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Saccadic impairments in Huntington’s disease

  • A. Peltsch
  • A. Hoffman
  • I. Armstrong
  • G. Pari
  • D. P. MunozEmail author
Research Article

Abstract

Huntington’s disease (HD), a progressive neurological disorder involving degeneration in basal ganglia structures, leads to abnormal control of saccadic eye movements. We investigated whether saccadic impairments in HD (N = 9) correlated with clinical disease severity to determine the relationship between saccadic control and basal ganglia pathology. HD patients and age/sex-matched controls performed various eye movement tasks that required the execution or suppression of automatic or voluntary saccades. In the “immediate” saccade tasks, subjects were instructed to look either toward (pro-saccade) or away from (anti-saccade) a peripheral stimulus. In the “delayed” saccade tasks (pro-/anti-saccades; delayed memory-guided sequential saccades), subjects were instructed to wait for a central fixation point to disappear before initiating saccades towards or away from a peripheral stimulus that had appeared previously. In all tasks, mean saccadic reaction time was longer and more variable amongst the HD patients. On immediate anti-saccade trials, the occurrence of direction errors (pro-saccades initiated toward stimulus) was higher in the HD patients. In the delayed tasks, timing errors (eye movements made prior to the go signal) were also greater in the HD patients. The increased variability in saccadic reaction times and occurrence of errors (both timing and direction errors) were highly correlated with disease severity, as assessed with the Unified Huntington’s Disease Rating Scale, suggesting that saccadic impairments worsen as the disease progresses. Thus, performance on voluntary saccade paradigms provides a sensitive indicator of disease progression in HD.

Keywords

Huntington’s disease Basal ganglia Motor control 

Notes

Acknowledgments

Special thanks to the Munoz Lab members for all of their editorial assistance, Don Brien for his role in preparing some of the figures for this paper, and Kim Moore for her assistance in data collection. This work was supported by a research operating grant from the Canadian Institute of Health Research to D.P.M. and G.P.

