Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Language fMRI abnormalities associated with FOXP2 gene mutation

Nature Neuroscience volume 6, pages 1230–1237 (2003)Cite this article

Abstract

Half the members of the KE family suffer from a speech and language disorder caused by a mutation in the FOXP2 gene. We examined functional brain abnormalities associated with this mutation using two fMRI language experiments, one involving covert (silent) verb generation and the other overt (spoken) verb generation and word repetition. The unaffected family members showed a typical left-dominant distribution of activation involving Broca's area in the generation tasks and a more bilateral distribution in the repetition task, whereas the affected members showed a more posterior and more extensively bilateral pattern of activation in all tasks. Consistent with previously reported bilateral morphological abnormalities, the affected members showed significant underactivation relative to the unaffected members in Broca's area and its right homolog, as well as in other cortical language-related regions and in the putamen. Our findings suggest that the FOXP2 gene is critically involved in the development of the neural systems that mediate speech and language.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Covert language task: group average fMRI activation in the unaffected and affected members of the KE family.
Figure 2: Covert language task: brain regions found to be underactive in the affected members using the interaction analysis.
Figure 3: Covert language task: percent signal change averaged across all generation/rest cycles and across subjects in each group, in representative regions of interest centered around local maxima obtained from the interaction analysis.
Figure 4: Imaging during overt language tasks.

Similar content being viewed by others

References

  1. Lai, C.S., Fisher, S.E., Hurst, J.A., Vargha-Khadem, F. & Monaco, A.P. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413, 519–523 (2001).

    Article  CAS  Google Scholar 

  2. Fisher, S.E., Vargha-Khadem, F., Watkins, K.E., Monaco, A.P. & Pembrey, M.E. Localisation of a gene implicated in severe speech and language disorder. Nat. Genet. 18, 168–170 (1998).

    Article  CAS  Google Scholar 

  3. Vargha-Khadem, F., Watkins, K.E., Alcock, K.J., Fletcher, P. & Passingham, R.E. Praxic and non-verbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proc. Natl. Acad. Sci. USA 92, 930–933 (1995).

    Article  CAS  Google Scholar 

  4. Alcock, K.J., Passingham, R.E., Watkins, K.E. & Vargha-Khadem, F. Oral dyspraxia in inherited speech and language impairment and acquired dysphasia. Brain Lang. 75, 17–33 (2000).

    Article  CAS  Google Scholar 

  5. Watkins, K.E., Dronkers, N.F. & Vargha-Khadem, F. Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia. Brain 125, 452–464 (2002).

    Article  CAS  Google Scholar 

  6. Hurst, J.A., Baraitser, M., Auger, E., Graham, F. & Norell, S. An extended family with a dominantly inherited speech disorder. Dev. Med. Child Neurol. 32, 352–355 (1990).

    Article  CAS  Google Scholar 

  7. Watkins, K.E. et al. MRI analysis of an inherited speech and language disorder: structural brain abnormalities. Brain 125, 465–478 (2002).

    Article  CAS  Google Scholar 

  8. Vargha-Khadem, F., Watters, G.V. & O'Gorman, A.M. Development of speech and language following bilateral frontal lesions. Brain Lang. 25, 167–183 (1985).

    Article  CAS  Google Scholar 

  9. Salmond, C.H., Ashburner, J., Vargha-Khadem, F., Gadian, D.G. & Friston, K.J. Detecting bilateral abnormalities with voxel-based morphometry. Hum. Brain Mapp. 11, 223–232 (2000).

    Article  CAS  Google Scholar 

  10. Belton, E., Salmond, C.H., Watkins, K.E., Vargha-Khadem, F. & Gadian, D.G. Bilateral brain abnormalities associated with dominantly inherited verbal and orofacial dyspraxia. Hum. Brain Mapp. 18, 194–200 (2003).

    Article  Google Scholar 

  11. Vargha-Khadem, F. et al. Neural basis of an inherited speech and language disorder. Proc. Natl. Acad. Sci. USA 95, 12695–12700 (1998).

    Article  CAS  Google Scholar 

  12. Friedman, L. et al. Brain activation during silent word generation evaluated with functional MRI. Brain Lang. 64, 231–256 (1998).

    Article  CAS  Google Scholar 

  13. Herholz, K. et al. Individual functional anatomy of verb generation. Neuroimage 3, 185–194 (1996).

    Article  CAS  Google Scholar 

  14. Paulesu, E., Frith, C.D. & Frackowiak, R.S.J. The neural correlates of the verbal component of verbal memory. Nature 362, 342–345 (1993).

    Article  CAS  Google Scholar 

  15. Tomaiulo, F. et al. Morphology, morphometry and probability mapping of the pars opercularis of the inferior frontal gyrus: an in vivo MRI analysis. Eur. J. Neurosci. 11, 3033–3046 (1999).

    Article  Google Scholar 

  16. Thierry, G., Boulanouar, K., Kherif, F., Ranjeva, J.P. & Demonet, J.F. Temporal sorting of neural components underlying phonological processing. Neuroreport 10, 2599–2603 (1999).

