Documenta Ophthalmologica

, Volume 105, Issue 2, pp 151–178 | Cite as

Factors affecting the use of multifocal electroretinography to monitor function in a primate model of glaucoma

  • Brad Fortune
  • Grant Cull
  • Lin Wang
  • E. Michael Van Buskirk
  • George A. Cioffi


While elevated intraocular pressure (IOP) undoubtedly plays a crucial role in many glaucoma patients, vascular dysregulation and chronic regional ischemia are also thought to contribute to the pathophysiology of glaucoma. In an effort to critically evaluate hypotheses involving vascular abnormalities in glaucoma, Cioffi, Van Buskirk and co-workers have developed a model of optic neuropathy based on chronic regional ischemia. The multifocal electroretinogram (MERG) has previously been used to assess function in non-human primates with experimental glaucoma induced by high-IOP. In this study, the MERG was used to monitor function in macaque monkeys with experimental glaucoma induced by chronic anterior optic nerve ischemia. Initial recordings from experimental eyes, which were later documented histologically to have moderate axon loss, revealed little difference from recordings of control eyes. This suggested that many of the signal components in the macaque MERG, which are known (from other studies) to be eliminated by intravitreal injections of NMDA/TTX or by high-IOP experimental glaucoma, may also be affected by the choice of anesthetic agents and MERG recording parameters. Subsequent experiments were performed to specifically evaluate the effects of bipolar versus monopolar signal derivation, anesthetic agents, MERG stimulus design and spatial scale. The results demonstrate that successful measurement of inner retinal and optic nerve head MERG components, especially those which have been shown by other investigators to originate with ganglion cell spiking activity, will depend critically upon the choice of anesthetic agents and recording parameters. One of the most important parameters seems to be use of a monopolar signal derivation, with the contralateral cornea serving as the reference position.

glaucoma ischemia isoflurane multifocal electroretinogram macaque optic nerve 


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  1. 1.
    Hoskins HD, Kass M. Becker-Shaffer's Diagnosis and Therapy of the Glaucomas. C.V. Mosby Co., St. Louis, ed. 6, 1989: p2.Google Scholar
  2. 2.
    Chandler PA, Grant WM (eds). Glaucoma. Lea and Febiger, Philadelphia, ed. 2. 1986: p3.Google Scholar
  3. 3.
    Levene RZ. Low-tension glaucoma. Surv Ophthalmol 1980; 24: 621–663.Google Scholar
  4. 4.
    Chauhan BC, Drance SM. The relationship between intraocular pressure and visual flied progression in glaucoma. Graefes Arch Clin Exp Ophthalmol 1992; 230: 521–526.Google Scholar
  5. 5.
    Hollows FC, Graham PA. Intraocular pressure, glaucoma and glaucoma suspects in a defined population. Br J Ophthalmol 1966; 50: 570–586.Google Scholar
  6. 6.
    Van Buskirk EM, Cioffi GA. Glaucomatous optic neuropathy. Am J Ophthalmol 1992; 113: 447–452.Google Scholar
  7. 7.
    Flammer J, Haefliger IO, Orgul S, Resink T. Vascular dysregulation: a principal risk factor for glaucomatous damage? J Glaucoma 1999; 8(3): 212–9.Google Scholar
  8. 8.
    Flammer J, Orgul S. Optic nerve blood-flow abnormalities in glaucoma. Prog Retinal Eye Res 1998; 17(2): 267–89.Google Scholar
  9. 9.
    Flammer J, Gasser P, Prünte C, Yao K. The probable involvement of factors other than intraocular pressure in the pathogenesis of glaucoma. In: Drance SM, Van Buskirk EM, Neufeld AH, eds. Pharmacology of Glaucoma. Baltimore: Williams & Wilkins, 1992: 273–83.Google Scholar
  10. 10.
