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1From the Department of Ophthalmology and Visual Sciences, Wisconsin Regional Primate Research Center, and 3Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin; and the 2College of Optometry, University of Houston, Houston, Texas.
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METHODS. The CLS was measured in 34 iridectomized eyes of 24 living rhesus monkeys, age 5.7 to 26 years, in the resting and accommodated state, and the orientation of the zonula and suspension of the lens during accommodation was assessed qualitatively.
RESULTS. The nonaccommodated CLS decreased significantly with age in both the nasal and temporal quadrants and tended to do so at a slightly faster rate in the temporal quadrant. The CLS correlated significantly with the accommodative amplitude: the greater the CLS the greater the accommodative amplitude. Multiple regression analysis indicated that age and CLS together are better predictors of accommodative amplitude than is age alone. The zonula appeared taut in the nonaccommodated eye throughout the age range despite the age-related decline in CLS.
CONCLUSIONS. Characterization of age-related changes in the accommodative apparatus may help to model the system for hypothesis testing. The CLS may be an indicator of presbyopia-related processes in surrounding tissues. However, these results do not prove that the width of the CLS, in and of itself, has a causal relationship with accommodative amplitude, or that changes in the CLS play a pathophysiological role in presbyopia.
The crystalline lens grows throughout life through proliferation of epithelial cells near the lens equator; the cells elongate toward the anterior and posterior poles of the lens and become lens fibers. The mass of the lens increases, and the axial lens thickness increases anteroposteriorly.7 18 19 20 In vivo human data, gathered using magnetic resonance imaging (MRI), demonstrates that the lens equatorial diameter in the nonaccommodated eye does not change systematically with age and that the anteroposterior (A-P) thickness increases with age.21 Although further research is needed because of the limitations of MRI, the MRI data provide the strongest available evidence against suggested age changes in lens diameter in vivo, especially absent any contravening in vivo data. In vitro data from excised lenses show increased equatorial diameter with age.22 However, young excised lenses are accommodated (diminishing the equatorial diameter) whereas old, presbyopic, and hardened lenses are not.3 18 23
Studies in which the ciliary ring diameter was directly measured in vivo in the human eye, by using MRI21 and histologic studies of human ciliary muscle24 show an age-related decrease in nonaccommodated ciliary muscle ring diameter. Scanning electron microscopy studies show no age-related change in zonular length, but show an anterior shift of the zonular insertion onto the lens anterior surface.9 This is suggested to be a factor in the loss of accommodation with increasing age.25 26 27
Whether the age-related decrease in ciliary ring diameter is the initial, middle, or end link in the chain of events that lead to presbyopia, it may affect the forces applied to the lens during accommodation and disaccommodation. The width of the circumlental space (CLS) may reflect the diminished ciliary ring diameter and therefore may be an indicator of age-related changes in the zonular forces applied to the lens.
The present studies were undertaken in living iridectomized rhesus monkeys to document the zonular orientation and suspension of the lens during accommodation and to quantify age-related changes of the CLS in the resting and accommodated eye.
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Materials and Methods |
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Goniovideography allowed a determination of age-related changes in the nonaccommodated and accommodated circumlental space (CLS) in the nasal and temporal quadrants. The CLS is the average closest distance from the tips of four to five ciliary processes (CPs) in the midregion of the nasal and temporal quadrants (i.e., 3 or 9 o’clock) to the equatorial edge of the lens. Relaxation or bending of the zonular fibers anywhere within the field of view was recorded.
After total iridectomy was performed29 in both eyes, a bipolar stimulating electrode was implanted into the Edinger-Westphal (E-W) nucleus.30 Surgical depth anesthesia was achieved before all procedures. A Hartinger coincidence refractometer (Aus Jena, Jena, Germany) was used to measure resting refractive error and accommodation.
Goniovideography images (Swan-Jacob gonioscopy lens) were recorded during E-W stimulation. Extreme care was taken to align the slit lamp observation tube with the A-P axis of the eye so that the ciliary processes, lens, and CLS could be visualized through the gonioscopy lens. In the resting eye, there were no convergence eye movements. Convergence eye movements during stimulation were minimized and measured (0.17 mm; n = 27).28 The effect of eye movement alone on CLS was determined by inducing 
0.17 mm of convergence eye movements without accommodation in four eyes28 and comparing the CLS measurements to baseline.
