Skip to main content

Measuring Inhibition and Cognitive Flexibility in Friedreich Ataxia

Abstract

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with subtle impact on cognition. Inhibitory processes and cognitive flexibility were examined in FRDA by assessing the ability to suppress a predictable verbal response. We administered the Hayling Sentence Completion Test (HSCT), the Trail Making Test, and the Stroop Test to 43 individuals with FRDA and 42 gender- and age-matched control participants. There were no significant group differences in performance on the Stroop or Trail Making Test whereas significant impairment in cognitive flexibility including the ability to predict and inhibit a pre-potent response as measured in the HSCT was evident in individuals with FRDA. These deficits did not correlate with clinical characteristics of FRDA (age of disease onset, disease duration, number of guanine-adenine-adenine repeats on the shorter or larger FXN allele, or Friedreich Ataxia Rating Scale score), suggesting that such impairment may not be related to the disease process in a straightforward way. The observed specific impairment of inhibition and predictive capacity in individuals with FRDA on the HSCT task, in the absence of impairment in associated executive functions, supports cerebellar dysfunction in conjunction with disturbance to cortico-thalamo-cerebellar connectivity, perhaps via inability to access frontal areas necessary for successful task completion.

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

References

  1. Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol. 2009;256:3–8.

    Article  PubMed  Google Scholar 

  2. Delatycki MB, Corben LA. Clinical features of Friedreich ataxia. J Child Neurol. 2012;27(9):1133–7.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Delatycki MB, Williamson R, Forrest SM. Friedreich ataxia: an overview. J Med Genet. 2000;37

  4. Cossée M, Dürr A, Schmitt M, Dahl N, Trouillas P, Allinson P, et al. Friedreich’s ataxia: point mutations and clinical presentation of compound heterozygotes. Ann Neurol. 1999;45(2):200–6.

    Article  PubMed  Google Scholar 

  5. Koeppen AH, Mazurkiewicz JE. Friedreich ataxia: neuropathology revised. J Neuropath Exp Neurol. 2013;72(2):78–90.

    CAS  Article  PubMed  Google Scholar 

  6. Koeppen AH, Davis AN, Morral JA. The cerebellar component of Friedreich’s ataxia. Acta Neuropath. 2011;122(3):323–30.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Mascalchi M. The cerebellum looks normal in Friedreich ataxia. Am J Neuroradiol. 2013;34(2):E22.

    CAS  Article  PubMed  Google Scholar 

  8. Stefanescu MR, Dohnalek M, Maderwald S, Thurling M, Minnerop M, Beck A, et al. Structural and functional MRI abnormalities of cerebellar cortex and nuclei in SCA3, SCA6 and Friedreich’s ataxia. Brain. 2015;138(Pt 5):1182–97.

    Article  PubMed  Google Scholar 

  9. Manto M, Lorivel T. Cognitive repercussions of hereditary cerebellar disorders. Cortex. 2011;47(1):81–100.

    Article  PubMed  Google Scholar 

  10. Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsy Clin Neurosci. 2004;16(3):367–78.

    Article  Google Scholar 

  11. Timmann D, Drepper J, Frings M, Maschke M, Richter S, Gerwig M, et al. The human cerebellum contributes to motor, emotional and cognitive associative learning. A review Cortex. 2010;46(7):845–57.

    CAS  Article  PubMed  Google Scholar 

  12. de Nóbrega E, Nieto A, Barrosso J, Montón F. Differential impairment in semantic, phonemic, and action fluency performance in Friedreich’s ataxia: possible evidence of prefrontal dysfunction. J Int Neuropsych Soc. 2007;13:944–52.

    Article  Google Scholar 

  13. Klopper F, Delatycki MB, Corben LA, Bradshaw JL, Rance G, Georgiou-Karistianis N. The test of everyday attention reveals significant sustained volitional attention and working memory deficits in Friedreich ataxia. J Int Neuropsych Soc. 2011;17:196–200.

    Article  Google Scholar 

  14. Nieto A, Correia R, de Nóbrega E, Montón F, Hess S, Barroso J. Cognition in Friedreich ataxia. Cerebellum. 2012;11(4):834–44.

    Article  PubMed  Google Scholar 

  15. Nachbauer W, Bodner T, Boesch S, Karner E, Eigentler A, Neier L, et al. Friedreich ataxia: executive control is related to disease onset and GAA repeat length. Cerebellum. 2014;13(1):9–16.

    CAS  Article  PubMed  Google Scholar 

  16. Corben LA, Akhlaghi H, Georgiou-Karistianis N, Bradshaw JL, Egan GF, Storey E, et al. Impaired inhibition of prepotent motor tendencies in Friedreich ataxia demonstrated by the Simon interference task. Brain Cog. 2011;76(1):140–5.

    CAS  Article  Google Scholar 

  17. Corben LA, Delatycki MB, Bradshaw JL, Horne MK, Fahey MC, Churchyard AC, et al. Impairment in motor reprogramming in Friedreich ataxia reflecting possible cerebellar dysfunction. J Neurol. 2010;257(5):782–91.

