The use of atropine and pilocarpine has allowed amplitude, starting point, and end point to be manipulated to evaluate their influence on accommodative and disaccommodative dynamics. In this study, pilocarpine was used to change the tonic status and configuration of the accommodative structures, and atropine was used to reduce response amplitude to study EW-stimulated accommodative dynamics on the assumption that the drugs per se do not influence the dynamics.
After pilocarpine, baseline refraction became more myopic, effectively shifting the starting point of the EW-stimulated accommodative response more proximally. Response amplitude to the submaximal EW stimulus remained nearly constant during the initial 45-minute myopic progression, suggesting that a fixed stimulus amplitude to the EW nucleus released a constant quantity of acetylcholine and that this was added at the neuromuscular junction to the pilocarpine already present. Although the EW-stimulated response amplitude remained constant to the submaximal stimulus, peak velocity of the accommodative response decreased and became slower in the more proximal range. This is a clear demonstration that, in anesthetized monkeys, response dynamics are dependent not only on response amplitude
5 but also on starting point, as has been demonstrated in humans.
12 13 It may be that as the starting point becomes more proximal, resting tension on the zonular fibers is partially released as the lens becomes more accommodated, the potential energy level of the accommodative plant is reduced, and the initial response velocity decreases.
In humans, voluntary accommodation has been reported to be slower in the near range (5–8 D
31 ), faster in the near range (4.5–6 D
12 and 4.6–8.6 D
32 ), or shows no change with starting point (3–4.5 D
33 ). In our study, in anesthetized monkeys, response velocity was found to be slower in the near range. Pilocarpine stimulation served to shift the baseline to a more proximal starting point. In humans, starting point is shifted proximally by a neuronally driven accommodative effort. This involves visual and neural feedback for the proximal shift in starting point and the additional accommodative response. Perhaps these differences or the fact that the monkeys were anesthetized in these experiments resulted in response dynamics being different from those of conscious humans. It has been suggested that, in conscious humans, the accommodative neural controller may compensate for reduced speed by increasing its neural output,
33 thus maintaining or increasing the peak velocity. It has also been suggested that the saturation of peak velocity in human subjects at higher accommodative amplitudes
3 is caused by mid-brain neurons firing with an initial pulse followed by a step (pulse-step).
33 Behavioral studies in monkeys also show that the EW neuron firing frequency increases with an increase in accommodative response.
34 35 In the experiments described here, EW-stimulated accommodation was achieved with a step stimulus with constant pulse frequency. EW stimuli of various forms and frequencies could have been constructed and tested for their effects on accommodative dynamics, but that was beyond the scope of the present study.
The main sequence relationship for low-amplitude, EW-stimulated responses before atropine instillation was not significantly different from the main sequence relationship for low-amplitude responses to maximal stimulations after atropine reduced the accommodative response amplitude. Previous studies show that delivering a
supramaximal stimulus to a nonatropinized eye results in greater peak velocity than occurs with
maximal stimulation.
9 Atropine bound to and blocked a proportion of the ciliary muscle receptors and decreased the response amplitude to the maximal stimulus, yet the peak velocity for this fixed stimulus amplitude decreased as the response amplitude decreased. The same maximal stimulus amplitude was delivered to the EW nucleus as before atropine instillation, so the same number of EW neurons were recruited and the same amount of acetylcholine was released at the neuromuscular junction, with diminished effect on the blocked receptors of the ciliary muscle. This suggests that, in anesthetized monkeys, peak velocity is influenced by the number of ciliary neuromuscular receptors activated. It also suggests that the increase in peak velocity that occurs with a supramaximal stimulus in the non–drug-treated eye occurs because maximal stimulus amplitude does not activate all available ciliary muscle receptors to achieve the maximum accommodative response amplitude. It is interesting that the post-atropine response amplitudes to the submaximal stimulus decreased even though the eye clearly had greater amplitude during this early period, suggesting that the constant amount of acetylcholine released with submaximal EW stimulation could not bind to free receptors and stimulate the ciliary muscle in the presence of low concentrations of atropine.
