Abstract
Diffuse flash stimuli applied to the ocular fundus evoke light reflectance decreases of the fundus illuminated with infrared observation light. This phenomenon, which is independent of the photopigment bleaching observed as an increase in the reflectance of visible light, is called intrinsic signals. Intrinsic signals, in general, are stimulus-evoked light reflectance changes of neural tissues due to metabolic changes, and they have been extensively investigated in the cerebral cortex. This noninvasive objective technique of functional imaging has good potential as a tool for the early detection of retinal dysfunction. Once the signal properties were studied in detail, however, it became apparent that the intrinsic signals observed in the retina have uniquely interesting properties of their own due to the characteristic layered structure of the retina. Experiments on anesthetized macaque monkeys are reviewed, and the possible origins of the intrinsic signals of the retina are discussed.
Similar content being viewed by others
References
Webb RH, Hughes GW. Scanning laser ophthalmoscope. IEEE Trans Biomed Eng 1981;28:488–492.
Mainster MA, Timberlake GT, Webb RH, Hughes GW. Scanning laser ophthalmoscopy. Clinical applications. Ophthalmology 1982;89:852–857.
Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991;254:1178–1181.
Hee MR, Izatt JA, Swanson EA, et al. Optical coherence tomography of the human retina. Arch Ophthalmol 1995;113:325–332.
Rushton WA. The difference spectrum and the photosensitivity of rhodopsin in the living human eye. J Physiol 1956;134:11–29.
Hood C, Rushton WA. The Florida retinal densitometer. J Physiol 1971;217:213–229.
Rushton WA. Cone pigment kinetics in the protanope. J Physiol 1963;168:374–388.
Alpern M, Maaseidvaag F, Oba N. The kinetics of cone visual pigments in man. Vision Res 1971;11:539–549.
Alpern M. Rhodopsin kinetics in the human eye. J Physiol 1971;217:447–471.
van Norren D, van de Kraats J. Retinal densitometer with the size of a fundus camera. Vision Res 1989;29:369–374.
Kilbride PE, Read JS, Fishman GA, Fishman M. Determination of human cone pigment density difference spectra in spatially resolved regions of the fovea. Vision Res 1983;23:1341–1350.
Kilbride PE, Keehan KM. Visual pigments in the human macula assessed by imaging fundus reflectometry. Appl Opt 1990;29:1427–1435.
Faulkner DJ, Kemp CM. Human rhodopsin measurement using a T.V.-based imaging fundus reflectometer. Vision Res 1984;24:221–231.
Kemp CM, Faulkner DJ, Jacobson SG. The distribution and kinetics of visual pigments in the cat retina. Invest Ophthalmol Vis Sci 1988;29:1056–1065.
Kemp CM, Jacobson SG, Faulkner DJ. Two types of visual dysfunction in autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci 1988;29:1235–1241.
van Norren D, van de Kraats J. Imaging retinal densitometry with a confocal scanning laser ophthalmoscope. Vis Res 1989;29:1825–1830.
Elsner AE, Burns SA, Hughes GW, Webb RH. Reflectometry with a scanning laser ophthalmoscope. Appl Opt 1992;31:3697–3710.
Elsner AE, Burns SA, Beausencourt E, Weiter JJ. Foveal cone photopigment distribution: small alterations associated with macular pigment distribution. Invest Ophthalmol Vis Sci 1998;39:2394–2404.
Zepeda A, Arias C, Sengpiel F. Optical imaging of intrinsic signals: recent developments in the methodology and its applications. J Neurosci Methods 2004;136:1–21.
Ts’o DY, Frostig RD, Lieke EE, Grinvald A. Functional organization of primate visual cortex revealed by high resolution optical imaging. Science 1990;249:417–420.
Frostig RD, Lieke EE, Ts’o DY, Grinvald A. Cortical functional architecture and local coupling between neuronal activity and the microcirculation revealed by in vivo high-resolution optical imaging of intrinsic signals. Proc Natl Acad Sci U S A 1990;87:6082–6086.
Roe AW, Ts’o DY. Visual topography in primate V2: multiple representation across functional stripes. J Neurosci 1995;15:3689–3715.
Ghose GM, Ts’o DY. Form processing modules in primate area V4. J Neurophysiol 1997;77:2191–2196.
Malonek D, Tootell RB, Grinvald A. Optical imaging reveals the functional architecture of neurons processing shape and motion in owl monkey area MT. Proc R Soc Lond B Biol Sci 1994;258:109–119.
Tsunoda K, Yamane Y, Nishizaki M, Tanifuji M. Complex objects are represented in macaque inferotemporal cortex by the combination of feature columns. Nat Neurosci 2001;4:832–838.