    Carter CJ, Brooks DE, Doyle DL, Drance SM. Investigations into a vascular etiology for low-tension glaucoma. Ophthalmol. 1990; 97: 49–55.Google Scholar
  11. 11.
    Hayreh SS. Progress in the understanding of the vascular etiology of glaucoma. Curr Opin Ophthalmol 1994; 5: 26–35.Google Scholar
  12. 12.
    Cioffi GA, Wang L. Optic nerve blood flow in glaucoma. Semin Ophthalmol. 1999; 14: 164–70.Google Scholar
  13. 13.
    Wang L, Cioffi GA, Van Buskirk, EM. The vascular pattern of the optic nerve and its potential relevance in glaucoma. Curr Opin Ophthalmol. 1998; 9(2): 24–9.Google Scholar
  14. 14.
    Cioffi GA, Orgül S, Onda E, Bacon DR, Van Buskirk EM. An in vivo model of chronic optic nerve ischemia: the dose-dependent effects of endothelin-1 on the optic nerve microvasculature. Curr Eye Res 1995; 14: 1147–53.Google Scholar
  15. 15.
    Orgül S, Cioffi GA, Wilson DJ, Bacon DR, Van Buskirk EM. An Endothelin-1 Induced Model of Optic Nerve Ischemia in the Rabbit. Invest Ophthalmol Vis Sci. 1996; 37(9): 1860–9.Google Scholar
  16. 16.
    Cioffi GA, Sullivan P. The Effect of Chronic Ischemia on the Primate Optic Nerve. Eur J Ophthalmol. 1999; 9(1): S34–6.Google Scholar
  17. 17.
    Orgül S, Cioffi GA, Bacon DR, Van Buskirk EM. An Endothelin-1 Model of Chronic Optic Nerve Ischemia in Rhesus Monkeys. J Glaucoma. 1996; 5(2): 135–8.Google Scholar
  18. 18.
    Cioffi GA, Sullivan P, Van Buskirk EM, Wang L. The Primate Optic Nerve Following Chronic Ischemia. In: Krieglstein, ed. Glaucoma Update VI, Springer/Heidelberg/Berlin-New York, 2000: 103–7.Google Scholar
  19. 19.
    Cioffi GA, Liebmann JM, Johnson CA, Weinreb RN. Structural-functional relationships of the optic nerve in glaucoma. J Glaucoma. 2000; 9(1): 3–4.Google Scholar
  20. 20.
    Harwerth RS, Smith EL 3rd, DeSantis L. Behavioral perimetry in monkeys. Invest Ophthalmol Vis Sci. 1993; 34: 31–40.Google Scholar
  21. 21.
    Harwerth RS, Smith EL 3rd, DeSantis L. Experimental glaucoma: perimetric field defects and intraocular pressure. J Glaucoma. 1997; 6(6): 390–401.Google Scholar
  22. 22.
    Korth M. The value of electrophysiologic testing in glaucomatous diseases. J. Glaucoma. 1997; 6(5): 331–43.Google Scholar
  23. 23.
    Graham SL, Klistorner A. Electrophysiology: A review of signal origins and applications to investigating glaucoma. Australian New Zeal J Ophthalmol. 1998; 26: 71–85.Google Scholar
  24. 24.
    Frishman LJ, Shen FF, Du L, Robson JG, Harwerth RS, Smith EL 3rd, Carter-Dawson L, Crawford ML. The scotopic electroretinogram of macaque after retinal ganglion cell loss from experimental glaucoma. Invest Ophthalmol Vis Sci. 1996; 37: 125–41.Google Scholar
  25. 25.
    Viswanathan S, Frishman LJ, Robson JG, Harwerth RS, Smith EL III. The photopic negative response of the macaque electroretinogram: reduction by experimental glaucoma. Invest Ophthalmol Vis Sci. 1999; 40: 1124–36.Google Scholar
  26. 26.
