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1 From the Department of Ophthalmology and Visual Science, University of Texas Medical School at Houston; and the 2 College of Optometry, University of Houston.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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METHODS. Monocular experimental glaucoma was induced in monkeys (Macaca mulatta and M. fascicularis) by applying a laser to the trabecular meshwork to increase intraocular pressure (IOP). After other behavioral and electrophysiological studies, the lateral geniculate nuclei (LGNs) and the primary visual cortices were analyzed for functional afference from surviving ganglion cells, indicated by cytochrome oxidase (CO) histochemistry.
RESULTS. CO reactivity (COR) indicated a general reduction in neural metabolism
with increasing severity of glaucoma. COR in the LGNs was reduced to
the same degree in both the P- and M-cellular layers. In layer 4Cß of
the V1 cortex, the reactivity was always reduced more than in the layer
4C
division.
CONCLUSIONS. Experimental glaucoma in monkeys reduces visual afference to the
central nervous system, thereby reducing the metabolic drive as
indicated by COR. The detrimental effect of glaucoma did not appear to
be any greater for the M-cell, rather than the P-cell pathway in the
LGN or in the visual cortex. Both are affected by the duration and
severity of the experimental glaucoma. Overall, the alterations in
metabolism of neurons in the parallel visual pathways supplied by the
P and Pß ganglion cells do not suggest that tests based on the
functional properties of one or the other would provide optimal
assessment of glaucoma.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A predominant form of this disorder is primary open-angle glaucoma (POAG), characterized by a slow increase in IOP without attendant symptoms during the early stages. By the time an individual is aware of a problem with vision, many ganglion cells have already died, and the lost vision cannot be restored. A major mechanism contributing to the death of ganglion cells in POAG is thought to be strangulation of their axons at the optic disc. The associated increased IOP is thought to produce shear forces in the tissues of the lamina cribrosa, obstructing the to-and-fro transport between the axon terminal and ganglion cell soma and leading to the death of the cell.9 10 11 Clinical intervention cannot restore lost vision. It can only slow or prevent subsequent death of ganglion cells by reducing IOP. The ganglion cell axons first affected are those entering the dorsal and ventral aspect of the optic disc—those serving the peripheral nasal visual hemifield projecting on the temporal retina. Therefore, the loss of these ganglion cells (which also happen to be some of the largest) creates a characteristic crescent scotoma pattern, beginning in the peripheral nasal hemifield and progressing toward central vision.4 12
The macaque monkey has been used as a basic research model for studying the neural effects of glaucoma. Argon laser application to the trabecular meshwork has been used to reduce aqueous humor outflow, thereby elevating the IOP and leading to an experimental approximation of POAG.13 Several studies have used the monkey model to describe the functional and anatomic changes that occur within the eye and optic nerve, in an effort to understand the sequelae to elevated IOP. For example, Quigley et al.14 and Glovinsky et al.15 16 have presented evidence that there is an early selective effect on the largest ganglion cells of the retina. These large ganglion cells purportedly comprise the magno (M)-cellular division of the geniculocortical projection. By measurements of the diameters of remaining ganglion cell axons in the optic nerve, they reported that the largest neurons are first affected (and first to die).6 16 This conclusion stimulated the search for an early diagnostic test for glaucoma based on stimulus characteristics thought to best stimulate the M-cellular pathway. However, in an earlier study, we found no differential effect of elevated IOP on either the encounter rate or receptive field characteristics of the parvo (P)- or M-cellular lateral geniculate neurons,17 and Vickers et al.18 have shown that metabolism in both divisions of the afferent pathway is reduced in experimental glaucoma.
