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Decreasing ADHD phenotypic heterogeneity: searching for neurobiological underpinnings of the restrictive inattentive phenotype

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Abstract

During the process of developing the DSM-5, a new phenotype of ADHD was proposed—the ADHD restrictive inattentive presentation (ADHD-RI), describing subjects with high endorsement of inattentive symptoms and a low level of hyperactivity. However, this phenotype was not included in the DSM-5 because of the lack of robust neurobiological data. We aimed to assess the specific neurobiological underpinnings of individuals presenting ADHD-RI. We compared a sample of 301 subjects (101 ADHD-Combined; 50 ADHD-RI; 50 ADHD predominantly inattentive type and 100 typically developing subjects) aged 8–15 years, using a complete neuropsychological battery, molecular genetic data (DRD4 and DAT1 most studied polymorphisms) and functional MRI during a Go-No/Go task. Subjects with ADHD-RI had a significantly different neuropsychological profile compared with the other groups, including lower psychomotor speeds, longer reaction times and the worst overall performance in the global neurocognitive index. The proportion of subjects with the presence of DRD4–7 repeat allele was significantly higher in ADHD-RI. The fMRI data suggested that more attention-related posterior brain regions (especially temporo-occipital areas) are activated in ADHD-RI during both Go and No-Go cues compared to TD controls and ADHD predominantly inattentive type. ADHD-RI may represent a different phenotype than other types of ADHD. In addition, our results suggest that reducing the phenotypic heterogeneity may aid in the search for the neurobiological underpinnings of ADHD.

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References

  1. Willcutt EG, Nigg JT, Pennington BF, Solanto MV, Rohde LA, Tannock R, Loo SK, Carlson CL, McBurnett K, Lahey BB (2012) Validity of DSM-IV attention deficit/hyperactivity disorder symptom dimensions and subtypes. J Abnorm Psychol 121(4):991–1010

    Article  PubMed Central  PubMed  Google Scholar 

  2. Scassellati C, Bonvicini C, Faraone SV, Gennarelli M (2012) Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses. J Am Acad Child Adolesc Psychiatry 51(10):1003–1019

    Article  PubMed  Google Scholar 

  3. APA (2013) Diagnostic and statistical manual of mental disorders, DSM-V, 5th edn. American Psychiatric Association, Washington DC

    Google Scholar 

  4. Geurts HM, Verté S, Oosterlaan J, Roeyers H, Sergeant JA (2005) ADHD subtypes: do they differ in their executive functioning profile? Arch Clin Neuropsychol 20(4):457–477

    Article  PubMed  Google Scholar 

  5. Goth-Owens T, Martinez-Torteya C, Martel M, Nigg JT (2010) Processing speed weakness in children and adolescents with non-hyperactive but inattentive ADHD (ADD). Child Neuropsychol 16(6):577–591

    Article  PubMed Central  PubMed  Google Scholar 

  6. Genro JP, Kieling C, Rohde LA, Hutz MH (2010) Attention-deficit/hyperactivity disorder and the dopaminergic hypotheses. Expert Rev Neurother 10(4):587–601

    Article  CAS  PubMed  Google Scholar 

  7. Gizer IR, Ficks C, Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Human Genet 126(1):51–90

    Article  CAS  Google Scholar 

  8. Ciliax BJ, Drash GW, Staley JK, Haber S, Mobley CJ, Miller GW, Mufson EJ, Mash DC, Levey AI (1999) Immunocytochemical localization of the dopamine transporter in human brain. J Comp Neurol 409(1):38–56

    Article  CAS  PubMed  Google Scholar 

  9. Noain D, Avale ME, Wedemeyer C, Calvo D, Peper M, Rubinstein M (2006) Identification of brain neurons expressing the dopamine D4 receptor gene using BAC transgenic mice. Eur J Neurosci 24(9):2429–2438

    Article  PubMed  Google Scholar 

  10. Shaw P, Gornick M, Lerch J, Addington A, Seal J, Greenstein D, Sharp W, Evans A, Giedd JN, Castellanos FX, Rapoport JL (2007) Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 64(8):921–931

    Article  PubMed  Google Scholar 

  11. Fair DA, Nigg JT, Iyer S, Bathula D, Mills KL, Dosenbach NU, Schlaggar BL, Mennes M, Gutman D, Bangaru S, Buitelaar JK, Dickstein DP, Di Martino A, Kennedy DN, Kelly C, Luna B, Schweitzer JB, Velanova K, Wang YF, Stewart M, Castellanos FX, Milham MP (2013) Distinct neural signatures detected for ADHD subtypes after controlling for micro-movements in resting state functional connectivity MRI data. Front Syst Neurosci 6:80. doi:10.3389/fnsys.2012.00080 (eCollection2012)