    Article  PubMed  Google Scholar 

  18. Akhlaghi H, Corben L, Georgiou-Karistianis N, Bradshaw J, Storey E, Delatycki MB, et al. Superior cerebellar peduncle atrophy in Friedreich’s ataxia correlates with disease symptoms. Cerebellum. 2011;10(1):81–7.

    Article  PubMed  Google Scholar 

  19. Della Nave R, Ginestroni A, Giannelli M, Tessa C, Salvatore E, Salvi F, et al. Brain structural damage in Friedreich’s ataxia. J Neurol Neurosurg Psych. 2008;79:82–5.

    CAS  Article  Google Scholar 

  20. Akhlaghi H, Yu J, Corben L, Georgiou-Karistianis N, Bradshaw JL, Storey E, et al. Cognitive deficits in Friedreich ataxia correlate with micro-structural changes in dentatorubral tract. Cerebellum. 2014;13(2):187–98.

    CAS  Article  PubMed  Google Scholar 

  21. Clemm von Hohenberg C, Schocke MF, Wigand MC, Nachbauer W, Guttmann CR, Kubicki M, et al. Radial diffusivity in the cerebellar peduncles correlates with clinical severity in Friedreich ataxia. Neurol Sci. 2013;34(8):1459–62.

    Article  PubMed  Google Scholar 

  22. Corben LA, Kashuk SR, Akhlaghi H, Jamadar S, Delatycki MB, Fielding J, et al. Myelin paucity of the superior cerebellar peduncle in individuals with Friedreich ataxia: an MRI magnetization transfer imaging study. J Neurol Sci. 2014;343(1–2):138–43.

    Article  PubMed  Google Scholar 

  23. Della Nave R, Ginestroni A, Tessa C, Salvatore E, Bartolomei I, Salvi F, et al. Brain white matter tracts degeneration in Friedreich ataxia. An in vivo MRI study using tract-based spatial statistics and voxel-based morphometry. Neurolmage. 2008;40(1):19–35.

    Article  Google Scholar 

  24. Egger K, Clemm von Hohenberg C, Schocke MF, Guttmann CR, Wassermann D, Wigand MC, et al. White matter changes in patients with Friedreich ataxia after treatment with erythropoietin. J Neuroimag. 2014;24(5):504–8.

    Article  Google Scholar 

  25. Zalesky A, Akhlaghi H, Corben LA, Bradshaw JL, Delatycki MB, Storey E, et al. Cerebello-cerebral connectivity deficits in Friedreich ataxia. Brain Struc Func. 2014;219(3):969–81.

    Article  Google Scholar 

  26. Vieira Karuta SC, Raskin S, de Carvalho NA, Gasparetto EL, Doring T, Teive HA. Diffusion tensor imaging and tract-based spatial statistics analysis in Friedreich’s ataxia patients. Park Rel Dis. 2015;21(5):504–8.

    Article  Google Scholar 

  27. Akhlaghi H, Corben L, Georgiou-Karistianis N, Bradshaw J, Delatycki MB, Storey E, et al. A functional MRI study of motor dysfunction in Friedreich’s ataxia. Brain Res. 2012;1471:138–54.

    CAS  Article  PubMed  Google Scholar 

  28. Georgiou-Karistianis N, Akhlaghi H, Corben LA, Delatycki MB, Storey E, Bradshaw JL, et al. Decreased functional brain activation in Friedreich ataxia using the Simon effect task. Brain Cog. 2012;79:200–8.

    CAS  Article  Google Scholar 

  29. Ginestroni A, Diciotti S, Cecchi P, Pesaresi I, Tessa C, Giannelli M, et al. Neurodegeneration in Friedreich’s ataxia is associated with a mixed activation pattern of the brain. A fMRI study. Hum Brain Map. 2012;33(8):1780–91.

    Article  Google Scholar 

  30. Keren-Happuch E, Chen SH, Ho MH, Desmond JE. A meta-analysis of cerebellar contributions to higher cognition from PET and fMRI studies. Hum Brain Map. 2014;35(2):593–615.

    Article  Google Scholar 

  31. Bellebaum C, Daum I. Cerebellar involvement in executive control. Cerebellum. 2007;6(3):184–92.

    Article  PubMed  Google Scholar 

  32. Moberget T, Gullesen EH, Andersson S, Ivry RB, Endestad T. Generalized role for the cerebellum in encoding internal models: evidence from semantic processing. J Neurosci. 2014;34(8):2871–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Mantovan MC, Martinuzzi A, Squarzanti F, Bolla A, Silvestri I, Liessi G, et al. Exploring mental status in Friedreich’s ataxia: a combined neuropsychological, behavioural and neuroimaging study. Eur J Neurol. 2006;13:827–35.

    CAS  Article  PubMed  Google Scholar 

  34. White M, Lalonde R, Botez-Marquard T. Neuropsychologic and neuropsychiatric characteristics of patients with Friedreich’s ataxia. Acta Neur Scand. 2000;102(4):222–6.

    CAS  Article  Google Scholar 

  35. Corben LA, Georgiou-Karistianis N, Bradshaw JL, Hocking DR, Churchyard AJ, Delatycki MB. The Fitts task reveals impairments in planning and online control of movement in Friedreich ataxia: reduced cerebellar-cortico connectivity? Neuroscience. 2011;192:382–90.