Goniovideography recordings of the ciliary body, zonule and lens equator accommodative movements were made at several different current amplitudes, as described.28 Beginning at minimum accommodation, the stimulus was increased by consistent increments available on the stimulus isolation unit up to maximum accommodation (maximal stimulus). The stimulus level was then increased again by the same increment (supramaximal stimulus). The supramaximal stimulus was retrospectively calculated from all monkeys to be between 0.1 to 0.2 mA or 26.2% ± 3.9% above that necessary to induce maximum accommodation. This ensured that maximum accommodation had been achieved as measured refractometrically, and allowed determination of whether the CP and lens accommodative movement had plateaued. The goal was to stimulate the muscle beyond the point at which dioptric accommodation plateaued, to determine the limiting factors in the accommodative response (i.e., CP or lens movement, and the impact on CLS). Images recorded during higher than supramaximal stimulation are also shown for comparison and indicated by the level of current provided with the image. Qualitative assessment of movements at other, submaximal stimulus levels is included, and the stimulus level is given for each case.
The CLS was measured from digitized images (Optimas software; Media Cybernetics Inc, Silver Spring, MD) taken from SVHS videotape before, during and after a 2.2-second stimulus duration.
Scheimpflug images were collected in phakic eyes.31 32
A 50-mHz ultrasound biomicroscopy (UBM) instrument (Humphrey model 840; Carl Zeiss Meditec, Dublin, CA) was used to image the lens, zonule and ciliary body configuration of the eye at rest.28 33 In addition to the 34 iridectomized eyes, five noniridectomized rhesus monkey eyes (6–8 years old) were imaged by UBM to determine the effect of the iris on the CLS.
Definitions
The maximal stimulus is the level of E-W stimulation necessary to induce maximum accommodation. The supramaximal stimulus is a level of E-W stimulus current 26.2% ± 3.9% (or 0.10–0.20 mA) above maximal stimulation.
Statistical Analysis
Simple linear regression (i.e., CLS versus age; CLS versus accommodation) and multiple regression analysis (i.e., accommodation versus age and CLS) were undertaken in all monkeys. The multiple regression analysis adjusts for the relatedness between two observations (i.e., instances in which there were two eyes from the same monkey) and has no associated correlation coefficient.
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Lens Equator and Anterior Zonula
In the nonaccommodated state, the zonular fibers, as visualized goniovideographically, appeared to be taut in both eyes in both the nasal and temporal quadrants of all 24 monkeys, regardless of age (Figs. 1B ; 2B; 3A, 3B; Movies 1, 2, available online at http://www.iovs.org/cgi/content/full/47/3/1087/DC1).
Young Eye.
At the supramaximal stimulus level, zonular fibers began to relax or bend in five of seven eyes in both quadrants; and in one of seven eyes, the zonular fibers began to relax or bend in the temporal but not the nasal quadrant. In one eye, the zonular fibers did not bend in either quadrant.
Older Eye.
During supramaximal stimulation, in older eyes in which the zonular fibers were clearly visualized in the goniovideography images, the temporal and nasal zonular fibers began to relax or bend in 9 of 9 and 9 of 10 eyes, respectively (Fig. 2) . Zonular relaxation and bending was observed, but less consistently, in these eyes at maximal (as opposed to supramaximal) stimulus currents. The zonular fibers were not readily visualized in six other older monkey eyes because of the illumination level required.
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0.35 mA above the maximal stimulus). In six other eyes, the lens did not fall with gravity (Figs. 1E 1F 3) . In one of these eyes, Scheimpflug images showed inferior CPs contacting the inferior lens equator (Fig. 3) . In the remaining 15 eyes, an unequivocal determination of whether the lens fell could not be made. Eight of these 15 were older eyes in which the CPs touched the lens during accommodation (Fig. S1, http://www.iovs.org/cgi/content/full/47/3/1087/DC1). In no case did the lens position ever move upward in the eye at any stimulus level compared with the resting state.
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Artificial convergence eye movements 
0.17 mm induced by pulling on extraocular muscle sutures (without accommodation) were analyzed, and averaged in the nasal quadrant (0.19 ± 0.01 mm; n = 17 image frames) and in the temporal quadrant (0.17 ± 0.01 mm; n = 24 image frames).28 The CLS decreased during convergent eye movement by 0.01 ± 0.01 mm (n = 8) in the nasal quadrant and increased by 0.003 ± 0.004 mm (n = 8) in the temporal quadrant, neither being significantly different from 0.0. Thus, variability was introduced by convergence eye movement, but of a magnitude insufficient to impact the overall results or conclusions.
