Brain Imaging and Behavior

, Volume 12, Issue 2, pp 499–508 | Cite as

Impaired engagement of the ventral attention system in neurofibromatosis type 1

  • Natalie A. Pride
  • Mayuresh S. Korgaonkar
  • Kathryn N. North
  • Jonathan M. Payne
Original Research


Individuals with neurofibromatosis type 1 (NF1) exhibit significant impairments in attention across multiple domains. Very little is known about the contributing neural networks. We used task-based functional magnetic resonance imaging (fMRI) to examine dorsal and ventral attention networks during auditory oddball processing in children and adolescents with NF1 and typically developing controls. Significant differences in neural activation patterns were identified within brain regions supporting the ventral attention system. Children with NF1 demonstrated hypoactivation in the temporoparietal junction and the anterior cingulate cortex compared to typically developing children. Hypoactivation in the anterior cingulate cortex was associated with poorer selective attention and attentional control in children with NF1. Results indicate an abnormality in bottom-up attention networks in NF1 that may lead to inefficient and faulty suppression of stimulus-driven information outside the current attentional set that play a significant role in the NF1 behavioral phenotype.


Neurofibromatosis 1 fMRI Attention Auditory oddball 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11682_2017_9717_MOESM1_ESM.pdf (220 kb)
ESM 1 (PDF 220 kb)


