGoogle Scholar
  22. 22.
    Karakas U, Ay OI, Ay ME, Wang W, Sungur MA, Cevik K, Dogru G, Erdal ME (2017) Regulating the regulators in attention-deficit/hyperactivity disorder: a genetic association study of microRNA biogenesis pathways. OMICS 21(6):352–358PubMedCrossRefGoogle Scholar
  23. 23.
    Srivastav S, Walitza S, Grunblatt E (2018) Emerging role of miRNA in attention deficit hyperactivity disorder: a systematic review. Atten Defic Hyperact Disord 10(1):49–63PubMedCrossRefGoogle Scholar
  24. 24.
    Banerjee E, Sinha S, Chatterjee A, Nandagopal K (2009) No causal role for the G482T and G689T polymorphisms in translation regulation of serotonin transporter (SLC6A4) or association with attention-deficit-hyperactivity disorder (ADHD). Neurosci Lett 454(3):244–248PubMedCrossRefGoogle Scholar
  25. 25.
    Kovacs-Nagy R, Sarkozy P, Hu J, Guttman A, Sasvari-Szekely M, Ronai Z (2011) Haplotyping of putative microRNA-binding sites in the SNAP-25 gene. Electrophoresis 32(15):2013–2020PubMedCrossRefGoogle Scholar
  26. 26.
    Nemeth N, Kovacs-Nagy R, Szekely A, Sasvari-Szekely M, Ronai Z (2013) Association of impulsivity and polymorphic microRNA-641 target sites in the SNAP-25 gene. PLoS One 8(12):e84207PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Ye C, Hu Z, Wu E, Yang X, Buford UJ, Guo Z, Saveanu RV (2016) Two SNAP-25 genetic variants in the binding site of multiple microRNAs and susceptibility of ADHD: a meta-analysis. J Psychiatr Res 81:56–62PubMedCrossRefGoogle Scholar
  28. 28.
    Barber JC, Rosenfeld JA, Foulds N, Laird S, Bateman MS, Thomas NS, Baker S, Maloney VK, Anilkumar A, Smith WE, Banks V, Ellingwood S, Kharbutli Y, Mehta L, Eddleman KA, Marble M, Zambrano R, Crolla JA, Lamb AN (2013) 8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients. Am J Med Genet A 161(3):487–500CrossRefGoogle Scholar
  29. 29.
    Sanchez-Mora C, Ramos-Quiroga JA, Garcia-Martinez I, Fernandez-Castillo N, Bosch R, Richarte V, Palomar G, Nogueira M, Corrales M, Daigre C, Martinez-Luna N, Grau-Lopez L, Toma C, Cormand B, Roncero C, Casas M, Ribases M (2013) Evaluation of single nucleotide polymorphisms in the miR-183-96-182 cluster in adulthood attention-deficit and hyperactivity disorder (ADHD) and substance use disorders (SUDs). Eur Neuropsychopharmacol 23(11):1463–1473PubMedCrossRefGoogle Scholar
  30. 30.
    Sery O, Paclt I, Drtilkova I, Theiner P, Kopeckova M, Zvolsky P, Balcar VJ (2015) A 40-bp VNTR polymorphism in the 3′-untranslated region of DAT1/SLC6A3 is associated with ADHD but not with alcoholism. Behav Brain Funct 11:21PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Garcia-Martinez I, Sanchez-Mora C, Pagerols M, Richarte V, Corrales M, Fadeuilhe C, Cormand B, Casas M, Ramos-Quiroga JA, Ribases M (2016) Preliminary evidence for association of genetic variants in pri-miR-34b/c and abnormal miR-34c expression with attention deficit and hyperactivity disorder. Transl Psychiatry 6(8):e879PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Kandemir H, Erdal ME, Selek S, Ay OI, Karababa IF, Kandemir SB, Ay ME, Yilmaz SG, Bayazit H, Tasdelen B (2014) Evaluation of several micro RNA (miRNA) levels in children and adolescents with attention deficit hyperactivity disorder. Neurosci Lett 580:158–162PubMedCrossRefGoogle Scholar
  33. 33.