Imaging through the gonioscopy lens introduced some prismatic distortion28 but any consequent variability due to variability in placement of the lens on the eye was random, small, and similar in all monkeys, and not enough to affect the overall results or conclusions. Evidence for this is that the SEM was small (Table 1) in both the young and old eyes and that the nasal and temporal CLS of the young eye were not significantly different from each other. Therefore, although nonsystematic variability may be introduced by slight prismatic distortion or eye movement, the data are reliable and the comparisons between young and older are valid. In addition, measurements analogous to the gonioscopically measured CLS width were taken using UBM.
Ultrasound Biomicroscopy
UBM also allowed visualization and measurement of the CLS (CLS-UBM), analogous to that measured by goniovideography, in five young noniridectomized and five young iridectomized monkey eyes. The presence or absence of the iris did not affect the width of the CLS-UBM significantly in either the nasal (noniridectomized 0.58 ± 0.02 mm versus iridectomized 0.59 ± 0.02 mm) or the temporal (noniridectomized 0.50 ± 0.02 mm versus iridectomized 0.53 ± 0.02 mm) quadrants. Further, the CLS-UBM and gonioscopically measured CLS were not significantly different (see the nonaccommodated young monkey eye; Table 1 ), validating the technique used to calibrate the goniovideography images. All references to CLS width outside the current section are based on the goniovideography images.
Regression Analysis: Goniovideography of Iridectomized Eyes
There was no correlation between the width of the CLS in the resting eye and the elapsed time between iridectomy and the imaging session in either quadrant (n = 30 eyes). The same was true at the maximal and supramaximal stimulus currents (data not shown).
Circumlental Space (CLS; 34 eyes, 24 monkeys).
The nonaccommodated CLS decreased significantly with age in both the nasal (–0.012 ± 0.004 mm/y; P < 0.03) and temporal (–0.016 ± 0.004 mm/y; P < 0.01) quadrants and tended to do so at a slightly faster rate in the temporal quadrant (Figs. 5A 5B) . The nonaccommodated nasal and temporal CLS was significantly correlated with the accommodative amplitude of each monkey (Fig. 6A) ; the greater the CLS the greater the accommodative amplitude. Similar results were seen in the maximally (Fig. 6B) and supramaximally (Fig. 6C) stimulated states. Because CLS and accommodative amplitude covaried with age, a multiple regression analysis that models accommodation as a linear function of age and nonaccommodated CLS was undertaken. A mixed model (using SAS Proc Mixed; SAS, Cary, NC) that recognizes that measurements taken from two eyes of the same monkey may correlate, was used, with the thought that the decrease in nonaccommodated CLS with age might explain the decrease in accommodative amplitude over and above what age could do alone. The multiple regression coefficient of nonaccommodated temporal (but not nasal) CLS was significantly different from 0.0 (P < 0.03), indicating that age and nonaccommodated temporal CLS together are better predictors of accommodative amplitude than is age alone (Table S1, http://www.iovs.org/cgi/content/full/47/3/1087/DC1). A similar multiple regression analysis using CLS measured during maximal stimulation showed significance in both quadrants, indicating that age and CLS during maximal stimulation together are better predictors of accommodative amplitude than is age alone (Table S1). Similar results were seen at the supramaximal stimulus level. The difference between the CLS in the nonaccommodated state and during maximal and supramaximal stimulation did not decline significantly with age in either quadrant. However, in the nasal quadrant, the supramaximally accommodated CLS minus the maximally accommodated CLS tended to decline with age (P = 0.053). The results of the multiple regression analysis and the corresponding F-statistic show that age (which typically has much larger F-statistics than CLS) explains nearly all of the variation in accommodative amplitude. However, a stated earlier, CLS was important in predicting accommodative amplitude over and above what age could do alone.
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Discussion |
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Reporting only the results of the maximal stimulus level would not have identified the fact that the CP can move more than required to induce maximum accommodation. Therefore, the results of both the maximal and supramaximal stimulus levels are reported. The CLS diminished by 0.09 to 0.11 mm during supramaximal stimulation in the young eye but diminished to a greater extent during accommodation in the older eye, due to the loss of lens centripetal accommodative movement with age, as shown from an analysis of the same goniovideography images presented elsewhere.28 Age and resting temporal CLS (but not nasal), together are better predictors of accommodative amplitude than age alone, suggesting that there is some presbyopia-related process that impacts the temporal CLS more dramatically than the nasal CLS. In vivo MRI data from the nonaccommodated human eye demonstrated that, with age, the ciliary ring diameter decreases, lens equatorial diameter does not change systematically, whereas lens A-P thickness increases.21 In excised partially dissected human eyes9 it was reported that there is an anterior zonular shift with increasing age, but "[t]he loss of zonular tension due to a decreased circumlental space does not occur since the insertion-ciliary body distance remains constant." The zonular insertion point onto the capsule is fixed for life, but with age the capsule stretches (to compensate for the increased lens thickness), possibly pulling the zonule–capsule insertion point farther onto the front surface of the lens.
