Sympathetic and parasympathetic innervation of pupillary dilation during sustained processing

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Abstract

The contributions of separate sympathetic and parasympathetic pathways to pupillary dilation during a sustained processing task were studied through environmental and pharmacological manipulations. In Experiment 1, 22 healthy volunteers (11 female) performed a serial Subtract 7 task while pupil diameter was recorded both during moderate room light and in darkness. In a control for verbalization, subjects performed an easier Add 1 task. In all conditions, pupil diameter increased significantly during the response period as compared to a pre-verbalization baseline period. Pupillary dilation was increased for the difficult task, and further increase in dilation was associated with recording in light. This suggests a major differential contribution to task difficulty mediated through inhibition of the parasympathetic pathway. In Experiment 2, a subgroup of 12 volunteers (seven female) repeated all conditions at three additional sessions in which one eye was instilled with tropicamide (to block the parasympathetic sphincter muscle), dapiprazole (to block the sympathetic dilator muscle) or placebo. All pharmacological conditions resulted in overall dilation during task performance. Differential performance similar to the placebo condition was seen only in the dapiprazole condition, when parasympathetic activation was intact. The findings suggest that sustained performance during a difficult task is modulated by cortical inhibition of the parasympathetic pathway at the oculomotor nucleus. Moreover, modulation of both ambient light intensity and pharmacological blockade of the final pupillary musculature were observed to provide converging approaches for quantifying the activity of identifiable central autonomic pathways.

Introduction

Many cognitive processes result in dilation of the pupil (Beatty, 1982b, Janisse, 1977, Loewenfeld, 1993). Experimental studies relating cognitive activity to pupillary changes have often used discrete stimuli, resulting in characteristic waveforms associated with reception and processing activities (e.g. Friedman et al., 1973, Steinhauer and Zubin, 1982). When task demand is increased over time (e.g. with increasing numbers of stored items in the digit span task), the pupil is observed to increase following presentation of each stimulus (Kahneman and Beatty, 1966, Peavler, 1974, Granholm et al., 1996). In such situations, the pupil decreases in diameter as stored information is then reported by the subject (Beatty and Kahneman, 1966). When overall diameter throughout the course of a task is examined, pupil diameter is larger as overall task demand is increased (e.g. Karatekin, 2004).

If processing demands are continuous, then pupil dilation is maintained (Beatty, 1982a). Such dilation is likely to be associated with brain regions having the ability to sustain attention and ongoing processing of information. Frontal cortical regions have been implicated as subserving such functions as indicated indirectly by neuropsychological deficits in patients with frontal damage (Sarter et al., 2001), and more directly by concurrent pupillometry and functional neuroimaging studies (Siegle et al., 2003). Yet, the extent to which cognitive activity is uniquely associated with sympathetic or parasympathetic activity is unclear. This is of importance because current knowledge regarding the neurophysiological systems that contribute to cognitive activities can be evaluated by monitoring pupillary dynamics; differential activation of these pathways can provide quantitative measurements of activation underlying central nervous system mechanisms.

Methodological approaches for dissociating autonomic pathways in the pupil: Though a variety of invasive approaches can be used to explore relative parasympathetic and sympathetic contributions to pupillary motility in animal models, the possibility of utilizing similar approaches to study higher cognitive function in humans is necessarily limited. The specific problem is in determining the extent of contributions by the sympathetic and parasympathetic divisions of the autonomic nervous system to pupillary dilation. The sympathetic branch, mediated by posterior hypothalamic nuclei, produces enlargement of the pupil by direct stimulation of the dilator muscles. The contribution of the parasympathetic pathway is mediated by central inhibition of the Edinger–Westphal complex of the oculomotor nucleus (n. III) in the midbrain, which is the motor center for parasympathetic pathway. Inhibition of this complex results in relaxation of the sphincter muscles and, thus, dilation. Two paradigms for exploring these relative autonomic contributions have been suggested (Steinhauer and Hakerem, 1992).

Differential effects of recording in dark and light adapted conditions: One method for manipulating the parasympathetic pathway is to modulate ambient light intensity. In darkness, active parasympathetic tone is minimal. Neural and muscular systems typically exhibit a resting level of activity even in the absence of specific stimulation. A tonic level of activity is present in the pupillary sphincter, so that even in the dark adapted pupil, there is still minimal constriction of the pupillary sphincter (Loewenfeld, 1993). Consequently, active inhibition of the parasympathetic center will have the least residual effect of dilation due to relaxation of the sphincter muscles for recordings obtained in darkness. In contrast, stimulation of the dilator should be present. Dilation occurring in response to cognitive activation during dark adapted conditions is well documented (Friedman et al., 1973, Steinhauer and Hakerem, 1992, Steinhauer and Zubin, 1982). Such findings indicate a significant sympathetic contribution to dilation in response to specific cognitive events.