    Article  PubMed Central  PubMed  Google Scholar 

  12. Volk HE, Todorov AA, Hay DA, Todd RD (2009) Simple identification of complex ADHD subtypes using current symptom counts. J Am Acad Child Adolesc Psychiatry 48(4):441–450

    Article  PubMed  Google Scholar 

  13. Nigg JT, Tannock R, Rohde LA (2010) What is to be the fate of ADHD subtypes? An introduction to the special section on research on the ADHD subtypes and implications for the DSM–V. J Clin Child Adolesc Psychol 39(6):723–725

    Article  PubMed  Google Scholar 

  14. Achenbach TM (1991) Integrative guide for the 1991 CBCL/4-18, YSR, and TRF profiles. Department of Psychiatry, University of Vermont, Burlington

    Google Scholar 

  15. Ercan ES, Amado S, Somer O, Çıkoğlu S (2001) Dikkat eksikliği hiperaktivite bozukluğu ve yıkıcı davranım bozuklukları için bir test bataryası geliştirme çabası. Çocuk ve Gençlik Ruh Sağlığı Dergisi 8(3):132–144

    Google Scholar 

  16. Gökler B, Ünal F, Pehlivantürk B, Kültür EÇ, Akdemir D, Taner Y (2004) Reliability and validity of schedule for affective disorders and schizophrenia for school age children-present and lifetime version-turkish version (K-SADS-PL-T). Turk J Child Adolesc Ment Health 11(3):109–116

    Google Scholar 

  17. Leckman JF, Sholomskas D, Thompson D, Belanger A, Weissman MM (1982) Best estimate of lifetime psychiatric diagnosis: a methodological study. Arch Gen Psychiatry 39(8):879–883

    Article  CAS  PubMed  Google Scholar 

  18. Gualtieri CT, Johnson LG (2008) Age-related cognitive decline in patients with mood disorders. Prog Neuro Psychopharmacol Biol Psychiatry 32(4):962–967

    Article  Google Scholar 

  19. Durston S, Thomas KM, Worden MS, Yang Y, Casey BJ (2002) The effect of preceding context on inhibition: an event-related fMRI study. NeuroImage 16(2):449–453

    Article  CAS  PubMed  Google Scholar 

  20. Smith SM, Zhang Y, Jenkinson M, Chen J, Mathhews PM, Federico A, De Stefano N (2002) Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. NeuroImage 17(1):479–489

    Article  PubMed  Google Scholar 

  21. Woolrich MW, Behrens TE, Beckmann CF, Jenkinson M, Smith SM (2004) Multilevel linear modelling for FMRI group analysis using Bayesian inference. NeuroImage 21(4):1732–1747

    Article  PubMed  Google Scholar 

  22. 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):636–647

    Article  CAS  PubMed  Google Scholar 

  23. Derefinko KJ, Adams ZW, Milich R, Fillmore MT, Lorch EP, Lynam DR (2008) Response style differences in the inattentive and combined subtypes of attention-deficit/hyperactivity disorder. J Abnorm Child Psychol 36(5):745–758

    Article  PubMed  Google Scholar 

  24. Rowe DC, Stever C, Giedinghagen LN, Gard JM, Cleveland HH, Terris ST, Mohr JH, Sherman S, Abramowitz A, Waldman ID (1998) Dopamine DRD4 receptor polymorphism and attention deficit hyperactivity disorder. Mol Psychiatry 3(5):419–426

    Article  CAS  PubMed  Google Scholar 

  25. McCracken JT, Smalley SL, McGough JJ, Crawford L, Del’Homme M, Cantor RM (2000) Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD). Mol Psychiatry 5(5):531–536

    Article  CAS  PubMed  Google Scholar 

  26. Schmidt LA, Fox NA, Perez-Edgar K, Hu S, Hamer DH (2001) Association of DRD4 with attention problems in normal childhood development. Psychiatr Genet 11(1):25–29

    Article  CAS  PubMed  Google Scholar 

  27. Cheuk DKL, Li SYH, Wong V (2006) Exon 3 polymorphisms of dopamine D4 receptor (DRD4) gene and attention deficit hyperactivity disorder in Chinese children. Am J Med Genet Part B Neuropsychiatr Genet 141(8):907–911

    Article  Google Scholar 

  28. Ahrendts J, Rüsch N, Wilke M, Philipsen A, Eickhoff SB, Glauche V, Perlov E, Ebert D, Hennig J, Tebartz van Elst Z (2011) Visual cortex abnormalities in adults with ADHD: a structural MRI study. World J Biol Psychiatry 12(4):260–270

    Article  PubMed  Google Scholar 

  29. Proal E, Reiss PT, Klein RG, Manuzza S, Gotimer K, Ramos-Olazagasti MA, Belsky ER, Hutchison JA, Lashua-Shriftman E, Castellanos FX (2011) Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood. Arch Gen Psychiatr 68(11):1122–1134

