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Positron Emission Tomography to Study the Effect of Eye Closure and Optic Nerve Damage on Human Cerebral Glucose Metabolism
Positron Emission Tomography-to Study the Effect of Eye Closure and Optic Nerve Damage on Human Cerebral Glucose Metabolism Motohiro Kiyosawa, M.D., Thomas M. Bosley, M.D., Michael Kushner, M.D., Dara Jamieson, M.D., Abass Alavi, M.D., Peter J. Savino, M.D., Robert C. Sergott, M.D., and Martin Reivich, M.'D.
We used 18F-2-tluoro-2-deoxyglucose and positron emission tomography to evaluate the effect of visual deprivation on brain glucose metabolism. In experiment 1, we compared local cerebral metabolic rates for glucose in seven normal volunteers studied with eyes closed to 11 age- and sex-matched normal volunteers studied with eyes open. Whole brain metabolism was similar in the two groups, and region/whole brain analysis of metabolic data showed that metabolism in the calcarine posterior cortex was decreased by 14% (P < .05) with eye closure. Glucose metabolism in other regions was not different between the two groups. In experiment 2, we compared glucose metabolism in six patients with severe bilateral optic neuropathies to 12 age- and sex-matched normal controls. Whole brain glucose metabolism was unchanged in the optic neuropathy group compared to controls. However, statistically significant reductions in glucose metabolism in the optic neuropathy group were found in anterior calcarine cortex (17%), posterior calcarine cortex (27%), peristriate cortex (27%), and lateral occipital cortex (15%). The meta-
Accepted for publication May 1, 1989. From the Cerebrovascular Research Center of the Department of Neurology (Drs. Kiyosawa, Bosley, Kushner, Jamieson, and Reivich) and Department of Nuclear Medicine (Dr. Alavi), University of Pennsylvania and the Neuro-Ophthalmology Service (Drs. Kiyosawa, Bosley, Savino, and Sergott), Wills Eye Hospital, Philadelphia, Pennsylvania. This study was supported by United States Public Health Service Program Project grant NS-14867-09. Dr. Kiyosawa was supported by Fight for Sight fellowship E-PD-IOO. Reprint requests to Thomas M. Bosley, M.D., NeuroOphthalmology Service, Wills Eye Hospital, Ninth and Walnut Sts., Philadelphia, PA 19107.
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bolic effects of damage to the pregeniculate visual system went well beyond those of simple eye closure. is ideal for studying human cortical metabolic activity because the type of afferent input and the degree of clinical deficit can be defined more objectively than in other cortical lesions. Using 18F-2-fluoro-2-deoxyglucose and positron emission tomography, we studied the effect on glucose metabolism in visual cortex of ischemic lesions affecting the occipital lobes and optic radiations'v and of visual stimulation in normal subjects." These and other positron emission tomography studies'" have shown the following: (1) calcarine cortex metabolism responds in a graded fashion to increasingly complex visual stimuli, (2) calcarine and visual association cortex metabolism responds regionally to hemifield visual stimulation in a fashion predictable by known neuroanatomic pathways, (3) calcarine cortex ischemia results in reduced glucose metabolism in cortical areas appropriate for visual field deficits, and (4) optic radiation ischemia produces more modest reductions in calcarine metabolic rate than infarction of the visual cortex itself. Cerebral metabolic studies in monkeysv'? have demonstrated a more widespread influence of visual stimulation on cerebral cortex (including portions of occipital, temporal, parietal, and frontal lobes) and subcortical structures (pulvinar, caudate, putamen, claustrum, amygdala). We undertook this study to evaluate the effect of visual deprivation on human brain glucose metabolism. In experiment 1, we compared brain glucose metabolism in normal volunteers studied with eyes closed to those studied with eyes open. In experiment 2, we THE AFFERENT VISUAL SYSTEM
JOURNAL OF OPHTHALMOLOGY 108:147-152, AUGUST, 1989
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evaluated the effect of severe bilateral optic neuropathy on brain glucose metabolism.
Material and Methods Subjects and Experimental Design Experiment I-Eighteen healthy male volunteers were included in this study. All had a visual acuity of 20/30 or better in each eye, with no history of significant ophthalmologic or general medical disease. Seven individuals, with a mean age of 25 years (range, 20 to 31 years), were studied after having their eyes closed and blindfolded from ten minutes before isotope injection until scan completion. Eleven individuals, with mean age of 26 years (range, 18 to 35 years), were instructed to keep their eyes open throughout the study and to look at the ceiling of the dimly lit positron emission tomography room without a specific target. Experiment 2-The subject group consisted of six patients with a visual acuity in each eye of 20/200 or poorer because of bilateral severe optic neuropathies (optic neuropathy group) of diverse origin and variable duration (Table 1). Clinical evaluation in each patient included complete neuro-ophthalmologic examination, Goldman kinetic perimetry, and computed tomography or magnetic resonance imaging, or both, within one month of positron emission tomography. In each case, neuro-ophthalmoTABLE 1
PATIENTS WITH OPTIC NEUROPATHY PATIENT NO.• AGE (YRS). SEX
DIAGNOSIS
1,31, F 2,44, F
Optic neuritis Optic neuritis
3,73, M
Cancer-associated retinopathy syndrome Inflammatory chiasmal syndrome Glaucoma Glaucoma
4,69, F
5,55, M 6,84, F
DURATION (MOS)
12 4
VISUAL ACUITY' R.E.