As ambient light intensity is increased, the sphincter muscle is stimulated, resulting in a smaller overall diameter. When central activity now reaches the same Edinger–Westphal sites, the effect is to result in relaxation of the sphincter muscle as an additional component of dilation. The extent of this dilation should be related to the initial stimulation of the pupil, i.e. brighter light and a smaller diameter should provide greater dilation amplitude mediated by the parasympathetic pathway, thus allowing differential measurement of sympathetic and parasympathetic contributions. This method is employed in Experiment 1.

Pharmacological dissociation of sympathetic and parasympathetic innervation: The second method for dissociating the pathways involves direct pharmacological blockade of the musculature. It is possible to use topical administration of standardly employed ophthalmological agents to produce transient blockade of the iris neuromusculature. Blocking the sympathetically mediated alpha-adrenergic receptor of the dilator allows parasympathetic contributions to be measured uniquely. In contrast, blocking of the muscarinic receptor of the sphincter muscles limits pupillary activity to the sympathetically mediated dilator muscles. What is critical to this approach is that neither blockade results in any changes to central neural activation related to cognitive tasks that may be conducted. This method is employed in Experiment 2.

There are numerous neuropsychological tests that involve continuing mental load, including continuous performance tests of vigilance as well as mathematical processing paradigms. Among these, we selected the serial seven subtraction task. This task is widely used to impose a difficult cognitive load, both in mental status examinations and in the psychology and psychophysiology laboratories. The task remains demanding even over repeated test sessions, making it useful for repeated measures designs as employed in the current study.

Section snippets

Subjects

The subject group for Experiment 1 consisted of 22 healthy volunteers (11 female), with a mean age of 30.6 years (S.D.=7.9), education 15.2 years (S.D.=2.1), 21 Caucasian, 1 African–American, with three left-handed. All subjects signed informed consent approved by the VA Pittsburgh Healthcare System and University of Pittsburgh IRBs. Subjects were screened to exclude history of DSM-IV AXIS I psychiatric disorder or other major medical disorder (e.g. head trauma, diabetes, heart disease). No

Experiment 1: Results

Baseline pupil diameter: Pupil diameter measured during the 5-s period before the subject began to respond was significantly smaller during recording in light than that during recording in darkness (as expected, due to the normal effect of light; Fig. 1) (F1,21=30.6, P<0.001, η2=0.593). In addition, there was a significant main effect for task, with larger diameters during the Subtract 7 task than that during the Add 1 task (F1,21=4.6, P=0.043, η2=0.181).

Pupil diameter during response period

Discussion, Experiment 1

Pupil diameter was increased when a demanding task was imposed (Subtract 7) as compared to a simple addition and verbalization requirement (Add 1). The increase in diameter was observed in both the baseline and response periods. This suggests that as soon as the nature of the task was told to the subject, differential preparation and processing were already occurring, and were responsible for the primary effects associated with task difficulty. The modulation of light intensity resulted in

Method, Experiment 2

Subjects for Experiment 2 were 12 of the subjects (seven female) who participated in Experiment 1, with mean age=28 years (S.D.=5.7), education 15.7 years (S.D.=1.6), all Caucasian, one left-handed. Before further participation, an ophthalmologic screening was conducted to exclude the presence of the condition called narrow angle, since use of mydriatics such as tropicamide can lead to increased intraocular pressure in the presence of narrow angle, resulting in acute narrow angle glaucoma. No

Results, Experiment 2

Effects of drug administration are depicted for each experimental condition for both baseline and response period diameters (Fig. 3) and extent of pupillary dilation (response minus baseline, see Fig. 4). As previously noted, use of tropicamide to block the post-synaptic receptor site of the sphincter muscle (Loewenfeld, 1993) results in activity that is attributable to the sympathetically mediated dilator muscle. Conversely, use of dapiprazole to block the alpha-adrenergic receptor site of the

Discussion

Two approaches for isolating contributions of the sympathetic and parasympathetic pathways to pupillary dilation indicated differential contributions of these pathways during a sustained processing task. Increasing task complexity was associated with greater pupillary diameter and dilation. Moreover, manipulations of light intensity indicated an enhanced effect mediated through inhibition of the parasympathetic system, which was best observed when light intensity was increased, and was most

Acknowledgements

This work was supported by USPHS Grant MH55762 and by the Department of Veterans Affairs. We thank Annette Holcomb, B.S., for valuable assistance, and the nursing staff and pharmacy service of the VA Pittsburgh Healthcare System for their support.

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