In this study we examined the effects of elevated monocular IOP on the metabolism of the P- and M-cellular divisions of the lateral geniculate nucleus (LGN) and in the primary V1 visual cortex, using cytochrome oxidase reactivity (COR) as an indicator of the visual afference from ganglion cells.19 Cytochrome oxidase (CO) is a mitochondrial membrane protein essential for brain oxidative metabolism. It catalyzes the last step in the formation of adenosine triphosphate (ATP), the energy source for neuronal function.20 21 The brain tissue content of CO is inhomogeneously distributed22 23 24 and varies with the metabolic demand attendant to neuronal activation.25 26 27 28 29 30 In the afferent visual system of primates, histochemistry has shown that COR decreases monotonically with the duration of sensory visual deprivation caused by enucleation or by tetrodotoxin (TTX) blockade.31 Therefore, COR varies with the level of activation of cells in the LGN and V1 cortex and serves as a functional correlate of the surviving ganglion cells in glaucoma.
An abstract of these results has been presented elsewhere.32
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Table 1 summarizes the experimental treatments and consequent degree and duration of the resultant IOP for the monkey subjects. Subjects OHT5 through OHT24 were M. mulatta, which has been described and reported in an earlier article on IOP and visual field defects.33 Subjects OHT2 and OHT3 were M. fascicularis reported in an earlier study on color vision anomalies after induction of experimental glaucoma34 and two other M. fascicularis, M165 and M167, were subjects reported in an earlier publication on electrophysiology of ganglion cell input to the LGN after experimentally induced glaucoma.17
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Optical Measurements
The relative CO content and distribution in brain tissue was
inferred from the relative histochemical COR on the assumption that the
higher the density of the COR product, the higher the CO content in the
tissue. A reduction in COR in the brain tissue connected with the
experimental eye was defined relative to the COR in the adjacent tissue
connected with the normal companion eye in the same tissue section and
was interpreted as a reduction in afferent stimulation from retinal
ganglion cells in the experimental eye. COR was measured in the layers
of the LGN and in the input layer of layer 4C of the V1 cortex by image
analysis software (ImagePro Plus; Media Cybernetics, Silver Spring,
MD). The stained sections were homogeneously back illuminated, imaged
with a CCD camera (Sony, Tokyo, Japan) and displayed on a monitor (NEC,
Tokyo, Japan), captured, and scaled 0 to 255, where 0 is opacity and
255 is the incident light. All measurements were taken before any
filtering or contrast enhancement of the image. COR =
I - T, where I is the incident
light (nominally a value of 255), and T is the light
transmitted through the tissue containing the COR product. The value of
COR from tissue connected with the experimental eye
(CORG) was always compared, in the same section,
with the value of comparable COR in the adjacent companion area (LGN
layer or V1 ocular dominance column; ODC) having input from the normal
eye (CORN). The ratio
CORG–CORN constituted the
primary data from which mean values and variances were calculated.
Normally, the mean COR ± SD of a standard 400-pixel array was
recorded at each tissue site, and the ratio of
CORG to CORN formed. A
minimum of 10 such ratios were then averaged for each tissue location.
Most often, the ratio
CORG–CORN was expressed as
a percentage reduction of COR, relative to that in the companion site
that had input from the normal eye.
The relative COR measurements were imported into a spreadsheet (QuattroPro; Corel, Ottawa, Ontario, Canada) for computation and graphing, and the paired t-test and Mann–Whitney rank sum test were applied using SigmaSTAT (Jandel Scientific, Corte Madera, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Figure 1E shows a section representing central vision for this same monkey. Note that the COR contrast between normal and glaucomatous layers was much less than that just described for the more peripheral retinal representation shown in Figure 1C , again suggesting that the glaucomatous retinal lesion had not spread to fully involve central vision. As was the case for the comparison between Figures 1C and 1D , the effects of experimental glaucoma are barely noticeable in Figure 1F , representing central vision in the contralateral left LGN. To summarize these data, experimental glaucoma in monkeys typically mimicked clinical glaucoma, in that the visual field defects frequently were first observed in the nasal visual field, affecting the temporal retina, which projected on the ipsilateral LGN where COR was reduced with the loss of ganglion cell afference. As the glaucomatous lesion spread over the retina to cross the vertical meridian, the effects began to appear in the contralateral left LGN.