    Article  CAS  Google Scholar 

  17. Thompson-Schill, S.L., D'Esposito,M. & Kan, I.P. Effects of repetition and competition on activity in left prefrontal cortex during word generation. Neuron 23, 513–522 (1999).

    Article  CAS  Google Scholar 

  18. Liegeois, F. et al. A direct test for lateralization of language activation using fMRI: comparison with invasive assessments in children with epilepsy. Neuroimage 17, 1861–1867 (2002).

    Article  CAS  Google Scholar 

  19. Thompson-Schill, S.L. et al. Verb generation in patients with focal frontal lesions: A neuropsychological test of neuroimaging findings. Proc. Natl. Acad. Sci. USA 95, 15855–15860 (1998).

    Article  CAS  Google Scholar 

  20. Warburton, E. et al. Noun and verb retrieval by normal subjects. Studies with PET. Brain 119, 159–179 (1996).

    Article  Google Scholar 

  21. Poldrack, R. et al. Functional specialization for semantic and phonological processing in the left inferior prefrontal cortex. Neuroimage 10, 15–35 (1999).

    Article  CAS  Google Scholar 

  22. Price, C.J. The anatomy of language: contributions from functional neuroimaging. J. Anat. 197, 335–359 (2000).

    Article  Google Scholar 

  23. Paulesu, E. et al. Functional heterogeneity of left inferior frontal cortex as revealed by fMRI. Neuroreport 8, 2011–2016 (1997).

    Article  CAS  Google Scholar 

  24. Price, C.J. et al. Hearing and saying. The functional neuroanatomy of auditory word processing. Brain 119, 919–931 (1996).

    Article  Google Scholar 

  25. Pickett, E.R., Kuniholm, E., Protopapas, A., Friedman, J. & Lieberman, P. Selective speech motor, syntax and cognitive deficits associated with bilateral damage to the putamen and the head of the caudate nucleus: a case study. Neuropsychologia 36, 173–188 (1998).

    Article  CAS  Google Scholar 

  26. Martin, A. & Chao, L.L. Semantic memory and the brain: structure and processes. Curr. Opin. Neurobiol. 11, 194–201 (2001).

    Article  CAS  Google Scholar 

  27. Dronkers, N.F. A new brain region for coordinating speech articulation. Nature 384, 159–161 (1996).

    Article  CAS  Google Scholar 

  28. Ullman, M.T. A neurocognitive perspective on language: the declarative/procedural model. Nat. Rev. Neurosci. 2, 717–726 (2001).

    Article  CAS  Google Scholar 

  29. Jueptner, M. & Weiller, C. A review of differences between basal ganglia and cerebellar control of movements as revealed by functional imaging studies. Brain 121, 1437–1449 (1998).

    Article  Google Scholar 

  30. Alexander, G.E. Basal ganglia-thalamocortical circuits: their role in control of movements. J. Clin. Neurophysiol. 11, 420–431 (1994).

    Article  CAS  Google Scholar 

  31. Di Pellegrino, G., Fadiga, L., Fogassi, L., Gallese, V. & Rizzolatti, G. Understanding motor events: a neurophysiological study. Exp. Brain Res. 91, 176–180 (1992).

    Article  CAS  Google Scholar 

  32. Rizzolatti, G. & Arbib, M.A. Language within our grasp. Trends Neurosci. 21, 188–194 (1998).

    Article  CAS  Google Scholar 

  33. Arbib, M.A. The mirror system, imitation, and the evolution of language. in Imitation in Animals and Artifacts (eds. Nehaniv, C. & Dautenhahn, K.) 229–280 (MIT Press, Cambridge, Massachusetts, 2002).

    Google Scholar 

  34. Enard, W. et al. Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418, 869–872 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank J. Ashburner and C. Salmond for statistical advice, J. Ho and H. Ducie for assistance with collection of the MRI data, and the members of the KE family for their participation. This work was supported by the Wellcome Trust. Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from Research and Development Funding from the NHS Executive.

Author information

Authors and Affiliations

  1. Developmental Cognitive Neuroscience Unit, Institute of Child Health, University College London, The Wolfson Centre, Mecklenburgh Square, London, WC1N 2AP, UK

    Frédérique Liégeois, Torsten Baldeweg & Faraneh Vargha-Khadem

  2. Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London, WC1N 3JH, UK

    Frédérique Liégeois, Torsten Baldeweg, Alan Connelly, David G Gadian & Faraneh Vargha-Khadem

  3. Radiology and Physics Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

    Alan Connelly & David G Gadian

  4. Laboratory of Neuropsychology, Building 49, Room 1B80, National Institute of Mental Health, Bethesda, 20892, Maryland, USA

    Mortimer Mishkin

Authors
  1. Frédérique Liégeois
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Torsten Baldeweg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alan Connelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David G Gadian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mortimer Mishkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Faraneh Vargha-Khadem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frédérique Liégeois.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liégeois, F., Baldeweg, T., Connelly, A. et al. Language fMRI abnormalities associated with FOXP2 gene mutation. Nat Neurosci 6, 1230–1237 (2003). https://doi.org/10.1038/nn1138

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1138

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing