Respiratory fluctuations in pupil size.

-AMERICAN JOURNAL OF PHYSIOLOGY Vol. 228, No. 4, April 1975. Printtd in U.S.A.

Respiratory

fluctuations

P. BORGDORFF Laboratory for Physiology,

in pupil

Free University,

Amsterdam,

B~RGDORFF, P. Respiratory fluctuations in pupil size. Am. J. Physiol. 228(4): 1094-l 102. 1975.-Regular fluctuations in pupil size of the cat were measured and the properties, nervous pathways, and origin of these oscillations were investigated. The rhythm of pupil movements under control conditions appeared to be either locked to the central respiratory cycle or to the artificial ventilator-y cycle. These movements were only seen in lightly anesthetized or tranquilized cats, but not in alert or deeply anesthetized cats (ether, halothane or pentobarbital). The fluctuations proved to be independent of sympathetic innervation but related to variations in parasympathetic outflow. At least two sources for pupil oscillations appeared to be involved: central respiratory activity and respiratory blood pressure fluctuations that modulated pupil width via sinoaortic baroreceptors. Lung movements per se, as a third possible factor, did not modulate pupil width, whereas electrical stimulation of the afferent lung vagi did; therefore the role of this mechanical factor is not clear. A review of the pertinent literature shows that in the organism there are many phenomena exhibiting respiratory oscillations. It seems likely that these oscillations have the same origin as the respiratory pupil fluctuations.

autonomic nervous system; waves; carotid sinus reflex; ments; reticular formation;

respiration center; baroreceptor denervation; central nervous system;

blood lung

pressure move-

cat

FROM INVESTIGATIONS OF respiratory fluctuations cf heart rate in dogs and cats, it was apparent that such fluctuations were also reflected in pupil diameter. Literature on this phenomenon proved to be scarce. Golenhofen and Petranyi (22) observed slight oscillations

in pupil size in their human subjects during dilatation of pupil after constriction evoked by a light stimulus. The dilatations were synchronous with inspirations, the constrictions with expirations. Respiratory pupil fluctuations were noted in pigeons also (49), but the relation with respiration was inverted. In these birds the sphincter is a striated muscle with somatomotor innervation. Furthermore, rhythmic pupil movements can occur in healthy subjects when they are relaxed (3, 9) and in narcoleptic patients when drowsy (64). This “hippus” has virtually the same rate as respiration but seems to be out of phase with it (9, 41). The cause of these various pupil fluctuations is not clear. In the present investigations we, tried to determine under what conditions respiratory pupil fluctuations occur in the cat, via what nervous pathways they are mediated, and how they are originated. the

METHODS

After anesthesia induction with initial surgery, a light anesthesia

sodium thiopental was maintained

and with

size

The Netherlands

halothane (1.5 ml/l00 ml of air). Most cats had neuromuscular blockade (succinylcholine) and were ventilated with room air (frequency ZO/min, tidal volume 10 ml/kg, maximum airway pressure 6 cmHsO), which gave arterial POT values of 89-103 mmHg, PCO~ values of ‘26.8-34.6 mmHg, and pH values of 7.35-7.43. Rectal temperature was kept at 37 & 1°C. Artificial respiration was recorded with a pressure transducer (Bell in the tube,

and

Howell)

connected

to a three-way

junction

and spontaneous respiration was recorded via a balloon catheter in the esophagus. Pupil movement was measured in dimmed light by an electronic pupillometer developed in our laboratory (8). The pupillometer is based on the principle of Lowenstein and Loewenfeld (42), but is simpler and especially adapted for experiments on animals. In the experiments in which the cervical sympathetic nerve was stimulated, recorded, or severed, the nerve was exposed 2-3 cm caudally to the superior ganglion and separated from the vagus and aortic nerve with a dissecting microscope. The phrenic nerve was exposed at C6 and Ce. Nerve activity was recorded by laying the intact nerve loosely across two hook-shaped platinum electrodes. A pool was formed by the wound edge and filled with liquid paraffin at 38°C. Amplifier bandwidth was 70-700 Hz. Nerve stimulation (150-200 mV, 20 Hz, 1 ms) was done with a square-wave stimulator isolated from ground and with constant current. A relatively large earth electrode around the stimulating electrodes prevented the stimulus from spreading to other nerves. In the experiments where sinus and aortic nerves were denervated, these nerves were identified by recording of action potentials and successively tied and cut. Arterial blood pressure was measured in a femoral artery by a Bell and Howell pressure transducer. In the experiments where an external air chamber (8) was used to abolish blood pressure waves in the carotid arteries, blocd pressure was measured via the connecticn between carotids and air chamber. Artificial variation cf arterial blocd pressure was accomplished by infusion and retraction of blood (kept at 38°C). A polyethylene catheter was introduced into the aortic arch via the left femoral artery and connected to a lo-ml syringe. Since pressure in the common carotid artery and femoral artery varied similarly and simultaneously c nly femoral artery pressure was measured. Central respiratory activity was suppressed by doubling the tidal volume (maximum airway pressure 10 cmH20). If this hyperventilation proved ineffective then instead a CO2 buffer (tris(hydroxymethyl)amincmethane (Tris)) (33, 53) was administered by an infusion pump into the left femoral

1094

Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (130.237.122.245) on August 20, 2018. Copyright © 1975 American Physiological Society. All rights reserved.

RESPIRATORY

PUPIL

1095

FLUCTUATIONS

vein. The Tris (250 mg/ml in 5 % glucose solution) was infused at the rate of 32 ml/h. After disappearance of .the phrenic discharges, i.e., after 5-10 minutes, the infusion rate was reduced to 3 ml/h. It should be mentioned that during Tris administration POT, Fco~, acd pH were, respectively, 69.3-78.5 mmHg, 16-23 mmHg, and 7.53-7.66. Recordings were made by means of a penwriter (Hellige) and Polaroid photographs taken frcm an oscilloscope screen (Knott). RESULTS

In cats under light anesthesia pupil diameter fluctuated with the rhythm of respiration. With spontaneous breathing every inspiration was accompanied by pupil dilatation, every expiration by pupil constriction. During artificial ventilation pupil dilatation (together with central inspiratory activity, as monitored frcm phrenic nerve activity) started during exsufflation and stopped halfway through insufflation (see Fig. 7). This happened in most of the exin which the central reperimen ts. In some experiments, spiratory cycle and the artificial ventilatory cycle were not occurred either during central locked, pupil dilatation inspiratory activity (see Fig. 9) or during exsufflation (see Fig. 10) and this relation could switch during an experiment. The amplitude of the pupil fluctuations varied from one cat to another and even during an experiment; it was generally between 0.2 and. 0.5 mm, but sometimes as much as 2 mm. art. r-p.

in

ex

‘(JdUL

pupil

4.5 set irregular

1. Example fluctuations

TABLE

1. Conditions

FIG.

Number of cats 6

108 7

incfIuencing

Experimental I. II.

20 20

of pupillary unrest: in pupil diameter.

Alert

rapidly

OCCUrrence

changing,

wide,

and

of respiratory pupd jktua

Fluctuations of 0.2 mm and larger can be observed with a magnifying glass, fluctuations of 0.3 mm and larger by the unaided eye. Occasionally pupil fluctuations with a frequency of 2-3/ min were seen, synchronous with Mayer waves in arterial blood pressure. ?hey occurred mainly in animals with low blood pressure and in poor condition. Scmetincs the pupillogram showed a very irregular course with rapidly varying fluctuations: this is known as pupillary unrest (Fig. 1). In such a state noises or pain stimuli caused pupil dilatation, which disappeared when anesthesia was intensified. Influence of Anesthesia on pu.d

TO find cut under which experimental conditicns pupil fluctuations cccur most clearly, several anesthetics were tried. In Table 1 the results are summarized. ‘It turned out that the occurrence of respiratory pupil fluctuations is locked to a state of light anesthesia or tranquilizaticn. In this state the light reflex is present and blood pressure normal but narcosis is then so deep that a sharp pinch in a leg or tail evokes no pain reacti’on in the form of pupil dilatation. Pupil fluctuations disappeared when the animal became alert or when anesthesia was slightly deepened. Nervous Pathways In order to study the contributions provided by the sympathetic and parasympathetic nerves, elimination and stimulation experiments were used. The results are summarized in Table 2. Elimination of sympathetic nerve activity by cervical sympathectomy (Fig. 2) or by local administration of sympathicolytic eye drops did not attenuate pupil fluctuations, not even when cervical sympathetic nerve activity showed respiratory fluctuations (see Fig. 9). . Neither electric stimulation of the cervical sympathetic nerves (Fig. 3) nor lccal application of drops of norepinephrine to the eye altered pupil fluctuations, not even when mean pupil diameter became as large as 10 mm. However, elimination of parasympathetic activity by tions

Condition

Respiratory Oscillations medium

Animals

Systemic Drugs deep pentobarbital recovering from

deep

light deeper

narcosis (0.3 vol.%) (up to 0.7 vol.%)

halothane halothane

3 7

deep ether

2

tranquilization (Libria,

Fluctuations

anaesthesia pentobarbital

ether anaesthesia followed by pentobarbital by benzodiazepine 20 mg/kg i.m.

miotic enlarging 2-5 2-5

m m

(depending on light)

slowly

none

none continuous

for

continuous reduced or

abolished

medium medium

none none

2-4

fluctuations

w

Pupil

several

hours

appear


P. BORGDORFF

1096 2. Infruence of symj?athetic or parasympathetic

TABLE

Number of cats

Experimental

acute aympathectomy 10% guanethidine drops

7 7

electric l&arterenol

stimulation drops

1% homatropine

in

drops

Effect

in

of sympathetic eye in

Average

pupil

art. resp.

sizes are given.