The progressive relative reduction in COR with severity of glaucoma (judged from visual field measurements; see Fig. 7 ) is shown in Figure 2 . Figures 2A and 2B show normal LGN sections representing the projection site of the midperipheral visual hemifields. With moderate glaucoma of approximately 1 year’s duration (Fig. 2C ; OHT20), ipsilateral LGN layers 2, 3, and 5 were CO poor, whereas the layers receiving input from the normal contralateral companion eye (layers 1, 4, and 6) showed robust COR. Again, in the left LGN (Fig. 2D) the contrast between relative COR in the glaucomatous and normal layers was much less, indicating the encroachment of the lesion into the nasal retina.
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The degrees of relative loss in COR within the P layers and the M layers were similar in experimental glaucoma (Fig. 3A ). Fifteen serial sections along the representation of the horizontal meridian were measured for the percentage COR reduction in ipsilateral P-cell layer 5, relative to normal P-cell layer 6. In the same sections, the M-cell layers 1 and 2 were similarly compared. The serial sections extended from the foveal representation to the depth of the glaucomatous lesion at approximately 25° in the periphery. In the ipsilateral right LGN, there was a monotonic reduction in COR from 2% to 13% over this range. Importantly, there were no significant differences in COR between the P- and M-layers throughout, indicating that the M-cells were no more sensitive to ocular hypertension than were the P-cells.
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Quantitative relative COR in normal LGN layers is shown in Figure 4A . The average COR for four LGNs from three control monkeys is shown for
comparison with LGNs from TTX-treated and glaucomatous monkeys (Figs. 4B
4C
4D)
. In four normal LGNs, adjacent layers were not
significantly different in COR: The average relative difference between
adjacent layers was only 1.7% (P-cell layer [P]6, 144.7 ± 7.6;
P5, 143.5 ± 8.1; P4, 144.7 ± 7.8; P3, 146.6 ± 7.4;
M-cell layer [M] 2, 150.2 ± 4.6; M1, 151.2 ± 6.0; F = 0.81, P < 0.55). Of note, there were no significant
differences in COR between the P- and the M-cell divisions of the
nucleus (e.g., Student’s t-test: 1.5 between M1 versus P5,
the largest mean differences between M- and P-cell layers,
P < 0.18, not significant). This result suggests that
the overall metabolic demands of neurons in the two divisions—each
known to have predominant input from different ganglion cell types
(smaller, ß-type ganglion cell input to neurons in the P-cell layers;
larger, -type ganglion cell input to neurons in the M-cell
layers)—are normally the same.
Figure 4B shows the quantification and comparison of the pattern of relative loss in COR in the contralateral left LGN after 3 weeks of TTX blockade, with Figure 4C showing a monkey after induction of experimental glaucoma. The pattern and magnitude of average COR loss (Fig. 4x) after complete TTX blockade of 3 weeks’ duration was virtually identical with that seen with a moderate level of glaucoma (Fig. 4g) . This result argues that it is the loss of ganglion cell afference that leads to the reduction in COR in the LGN. Although the pattern (and in this case, the magnitude) of relative change may be the same, the magnitude of the change with experimental glaucoma may be considerably greater, as illustrated in Figure 4D . As was typical for all the results, the relative loss (Fig. 4g) in layers 1, 4, and 6 of the contralateral left LGN was 19%, 23%, and 27%, respectively, whereas the relative loss in glaucoma-affected layers in the ipsilateral right LGN was much greater, at 63%, 71%, and 17% less than normal (Fig. 4n) .
Table 2 summarizes the percentage of relative loss in COR in the LGNs of 12 monkeys for which we had both visual field measurements and complete COR measurements in both LGNs. The monkeys are arranged in the table based on increasing severity of loss in the VFM (see the Methods section and Fig. 6 ). Table 2 shows that the average reduction in COR was virtually identical at 15% for both the P- and M-cell layers of the ipsilateral right LGN. From these results, it is clear that experimental glaucoma did not have a selective and more detrimental effect on the M-cell pathway. However, in the contralateral left LGN, the reduction in COR was significantly less, with the least detrimental effect seen in the M-cell layers.
When the data from the other monkeys (many showing the more severe effect illustrated in Figs. 6E and 6F ) were added to include all 20 monkeys, the pattern of loss remained essentially the same, whereas the degree of COR loss increased. Figure 5 graphs the average loss in COR in the LGNs of all monkeys. As would be expected, the average percentage reduction in COR was significantly greater in the ipsilateral layers of the right LGN (22%) than in the contralateral left LGN (13%; t = 3.67; df = 17; P < 0.001). This reflects the characteristic progression of the glaucomatous lesion, beginning in the temporal retina and spreading into the nasal retina. The percentage loss in the ipsilateral P-cell layers 5 and 6 was significantly greater (24%) than the loss in the ipsilateral M-cell layers 2 and 1 (20%; t = 2.51; P < 0.05), suggesting that glaucoma had a greater effect on the metabolism of the P-cells than on the M-cell system.
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Figure 6B shows the VFM of another monkey, OHT19, judged from the VFM in a way similar to OHT24 to have minimal sensitivity loss. However, the histogram for the ipsilateral right LGN shows that the reduction in COR was substantial, with the P-cell layers 5 and 3 showing a 4% and 8% reduction, respectively. The reduction of 7% in the M-cell layer was comparable to the average P-cell layer reduction of 6%. The histogram data to the right shows that these significant LGN reductions in COR were reflected in metabolic reductions in the respective input layer 4C sublayers of V1 cortex.
Taken together, these two examples show that by the time a defect became evident in the VFM, substantial effects of glaucoma could be seen in the COR of the downstream pathways. This is in agreement with the relationship we have described recently between the loss of ganglion cells and the VFM, in which more than half the ganglion cells of the macaque retina are lost by the time a sensitivity loss can be detected in the VFM.36
Figure 6C shows the VFM of subject OHT20, a monkey that was judged to have a moderate loss in visual field sensitivity, based on the size, location, and depth of the defect. Correspondingly, the histogram for the right LGN shows that the loss in COR in the P-cell layers of the LGN was increased to an average 13%, whereas the M-cell layer had a slightly and insignificantly larger 17% loss. Compared with the previous examples (Figs. 6A 6B) , there was a greater loss in COR of approximately 10% in the input layers of V1 cortex.
The VFM of subject OHT18, another monkey judged to have a moderate loss in sensitivity, is shown in Figure 6D . Comparable to the effects seen in OHT20, the histogram shows that the P-cell layers of the LGN lost an average of 11% in COR, whereas the M-cell layer lost 13%. The relay of these effects to the V1 cortex, again seen to the right of the figure, indicate that there was an overall loss of 12% in COR.
Judged to have relatively moderate losses according to the VFMs, these two monkeys showed a greater average LGN reduction in COR of 12% compared with the average 8% reduction seen in the two examples judged to have mild losses. Correspondingly, these greater reductions of COR in LGN were relayed to the V1 cortex.
Figures 6E and 6F are the VFMs of monkeys OHT14 and OHT22, respectively. These monkeys were judged to have a severe loss in sensitivity. In these monkeys, both the P- and the M-cell layers of the LGN showed approximately a 14% to 20% reduction in COR, with the relay of these effects to the V1 cortex manifesting losses of 7% and 20%, respectively.
These latter two relatively severe cases of VFM defect show the greatest average reduction in LGN COR of 17%, compared with 12% for the two moderate cases and the 8% found in the mild cases. In short, there was a monotonic increase in the loss in COR within the LGN and the V1 cortex with the degree of severity of the VFM defect. Figure 7 summarizes the average relationship between the COR (mean ± SD of the five measurement sites in LGN and V1) and the VFM for these six monkeys. The mild stage of glaucoma was significantly different from both the moderate and the severe levels of glaucoma (analysis of variance; F = 6.1, P < 0.006), whereas there was no difference between the moderate and severe levels.
Glaucoma and V1 Cortex
With experimental glaucoma, afferent input to the primary V1
visual cortex is dramatically altered consequent to the changes in LGN.
We next describe the details of these effects. Figure 8
is a tangential view of three serial CO-stained sections from the
posterior bank of the lunate sulcus (A) extending into the cortical
representation of the lower visual field of paracentral vision (C) from
a monkey with glaucoma. CO-rich layer 4C ODCs, receiving input from the
normal left eye (vertical white arrows), and the adjacent CO-poor ODCs,
receiving input from the glaucomatous right eye, are seen clearly. As
would be expected in adult monkeys, the widths of the columns were
about the same,37
differing only in COR, which varied
between animals depending on the cortical location of the
representation of the visual hemifield and on the severity of the
glaucomatous condition. Owing to the cortical curvature in this
nonflattened cortex, the CO-rich ODC of layer 4C (Fig. 8A
, white
vertical arrow) was seen in subsequent sections to lead to the rows of
interconnected CO-blobs that overlay layers 2 and 3. In a similar
manner, the adjacent CO-poor layer 4C ODC, receiving input from the
glaucomatous eye, led to a row of smaller CO-blobs, a row of blobs that
had no interconnecting COR. The horizontal arrows indicate a pair of
blood vessels in each section, which served as fiducial marks for
alignment of the three images.
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sublamina is seen to be considerably darker. Figure 9B
shows the same
phenomenon for another glaucomatous monkey, whereas Figure 9C
shows
that this differential effect on the COR in these two V1 input
divisions could be seen after only a few months of experimental
glaucoma. The horizontal rectangles in Figure 9A
indicate the loci
where COR was measured and the differential loss in COR computed in all
the monkeys.
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) and for the
P-cell (4Cß) input divisions to V1 cortex. The mean percentage loss
(±1 SD) in COR for 10 samples each is shown for the 17 monkeys for
which complete measurements were obtained for both V1 cortices (in some
of the mild glaucoma cases, columns could not be discerned in the
contralateral left cortex). The average percentage loss in relative COR
in the right cortex (mean R4C = 8.1%, mean R4Cß =
13.8%; t = 9.1; P < 0.0001) was nearly the
same in the left cortex (mean L4C = 8.3%, mean L4Cß =
14.9%; t = 7.2; P < 0.0001). In both
cortices, the reduction in relative COR was significantly less in the
M- than in the P-cellular input sublamina. In every monkey, the
relative COR loss was significantly less in the M-cell input layer than
in the P-cell input layer. On average, the loss was 8% in the 4C
layer and almost double that at 14% in the 4Cß sublayer.
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, created a CO lesion
first in the ipsilateral visual brain representing the nasal visual
hemifield of the glaucomatous eye, and then progressed to the
contralateral visual brain as the retinal scotoma enlarged. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ganglion cells of the M-pathway, rather than the Pß ganglion cells.
However, Johnson38
has reinterpreted the data of Quigley
et al.39
and suggested that the original data show, at
best, a modest trend for a selective early loss in large-diameter
axons—that is, in the M-pathway. Although we have yet to measure the
actual differential loss in different sizes of ganglion cells, the
results of our metabolic study of the downstream brain targets in
monkeys with mild visual field defects are not consonant with the idea
that glaucoma has a more detrimental early effect on neurons in the
M-cell pathway. Vickers et al.18
have shown that
experimental glaucoma in monkey affects the metabolism in both
divisions of the geniculocortical afferent pathway, but they did not
quantify the differences. Beginning in the LGN, the reduction in COR within the P- and the M-cell laminae were shown in the current results to be very much the same, with the magnitude of the change being associated with the degree of the visual field defect (Figs. 6 7) . Although this association was the general finding, there were notable exceptions (Table 2 , OHT23; also see Fig. 1 of Reference 36) when there were only moderate changes in the VFM but a dramatic change in COR. Although the period between the last VFM measurements and the termination of the monkey was relatively short (<2 weeks), we cannot rule out additional loss in ganglion cell function during this interval. There was a second case, however (Table 2 , OHT9; also Fig. 4A in Reference 36), in which the VFM showed a severe loss in sensitivity, but the subsequent loss in COR was relatively mild. These two exceptions to the general finding of a progressive loss in COR with increasing loss in visual sensitivity had similar treatment histories (Table 1) . As in clinical glaucoma, the progression of the defect in the VFM in experimental glaucoma is often variable in rate and degree of loss in sensitivity, contributing to variability in the association between COR and the VFM.