NLP
L.E.
LP CF at 2 ft
4
CFat 2ft HM
11
20/400
20/800
36 36
20/200 NLP
NLP CF at 6ft
HM
*NLP, no light perception; LP, light perception; HM, hand motions; CF, counting fingers.
August, 1989
logic examination documented bilateral optic atrophy, abnormal pupillary reaction, and visual field loss diagnostic of bilateral optic neuropathy. In addition to pale optic nerves, Patient 3 had constricted visual fields and mild retinal pigmentary changes compatible with retinopathy as a remote effect of his lung cancer. 11•12 No patient had evidence of neurologic disease outside of the pregeniculate afferent visual system by history, symptoms, physical examination, or neuro-imaging. Positron emission tomography was performed with patients' eyes open. Twelve normal volunteers of similar age and sex were selected as controls for positron emission tomography (mean age, 57 years; range, 27 to 73 years). Each normal volunteer had a visual acuity of 20/30 or better in each eye and no history of ophthalmologic or general medical problems. All 12 controls were studied with eyes open and were given the same instructions as patients in the optic neuropathy group. Informed consent was obtained from each patient and control subject, and all procedures were approved by the Committee on Studies Involving Human Beings of the University of Pennsylvania. Participation in this study did not alter diagnostic or therapeutic plans of the responsible physicians. Positron Emission Tomography Each individual was studied in the quiet, dimly lit positron emission tomography laboratory. Fluorodeoxyglucose, 6 to 8 mCi, was injected 30 minutes before positioning the individual's head 20 degrees hyperextended from the orbitomeatal line in a modified PETT V scanner." Data collection began 40 minutes after isotope injection, and brain images of local cerebral metabolic rates for glucose were obtained using the Phelps and associates'!' modification of the method of Reivich and associates." Characteristics of the positron emission tomography system and the data collection protocol have been described previously. 16,17 Data Analysis Regions of interest were placed on the metabolic images by a computerized overlay system based on normal human anatomy" as described previously," Whole brain metabolic rates were calculated by two methods. Computed whole brain metabolic rates were obtained by the volume-weighted mean of metabolic rates of all regions of interest. Recovery whole brain meta-
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bolic rates were calculated by assuming that the total brain radioactivity (total number of disintegrations detected during the positron emission tomography session) originated from one large region of interest. 19 Lobar metabolic rates were derived from metabolic rates for regions of interest within each lobe. To reduce variability in glucose metabolism values between subjects, metabolic rates for each region of interest were normalized by the individual's computed whole brain value using the equation: normalized local cerebral metabolic rate = (local cerebral metabolic rate/ computed whole brain metabolic rate) x 100. Statistical evaluation in each experiment was performed using Student's t-test for independent samples in anterior and posterior calcarine cortex, peristriate cortex (Brodman's regions 18 and 19), and lateral occipital cortex (visual association cortex). For experiment 2, statistical comparison by Student's t-test was also performed for lobar metabolic rates. The Bonferroni correction for multiple comparisons was not applied to these probability values. Results Experiment 1 Table 2 compares regional brain glucose metabolism in individuals studied with eyes closed to those studied with eyes open in visual cortex of four regions of interest in both hemispheres. Whole brain glucose metabolism was not different between eyes-closed and eyesopen groups (Table 2). Posterior calcarine cortex metabolism was 13% to 15% lower in the eyes-closed group (P $ .05), but changes in other brain regions were not statistically significant. Experiment 2 Figure 1 shows typical positron emission tomography images from a control subject (Figure, left) and Patient 1 with bilateral optic neuritis (Figure, right). Relatively decreased glucose metabolism in calcarine, peristriate, and lateral occipital cortex was apparent in the patient with optic neuropathy. Table 3 compares glucose metabolism of the optic neuropathy group to the eyes open control group in four visual regions of interest from each hemisphere. Whole brain glucose metabolism was unchanged in the optic neuropathy group compared to controls (Table 3). Statistically significant reductions in glucose
TABLE 2 CEREBRAL GLUCOSE METABOLISM· IN EXPERIMENT 1 EYES CLOSED AREA
LEFT
Anterior calcarine 109 ± 6 cortex Posterior calcarine 94 ± 71 cortex 9O± 5 Lateral occipital cortex 94 ± 10 Peristriate cortex Whole brain! 6.29 ±
RIGHT
EYESOPEN RIGHT
LEFT
107 ± 11 109 ±
9
94 ± 5§ 107 ± 12 109 ±
9
91 ±
4
108 ± 8
89 ± 5 97 ± 9 1.04
7
91 ±
96 ± 14 100 ± 11 5.41 ± 0.84
'Values shown as (regional glucose metabolism/computed whole brain glucose metabolism) x 100 ± S.D. !Whole brain values by recovery shown as mg of glucose/100 g of brain/minute.