    Dong CJ, Hare WA. Contribution to the kinetics and amplitude of the electroretinogram b-wave by third-order retinal neurons in the rabbit retina. Vis Res. 2000; 40: 579–89.Google Scholar
  27. 27.
    Viswanathan S, Frishman LJ, Robson JG. The uniform field and pattern ERG in macaques with experimental glaucoma: removal of spiking activity. Invest Ophthalmol Vis Sci. 2000; 41: 2797–810.Google Scholar
  28. 28.
    Porciatti V, Falsini B. Inner retina contribution to the flicker electroretinogram: a comparison with the pattern electroretinogram. Clin Vis Sci. 1993; 8: 435–47.Google Scholar
  29. 29.
    Vaegan, Graham Sl, Goldberg I, Buckland L, Hollows FC. Flash and pattern electroretinogram changes with optic atrophy and glaucoma. Exp Eye Res. 1995; 60: 697–706.Google Scholar
  30. 30.
    Viswanathan S, Frishman LJ, Robson JG, Walters JW. The photopic negative response of the flash electroretinogram in primary open angle glaucoma. Invest Ophthalmol Vis Sci. 2001; 42: 514–22.Google Scholar
  31. 31.
    Maffei L, Fiorentini A. Electroretinographic responses to alternating gratings before and after section of the optic nerve. Science. 1981; 211(27): 953–5.Google Scholar
  32. 32.
    Maffei L, Fiorentini A, Bisti S, Hollander H. Pattern ERG in the monkey after section of the optic nerve. Exp Brain Res. 1985; 59: 423–5.Google Scholar
  33. 33.
    Graham SL, Drance SM, Chauhan BC, Swindale NV, Hnik P, Mikelberg FS, Douglas GR. Comparison of psychophysical and electrophysiological testing in early glaucoma. Invest Ophthalmol Vis Sci. 1996; 37: 2651–62.Google Scholar
  34. 34.
    Marx MS, Podos SM, Bodis-Wollner I, Howard-Williams JR, Siegel MJ, Teitelbaum CS, Maclin EL, Severin C. Flash and pattern electroretinograms in normal and laserinduced glaucomatous primate eyes. Invest Ophthalmol Vis Sci. 1986; 27(3): 378–86.Google Scholar
  35. 35.
    Johnson MA, Drum BA, Quigley HA, Sanchez RM, Dunkelberger GR. Pattern-evoked potentials and optic nerve fiber loss in monocular laser-induced glaucoma. Invest Ophthalmol Vis Sci. 1989; 30: 897–907.Google Scholar
  36. 36.
    Sutter EE, Tran D. The field topography of ERG components in man-I: the photopic luminance response. Vis Res. 1992; 32: 433–46.Google Scholar
  37. 37.
    Hood DC. Assessing retinal function with the multifocal technique. Prog Retinal Eye Res. 2000; 19(5) 607–46.Google Scholar
  38. 38.
    Bearse MA, Sutter EE, Sim D, Stamper R. Glaucomatous dysfunction revealed in higher order components of the electroretinogram. Vis Sci App. OSA Tech Dig Ser, Vol. 1, Washington, DC: 1996: 104–7.Google Scholar
  39. 39.
    Vaegan, Buckland L. The spatial distribution of ERG losses across the posterior pole of glaucomatous eyes in multifocal recordings. Aust New Zeal J Ophthalmol. 1996; 24(Suppl 2): 28–31.Google Scholar
  40. 40.
    Chan HL, Brown B. Multifocal ERG changes in glaucoma. Ophthal Physiol Optics. 1999; 19(4): 306–16.Google Scholar
  41. 41.
    Hasegawa S, Takagi M, Usui T, Takada R, Abe H. Waveform changes of the first-order multifocal electroretinogram in patients with glaucoma. Invest Ophthalmol Vis Sci. 2000; 41: 1597–1603.Google Scholar
  42. 42.