References

  1. Albin RL, Reiner A, Anderson KD, Penney JB, Young AB (1990) Striatal and nigral neuron subpopulations in rigid Huntington’s disease: implications for the functional anatomy of chorea and rigidity-akinesia. Ann Neurol 27(4):357–365PubMedCrossRefGoogle Scholar
  2. Amador N, Schlag-Rey M, Schlag J (2004) Primate antisaccade II. supplementary eye field neural activity predicts correct performance. J Neurophys 91:1672–1689CrossRefGoogle Scholar
  3. Aylward EH, Sparks BF, Field KM, Yallapragada V, Shpritz BD, Rosenblatt A, Brandt J, Gourley LM, Liang K, Zhou H, Margolis RL, Ross CA (2004) Onset and rate of striatal atrophy in preclinical Huntington’s disease. Neurology 63:66–72PubMedGoogle Scholar
  4. Berardelli A, Noth J, Thompson P, Bollen E, Curra A, Deuschl G, van Dijk JG, Töpper R, Schwarz M, Roos R (1999) Pathophysiology of chorea and bradykinesia in Huntington’s disease: review. Mov Disord 14(3):398–403PubMedCrossRefGoogle Scholar
  5. Blekher T, Johnson SA, Marshall BS, White K, Hui MS, Weaver M, Gray J, Yee R, Stout JC, Beristain X, Wojcieszek J, Foroud T (2006) Saccades in presymptomatic and early stages of Huntington disease. Neurology 67:394–399PubMedCrossRefGoogle Scholar
  6. Blekher TM, Yee RD, Kirkwood SC, Hake AM, Stout JC, Weaver MR, Foroud TM (2004) Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington’s disease. Vis Res 44:2729–2736PubMedCrossRefGoogle Scholar
  7. Bollen E, Reulen JPH, Den Heyer JC, Van der Kamp W, Roos RAC, Buruma OJS (1986) Horizontal and vertical saccadic eye movement abnormalities in Huntington’s chorea. J Neurol Sci 74:11–22PubMedCrossRefGoogle Scholar
  8. Chan F, Armstrong I, Pari G, Riopelle R, Munoz D (2005) Deficits in saccadic eye- movement control in Parkinson’s disease. Neuropsychologia 43(5):784–796PubMedCrossRefGoogle Scholar
  9. Condy C, Wattiez N, Rivaud-Pechoux S, Tremblay L, Gaymard B (2007) Antisaccade deficit after inactivation of the principal sulcus in monkeys. Cereb Cortex 17(1):221–229PubMedCrossRefGoogle Scholar
  10. Crossman AR, Mitchell IJ, Sambrook MA, Jackson A (1988) Chorea and myoclonus in the monkey induced by gamma-aminobutyric acid antagonism in the lentiform complex. Brain 111:1211–1233PubMedCrossRefGoogle Scholar
  11. Dias EC, Segraves MA (1999) Muscimol-induced inactivation of monkey frontal eye field: effects on visually and memory-guided saccades. J Neurophys 81(5):2191–2214Google Scholar
  12. Everling S, Munoz DP (2000) Neuronal correlates for preparatory set associated with pro-saccades and antisaccades in the primate frontal eye field. J Neurosci 20:387–400PubMedGoogle Scholar
  13. Folstein SE (1989) Huntington’s disease: a disorder of families. John Hopkins University Press, BaltimoreGoogle Scholar
  14. Gaymard B, Ploner CJ, Rivaud S, Vermersch AI, Pierrot-Deseilligny C (1998) Cortical control of saccades. Exp Brain Res 123(1–2):159–163PubMedCrossRefGoogle Scholar
  15. Goldring JE, Dorric MC, Corneil BD, Ballantyne PA, Munoz DP (1996) Combined eye-head gaze shifts to visual and auditory targets in humans. Exp Brain Res 111(1):68–78PubMedCrossRefGoogle Scholar
  16. Goodin DS, Aminoff MJ (1992) Evaluation of dementia by event-related potentials. Review. J Clin Neurophys 9(4):521–525CrossRefGoogle Scholar
  17. Guitton D, Buchtel HA, Douglas RM (1985) Frontal lobe lesions in man cause difficulties in suppressing reflexive glances and in generating goal-directed saccades. Exp Brain Res 58(3):455–472PubMedCrossRefGoogle Scholar
  18. Hanes DP, Wurtz RH (2001) Interaction of the frontal eye field and superior colliculus for saccade generation. J Neurophys 85(2):804–815Google Scholar
  19. Hays AV, Richmond BJ, Optician LM (1982) A UNIX-based multiple process system for real-time data acquisition and control. Proc WESCON 2:1–10Google Scholar