MacVicar BA, Hochman D. Imaging of synaptically evoked intrinsic optical signals in hippocampal slices. J Neurosci 1991;11:1458–1469.
Bonhoeffer T, Grinvald A. Optical imaging based on intrinsic signals: the methodology. In: Toga AW, Mazziotta JC, editors. Brain mapping. San Diego: Academic Press; 1996. p. 55–97.
Weliky M, Kandler K, Fitzpatrick D, Katz LC. Patterns of excitation and inhibition evoked by horizontal connections in visual cortex share a common relationship to orientation columns. Neuron 1995;15:541–552.
Das A, Gilbert CD. Long-range horizontal connections and their role in cortical reorganization revealed by optical recording of cat primary visual cortex. Nature 1995;375:780–784.
Tsunoda K, Oguchi Y, Hanazono G, Tanifuji M. Mapping cone- and rod-induced retinal responsiveness in macaque retina by optical imaging. Invest Ophthalmol Vis Sci 2004;45:3820–3826.
Crittin M, Riva CE. Functional imaging of the human papilla and peripapillary region based on flicker-induced reflectance changes. Neurosci Lett 2004;360:141–144.
Abramoff MD, Kwon YH, Ts’o D, et al. Visual stimulus-induced changes in human near-infrared fundus reflectance. Invest Ophthalmol Vis Sci 2006;47:715–721.
Grieve K, Roorda A. Intrinsic signals from human cone photoreceptors. Invest Ophthalmol Vis Sci 2008;49:713–719.
Nelson DA, Krupsky S, Pollack A, et al. Special report: noninvasive multi-parameter functional optical imaging of the eye. Ophthalmic Surg Lasers Imaging 2005;36:57–66.
Harary HH, Brown JE, Pinto LH. Rapid light-induced changes in near infrared transmission of rods in Bufo marinus. Science 1978;202:1083–1085.
Yao XC, Yamauchi A, Perry B, George JS. Rapid optical coherence tomography and recording functional scattering changes from activated frog retina. Appl Opt 2005;44:2019–2023.
Hanazono G, Tsunoda K, Shinoda K, Tsubota K, Miyake Y, Tanifuji M. Intrinsic signal imaging in macaque retina reveals different types of flash-induced light reflectance changes of different origins. Invest Ophthalmol Vis Sci 2007;48:2903–2912.
Inomata K, Tsunoda K, Hanazono G, et al. Distribution of retinal responses evoked by transscleral electrical stimulation detected by intrinsic signal imaging in macaque monkeys. Invest Ophthalmol Vis Sci 2008;49:2193–2200.
Hanazono G, Tsunoda K, Kazato Y, Tsubota K, Tanifuji M. Evaluating neural activity of retinal ganglion cells by flash-evoked intrinsic signal imaging in macaque retina. Invest Ophthalmol Vis Sci 2008;49:4655–4663.
Wali N, Leguire LE. The photopic hill: a new phenomenon of the light adapted electroretinogram. Doc Ophthalmol 1992;80:335–345.
Wagman IH, Waldman J, Naidoff D, Feinschil LB, Cahan R. The recording of the electroretinogram in humans and in animals; investigation of retinal sensitivity following brief flashes of light. Am J Ophthalmol 1954;38:60–69.
Mahroo OA, Lamb TD. Recovery of the human photopic electroretinogram after bleaching exposures: estimation of pigment regeneration kinetics. J Physiol 2004;554:417–437.
Weinhaus RS, Burke JM, Delori FC, Snodderly DM. Comparison of fluorescein angiography with microvascular anatomy of macaque retinas. Exp Eye Res 1995;61:1–16.
Roy C, Sherrington C. On the regulation of the blood supply of the brain. J Physiol 1890;11:85–108.
Villringer A, Dirnagl U. Coupling of brain activity and cerebral blood flow: basis of functional neuroimaging. Cerebrovasc Brain Metab Rev 1995;7:240–276.
Bizheva K, Pflug R, Hermann B, et al. Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography. Proc Natl Acad Sci U S A 2006;103:5066–5071.
Dawson WW, Trick GL, Litzkow CA. Improved electrode for electroretinography. Invest Ophthalmol Vis Sci 1979;18:988–991.
Gekeler F, Messias A, Ottinger M, Bartz-Schmidt KU, Zrenner E. Phosphenes electrically evoked with DTL electrodes: a study in patients with retinitis pigmentosa, glaucoma, and homonymous visual field loss and normal subjects. Invest Ophthalmol Vis Sci 2006;47:4966–4974.
Crapper DR, Noell WK. Retinal excitation and inhibition from direct electrical stimulation. J Neurophysiol 1963;26:924–947.
Knighton RW. An electrically evoked slow potential of the frog’s retina. I. Properties of response. J Neurophysiol 1975;38:185–197.
Stett A, Barth W, Weiss S, Haemmerle H, Zrenner E. Electrical multisite stimulation of the isolated chicken retina. Vision Res 2000;40:1785–1795.
Kaneko A, Saito T. Ionic mechanisms underlying the responses of off-center bipolar cells in the carp retina. II. Studies on responses evoked by transretinal current stimulation. J Gen Physiol 1983;81:603–612.
Toyoda J, Fujimoto M. Application of transretinal current stimulation for the study of bipolar-amacrine transmission. J Gen Physiol 1984;84:915–925.
Shimazu K, Miyake Y, Watanabe S. Retinal ganglion cell response properties in the transcorneal electrically evoked response of the visual system. Vision Res 1999;39:2251–2260.
Margalit E, Thoreson WB. Inner retinal mechanisms engaged by retinal electrical stimulation. Invest Ophthalmol Vis Sci 2006; 47:2606–2612.
Byzov AL, Trifonov JA. The response to electric stimulation of horizontal cells in the carp retina. Vis Res 1968;8:817–822.
Murakami M, Takahashi K. Calcium action potential and its use for measurement of reversal potentials of horizontal cell responses in carp retina. J Physiol 1987;386:165–180.
Takahashi K, Murakami M. Calcium action potential in ON-OFF transient amacrine cell of the carp retina. Brain Res 1988; 456:29–37.
Li L, Hayashida Y, Yagi T. Temporal properties of retinal ganglion cell responses to local transretinal current stimuli in the frog retina. Vis Res 2005;45:263–273.
Potts AM, Inoue J, Buffum D. The electrically evoked response of the visual system (EER). Invest Ophthalmol 1968;7:269–278.
Potts AM, Inoue J. The electrically evoked response (EER) of the visual system. II. Effect of adaptation and retinitis pigmentosa. Invest Ophthalmol 1969;8:605–612.
Potts AM, Inoue J. The electrically evoked response of the visual system (EER). 3. Further contribution to the origin of the EER. Invest Ophthalmol 1970;9:814–819.
Miyake Y, Yanagida K, Yagasaki K. Clinical application of EER (electrically evoked response). 1. Analysis of EER in normal subjects [in Japanese]. Nippon Ganka Gakkai Zasshi 1980;84:354–360.
Miyake Y, Yanagida K, Yagasaki K. Clinical application of EER (electrically evoked response). 2. Analysis of EER in patients with dysfunctional rod or cone visual pathway [in Japanese]. Nippon Ganka Gakkai Zasshi 1980;84:502–509.
Miyake Y, Yanagida K, Yagasaki K. Clinical application of EER (electrically evoked response). 3. Analysis of EER in patients with central retinal arterial occlusion [in Japanese]. Nippon Ganka Gakkai Zasshi 1980;84:587–593.
Miyake Y, Yanagida K, Yagasaki K. Clinical application of EER (electrically evoked response). Analysis of EER in patients with optic nerve disease [in Japanese]. Nippon Ganka Gakkai Zasshi 1980;84:2047–2052.
Brindley GS. The site of electrical excitation of the human eye. J Physiol 1955;127:189–200.
Toi VV, Riva CE. Variations of blood flow at optic disc nerve head induced by sinusoidal flicker stimulation in cats. J Physiol 1994;482:189–202.
Falsini B, Riva CE, Logean E. Flicker-evoked changes in human optic nerve blood flow: relationship with retinal neural activity. Invest Ophthalmol Vis Sci 2002;43:2309–2316.
Riva CE, Logean E, Falsini B. Temporal dynamics and magnitude of the blood flow response at the optic disk in normal subjects during functional retinal flicker-stimulation. Neurosci Lett 2004;356:75–78.
Riva CE, Salgarello T, Logean E, Colotto A, Galan EM, Falsini B. Flicker-evoked response measured at the optic disc rim is reduced in ocular hypertension and early glaucoma. Invest Ophthalmol Vis Sci 2004;45:3662–3668.
Kelly DH. Visual response to time-dependent stimuli. I. Amplitude sensitivity measurements. J Opt Soc Am 1961;51:422–429.
Gebhard JW. Thresholds of the human eye for electric stimulation by different wave forms. J Exp Psychol 1952;44:132–140.
Regan D. A high frequency mechanism which underlies visual evoked potentials. Electroencephalogr Clin Neurophysiol 1968;25:231–237.
Tanino T, Kato S, Kawasumi M. Studies on electrically evoked pupillary reflex-indirect reflex and its frequency characteristic. Jpn J Ophthalmol 1981;25:423–429.