Ip es .05. §P oS .01.
metabolism in the optic neuropathy group were found in anterior calcarine cortex (17%), posterior calcarine cortex (27%), peristriate cortex (27%), and lateral occipital cortex (15%) when compared to controls. Table 4 shows lobar metabolic data for patients with optic neuropathy and controls. Occipital lobe metabolism was significantly decreased in the optic neuropathy group compared to that in the control group. Additionally, frontal lobe glucose metabolism was significantly increased in both hemispheres in patients with optic neuropathy (7%) compared to that in controls. Discussion In studying the metabolic effects of eye closure and of bilateral severe optic nerve disease, we found two different patterns of metabolic sequelae. Eye closure resulted in a mild decrease in posterior calcarine glucose metabolism, with no statistically significant changes in other brain areas. Bilateral optic nerve disease, on the other hand, was associated with relatively profound decreases in metabolism in areas of the cortex known to be responsible for vision. Clearly, these two different types of visual deprivation were not metabolically equivalent. Control subjects for both experiments were
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Figure (Kiyosawa and associates). Left, Positron emission tomography image from an eyes-open control subject at the level of the thalamus and superior primary visual cortex. Small arrow indicates area of greatest glucose uptake in posterior midline corresponding to calcarine (primary visual) cortex. Large arrow indicates lateral occipital (visual association) cortex. Right, Positron emission tomography image at same level as in Figure, left from Patient 1 in experiment 2 with bilateral severe optic neuritis without visual recovery. Primary visual cortex and visual association cortex have relatively low glucose uptake.
studied after lying quietly for 40 minutes with their eyes open looking at the ceiling of a dimly lit laboratory. Such a bland visual stimulus may TABLE 3 CEREBRAL GLUCOSE METABOLISM· IN EXPERIMENT 2
AREA
Anterior calcarine
OPTIC NEUROPATHY
EYES OPEN
GROUP
GROUP
RIGHT
LEFT
103 ±
121
105 ±
LEFT
71
RIGHT
124 ± 18 128 ± 19
cortex Posterior calcarine
81 ± 12§
cause little coordinated neural activity in the visual cortex, resulting in the minimal difference in visual cortex metabolism between individuals studied with eyes closed and those with eyes open in experiment 1. In experiment 2, all areas of visual cortex in patients with optic neuropathy were significantly hypo metabolic in a fashion that went well beyond the effects of the short-term visual TABLE 4 LOBAR GLUCOSE METABOLISM· IN EXPERIMENT 2
85 ± 13§ 122 :!: 14 123 ± 18
cortex Lateral occipital
81 ±
101
76 ±
5§
85 ±
91
94:!: 10
96 ±
LOBE
Whole brain'
79 ± 5.62 ± 1.77
9§ 101 ± 11 107 ± 12 4.92 ± 0.74
·Values shown as (regional glucose metabolism/computed whole brain glucose metabolism) x 100 ± S.D. 'Whole brain values by recovery shown as mg of glucose/1 00 g of brain/minute.
Ip
s;
.05.
§P -s .001.
EYES OPEN
GROUP
GROUP
8
cortex Peristriate cortex
OPTIC NEUROPATHY
RIGHT
LEFT
114 ±
Frontal
6' 96 ± 12
Parietal Temporal Occipital
LEFT
116 ±
9' 93 ± 12
88 ±
8
94 ±
82 ±
61
86 ±
9 41
107 ± 93 ±
RIGHT
7 7
92 ± 14 105 ±
7
106 ± 8 91 ± 10 99 ± 9 108 ±
8
·Values shown as (regional glucose metabolism/computed whole brain glucose metabolism) x 100 :!: S.D.
'P
s;
.05.
Ip
s;
.001.
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Vision and Positron Emission Tomography
deprivation in experiment 1. These patients had been visually deprived for a period of months or years (rather than 40 minutes), and increasing duration of sensory deprivation may have caused a progressive decline in visual cortex metabolism. However, metabolism of visual cortex did not correlate with duration of optic nerve damage within this small group of patients, and animal studies imply that recovery of cortical metabolism after permanent acquired deafferentation may be more common than a progressive decline in metabolism. 20-22 The pregeniculate afferent visual system may have a specific coordinating or modulating effect on metabolism of the primary visual cortex that is independent of visual stimulation. For example, the pattern of electrical activity in the cat lateral geniculate body during eye closure reflects the pattern of ongoing electrical activity in the optic nerve. 23 This neural activity may play a role in priming the visual cortex to receive visual input, and the coordinating effect may be lost after damage to the pregeniculate afferent visual system. Alternatively, transsynaptic transfer of small molecules from pregeniculate afferent fibers to lateral geniculate neurons may have a trophic effect reflected in reduced visual cortex metabolism after optic nerve damage." Increased glucose metabolism in frontal cortex has not been reported previously with damage to the afferent visual system. This result was not anticipated, and uncontrolled factors in the study protocol may have resulted in spurious alterations in metabolism. Macko and coworkers" reported decreased frontal lobe metabolism ipsilateral to optic tract lesions in callosectomized monkeys. In addition to obvious differences in species and experimental technique, it may be important that these animals had intact vision in one homonymous visual field. The frontal cortex is involved in attention mechanisms;" and visual deficits in these patients may have required increased attention to spatial relations and physical activities or may have caused increased anxiety over the scanning process itself." Electrophysiologic coordination between OCcipital and frontal lobes is obvious on electroencephalography.F'P and monosynaptic and polysynaptic subcortical connections between occipital and frontal lobes may have a predominantly inhibitory influence in certain circumstances. 29,30 Profound occipital hypometabolism in patients with optic neuropathy could permit frontal hypermetabolism by release of tonic inhibition.