    Hood DC, Greenstein VC, Holopigian, K, Bauer R, Firoz B, Liebmann JM, Odel JG, Ritch R. An attempt to detect glaucomatous damage to the inner retina with the multifocal ERG. Invest Ophthalmol Vis Sci. 2000; 41: 1570–9.Google Scholar
  43. 43.
    Fortune B, Cioffi GA, Johnson CA, Kondo Y, Mochizuki K, Kitazwa Y. The relationship between multifocal electroretinogram and standard automated perimetry findings in normal tension glaucoma. In: Weinreb RN, Krieglstein GK, Kitazawa Y, eds. Glaucoma in the 21st Century. London: Harcourt Publishers Ltd. 2000: pp 73–8.Google Scholar
  44. 44.
    Palmowski AM, Allgayer R, Heinemann-Vernaleken B. The multifocal ERG in open angle glaucoma: A comparison of high and low contrast recordings in high-and low-tension open angle glaucoma. Doc Ophthalmol. 2000. 101(1): 35–49.Google Scholar
  45. 45.
    Hare W, Ton H, Woldemussie E, Ruiz G, Feldmann B, Wijono M. Electrophysiological and histological measures of retinal injury in chronic ocular hypertensive monkeys. Eur J Ophthalmol. 1999; 9(Suppl 1), S30–33.Google Scholar
  46. 46.
    Frishman LJ, Saszik S, Harwerth RS, Viswanathan S, Li Y, Smith EL, Robson JG, Barnes G. Effects of experimental glaucoma in macaques on the multifocal ERG. Doc Ophthalmol. 2000. 100(2-3): 231–51.Google Scholar
  47. 47.
    Wang L, Cioffi GA, Hernandez MR, Fortune B, Cull G, Oguri A, Van Buskirk EM. Topographic, functional and histological changes of the optic nerve in a primate chronic ischemia model. Invest Ophthalmol Vis Sci. 2000; 41, S898 [ARVO Abstract no. 4778].Google Scholar
  48. 48.
    Hood DC, Frishman LJ, Robson JG, Shady S, Ahmed J, Viswanathan S. A frequency analysis of the regional variation in the contribution from action potentials to the primate multifocal ERG. Vis Sci App. OSA Tech Dig Ser, Vol. 1, Washington, DC: 1999; 1: 56–9.Google Scholar
  49. 49.
    Hood DC, Frishman LJ, Viswanathan S, Robson JG, Ahmed J. Evidence for a ganglion cell contribution to the primate electroretinogram (ERG): effects of TTX on the multifocal ERG in macaque. Vis. Neurosci. 1999; 16: 411–16.Google Scholar
  50. 50.
    Hare WA, Ton H. Effects of APB, PDA, and TTX on the first and second order responses of the multifocal ERG response in monkey. Invest Ophthalmol Vis Sci. 2000; 41, S492, [ARVO Abstract No. 2642].Google Scholar
  51. 51.
    Hood DC, Bearse MA, Sutter EE, Viswanathan S, Frishman LJ. The optic nerve head component of the monkey's (Macaca mulatta) multifocal electroretinogram (mERG). Vis Res. 2001; 41: 2029–41.Google Scholar
  52. 52.
    Cull G, Fortune B, Wang L, Oguri A, Cioffi GA. Effects of isoflurane anesthesia on photopic mulitfocal and ganzfeld flash electroretionograms innormal macaque eyes. Invest Ophthalmol Vis Sci. 2000; 41, S500 [ARVO Abstract no. 2661].Google Scholar
  53. 53.
    Sutter EE, Shimada Y, Li Y, Bearse MA. Mapping inner retinal function through enhancement of adaptive components in the M-ERG. Vis Sci App. OSA Tech Dig Ser, Vol. 1, Washington, DC: 1999; 1, 52–5.Google Scholar
  54. 54.
    Sutter EE, Bearse MA, Shimada Y, Li Y. A multifocal ERG protocol for testing retinal ganglion cell function. Invest Ophthalmol Vis Sci 40: S15 [ARVO abstract no. 79] 2000.Google Scholar
  55. 55.