Regarding the differential effect of glaucoma on the M- over the
P-ganglion cells, it could be argued that there is an early selective
effect on M-cells,15
but that our experimental series did
not cover the proper period. This seems unlikely, because our series of
monkeys included those with a just-detectable VFM defect to those with
end-state defects, and the relative pattern of the effect on the two
pathways remained the same. In addition, the pattern of the spread of
the glaucomatous lesion over the retina was such that it finally
involved input to the contralateral brain structures, where any
preferential detrimental effect on the M-cell targets would be expected
to show up. On the contrary, the greater reduction in COR was instead
seen in the P-cell projection sites (Table 2
and Fig. 9
). These
collective data show that experimental glaucoma has a greater impact on
the metabolism of the P-cell pathway in both the LGN (Fig. 5)
and especially in the input layer 4Cß of the V1 cortex (Figs. 9 10)
.
In every monkey, the COR reduction in the layer 4Cß was significantly
greater than that in the companion input layer 4C, the recipient
zone for the M-cell input from the LGN. Because the afference to these
sublaminae is dependent on the LGN input,40
this
difference in COR may well reflect what is relayed to V1 from the LGN.
In short, the COR in the LGN showed a greater effect of glaucoma on the
P-cell pathway than on the M-cell pathway, and these differences were
relayed and exacerbated in the corresponding COR in the layer 4C
sublaminae.
By the time there is a detectable defect in the VFM, more than half the ganglion cells have died.36 Therefore, the standard VFM cannot be used for the detection of the earliest vulnerability of ganglion cells in glaucoma. It may well be that by the time the retinal defect has progressed to the point of a detectable VFM defect, any initial differences that glaucoma had on the two afferent pathways may have been obliterated. Weber et al.41 examined the issue of greater differential effects of experimental glaucoma on the morphology of parasol (M-cells) and midget (P-cells) ganglion cells. Although they found no substantial differences in the soma size between ganglion cell class with progression of the disease, there were qualitative differences in the size and complexity of M-cell dendritic arbors earlier in the disease. This finding is consistent with an initial degenerative effect beginning with the M-cells and is consonant with the results of Glovinsky et al.15 The mechanism of this early period in ganglion cell death deserves more investigation, and a search should be made for a more sensitive method for the early detection of glaucoma.
The precipitating event for these metabolic changes in the LGN and V1 cortex is the functional impairment or death of retinal ganglion cells. Functional blockade by TTX is shown to be sufficient to reduce COR in the afferent recipient zones of the LGN and V1, in a pattern (if not in degree) similar to enucleation. However, there are important differences between the effects of TTX or enucleation and ganglion cell loss in glaucoma, experimental or clinical. TTX blockade and enucleation result in total and immediate loss of afference to downstream targets, whereas the loss from POAG is generally more gradual, progressing over a period of months to years. We cannot differentiate between the relative contributions of the death of ganglion cells or the functional impairment of ganglion cells in reduction of COR presented in the current study. However, in those cases in which we have compared ganglion cell death with the loss of visual field sensitivity, those monkeys showing the earliest of field defects had already lost more than 60% of their ganglion cells.36 Therefore, it is likely that the reductions in COR reported here were due to the loss of afference consequent to the death, rather than the inactivity, of ganglion cells.
The effects of experimental glaucoma reported here are likely to occur clinically, because the characteristics of increasing IOP in the monkey are, in the main, similar to those of clinical glaucoma.42 43 44 The main difference is in the time course of the process, which takes only months in monkeys (and with a usually higher elevation of IOP in the monkey) and years in people. Experimentally, these effects on metabolism are much more readily discernable in the monkey model than in human material, because there is always an adjacent target tissue that receives input from a normal companion eye.
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Acknowledgements |
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Footnotes |
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Submitted for publication July 20, 1999; revised December 22, 1999; accepted January 26, 2000.
Commercial relationships policy: N.
Corresponding author: Morris L. J. Crawford, 6431 Fannin, Suite 7.024, Houston, TX 77030. crawford{at}eye.med.uth.tmc.edu
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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