151
Previous studies have shown that visual stimulation influences visual cortex metabolism. 3,5,6 We found that the level of visual stimulation is clearly not the only determinant of visual cortex metabolism because eye closure resulted in minimal metabolic changes whereas severe optic nerve damage was associated with profound decreases in metabolism throughout primary and association visual areas. Other determinants of visual cortex metabolism include the competence of the pregeniculate afferent system, the optic radiations.l-" and the calcarine cortex.':" and perhaps other factors as yet unidentified. Visual stimulation or neural activity in the visual cortex may also have important effects on metabolism in the frontal cortex.
References 1. Bosley, T. M., Rosenquist, A. C., Kushner, M., Burke, A., Stein, A., Dann, R., Cobbs, W., Savino, P. J., Schatz, N. J., Alavi, A., and Reivich, M.: Ischemic lesions of the occipital cortex and optic radiations. Positron emission tomography. Neurology 35:470, 1985. 2. Kiyosawa, M., Mizuno, K., Hatazawa, J., Fukuda, H., Yamada, K., Ito, M., Matsuzawa, T., Watanuki, S., and Ido, T.: Metabolic imaging in hemianopsia using positron emission tomography with 18F-deoxyfluoroglucose. Am. J. Ophthalmol. 101:310, 1986. 3. Kushner, M. J., Rosenquist, A., Alavi, A., Rosen, M., Dann, R., Fazekas, F., Bosley, T., Greenberg, J., and Reivich, M.: Cerebral metabolism and patterned visual stimulation. Positron emission tomographic study of the human visual cortex. Neurology 38:89, 1988. 4. Kuhl, D. E., Phelps, M. E., KowelI, A. P., Metter, E. J., Serin, c.. and Winter, J.: The effect of stroke on local cerebral metabolism and perfusion. Mapping by emission computed tomography of 18-FDG and 13-NH3. Ann. Neurol. 8:47, 1980. 5. Phelps, M. E., Kuhl, D. E., and Mazziotta, J. c.: Metabolic mapping of the brain's response to visual stimulation. Studies in man. Science 211:1445, 1981. 6. Phelps, M. E., Mazziotta, J. c.. Kuhl, D. E., Nuwer, M., Packwood, J., Metter, J., and Engel, J., [r.: Tomographic mapping of human cerebral metabolism. Visual stimulation and deprivation. Neurology 31:517, 1981. 7. Greenberg, J. H., Reivich, M., Alavi, A., Hand, P., Rosenquist, A., Rintelmann, W., Stein, A., Tusa, R., Darin, R., Christman, D., Fowler, J., MacGregor, B., and Wolf, A.: Metabolic mapping of functional
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activity in man with the 18F-fluoro-deoxyglucose technique. Science 212:678, 1981. 8. Mazziotta, J. c.. Phelps, M. E., Carson, R. E., and Kuhl, D. E.: Tomographic mapping of human cerebral metabolism. Sensory deprivation. Ann. Neurol. 12:435, 1982. 9. Macko, K. A., Jarvis, c. D., Kennedy, c.. Miyaoka, M., Shinohara, M., Sokoloff, L., and Mishkin, M.: Mapping the primate visual system with [2_ 14C] deoxyglucose. Science 218:394, 1982. 10. Kennedy, C,; Des Rosiers, M. H., Sakurada, 0., Shinohara, M., Reivich, M., Jehle, J. W., and Sokoloff, L.: Metabolic mapping of the primary visual system of the monkey by means of the autoradiographic p4C] deoxyglucose technique. Proc. Natl. Acad. Sci. U.S.A. 73:4230, 1976. 11. Keltner, J. L., Roth, A. M., and Chang, S.: Photoreceptor degeneration. A possible autoimmune disorder. Arch. Ophthalmol. 101:564, 1983. 12. Sawyer, R. A., Selhorst, J. B., Zimmerman, L. E., and Hoyt, W. F.: Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am. J. Ophthalmol. 81:606, 1976. 13. Ter-pogossian, M. M., Mullan, N. A., and Hood, J. T.: Design considerations for a positron emission tomograph (PETT V) for imaging of the brain. J. Comput. Assist. Tomogr. 2:539, 1978. 14. Phelps, M. E., Huang, S. c.. Hoffman, E. J., Selin, c.. Sokoloff, L., and Kuhl, D. E.: Tomographic measurement of local cerebral glucose metabolic rate in humans with F-18-fluoro-2-deoxy-D-glucose. Validation of method. Ann. Neurol. 6:371, 1979. 15. Reivich, M., Kuhl, D., Wolf, A., Greenberg, J., Phelps, M., Ido, T., Casella, V., Fowler, J., Hoffman, E., Alavi, A., Som, P., and Sokoloff, L.: The 18F-fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man. Circ. Res. 44:127, 1979. 16. Kushner, M., Reivich, M., Alavi, A., Darin, R., Burke, A., and Robinson, G.: Contralateral cerebellar hypometabolism following cerebral insult. A PET study. Ann. Neurol. 15:425, 1984. 17. Alavi, A., Darin, R., Chawluk, J., Alavi, J., Kushner, M., and Reivich, M.: Positron emission tomography imaging of regional cerebral glucose metabolism. Semin. Nucl. Med. 1:2, 1986. 18. Dann, R., Muehllehner, G., and Rosenquist, A.: Computer aided data analysis of ECT data. J. Nucl. Med. 24:82, 1983. 19. Kushner, M., Schwartz, R., Alavi, A., Dann, R., Rosen, M., Silver, F., and Reivich, M.: Cerebral activation by nonmeaningful monaural verbal auditory stimulation. Brain Res. 409:79, 1987.