  1. Adviento, B., Corbin, I. L., Widjaja, F., Desachy, G., Enrique, N., Rosser, T., et al. (2014). Autism traits in the RASopathies. Journal of Medical Genetics, 51(1), 10–20.CrossRefPubMedGoogle Scholar
  2. Ashburner, J. (2007). A fast diffeomorphic image registration algorithm. NeuroImage, 38(1), 95–113.CrossRefPubMedGoogle Scholar
  3. Barton, B., & North, K. (2004). Social skills of children with neurofibromatosis type 1. Developmental Medicine & Child Neurology, 46(8), 553–563.CrossRefGoogle Scholar
  4. Billingsley, R. L., Jackson, E. F., Slopis, J. M., Swank, P. R., Mahankali, S., & Moore, B. D. (2003). Functional magnetic resonance imaging of phonologic processing in neurofibromatosis 1. Journal of Child Neurology, 18, 731–740.CrossRefPubMedGoogle Scholar
  5. Billingsley, R. L., Jackson, E. F., Slopis, J. M., Swank, P. R., Mahankali, S., & Moore, B. D. (2004). Functional MRI of visual-spatial processing in neurofibromatosis, type I. Neuropsychologia, 42(3), 395–404.CrossRefPubMedGoogle Scholar
  6. Bressler, S. L., & Menon, V. (2010). Large-scale brain networks in cognition: Emerging methods and principles. Trends in Cognitive Science, 14, 277–290.CrossRefGoogle Scholar
  7. Brown, J. A., Xu, J., Diggs-Andrews, K. A., Wozniak, D. F., Mach, R. H., & Gutmann, D. H. (2011). PET imaging for attention deficit preclinical drug testing in neurofibromatosis- 1 mice. Experimental Neurology, 232, 333–338.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bush, G., Luu, P., Posner, M. I. (2000). Cognitive and emotional influences in anterior cingulate cortex. Trends in Cognitive Sciences, 4(6), 215–222.Google Scholar
  9. Chabernaud, C., Mennes, C., Kardel, P. G., Gaillard, W. D., Kalbfleisch, M. L., VanMeter, J. W., et al. (2012). Lovastatin regulates brain spontaneous low-frequency brain activity in Neurofibromatosis type 1. Neuroscience Letters, 515(28–33).Google Scholar
  10. Conners, C. K. (2008). Conners 3rd Edition parent assessment long form. Toronto, Ontario: Multi-Health Systems Inc..Google Scholar
  11. Corbetta, M., Patel, G., & Shulman, G. L. (2008). The reorienting system of the human brain: From environment to theory of mind. Neuron, 58(3), 306–324.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Corbetta, M., & Shulman, G. L. (2002). Control of goal-directed and stimulus driven attention in the brain. Nature Reviews Neuroscience, 3, 201–215.CrossRefPubMedGoogle Scholar
  13. Cortese, S., Kelly, C., Chabernaud, C., Proal, E., Di Martino, A., Milham, M. P., et al. (2012). Toward systems neuroscience of ADHD: A meta-analysis of 55 fMRI studies. American Journal of Psychiatry, 169, 1038–1055.CrossRefPubMedGoogle Scholar
  14. Crottaz-Herbette, S., & Menon, V. (2006). Where and when the anterior cingulate cortex modulates attentional response: Combined fMRI and ERP evidence. Journal of Cognitive Neuroscience, 18(5), 766–780.CrossRefPubMedGoogle Scholar
  15. Debener, S., Kranczioch, C., Herrmann, C. S., & Engel, A. K. (2002). Auditory oddball allows reliable distinction of top-down and bottom-up processes of attention. International Journal of Psychophysiology, 46, 77–84.CrossRefPubMedGoogle Scholar
  16. Dichter, G. S., Felder, J. N., & Bodwish, J. W. (2009). Autism is charactersied by dorsal anterior cingulate hyperactivation during social target detection. Scan, 4, 215–226.PubMedPubMedCentralGoogle Scholar
  17. Diggs-Andrews, K. A., & Gutmann, D. H. (2013). Modeling cognitive dysfunction in neurofibromatosis-1. Trends in Neuroscience, 36(4), 237–247.CrossRefGoogle Scholar
  18. Evans, A. C., & Group., B. D. C. (2006). The NIH MRI study of normal brain development. NeuroImage, 30(1), 184–202.CrossRefGoogle Scholar
  19. Evans, G., Howard, E., Giblin, C., Clancy, T., Spencer, H., Huson, S. M., et al. (2010). Birth incidence and prevalence of tumour-prone syndromes: Estimates from a UK family register service. American Journal of Medical Genetics Part A, 152A, 327–332.CrossRefPubMedGoogle Scholar
  20. Ferner, R. E., Hughes, R. A., & Weinman, J. (1996). Intellectual impairment in neurofibromatosis 1. Journal of the Neurological Sciences, 138(1–2), 125–133.CrossRefPubMedGoogle Scholar
  21. Fox, M. D., Snyder, A. Z., Vincent, J. L., Corbetta, M., Van Essen, D., & Raichle, M. (2005). The human brain is intrinsically organised into dynamic anticorrelated functional networks. Proceedings of the National Academy of Sciences, 102, 9673–9678.CrossRefGoogle Scholar
  22. Garg, S., Green, J., Leadbitter, K., Emsley, R., Lehtonen, A., Evans, D. G., et al. (2013a). Neurofibromatosis type 1 and autism spectrum disorder. Paediatrics, 132(6). doi: 10.1542/peds.2013-1868.