    Bearse MA Jr., Stamper RL, Sutter EE. Detection of functional abnormalities in glaucoma using a new multifocal ERG paradigm. Invest Ophthalmol Vis Sci. 2000; 41, S103 [ARVO Abstract no. 536].Google Scholar
  56. 56.
    Fortune B, Cioffi GA, Johnson GA, Bearse MA Jr., Johnson MA. Topographic Assessment of Function in Glaucoma: Comparison of Three Different Modes of Multifocal ERG Stimulation. Invest Ophthalmol Vis Sci. 2000; 41, S326 [ARVO Abstract no. 1716].Google Scholar
  57. 57.
    Sutter EE, Bearse MA. The optic nerve head component of the human ERG. Vis Res. 1999; 39: 419–36.Google Scholar
  58. 58.
    Wongpichedchai S, Hansen RM, Koka B, Guda VM, Fulton AB. Effects of halothane on children's electroretinograms. Ophthalmol. 1992; 99(8): 1309–12.Google Scholar
  59. 59.
    Tashiro C, Muranishi R, gomyo I, Mashimo T, Tomi K, Yoshiya I. Electroretinogram as a possible monitor of anesthetic depth. Graefe's Arch Clin Exp Ophthalmol. 1986; 224: 473-6.Google Scholar
  60. 60.
    Franks NP, Lieb WR. Stereospecific effects of inhalational general anesthetic optical isomers on neerve ion channels. Science. 1991; 254: 427-30.Google Scholar
  61. 61.
    Koltchine VV, Finn SE, Jenkins A, Nikolaeva N, Lin A, Harrison NL. Agonist gating and isoflurane potentiation in the human gamma-aminobutyric acid type A receptor determined by the volume of a second transmembrane domain residue. Mol Pharmacol. 1999; 56(5): 1087–93.Google Scholar
  62. 62.
    Yamashita M, Ikemoto Y, Nielsen M, Yano, T. Effects of isoflurane and hexafluorodiethyl ether on human recombinant GABA(A) receptors expressed in Sf9 cells. Eur J Pharmacol. 1999; 378(2): 223–31.Google Scholar
  63. 63.
    Antkowiak B. different actions of general anesthetics on the firing patterns of neocortical neurons mediated by the GABA(A) receptor. Anesthesiology. 1999; 91(2): 500–11.Google Scholar
  64. 64.
    Jenkins A, Franks NP, Lieb WR. Effects of temperature and volatile anesthetics on GABA(A) receptors. Anesthesiology. 1999; 90(2): 484–91.Google Scholar
  65. 65.
    Ueno S, Trudell JR, Eger EI 2nd, Harris RA. Actions of fluorinated alkanols on GABA(A) receptors: Relevance to theories of narcosis. Anesth Analg. 1999; 88(4): 877–83.Google Scholar
  66. 66.
    Duch DS, Rehberg B, Vysotskaya TN. Volatile anesthetics significantly suppress central and peripheral mammalian sodium channels. Toxicology Letters 1998; 100-101: 255–63.Google Scholar
  67. 67.
    Bearse MA, Sutter EE. Contrast dependence of multifocal ERG components. Vis Sci App. OSA Tech Dig Ser, Vol. 1, Washington, DC: 1998: 24–7.Google Scholar
  68. 68.
    Hood DC, Greenstein V, Frishman L, Holopigian K, Viswanathan S, Seiple W, Ahmed J, Robson JG. Identifying inner retinal contributions to the human multifocal ERG. Vis Res. 1999; 39: 2285–91.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Brad Fortune
    • 1
  • Grant Cull
    • 1
  • Lin Wang
    • 1
  • E. Michael Van Buskirk
    • 1
  • George A. Cioffi
    • 1
  1. 1.Discoveries in Sight Research LaboratoriesDevers Eye InstitutePortlandUSA

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