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20. Cooper, R. M., and Thurlow, G. A.: Depression and recovery of metabolic activity in rat visual system after eye removal. Exp. Neurobiol. 89:322, 1985. 21. Kiyosawa, M., Pappata, S., Duverger, D., Riche, D., Cambon, H., Mazoyer, B., Samson, Y., Crouzel, C.; Naquet, R., MacKenzie, E. T., and Barron, J. c.: Cortical hypometabolism and its recovery following nucleus basalis lesions in baboons. A PET study. J. Cereb. Blood Flow Metab. 7:812, 1987. 22. Kiyosawa, M., Hamel, E., Pappata, S., Duverger, D., Riche, D., Mazoyer, B., Naquet, R., MacKenzie, E. T., and Barron, J. c.: Effect of unilateral lesions of the nucleus basalis of Meynert on regional cortical glucose utilization in baboons. A PET study. Neurology 38(suppl. 1):369, 1988. 23. Hubel, D. H.: Single unit activity in lateral geniculate body and optic tract of unrestricted cats. J. Physiol. 150:91, 1960. 24. Purves, D., and Lichtman, J. W.: Principles of Neural Development. Sunderland, Mass., Sinauer Associates Inc., 1985, pp. 179-204. 25. Mesulam, M. M.: A cortical network for directed attention and unilateral neglect. Ann. Neurol. 10:309, 1981. 26. Reivich, M., and Gur, R.: Cerebral metabolic effects of sensory and cognitive stimuli in normal subjects. In Reivich, M., and Alavi, A. (eds.): Positron Emission Tomography. New York, Alan R. Liss, 1985, pp. 329-344. 27. Kellaway, P.: An orderly approach to visual analysis. The parameters of the normal EEG in adult and children. In Klass, D. W., and Daly, D. D. (eds.): Current Practice of Clinical Electroencephalography. New York, Raven Press, 1979, pp. 69-147. 28. Etevenon, P., Tontrat, D., and Benkelfat, c.. Electroencephalographic cartography. II. By means of statistical group studies-activation by visual attention. Neuropsychobiology 13:141, 1985. 29. Heilman, K. M., Valenstein, E., and Watson, R. T.: Neglect. In Asbury, A. K., McKhann, G. M., and McDonald, W. I. (eds.): Diseases of the Nervous System. Clinical Neurology. Philadelphia, W. B. Saunders Company, 1986, pp. 855-866. 30. Pandya, D. M., and Kuypers, H. G. J. M.: Cortico-cortical connections in the rhesus monkey. Brain Res. 13:13, 1969. 31. Bosley, T. M., Dann, R., Silver, F. L., Alavi, A., Kushner, M., Chawluk, J. B., Savino, P. J., Sergott, R. C,; Schatz, N., and Reivich, M.: Recovery of vision after ischemic lesions. Positron emission tomography. Ann. Neurol. 21:444, 1987.