  23. Garg, S., Lehtonen, A., Huson, S. M., Emsley, R., Trump, D., Evans, D. G., et al. (2013b). Autism and other psychiatric comorbidity in neurofibromatosis type 1: Evidence from a population-based study. Developmental Medicine & Child Neurology, 55(2), 139–145.CrossRefGoogle Scholar
  24. Gomot, M., Bernard, F. A., Davis, M. H., Belmonte, M. K., Ashwin, C., Bullmore, E. T., et al. (2005). Change detection in children with autism: An auditory event-related fMRI study. NeuroImage, 29, 475–484.CrossRefPubMedGoogle Scholar
  25. Helenius, P., Laasonen, M., Hokkanen, L., Paetau, R., & Niemivirta, M. (2011). Impaired engagement of the ventral attentional pathway in ADHD. Neuropsychologia, 49, 1889–1896.CrossRefPubMedGoogle Scholar
  26. Hofman, K. J., Harris, E. L., Bryan, R. N., & Denckla, M. B. (1994). Neurofibromatosis type 1: The cognitive phenotype. The Journal of Pediatrics, 124(4), S1–S8.CrossRefPubMedGoogle Scholar
  27. Huijbregts, S., Jahja, R., De Sonneville, L., de Breij, S., Swaab-Barneveld, H. (2010). Social information processing in children and adolescents with neurofibromatosis type 1. Developmental Medicine & Child Neurology, 52(7), 620–625Google Scholar
  28. Hyman, S. L., Shores, A., & North, K. (2005). The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology, 65(7), 1037–1044.CrossRefPubMedGoogle Scholar
  29. IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.Google Scholar
  30. Joy, P., Roberts, C., North, K., & de Silva, M. (1995). Neuropsychological function and MRI abnormalities in neurofibromatosis type 1. Developmental Medicine and Child Neurology, 37(10), 906–914.CrossRefPubMedGoogle Scholar
  31. Karlsgodt, K. H., Rosser, T., Lutkenhoff, E. S., Cannon, T. D., Silva, A. J., & Bearden, C. E. (2012). Alterations in white matter microstructure in neurofibromatosis-1. PloS One, 7(10).Google Scholar
  32. Keehn, B., Nair, A., Lincoln, A. J., Townsend, J., & Muller, R. A. (2016). Under-reactive but easily distracted: An fMRI investigation of attentional capture in autism spectrum disorder. Developmental Cognitive Neuroscience, 17, 46–56.CrossRefPubMedGoogle Scholar
  33. Kim, H. (2014). Involvement of the dorsal and ventral attention networks in oddball stimulus processing: A meta-analysis. Human Brain Mapping, 35, 2265–2284.CrossRefPubMedGoogle Scholar
  34. Koini, M., Rombouts, S. A. R. B., Veer, I. M., Van Buchem, M. A., & Huijbregts, S. C. J. (2016). White matter microstrucutre of patients with neurofibromatosis type 1 and its relation to inhibitory control. Brain Imaging and Behavior, 1–10. doi: 10.1007/s11682-016-9641-3.
  35. Korgaonkar, M. S., Grieve, S. M., Etkin, A., Koslow, S. H., & Williams, L. M. (2013). Using standardised fMRI protocols to identify patterns of prefrontal circuit dysregulation that are common and specific to cognitive and emotional tasks in major depressive disorder: First wave results from the iSPOT-D study. Neuropsychopharmacology, 38(5), 863–871.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Laird, A. R., Robinson, J. L., McMillian, K. M., Tordesillas-Gutierrez, D., Moran, S. T., Gonzales, S. M., et al. (2010). Comparison of the disparity between Talairach and MNI coordinates in functional neuroimaging data: Validation of the Lancaster transform. NeuroImage, 51, 677–683.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Lehtonen, A., Howie, E., Trump, D., & Huson, S. M. (2013). Behaviour in children with neurofibromatosis type 1: Cognition, executive function, attention, emotion, and social competence. Developmental Medicine & Child Neurology, 55(2), 111–125.CrossRefGoogle Scholar
  38. Li, W., Cui, Y., Kushner, S. A., Brown, R. A., Jentsch, J. D., Frankland, P. W., et al. (2005). The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Current Biology, 15(21), 1961–1967.CrossRefPubMedGoogle Scholar
  39. Manly, T., Robertson, I. H., Anderson, V., & Nimmo-Smith, I. (1999). The test of Everyday attention for children. London, England: Battley Brothers.Google Scholar
  40. Mascaluso, E. (2010). Orienting of spatial attention and the interplay between the senses. Cortex, 46, 282–297.CrossRefGoogle Scholar
  41. Mautner, V. F., Kluwe, L., Thakker, S. D., & Leark, R. A. (2002). Treatment of ADHD in neurofibromatosis type 1. Developmental Medicine and Child Neurology, 44(164–170).Google Scholar
  42. Mazzocco, M. M. M., Turner, J. E., Denckla, M. B., Hofman, K. J., Scanlon, D. C., & Vellutino, F. R. (1995). Language and reading deficits associated with Neurofibromatosis type 1: Evidence for a not-so-nonverbal learning disability. Developmental Neuropsychology, 11(4), 503–522.CrossRefGoogle Scholar