  20. Hikosaka O, Nakamura K, Nakahara H (2006) Basal ganglia orient eyes to reward. Review. J Neurophys 95(2):567–584CrossRefGoogle Scholar
  21. Hikosaka O, Takikawa Y, Kawagoe R (2000) Role of basal ganglia in the control of purposive saccadic eye movements. Phys Rev 80(3):953–978Google Scholar
  22. Hikosaka O, Wurtz RH (1985a) Modification of saccadic eye movements by GABA-related substances. I. Effect of muscimol and bicuculline in monkey superior colliculus. J Neurophys 53(1):266–291Google Scholar
  23. Hikosaka O, Wurtz RH (1985b) Modification of saccadic eye movements by GABA-related substances. II. Effect of muscimol in monkey substantia nigra pars reticulata. J Neurophys 53(1):292–308Google Scholar
  24. Huntington Study Group (1996) Unified Huntington’s disease rating scale: reliability and consistency. Mov Dis, 11(2):136–142CrossRefGoogle Scholar
  25. Jackson A, Crossman AR (1984) Experimental choreoathetosis produced by injection of a gamma-aminobutyric acid antagonist into the lentiform nucleus in the monkey. Neurosci Lett, 46:41–45PubMedCrossRefGoogle Scholar
  26. Johnson KA, Cunnington R, Lansek R, Bradshaw JL, Georgiou N, Chiu E (2001) Movement-related potentials in Huntington’s disease: movement preparation and execution. Exp Brain Res 138:492–499PubMedCrossRefGoogle Scholar
  27. Kassubek J, Juengling FD, Ecker D (2005) Thalamic atrophy in Huntington’s disease co-varies with cognitive performance: a morphometric MRI analysis. Cereb Cortex 15:846–853PubMedCrossRefGoogle Scholar
  28. Kimmig H, Haussmann K, Mergner T, Lucking CH (2002) What is pathological with gaze shift fragmentation in Parkinson’s disease? J Neurol 249(6):683–692PubMedCrossRefGoogle Scholar
  29. Lasker AG, Zee DS (1996) Ocular motor abnormalities in Huntington’s disease. Vis Res 37(24):3639–3645CrossRefGoogle Scholar
  30. Lasker AG, Zee DS, Hain TC, Folstein SE, Singer HS (1988) Saccades in Huntington’s disease; slowing and dysmetria. Neurology 38:427–431PubMedGoogle Scholar
  31. Lasker AG, Zee DS, Hain TC, Folstein SE, Singer HS (1987) Saccades in Huntington’s disease; initiation defects and distractibility. Neurology 37:364–370PubMedGoogle Scholar
  32. Lee C, Rohrer WH, Sparks DL (1988) Population coding of saccadic eye movements by neurons in the superior colliculus. Nature 332(6162):357–360PubMedCrossRefGoogle Scholar
  33. Leigh RJ, Kennard C (2004) Using saccades as a research tool in the clinical neurosciences. Brain 127(3):460–477PubMedCrossRefGoogle Scholar
  34. Leigh RJ, Newman SA, Folstein SE, Lasker AG, Jensen BA (1983) Abnormal ocular motor control in Huntington’s disease. Neurology 33:1268–1275PubMedGoogle Scholar
  35. Leigh RJ, Zee DS (1999) The neurology of eye movements, 3rd edn. Oxford University Press, New YorkGoogle Scholar
  36. LeVasseur AL, Flanagan JR, Riopelle RJ, Munoz DP (2001) Control of volitional and reflexive saccades in Tourette’s syndrome. Brain 124(10):2045–2058PubMedCrossRefGoogle Scholar
  37. Macmillan J, Quarrel O (1996) The neurobiology of Huntington’s disease. In: Harper PS (ed) Huntington’s disease. Saunders, London, pp 317–358Google Scholar
  38. Miller EK, Cohen JD (2001) An integrative theory of prefrontal cortex function. Ann Rev Neurosci 24:167–202PubMedCrossRefGoogle Scholar
  39. Mitchell J, Jackson A, Sambrook MA, Crossman AR (1989) The role of the subthalamic nucleus in experimental chorea. Evidence from 2-deoxyglucose metabolic mapping and horseradish peroxidase tracing studies Brain 112:1533–1548PubMedCrossRefGoogle Scholar
  40. Munoz DP (2002). Commentary: saccadic eye movements: overview of neural circuitry. Review. Prog Brain Res 140:89–96PubMedGoogle Scholar