    CAS  Article  PubMed  Google Scholar 

  36. Corben LA, Delatycki MB, Bradshaw JL, Churchyard AJ, Georgiou-Karistianis N. Utilization of advance motor information is impaired in Friedreich ataxia. Cerebellum. 2011;10(4):793–803.

    Article  PubMed  Google Scholar 

  37. Wollmann T, Barroso J, Monton F, Nieto A. Neuropsychological test performance of patients with Friedreich’s ataxia. J Clin Exp Neuropsych. 2002;24(5):677–86.

    Article  Google Scholar 

  38. Burgess P, Shallice T. Response suppression, initiation and strategy use following frontal lobe lesions. Neuropsychologia. 1996;34(4):263–72.

    CAS  Article  PubMed  Google Scholar 

  39. Burgess P, & Shallice T, Inventors; Thames Valley Test Company Limited, assignee. The Hayling and Brixton Tests- Manual. Bury St Edmonds, England: 1997.

  40. Golden CJ. Stroop color and word test. A manual for clinical and experimental uses. Illinois: Stoelting; 2002.

    Google Scholar 

  41. Reitan MN. The relation of the trail making test to organic brain damage. J Consult Psych. 1955;19(5):393–4.

    CAS  Article  Google Scholar 

  42. Subramony SH, May W, Lynch D, Gomez C, Fischbeck K, Hallett M, et al. Measuring Friedreich ataxia: interrater reliability of a neurologic rating scale. Neurology. 2005;64(7):1261–2.

    CAS  Article  PubMed  Google Scholar 

  43. Nelson HE, Wilson J. National Adult Reading Test (NART). Windsor: NFER-Nelson; 1991.

    Google Scholar 

  44. Dogan I, Tinnemann E, Romanzetti S, Mirzazade S, Costa AS, Werner CJ, et al. Cognition in Friedreich’s ataxia: a behavioral and multimodal imaging study. Ann Clin Trans Neurol. 2016;1-16

  45. Sanchez-Cubillo I, Perianez JA, Adrover-Roig D, Rodriguez-Sanchez JM, Rios-Lago M, Tirapu J, et al. Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsych Soc. 2009;15(3):438–50.

    CAS  Article  Google Scholar 

  46. Stroop JR. Studies of interference in serial verbal reactions. J Exp Psych. 1935;18:633–62.

    Article  Google Scholar 

  47. Collette F, Van der Linden M, Delfiore G, Degueldre C, Luxen A, Salmon E. The functional anatomy of inhibition processes investigated with the Hayling task. NeuroImage. 2001;14(2):258–67.

    CAS  Article  PubMed  Google Scholar 

  48. Moberget T, Ivry RB. Cerebellar contributions to motor control and language comprehension: searching for common computational principles. Ann New York Acad Sci. 2016;1369(1):154–71.

    Article  Google Scholar 

  49. Chuderski A, Smolen T. An integrated utility-based model of conflict evaluation and resolution in the Stroop task. Psych Rev. 2016;123(3):255–90.

    Article  Google Scholar 

  50. Corben LA, Georgiou-Karistianis N, Fahey MC, Storey E, Churchyard A, Horne MK, et al. Towards an understanding of cognitive function in Friedreich ataxia. Brain Res Bull. 2006;70:197–202.

    Article  PubMed  Google Scholar 

  51. Ciancarelli I, Cofini V, Carolei A. Evaluation of neuropsychological functions in patients with Friedreich ataxia before and after cognitive therapy. Func Neurol. 2010;25(2):81–5.

    Google Scholar 

  52. França AE, D’Abreu A, Yasuda CL, Bonadia LC, Santos da Silva M, Nucci A, et al. A combined voxel-based morphometry and 1H-MRS study in patients with Friedreich’s ataxia. J Neurol. 2009;256:1114–20.

    Article  PubMed  Google Scholar 

  53. Georgiou-Karistianis N, Akhlaghi H, Corben LA, Delatycki MB, Storey E, Bradshaw JL, et al. Decreased functional brain activation in Friedreich ataxia using the Simon effect task. Brain Cog. 2012;79(3):200–8.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank the participants who so willingly gave their time and continued to support our research. Funding was received from the Friedreich Ataxia Research Association (Australasia) and the Friedreich Ataxia Research Alliance (USA). This work was supported by the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Louise A. Corben.

Ethics declarations

Study approval was obtained from the Monash Health and Monash University Human Research Ethics Committees (ref no: 04052C). All participants gave their informed, written consent in accordance with the Declaration of Helsinki.

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Corben, L.A., Klopper, F., Stagnitti, M. et al. Measuring Inhibition and Cognitive Flexibility in Friedreich Ataxia. Cerebellum 16, 757–763 (2017). https://doi.org/10.1007/s12311-017-0848-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-017-0848-7

Keywords

  • Ataxia, Friedreich
  • Cognitive flexibility
  • Inhibition (psychology)
  • Verbal response suppression
  • Cerebellum