We used 18F-2-tluoro-2-deoxyglucose and positron emission tomography to evaluate the effect of visual deprivation on brain glucose metabolism. In experiment 1, we compared local cerebral metabolic rates for glucose in seven normal volunteers studied with eyes closed to 11 age- and sex-matched normal volunteers studied with eyes open. Whole brain metabolism was similar in the two groups, and region/whole brain analysis of metabolic data showed that metabolism in the calcarine posterior cortex was decreased by 14% (P < .05) with eye closure. Glucose metabolism in other regions was not different between the two groups. In experiment 2, we compared glucose metabolism in six patients with severe bilateral optic neuropathies to 12 age- and sex-matched normal controls. Whole brain glucose metabolism was unchanged in the optic neuropathy group compared to controls. However, statistically significant reductions in glucose metabolism in the optic neuropathy group were found in anterior calcarine cortex (17%), posterior calcarine cortex (27%), peristriate cortex (27%), and lateral occipital cortex (15%). The meta-
Accepted for publication May 1, 1989. From the Cerebrovascular Research Center of the Department of Neurology (Drs. Kiyosawa, Bosley, Kushner, Jamieson, and Reivich) and Department of Nuclear Medicine (Dr. Alavi), University of Pennsylvania and the Neuro-Ophthalmology Service (Drs. Kiyosawa, Bosley, Savino, and Sergott), Wills Eye Hospital, Philadelphia, Pennsylvania. This study was supported by United States Public Health Service Program Project grant NS-14867-09. Dr. Kiyosawa was supported by Fight for Sight fellowship E-PD-IOO. Reprint requests to Thomas M. Bosley, M.D., NeuroOphthalmology Service, Wills Eye Hospital, Ninth and Walnut Sts., Philadelphia, PA 19107.
©AMERICAN
bolic effects of damage to the pregeniculate visual system went well beyond those of simple eye closure. is ideal for studying human cortical metabolic activity because the type of afferent input and the degree of clinical deficit can be defined more objectively than in other cortical lesions. Using 18F-2-fluoro-2-deoxyglucose and positron emission tomography, we studied the effect on glucose metabolism in visual cortex of ischemic lesions affecting the occipital lobes and optic radiations'v and of visual stimulation in normal subjects." These and other positron emission tomography studies'" have shown the following: (1) calcarine cortex metabolism responds in a graded fashion to increasingly complex visual stimuli, (2) calcarine and visual association cortex metabolism responds regionally to hemifield visual stimulation in a fashion predictable by known neuroanatomic pathways, (3) calcarine cortex ischemia results in reduced glucose metabolism in cortical areas appropriate for visual field deficits, and (4) optic radiation ischemia produces more modest reductions in calcarine metabolic rate than infarction of the visual cortex itself. Cerebral metabolic studies in monkeysv'? have demonstrated a more widespread influence of visual stimulation on cerebral cortex (including portions of occipital, temporal, parietal, and frontal lobes) and subcortical structures (pulvinar, caudate, putamen, claustrum, amygdala). We undertook this study to evaluate the effect of visual deprivation on human brain glucose metabolism. In experiment 1, we compared brain glucose metabolism in normal volunteers studied with eyes closed to those studied with eyes open. In experiment 2, we THE AFFERENT VISUAL SYSTEM
JOURNAL OF OPHTHALMOLOGY 108:147-152, AUGUST, 1989
147
148
AMERICAN JOURNAL OF OPHTHALMOLOGY
evaluated the effect of severe bilateral optic neuropathy on brain glucose metabolism.
Material and Methods Subjects and Experimental Design Experiment I-Eighteen healthy male volunteers were included in this study. All had a visual acuity of 20/30 or better in each eye, with no history of significant ophthalmologic or general medical disease. Seven individuals, with a mean age of 25 years (range, 20 to 31 years), were studied after having their eyes closed and blindfolded from ten minutes before isotope injection until scan completion. Eleven individuals, with mean age of 26 years (range, 18 to 35 years), were instructed to keep their eyes open throughout the study and to look at the ceiling of the dimly lit positron emission tomography room without a specific target. Experiment 2-The subject group consisted of six patients with a visual acuity in each eye of 20/200 or poorer because of bilateral severe optic neuropathies (optic neuropathy group) of diverse origin and variable duration (Table 1). Clinical evaluation in each patient included complete neuro-ophthalmologic examination, Goldman kinetic perimetry, and computed tomography or magnetic resonance imaging, or both, within one month of positron emission tomography. In each case, neuro-ophthalmoTABLE 1
PATIENTS WITH OPTIC NEUROPATHY PATIENT NO.• AGE (YRS). SEX
DIAGNOSIS
1,31, F 2,44, F
Optic neuritis Optic neuritis
3,73, M
Cancer-associated retinopathy syndrome Inflammatory chiasmal syndrome Glaucoma Glaucoma
4,69, F
5,55, M 6,84, F
DURATION (MOS)
12 4
VISUAL ACUITY' R.E.
NLP
L.E.
LP CF at 2 ft
4
CFat 2ft HM
11
20/400
20/800
36 36
20/200 NLP
NLP CF at 6ft
HM
*NLP, no light perception; LP, light perception; HM, hand motions; CF, counting fingers.