  41. Munoz DP, Broughton JR, Goldring JE, Armstrong IT (1998) Age-related performance of human subjects on saccadic eye movement tasks. Exp Brain Res 121(4):391–400PubMedCrossRefGoogle Scholar
  42. Munoz DP, Everling S (2004) Look away: the anti-saccade task and the voluntary control of eye movement. Nat Rev Neurosci 5(3):218–228PubMedCrossRefGoogle Scholar
  43. O’Walker F (2007) Huntington’s disease. Lancet 369:218–228CrossRefGoogle Scholar
  44. Pierrot-Deseilligny C, Rosa A, Masmoudi K, Rivaud S, Gaymard B (1991) Saccade deficits after a unilateral lesion affecting the superior colliculus. J Neurosurg Psych 54(12):1106–1109Google Scholar
  45. Purdon SE, Mohr E, Ilivitsky V, Jones BDW (1994) Huntington’s disease: pathogenesis, diagnosis and treatment. Review. J Psychiatric Neurosci 19(5):359–367Google Scholar
  46. Reiner A, Medina L, Veenman CL (1998) Structural and functional evolution of the basal ganglia in vertebrates. Review. Brain Res 28(3):235–285CrossRefGoogle Scholar
  47. Scudder CA, Kaneko CS, Fuchs AF (2002) The brainstem burst generator for saccadic eye movements: a modern synthesis. Exp Brain Res 142:439–462PubMedCrossRefGoogle Scholar
  48. Segraves MA, Goldberg ME (1987) Functional properties of corticotectal neurons in the monkey’s frontal eye field. J Neurophys 58(6):1387–1419Google Scholar
  49. Sharp A, Ross C (1996) Neurobiology of Huntington’s disease (Review). Neurobiol Dis 3(1):3–15PubMedCrossRefGoogle Scholar
  50. Smith M, Brandt J, Shadmehr R (2000) Motor disorder in Huntington’s disease begins as a dysfunction in error feedback control. Lett Nat 403:544–549CrossRefGoogle Scholar
  51. Sommer MA, Tehovnik EJ (1999) Reversible inactivation of macaque dorsomedial frontal cortex: effects on saccades and fixations. Exp Brain Res 124(4):429–446PubMedCrossRefGoogle Scholar
  52. Storey E, Beal MF (1993) Neurochemical substrates of rigidity and chorea in Huntington’s disease. Brain 116:1201–1222PubMedCrossRefGoogle Scholar
  53. Tian JR, Zee DS, Lasker AG, Folstein SE (1991) Saccades in Huntington’s disease: Predictive tracking and interaction between release of fixation and initiation of saccades. Neurology 41:875–881PubMedGoogle Scholar
  54. Tsai TT, Lasker A, Zee DS (1995) Visual attention in Huntington’s disease: the effect of cueing on saccade latencies and manual reaction times. Neuropsychologia 33(12):1617–1626PubMedCrossRefGoogle Scholar
  55. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EPJ (1985) Neuropathological classification of Huntington’s disease. Neuropath Exp Neurol 44:559–577CrossRefGoogle Scholar
  56. Winograd-Gurvich CT, Georgiou-Karistianis N, Evans A, Millist L, Bradshaw JL, Churchyard A, Chiu E, White OB (2003) Hypometric primary saccades and increased variability in visually-guided saccades in Huntington’s disease. Neuropsychologia 41(12):1683–1692PubMedCrossRefGoogle Scholar
  57. Young AB, Shoulson I, Penney JB, Starosta-Rubinstein S, Gomez F, Travers H, Ramos- Arroyo MA, Snodgrass SR, Bonilla E, Moreno H et al (1986) Huntington’s disease in Venezuela: neurologic features and functional decline. Neurology 36(2):244–249PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • A. Peltsch
    • 1
    • 5
  • A. Hoffman
    • 2
    • 5
  • I. Armstrong
    • 1
    • 5
  • G. Pari
    • 1
    • 3
  • D. P. Munoz
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  1. 1.Centre for Neuroscience StudiesQueen’s UniversityKingstonCanada
  2. 2.Department of PhysiologyQueen’s UniversityKingstonCanada
  3. 3.Department of MedicineQueen’s UniversityKingstonCanada
  4. 4.Department of PsychologyQueen’s UniversityKingstonCanada
  5. 5.CIHR Group in Sensory-Motor SystemsQueen’s UniversityKingstonCanada

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