In contrast to atropine, after pilocarpine, the accommodative dynamics for the maximum stimulus showed a small but significant increase in the intercept of the main sequence relationship
(Fig. 3A) , apparently largely caused by individual variability in the response dynamics of one eye. As the baseline starting point became more proximal after pilocarpine administration, less EW-stimulated accommodative range was available, yet the same maximal stimulus amplitude was delivered. Therefore, as with atropine, the maximal stimulus effectively became a supramaximal stimulus by the release of excess acetylcholine over what was required to achieve the maximum available response amplitude. However, peak velocity was decreased rather than maintained. In this case, some of the neuromuscular receptors were already bound by pilocarpine when the EW stimulus was delivered. As pilocarpine bound to the receptors, fewer unbound receptors were available for the acetylcholine released by EW stimulation. Thus, in the presence of the maximal EW stimulus, peak velocity decreased as the number of receptors activated by the EW stimulation decreased, the EW-stimulated response amplitude decreased, and the starting point of the response became more proximal. In the case of the submaximal EW stimulation in the presence of pilocarpine, the first two points did not apply, but peak velocity still decreased as the starting point became more proximal. Therefore, it appears that in the absence of a change in amplitude, it was the proximal shift in starting point that was the predominant influence on the response dynamics.
The slope and intercept of the post-atropine and post-pilocarpine disaccommodation main sequence remained unchanged compared with the pre-drug condition, suggesting that the dynamics of disaccommodation are dependent on the response amplitude and the restoration of forces of the accommodative structures rather than stimulus amplitude in the absence of consciousness.
5 In our study of anesthetized monkeys, peak velocity of disaccommodation was independent of starting point for a constant amplitude response. This is in contrast to studies in humans, which show that the speed of step responses for disaccommodation depends on the starting point. In anesthetized monkeys, visual feedback was absent, and disaccommodation was totally passive and included no neural firing. However, it has been suggested that disaccommodation is influenced by neural firing and is not a passive process in humans.
13 Neural firing when focusing from near to far has also been demonstrated in alert rhesus monkeys with single-unit recording techniques.
36 The results shown here also demonstrate that the dynamics of disaccommodation are dependent on the amplitude of the response and on the disaccommodative end point. Peak velocity for disaccommodative responses with the same end point depends on the response amplitude.
Given the use of pharmacologic agents to alter the refractive state, starting point, and accommodative amplitude, it might not have been entirely clear to what extent the altered accommodative dynamics were caused by receptor blockage, altered amplitude, or altered starting point. However, experiments in which the starting point and therefore the amplitude are manipulated by EW stimulation, without pharmacology, may shed more light on the extent to which receptor activation or blockage can affect accommodative dynamics. It is possible to shift the starting point proximally under neuronal control in rhesus monkeys using a digital stimulator. This would eliminate the pharmacology and resultant receptor blockage and may provide more insight into the cause of the altered response dynamics.
In vitro studies have suggested that accommodative dynamics are dictated by the accommodative plant, mainly the lens and ciliary body,
37 and that the starting configuration of the lens substance and capsule dictate the elastic forces of the lens capsule.
38 39 Although results from a study in humans support this suggestion,
12 results from the present study suggest that accommodative dynamics to EW-stimulated accommodation in anesthetized rhesus monkeys depends on neural and biomechanical contributions because amplitude of accommodation (from the same starting point) and starting point (with the same amplitude) influence accommodative dynamics.
In conclusion, topical application of pharmacologic agents has allowed manipulation of resting refraction, accommodative amplitude, starting point of the response, and neural and receptor activation to gain a better understanding of the various contributions to accommodative and disaccommodative dynamics. This ultimately may enable us to understand how aging affects the biomechanics of the accommodative plant and, perhaps, influences accommodative dynamics.