Average

chain

enlarged dilatation

eye

control

on Pupil

reduced reduced

eye

dilatation

light stimulation up to 500 lux 0.25% physostigmine drops in eye stimulation of sympathetic chain during light stimulation

7 7 7

pujd _fEuctuations

Procedure

7 7.

14

activity on resjiratory

size varied

between

3.3

and

Effect Pupil

mm mm

0.5 0.6

on Respiratory Fluctuations

none none

up to 10 mm to 6.25 mm

none none

to 7.3 mm

gradually

abolished

to 2.8 to 2.9

mm mm

decreased gradually

or abolished abolished

size

no fluctuations

constriction constriction dilation

Size

to control

.

4 mm.

i+ ’ ex in

JJJnddd

I

7.8 7.5m

I

3.8

pupil

2.0

mm

3.5

pupil ca 25 min

4. Effect of fluctuation. Amplitude 25 min, fluctuations has increased. FIG.

t sympathicotouxy

local administration of homatropine on pupil of fluctuations slowly decreases. At end of about are no longer perceptible. Mean pupil diameter

set FIG.

Amplitude

2. Effect of cervical sympathectomy of fluctuations hardly changes.

on

pupil

fluctuations. 3.8

pupi 1

1m

5.3 light

1

J 500

lux

set

PI

nmr FIG.

tions ously pupil el. stim.

/bvvPf .

FIG. 3. Effect of electrical on pupil width. Amplitude pupil diameter increases.

i2*s 200

.-

mv

J

stimulation of fluctuations

of cervical hardly

sympathetic changes, but

nerve mean

application of homatropine drops to one eye did gradually decrease the amplitude of the fluctuations, which finally ceased altogether (Fig. 4). In the other, untreated eye, pupil fluctuations remained present. After elimination of the parasympathetic activity pupil fluctuations only returned

5. Effect of light on pupil fluctuation. Amplitude decreases with larger light intensity; pupil diameter decreases.

of fluctuasimultane-

during a prolonged standstill of ventilation (longer than 0.5 min), indicating that pupil fluctuations can be mediated by the sympathetics as well, provided that sympathetic activity is strong enough. Enhancement of parasympathetic tone via the consensual light reaction (Fig. 5) or instillation of parasympathomimetic drops into the eye made the fluctuations disappear. Mean pupil diameter decreased to about 3 mm. Enlarging pupil diameter to control size, by means of sympathetic stimulation, did not restore pupil fluctuations (Fig. 6), indicating that the disappearance was not caused by a mechanical limitation of the sphincter, but by an increase in parasympathetic tone.


RESPIRATORY

PUPIL

FLUCTUATIONS

Origin

Three factors were studied: the rhythmic activity of the respiratory center, respiratory fluctuations in arterial blood pressure, and respiratory lung movements. Mutual influence was avoided by varying one factor while keeping the other two constant. Influence of respiratory

center. ARREST

OF VENTILATION.

In

14

paralyzed cats the influence of the respiratory center was studied while lung movements and arterial blood pressure fluctuations were arrested by discontinuing the artificial ventilation. As Fig. 7 shows, pupil fluctuations continued in the rhythm of phrenic discharge although respiration was stopped. In 4 of the 14 animals the experiment was successful only after the tidal volume had been reduced for some time to x of the initial tidal volume. The time elapsing between the start of phrenic discharge and pupil dilatation is 2001,000 ms. This latency varied from one cat to another and often changed during the course of an experiment. If the arrest of ventilation was maintained longer than about 20 s the phrenic discharges increased and pupil fluctuations grew larger and larger (fluctuations of 2 mm were no exception).

Mean pupil - * width increased as well (Fig. 8). It was clear that blood pressure and heart rate also started to vary strongly with phrenic discharge (Traube-Hering waves and sinus arrhythmia, respectively). ELIMINATION OF CENTRALRESPIRATORY ACTIVITY. To find out whether pupil fluctuations not only proceeded synchronously with central respiratory activity, but were also dependent on it, in the same 14 cats central respiratory activity was suppressed by hyperventilation (5 cats) or a Tris infusion (9 cats). When ventilation then was stopped the fluctuations ceased (Fig. 11). As soon as the phrenic nerve recovered its activity the pupil width started to fluctuate again and the mean pupil width increased. Injluence of blood pressure Jluctuations.