    Wu LH, Peng M, Yu M, Zhao QL, Li C, Jin YT, Jiang Y, Chen ZY, Deng NH, Sun H, Wu XZ (2015) Circulating MicroRNA let-7d in attention-deficit/hyperactivity disorder. Neuromolecular Med 17(2):137–146PubMedCrossRefGoogle Scholar
  34. 34.
    Wang LJ, Li SC, Lee MJ, Chou MC, Chou WJ, Lee SY, Hsu CW, Huang LH, Kuo HC (2018) Blood-bourne MicroRNA biomarker evaluation in attention-deficit/hyperactivity disorder of Han Chinese individuals: an exploratory study. Front Psychiatry 9:227PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Frei JA, Stoeckli ET (2017) SynCAMs—from axon guidance to neurodevelopmental disorders. Mol Cell Neurosci 81:41–48PubMedCrossRefGoogle Scholar
  36. 36.
    Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N (1997) 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 36(7):980–988CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ashburner J (2007) A fast diffeomorphic image registration algorithm. Neuroimage 38(1):95–113CrossRefGoogle Scholar
  38. 38.
    Baron IS (2005) Test review: Wechsler intelligence scale for children-fourth edition (WISC-IV). Child Neuropsychol 11(5):471–475PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang S, Faries DE, Vowles M, Michelson D (2005) ADHD rating scale IV: psychometric properties from a multinational study as a clinician-administered instrument. Int J Methods Psychiatr Res 14(4):186–201PubMedCrossRefGoogle Scholar
  40. 40.
    Talairach J (1998) P T: Co-planar stereotaxic atlas of the human brain: 3-dimensional proportional system: an approach to cerebral imaging. Georg Thieme, StuttgartGoogle Scholar
  41. 41.
    Narr KL, Woods RP, Lin J, Kim J, Phillips OR, Del’Homme M, Caplan R, Toga AW, McCracken JT, Levitt JG (2009) Widespread cortical thinning is a robust anatomical marker for attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 48(10):1014–1022PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Wang S, Yang Y, Xing W, Chen J, Liu C, Luo X (2013) Altered neural circuits related to sustained attention and executive control in children with ADHD: an event-related fMRI study. Clin Neurophysiol 124(11):2181–2190PubMedCrossRefGoogle Scholar
  43. 43.
    D’Alberto N, Chaarani B, Orr CA, Spechler PA, Albaugh MD, Allgaier N, Wonnell A, Banaschewski T, Bokde ALW, Bromberg U, Buchel C, Quinlan EB, Conrod PJ, Desrivieres S, Flor H, Frohner JH, Frouin V, Gowland P, Heinz A, Itterman B, Martinot JL, Paillere Martinot ML, Artiges E, Nees F, Papadopoulos Orfanos D, Poustka L, Robbins TW, Smolka MN, Walter H, Whelan R, Schumann G, Potter AS, Garavan H (2018) Individual differences in stop-related activity are inflated by the adaptive algorithm in the stop signal task. Hum Brain Mapp 39(8):3263–3276PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Rubia K, Alegria AA, Brinson H (2014) Brain abnormalities in attention-deficit hyperactivity disorder: a review. Rev Neurol 58(Suppl 1):S3–S16PubMedGoogle Scholar
  45. 45.
    Cubillo A, Halari R, Smith A, Taylor E, Rubia K (2012) A review of fronto-striatal and fronto-cortical brain abnormalities in children and adults with attention deficit hyperactivity disorder (ADHD) and new evidence for dysfunction in adults with ADHD during motivation and attention. Cortex 48(2):194–215PubMedCrossRefGoogle Scholar
  46. 46.
    Shaw P, Malek M, Watson B, Sharp W, Evans A, Greenstein D (2012) Development of cortical surface area and gyrification in attention-deficit/hyperactivity disorder. Biol Psychiatry 72(3):191–197PubMedCrossRefGoogle Scholar
  47. 47.