August, 1989
logic examination documented bilateral optic atrophy, abnormal pupillary reaction, and visual field loss diagnostic of bilateral optic neuropathy. In addition to pale optic nerves, Patient 3 had constricted visual fields and mild retinal pigmentary changes compatible with retinopathy as a remote effect of his lung cancer. 11•12 No patient had evidence of neurologic disease outside of the pregeniculate afferent visual system by history, symptoms, physical examination, or neuro-imaging. Positron emission tomography was performed with patients' eyes open. Twelve normal volunteers of similar age and sex were selected as controls for positron emission tomography (mean age, 57 years; range, 27 to 73 years). Each normal volunteer had a visual acuity of 20/30 or better in each eye and no history of ophthalmologic or general medical problems. All 12 controls were studied with eyes open and were given the same instructions as patients in the optic neuropathy group. Informed consent was obtained from each patient and control subject, and all procedures were approved by the Committee on Studies Involving Human Beings of the University of Pennsylvania. Participation in this study did not alter diagnostic or therapeutic plans of the responsible physicians. Positron Emission Tomography Each individual was studied in the quiet, dimly lit positron emission tomography laboratory. Fluorodeoxyglucose, 6 to 8 mCi, was injected 30 minutes before positioning the individual's head 20 degrees hyperextended from the orbitomeatal line in a modified PETT V scanner." Data collection began 40 minutes after isotope injection, and brain images of local cerebral metabolic rates for glucose were obtained using the Phelps and associates'!' modification of the method of Reivich and associates." Characteristics of the positron emission tomography system and the data collection protocol have been described previously. 16,17 Data Analysis Regions of interest were placed on the metabolic images by a computerized overlay system based on normal human anatomy" as described previously," Whole brain metabolic rates were calculated by two methods. Computed whole brain metabolic rates were obtained by the volume-weighted mean of metabolic rates of all regions of interest. Recovery whole brain meta-
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bolic rates were calculated by assuming that the total brain radioactivity (total number of disintegrations detected during the positron emission tomography session) originated from one large region of interest. 19 Lobar metabolic rates were derived from metabolic rates for regions of interest within each lobe. To reduce variability in glucose metabolism values between subjects, metabolic rates for each region of interest were normalized by the individual's computed whole brain value using the equation: normalized local cerebral metabolic rate = (local cerebral metabolic rate/ computed whole brain metabolic rate) x 100. Statistical evaluation in each experiment was performed using Student's t-test for independent samples in anterior and posterior calcarine cortex, peristriate cortex (Brodman's regions 18 and 19), and lateral occipital cortex (visual association cortex). For experiment 2, statistical comparison by Student's t-test was also performed for lobar metabolic rates. The Bonferroni correction for multiple comparisons was not applied to these probability values. Results Experiment 1 Table 2 compares regional brain glucose metabolism in individuals studied with eyes closed to those studied with eyes open in visual cortex of four regions of interest in both hemispheres. Whole brain glucose metabolism was not different between eyes-closed and eyesopen groups (Table 2). Posterior calcarine cortex metabolism was 13% to 15% lower in the eyes-closed group (P $ .05), but changes in other brain regions were not statistically significant. Experiment 2 Figure 1 shows typical positron emission tomography images from a control subject (Figure, left) and Patient 1 with bilateral optic neuritis (Figure, right). Relatively decreased glucose metabolism in calcarine, peristriate, and lateral occipital cortex was apparent in the patient with optic neuropathy. Table 3 compares glucose metabolism of the optic neuropathy group to the eyes open control group in four visual regions of interest from each hemisphere. Whole brain glucose metabolism was unchanged in the optic neuropathy group compared to controls (Table 3). Statistically significant reductions in glucose
TABLE 2 CEREBRAL GLUCOSE METABOLISM· IN EXPERIMENT 1 EYES CLOSED AREA
LEFT
Anterior calcarine 109 ± 6 cortex Posterior calcarine 94 ± 71 cortex 9O± 5 Lateral occipital cortex 94 ± 10 Peristriate cortex Whole brain! 6.29 ±
RIGHT
EYESOPEN RIGHT
LEFT
107 ± 11 109 ±
9
94 ± 5§ 107 ± 12 109 ±
9
91 ±
4
108 ± 8
89 ± 5 97 ± 9 1.04
7
91 ±
96 ± 14 100 ± 11 5.41 ± 0.84
'Values shown as (regional glucose metabolism/computed whole brain glucose metabolism) x 100 ± S.D. !Whole brain values by recovery shown as mg of glucose/100 g of brain/minute.
Ip es .05. §P oS .01.
metabolism in the optic neuropathy group were found in anterior calcarine cortex (17%), posterior calcarine cortex (27%), peristriate cortex (27%), and lateral occipital cortex (15%) when compared to controls. Table 4 shows lobar metabolic data for patients with optic neuropathy and controls. Occipital lobe metabolism was significantly decreased in the optic neuropathy group compared to that in the control group. Additionally, frontal lobe glucose metabolism was significantly increased in both hemispheres in patients with optic neuropathy (7%) compared to that in controls. Discussion In studying the metabolic effects of eye closure and of bilateral severe optic nerve disease, we found two different patterns of metabolic sequelae. Eye closure resulted in a mild decrease in posterior calcarine glucose metabolism, with no statistically significant changes in other brain areas. Bilateral optic nerve disease, on the other hand, was associated with relatively profound decreases in metabolism in areas of the cortex known to be responsible for vision. Clearly, these two different types of visual deprivation were not metabolically equivalent. Control subjects for both experiments were
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Figure (Kiyosawa and associates). Left, Positron emission tomography image from an eyes-open control subject at the level of the thalamus and superior primary visual cortex. Small arrow indicates area of greatest glucose uptake in posterior midline corresponding to calcarine (primary visual) cortex. Large arrow indicates lateral occipital (visual association) cortex. Right, Positron emission tomography image at same level as in Figure, left from Patient 1 in experiment 2 with bilateral severe optic neuritis without visual recovery. Primary visual cortex and visual association cortex have relatively low glucose uptake.