    Article  PubMed Central  PubMed  Google Scholar 

  30. Castellanos FX, Proal E (2012) Large-scale brain systems in ADHD: beyond the prefrontal–striatal model. Trend Cognit Sci 16(1):17–26

    Article  Google Scholar 

  31. 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(11):1038–1055

    Article  PubMed  Google Scholar 

  32. Hart H, Radua J, Mataix-Cols D, Rubia K (2012) Meta-analysis of fMRI studies of timing in attention-deficit hyperactivity disorder (ADHD). Neurosci Biobehav Rev 36(10):2248–2256

    Article  PubMed  Google Scholar 

  33. Dillo W, Göke A, Prox-Vagedes V, Szycik GR, Roy M, Donnerstag F, Emrich HM, Ohlmeier MD (2010) Neuronal correlates of ADHD in adults with evidence for compensation strategies—a functional MRI study with a Go/No-Go paradigm. Ger Med Sci GMS (e-journal 8:Doc09)

  34. Schneider-Garces NJ, Gordon BA, Brumback-Peltz CR, Shin E, Lee Y, Sutton BP, Fabiani M (2010) Span, CRUNCH, and beyond: working memory capacity and the aging brain. J Cognit Neurosci 22(4):655–669

    Article  Google Scholar 

  35. Kessler RC, Green JG, Adler LA, Barkley LA, Chatterji S, Faraone SV, Finkelman M, Greenhill LL, Gruber MJ, Jewell M, Russo LJ, Sampson NA, Van Brunt DL (2010) Structure and diagnosis of adult attention-deficit/hyperactivity disorder: analysis of expanded symptom criteria from the Adult ADHD Clinical Diagnostic Scale. Arch Gen Psychiatry 67(11):1168–1178

    Article  PubMed Central  PubMed  Google Scholar 

  36. Guney E, Iseri E, Ergun SG, Percin EF, Ergun MA, Yalcin O (2013) The correlation of attention deficit hyperactivity disorder with DRD4 gene polymorphism in Turkey. Int J Hum Genet 13(3):145–152

    CAS  Google Scholar 

  37. Woo CW, Krishnan A, Wager TD (2014) Cluster-extent based thresholding in fMRI analyses: pitfalls and recommendations. NeuroImage 91:412–419

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partially supported by research grants from the following: Ege University Scientific Research Project Commission, Izmir, Turkey, the National Council for Scientific and Technological Development (CNPq, Brazil), and Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil. The authors thank Dr Cahide Aydın for contribution in case enrollment process.

Conflict of interest

Dr Ercan is a member of the advisory boards for Eli Lilly Turkey and Janssen Turkey. Dr. Luis Augusto Rohde was on the speakers’ bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis and Shire in the last three years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Eli-Lilly, Janssen-Cilag, Novartis, and Shire. He also receives research support from Brazilian government institutions (CNPq, FAPERGS, HCPA and CAPES), authorship royalties from Oxford Press and ArtMed and received travel awards for taking part of 2014 APA meeting from Shire. All other authors have declared that they have no competing or potential conflicts of interest in relation to this work.

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Authors and Affiliations

  1. Child and Adolescent Psychiatry Department, Medical Faculty, Ege University, Izmir, Turkey

    Eyup Sabri Ercan

  2. Hospital for Psychiatry, Samsun, Turkey

    Serkan Suren

  3. Children Hospital, Gaziantep, Turkey

    Ali Bacanlı

  4. Child and Adolescent Psychiatry Department, Medical Faculty, Fırat University, Elazig, Turkey

    Kemal Utku Yazici

  5. Radiology Department, Medical Faculty, Ege University, Izmir, Turkey

    Cem Callı

  6. Institute of Biomedical Engineering, Bogazici University, Istanbul, Turkey

    Onur Ozyurt

  7. Medical Biology Department, Medical Faculty, Ege University, Izmir, Turkey

    Duygu Aygunes & Buket Kosova

  8. Brain Institute of Rio Grande do Sul (InsCer), PUCRS, Porto Alegre, Brazil

    Alexandre Rosa Franco

  9. School of Engineering, PUCRS, Porto Alegre, Brazil

    Alexandre Rosa Franco

  10. Department of Psychiatry, ADHD Outpatient Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

    Luis Augusto Rohde

  11. National Institute of Developmental Psychiatry for Children and Adolescents, São Paulo, Brazil

    Luis Augusto Rohde

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  1. Eyup Sabri Ercan
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Correspondence to Eyup Sabri Ercan.

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Ercan, E.S., Suren, S., Bacanlı, A. et al. Decreasing ADHD phenotypic heterogeneity: searching for neurobiological underpinnings of the restrictive inattentive phenotype. Eur Child Adolesc Psychiatry 25, 273–282 (2016). https://doi.org/10.1007/s00787-015-0731-3

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  • DOI: https://doi.org/10.1007/s00787-015-0731-3

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