Malonek D, Grinvald A. Interactions between electrical activity and cortical microcirculation revealed by imaging spectroscopy: implications for functional brain mapping. Science 1996;272:551–554.
Pouratian N, Toga A. Optical imaging based on intrinsic signals. In: Toga AW, Mazziotta JC, editors. Brain mapping. San Diego: Academic Press; 2002. p. 97–140.
Barriga ES, Pattichis M, Ts’o D, et al. Spatiotemporal independent component analysis for the detection of functional responses in cat retinal images. IEEE Trans Med Imaging 2007; 26:1035–1045.
Fukuda M, Rajagopalan UM, Homma R, Matsumoto M, Nishizaki M, Tanifuji M. Localization of activity-dependent changes in blood volume to submillimeter-scale functional domains in cat visual cortex. Cereb Cortex 2005;15:823–833.
Longo A, Geiser M, Riva CE. Subfoveal choroidal blood flow in response to light-dark exposure. Invest Ophthalmol Vis Sci 2000;41:2678–2683.
Riva CE, Harino S, Shonat RD, Petrig BL. Flicker evoked increase in optic nerve head blood flow in anesthetized cats. Neurosci Lett 1991;128:291–296.
Riva CE, Falsini B, Logean E. Flicker-evoked responses of human optic nerve head blood flow: luminance versus chromatic modulation. Invest Ophthalmol Vis Sci 2001;42:756–762.
Viswanathan S, Frishman LJ, Robson JG, Harwerth RS, Smith EL 3rd. The photopic negative response of the macaque electroretinogram: reduction by experimental glaucoma. Invest Ophthalmol Vis Sci 1999;40:1124–1136.
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;42:514–522.
Narahashi T. Chemicals as tools in the study of excitable membranes. Physiol Rev 1974;54:813–889.
Bloomfield SA. Effect of spike blockade on the receptive-field size of amacrine and ganglion cells in the rabbit retina. J Neurophysiol 1996;75:1878–1893.
Quigley HA, Green WR. The histology of human glaucoma cupping and optic nerve damage: clinicopathologic correlation in 21 eyes. Ophthalmology 1979;86:1803–1830.
Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol 1982;100:135–146.
Quigley HA, Dunkelberger GR, Green WR. Retinal ganglion cell atrophy correlated with automated perimetry in human eyes with glaucoma. Am J Ophthalmol 1989;107:453–464.
Glovinsky Y, Quigley HA, Dunkelberger GR. Retinal ganglion cell loss is size dependent in experimental glaucoma. Invest Ophthalmol Vis Sci 1991;32:484–491.
Frishman LJ, Shen FF, Du L, et al. The scotopic electroretinogram of macaque after retinal ganglion cell loss from experimental glaucoma. Invest Ophthalmol Vis Sci 1996;37:125–141.
Kerrigan-Baumrind LA, Quigley HA, Pease ME, Kerrigan DF, Mitchell RS. Number of ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons. Invest Ophthalmol Vis Sci 2000;41:741–748.
Mcilwain JT. Receptive fields of optic tract axons and lateral geniculate cells: peripheral extent and barbiturate sensitivity. J Neurophysiol 1964;27:1154–1173.
Mcilwain JT. Some evidence concerning physiological basis of periphery effect in cats retina. Exp Brain Res 1966;1:265–271.
Derrington AM, Lennie P, Wright MJ. Mechanism of peripherally evoked-responses in retinal ganglion-cells. J Physiol 1979;289:299–310.
Toth LJ, Rao SC, Kim DS, Somers D, Sur M. Subthreshold facilitation and suppression in primary visual cortex revealed by intrinsic signal imaging. Proc Natl Acad Sci U S A 1996;93:9869–9874.
Kaplan E, Benardete E. The dynamics of primate retinal ganglion cells. Prog Brain Res 2001;134:17–34.
Yao XC, Zhao YB. Optical dissection of stimulus-evoked retinal activation. Opt Exp 2008;16:12446–12459.
Zhao YB, Yao XC. Intrinsic optical imaging of stimulus-modulated physiological responses in amphibian retina. Opt Lett 2008;33:342–344.
Srinivasan VJ, Wojtkowski M, Fujimoto JG, Duker JS. In vivo measurement of retinal physiology with high-speed ultrahigh-resolution optical coherence tomography. Opt Lett 2006;31:2308–2310.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Tsunoda, K., Hanazono, G., Inomata, K. et al. Origins of retinal intrinsic signals: A series of experiments on retinas of macaque monkeys. Jpn J Ophthalmol 53, 297–314 (2009). https://doi.org/10.1007/s10384-009-0686-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10384-009-0686-3