studied after lying quietly for 40 minutes with their eyes open looking at the ceiling of a dimly lit laboratory. Such a bland visual stimulus may TABLE 3 CEREBRAL GLUCOSE METABOLISM· IN EXPERIMENT 2
AREA
Anterior calcarine
OPTIC NEUROPATHY
EYES OPEN
GROUP
GROUP
RIGHT
LEFT
103 ±
121
105 ±
LEFT
71
RIGHT
124 ± 18 128 ± 19
cortex Posterior calcarine
81 ± 12§
cause little coordinated neural activity in the visual cortex, resulting in the minimal difference in visual cortex metabolism between individuals studied with eyes closed and those with eyes open in experiment 1. In experiment 2, all areas of visual cortex in patients with optic neuropathy were significantly hypo metabolic in a fashion that went well beyond the effects of the short-term visual TABLE 4 LOBAR GLUCOSE METABOLISM· IN EXPERIMENT 2
85 ± 13§ 122 :!: 14 123 ± 18
cortex Lateral occipital
81 ±
101
76 ±
5§
85 ±
91
94:!: 10
96 ±
LOBE
Whole brain'
79 ± 5.62 ± 1.77
9§ 101 ± 11 107 ± 12 4.92 ± 0.74
·Values shown as (regional glucose metabolism/computed whole brain glucose metabolism) x 100 ± S.D. 'Whole brain values by recovery shown as mg of glucose/1 00 g of brain/minute.
Ip
s;
.05.
§P -s .001.
EYES OPEN
GROUP
GROUP
8
cortex Peristriate cortex
OPTIC NEUROPATHY
RIGHT
LEFT
114 ±
Frontal
6' 96 ± 12
Parietal Temporal Occipital
LEFT
116 ±
9' 93 ± 12
88 ±
8
94 ±
82 ±
61
86 ±
9 41
107 ± 93 ±
RIGHT
7 7
92 ± 14 105 ±
7
106 ± 8 91 ± 10 99 ± 9 108 ±
8
·Values shown as (regional glucose metabolism/computed whole brain glucose metabolism) x 100 :!: S.D.
'P
s;
.05.
Ip
s;
.001.
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Vision and Positron Emission Tomography
deprivation in experiment 1. These patients had been visually deprived for a period of months or years (rather than 40 minutes), and increasing duration of sensory deprivation may have caused a progressive decline in visual cortex metabolism. However, metabolism of visual cortex did not correlate with duration of optic nerve damage within this small group of patients, and animal studies imply that recovery of cortical metabolism after permanent acquired deafferentation may be more common than a progressive decline in metabolism. 20-22 The pregeniculate afferent visual system may have a specific coordinating or modulating effect on metabolism of the primary visual cortex that is independent of visual stimulation. For example, the pattern of electrical activity in the cat lateral geniculate body during eye closure reflects the pattern of ongoing electrical activity in the optic nerve. 23 This neural activity may play a role in priming the visual cortex to receive visual input, and the coordinating effect may be lost after damage to the pregeniculate afferent visual system. Alternatively, transsynaptic transfer of small molecules from pregeniculate afferent fibers to lateral geniculate neurons may have a trophic effect reflected in reduced visual cortex metabolism after optic nerve damage." Increased glucose metabolism in frontal cortex has not been reported previously with damage to the afferent visual system. This result was not anticipated, and uncontrolled factors in the study protocol may have resulted in spurious alterations in metabolism. Macko and coworkers" reported decreased frontal lobe metabolism ipsilateral to optic tract lesions in callosectomized monkeys. In addition to obvious differences in species and experimental technique, it may be important that these animals had intact vision in one homonymous visual field. The frontal cortex is involved in attention mechanisms;" and visual deficits in these patients may have required increased attention to spatial relations and physical activities or may have caused increased anxiety over the scanning process itself." Electrophysiologic coordination between OCcipital and frontal lobes is obvious on electroencephalography.F'P and monosynaptic and polysynaptic subcortical connections between occipital and frontal lobes may have a predominantly inhibitory influence in certain circumstances. 29,30 Profound occipital hypometabolism in patients with optic neuropathy could permit frontal hypermetabolism by release of tonic inhibition.
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Previous studies have shown that visual stimulation influences visual cortex metabolism. 3,5,6 We found that the level of visual stimulation is clearly not the only determinant of visual cortex metabolism because eye closure resulted in minimal metabolic changes whereas severe optic nerve damage was associated with profound decreases in metabolism throughout primary and association visual areas. Other determinants of visual cortex metabolism include the competence of the pregeniculate afferent system, the optic radiations.l-" and the calcarine cortex.':" and perhaps other factors as yet unidentified. Visual stimulation or neural activity in the visual cortex may also have important effects on metabolism in the frontal cortex.
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