The decrease in resting CLS with age is most likely a product of diminished ciliary ring diameter21 24 and increased A-P thickness21 and not due to increased lens equatorial diameter.15 To achieve zonular relaxation with accommodation in the young eye, the CLS need only be diminished by 0.09 (nasal) and 0.11 (temporal) mm. Also, the CLS in the older eye was significantly narrower than that in the young eye by 0.17 (nasal) and 0.26 (temporal) mm. If the nonaccommodated CLS diminished with age, either due to diminished ciliary ring diameter alone or increased lens equatorial diameter alone (without anterior zonular shift), a relaxed zonula would have been observed in the nonaccommodated older eye. Instead, the zonular fibers clearly appeared taut in the nonaccommodated older eye.
Previous reports have postulated that an age-related overall steepening of lens curvature occurs, to counteract the concomitant reduction in the gradient refractive index of the lens35 and that the age-related remodeling of the ciliary muscle may be important to maintain emmetropia.24 The geometric theory suggests that the geometry of the lens/zonular fibers and thereby the direction of the zonular force changes with age. The ciliary ring diameter diminishes with age, zonular fiber length remains constant, the lens thickens, but the lens equatorial diameter does not change. An increase in A-P lens thickness, which in turn places increased tension on the anterior zonular fibers, could pull centripetally on the ciliary ring causing, over a long period, the ciliary ring diameter to diminish. In this scenario, the zonular fibers would remain taut, possibly becoming increasingly taut with increasing age. Surgical manipulations of the eye show that the capsule supplies centripetal force to aid centripetal accommodative velocity and amplitude of movement of the ciliary body (Croft MA, et al. IOVS 1999;40:ARVO Abstract 1918). The fact that the CLS is narrower in the temporal versus the nasal quadrant of the older resting eye suggests that there may be more zonular tension pulling the lens toward the temporal quadrant in the resting older eye.
In one 6-year-old monkey eye (Scheimpflug; Fig. 4 ) the inferior lens equator moved away from the inferior sclera at half maximal accommodation but seemed to move back toward it during maximal and supramaximal stimulation. During the half-maximum accommodative response, sufficient zonular tension is still present, but as the zonular fibers relax at the maximal and supramaximal stimulus, the lens falls with gravity.
That the lens falls with gravity is in opposition to the Schachar theory of accommodation. Schachar et al.15 posited that the lens equator moves toward, rather than away from, the sclera during accommodation due to increased equatorial zonular tension and that presbyopia occurs because the lens increases in diameter with increasing age.13 If Schachar were correct (i.e., equatorial zonular tension increases during accommodation), the lens should be held in position during accommodation and should not move inferiorly due to gravitational pull. The lens fall with gravity that we report herein is documented by evidence of both positional change and zonular reorientation.
Inferior CPs that contact the lens equator during accommodation may inhibit a pronounced downward movement of the lens, and this may be why the sagging of the lens under the influence of gravity is not seen in all eyes. The movement of the inferior lens equator toward the sclera during accommodation (before coming in contact with the inferior CPs) cannot be interpreted as corroboration of the Schachar theory of accommodation,15 because the zonular fibers relax with accommodation, and the lens equator moves away from the sclera in the nasal, temporal, and superior (Fig. 4D) quadrants.
Characterization of any ocular parameters related to the accommodative apparatus that change with age may help to model the system for hypothesis testing. The CLS may be an indicator of a presbyopia-related process or processes that affect accommodation, such as the age-related loss of lens equator accommodative movement, diminished ciliary ring diameter, and lens A-P thickening. However, these results do not prove that the width of the CLS in and of itself has a causal relationship to accommodative amplitude, or that changes in the CLS play a pathophysiological role in presbyopia.
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Acknowledgements |
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Footnotes |
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Submitted for publication December 27, 2004; revised June 21 and September 23, 2005; accepted January 23, 2006.
Disclosure: M.A. Croft, None; A. Glasser, None; G. Heatley, None; J. McDonald, None; T. Ebbert, None; N.V. Nadkarni, None; P.L. Kaufman, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Mary Ann Croft, Department of Ophthalmology and Visual Sciences, University of Wisconsin Clinical Science Center, 600 Highland Avenue, F4/328 CSC 3220, Madison, WI 53792-3284; macroft{at}wisc.edu.
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