  43. NIH. (1988). Neurofibromatosis conference statement. National Institutes of Health consensus development conference. Archives of Neurology, 45(5), 575–578.CrossRefGoogle Scholar
  44. Payne, J. M., Hyman, S. L., Shores, E. A., & North, K. (2011). Assessment of executive function and attention in children with neurofibromatosis type 1: Relationships between cognitive measures and real-world behavior. Child Neuropsychology, 17(4), 313–329.CrossRefPubMedGoogle Scholar
  45. Pride, N. A., Korgaonkar, M. S., Barton, B., Payne, J. M., & North, K. N. (2013). The genetic and neuroanatomical basis of social dysfunction: Lessons from neurofibromatosis type 1. Human Brain Mapping, 35(5), 2372–2382.CrossRefPubMedGoogle Scholar
  46. Pride, N. A., Payne, J. M., & North, K. N. (2012). The impact of ADHD on the cognitive and academic functioning of children with NF1. Developmental Neuropsychology, 37(7), 590–600.CrossRefPubMedGoogle Scholar
  47. Rowbotham, I., Pit-ten Cate, I. M., Sonuga-Barke, E. J. S., & Huijbregts, S. C. J. (2009). Cognitive control in adolescents with neurofibromatosis type 1. Neuropsychology, 23(1), 50–60.CrossRefPubMedGoogle Scholar
  48. Sangster, J., Shores, E. A., Watt, S., & North, K. (2011). The cognitive profile of preschool-aged children with neurofibromatosis type 1. Child Neuropsychology, 17(1), 1–16.CrossRefPubMedGoogle Scholar
  49. Sestieri, C., Shulman, G. L., & Corbetta, M. (2012). Orienting to the environment: Separate contributions of dorsal and ventral fronto-parietal attention networks. In G. R. Mangun (Ed.), The neuroscience of attention: Attentional control and selection (pp. 100–130). New York: Oxford University Press.CrossRefGoogle Scholar
  50. Sheehan, D. V., Sheehan, K. H., Shytle, R. D., Janavs, J., Bannon, Y., Rogers, J. E., et al. (2010). Reliability and validity of the Mini international neuropsychiatric interview for children and adolescents (MINI-KID). Journal of Clinical Psychiatry, 71(3), 313–326.CrossRefPubMedGoogle Scholar
  51. Shilyansky, C., Karlsgodt, K. H., Cummings, D. M., Sidiropoulou, K., Hardt, M., James, A. S., et al. (2010). Neurofibromin regulates corticostriatal inhibitory networks during working memory performance. Proceedings of the National Academy of Sciences, 107(29), 13141–13146.CrossRefGoogle Scholar
  52. Stevens, M. C., Pearlson, G. D., & Kiehl, K. A. (2007). An FMRI auditory oddball study of combined-subtype attention deficit hyperactivity disorder. American Journal of Psychiatry, 164(11), 1737–1749.CrossRefPubMedGoogle Scholar
  53. Tomson, S. N., Schreiner, M. J., Narayan, M., Rosser, T., Enrique, N., Silva, A. J., et al. (2015). Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1. Human Brain Mapp, 36, 4566–4581.CrossRefGoogle Scholar
  54. Violante, I. R., Ribeiro, M. J., Edden, A. E., Guimaraes, P., Bernardino, I., Rebola, J., et al. (2013). GABA deficit in the visual cortex of patients with neurofibromatosis type 1: Genotype-phenotype correlations and functional impact. Brain, 136, 918–925.CrossRefPubMedGoogle Scholar
  55. Vossel, S., Geng, J. J., & Fink, G. R. (2014). Dorsal and ventral attention systems. The Neuroscientist, 20(2), 150–159.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Walsh, K., Valez, J., Kardel, P., Imas, D., Muenke, M., Packer, R., et al. (2013). Autism spectrum disorder (ASD) symptomatology in a neurofibromatosis type 1 (NF1) population. Developmental Medicine and Child Neurology, 55(2), 131–138.CrossRefPubMedGoogle Scholar
  57. Wilke, M., Holland, S. K., Altaye, M., & Gaser, C. (2008). Template-O-Matic: A toolbox for creating customised paedaitric templates. NeuroImage, 41, 903–913.CrossRefPubMedGoogle Scholar
  58. Wu, Q., Chang, C. F., Xi, S., Huan, W., Liu, Z., Juan, C. H., et al. (2015). A critical role of temporoparietal junction in the integration of top-down and bottom-up attentional control. Human Brain Mapping, 36(11), 4317–4333.CrossRefPubMedPubMedCentralGoogle Scholar
  59. Zoller, M. E., Rembeck, B., & Backman, L. (1997). Neuropsychological deficits in adults with neurofibromatosis type 1. Acta Neurologica Scandinavica, 95(4), 225–232.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Natalie A. Pride
    • 1
  • Mayuresh S. Korgaonkar
    • 2
    • 3
  • Kathryn N. North
    • 1
    • 4
    • 5
  • Jonathan M. Payne
    • 1
    • 4
    • 5
  1. 1.Institute for Neuroscience and Muscle ResearchThe Children’s Hospital at WestmeadWestmeadAustralia
  2. 2.Brain Dynamics CentreWestmead Institute for Medical ResearchSydneyAustralia
  3. 3.University of Sydney Medical SchoolSydneyAustralia
  4. 4.Murdoch Childrens Research InstituteThe Royal Children’s HospitalMelbourneAustralia
  5. 5.Department of PaediatricsUniversity of MelbourneMelbourneAustralia

Personalised recommendations