    Arcos-Burgos M, Velez JI, Solomon BD, Muenke M (2012) A common genetic network underlies substance use disorders and disruptive or externalizing disorders. Hum Genet 131(6):917–929PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    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. Am J Psychiatry 166(1):58–63PubMedCrossRefGoogle Scholar
  49. 49.
    Grunblatt E, Bartl J, Walitza S (2018) Methylphenidate enhances neuronal differentiation and reduces proliferation concomitant to activation of Wnt signal transduction pathways. Transl Psychiatry 8(1):51PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Hayden BY, Platt ML (2010) Neurons in anterior cingulate cortex multiplex information about reward and action. J Neurosci 30(9):3339–3346PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    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(12):1542–1552PubMedCrossRefGoogle Scholar
  52. 52.
    Weiner KS, Zilles K (2016) The anatomical and functional specialization of the fusiform gyrus. Neuropsychologia 83:48–62PubMedCrossRefGoogle Scholar
  53. 53.
    Kibby MY, Dyer SM, Vadnais SA, Jagger AC, Casher GA, Stacy M (2015) Visual processing in reading disorders and attention-deficit/hyperactivity disorder and its contribution to basic reading ability. Front Psychol 6:1635PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Maldonado-Lasuncion I, Atienza M, Sanchez-Espinosa MP, Cantero JL (2018) Aging-related changes in cognition and cortical integrity are associated with serum expression of candidate MicroRNAs for Alzheimer disease. Cereb Cortex.  https://doi.org/10.1093/cercor/bhy323 PubMedCrossRefGoogle Scholar
  55. 55.
    Shiotani A, Murao T, Kimura Y, Matsumoto H, Kamada T, Kusunoki H, Inoue K, Uedo N, Iishi H, Haruma K (2013) Identification of serum miRNAs as novel non-invasive biomarkers for detection of high risk for early gastric cancer. Br J Cancer 109(9):2323–2330PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Aushev VN, Zborovskaya IB, Laktionov KK, Girard N, Cros MP, Herceg Z, Krutovskikh V (2013) Comparisons of microRNA patterns in plasma before and after tumor removal reveal new biomarkers of lung squamous cell carcinoma. PLoS One 8(10):e78649PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Hu Q, Gong W, Gu J, Geng G, Li T, Tian R, Yang Z, Zhang H, Shao L, Liu T, Wan L, Jia J, Yang C, Shi Y, Shi H (2018) Plasma microRNA profiles as a potential biomarker in differentiating adult-onset still’s disease from sepsis. Front Immunol 9:3099PubMedCrossRefGoogle Scholar
  58. 58.
    Chen Z, Wang H, Xia Y, Yan F, Lu Y (2018) Therapeutic potential of mesenchymal Cell-derived miRNA-150-5p-expressing exosomes in rheumatoid arthritis mediated by the modulation of MMP14 and VEGF. J Immunol 201(8):2472–2482PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Yoshizawa S, Umezu T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, Ohyashiki JH, Ohyashiki K (2018) Exosomal miRNA signatures for late-onset acute graft-versus-host disease in allogenic hematopoietic stem cell transplantation. Int J Mol Sci 19(9):E2493PubMedCrossRefGoogle Scholar
  60. 60.
    Schwarzenbach H (2017) Clinical relevance of circulating, cell-free and exosomal microRNAs in plasma and serum of breast cancer patients. Oncol Res Treat 40(7–8):423–429PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
  2. 2.Department of Chinese MedicineChang Gung UniversityTaoyuanTaiwan
  3. 3.Genomics and Proteomics Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
  4. 4.Department of Pediatrics, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
  5. 5.Kawasaki Disease CenterKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
  6. 6.Department of Psychiatry, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan
  7. 7.Department of Psychology, Clinical Psychological RoomChung Shan Medical University HospitalTaichungTaiwan
  8. 8.Department of PsychiatryKaohsiung Veterans General HospitalKaohsiungTaiwan
  9. 9.Department of Psychiatry, College of Medicine, Graduate Institute of Medicine, School of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  10. 10.Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan

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