BLOOD

PRESSURE

VARI-

For this investigation the central respiratory activity was eliminated by means of hyperventilation or a Tris infusion and lung movement was stopped through arrest of ventilation., Mean arterial blood pressure was artificially varied by means of a catheter introduced into the aortic arch and connected to a lo-ml syringe. Figure 12 shows that reduction in blood pressure induced a pupil dilatation and increase in blood pressure produced a pupil constriction, ATION.

art. resp. phren.

pupil /-

light el. stim.

q

1400

lux

]I50

mV

set

FIG. 6. Combined influence of light and cervical sympathetic stimulation on pupil diameter. More hght causes fluctuations to cease and pupil width to decrease. By means of sympathetic stimulation pupil width can be restored to its original magnitude, but fluctuations do not return.

FIG. 8. Influence of prolonged arrest of ventilation on some phenomena controlled by autonomic nerves. Pupil fluctuations remain, while mean pupil diameter increases. Heart rate and blood pressure clearly also start to oscillate in the rhythm of phrenic discharges.

blood .presi

~

phren

-1

WV.

-]50

1.6 phren.

-

4 II,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

-115

,,v,

3 ::irn

Hg

50 w uv 3.9

pupil

set

FIG. 7. Influence of arrest of ventilation on pupil fluctuations. During arrest, pupil fluctuations remain and are in the rhythm of phrenic discharges (phren.). Respiratory fluctuations in arterial blood pressure cease almost entirely during arrest of respiration. Art. resp. = artificial respiration.

&I FIG.

in rhythm

9. Example of a recording with phrenic discharges

3.3 m set in which pupil fluctuations do occur but not in rhythm with ventilation.


1098

P. BORGDORFF

z.

pupil

phrcn.

so rv

‘I

blood press.

pupil

blood press.

phren.

1

art. resp.

t in t ex II,,,,,,,,,,,,,,,,,,,,,

PIG. 10. Example of a recording in which in rhythm with ventilation hut not in rhythm

phrea.

pupil fluctuations occur with phrenic discharges.

3

**II’IItIll*ll

set

PIG. 12. Effect of artificial blood pressure fluctuations width after hyperventilation and during arrest of ventilation. pupil fluctuations resemble those before arrest of ventilation.

on pupil Evoked

so PV 190 blood press.

pupil

mm Hg 130

pupil

blood press.

3.0

phren. 11111111111111111111111111111111_

see

both with a latency of 700-800 ms. If the blood prersure fluctuation was given the-same pattern as that during artificial ventilation, pupil fluctuations occurred that were very similar to the original pupiI fluctuations. This effect of blood pressure variation on the pupil size was demonstrable only when pupil fluctuations were already present just before arrest of ventilation, i.e., in 30 of the 49 experiments. BLOOD

PRESSURE

VARIATION

AFTER

BARORECEPTOR

.

L I

FIG. 11. Influence of arrest of ventilation on pupil fluctuations after activity of respiratory center has been temporarily eliminated by hyperventilation. Activity of phrenic is very slight. Original fluctuations disappear during arrest of ventilation.

DE-

The influence of arterial blood pressure on pupil diameter can neither be mediated by an increased filling of the iris vessels (41) nor by fluctuations in intraocular pressure (16). Therefore we focused our attention on the baroreceptors in the arterial system. The most important baroreceptors, i.e., those in the carotid sinus, the aortic arch, and the subclavian artery, were denervated by severing both the right and left aortic nerves and the right and left sinus nerves. This was accompanied by an increase of mean pupil diameter (average 1.1 mm) and a rise in mean blood. pressure (average 35 mmHg). When, during arrest of ventilation, blood pressure was again varied, no fluctuations in pupil size were found (Fig. 13). Even raising the blood

NERVATION.

3.2 mm

a]

50 uv

FIG. 13. Influence of artificial blood pressure changes on pupil diameter after denervation of baroreceptors. Measurements were made after hyperventilation and during arrest of ventilation. No influence of blood pressure on pupil width is now observed.

pressure by as much as 90 mmHg proved to have no effect on pupil diameter. In these experiments it was notable that the influence of blood pressure on the pupil did not decrease as long as not all baroreceptors mentioned were eliminated, regardless of the order of elimination. The same phenomenon has been found by others for the cardiodecelerator reflex (19). Infuence of lung movements. As can be seen in Fig. 13, after baroreceptor drnervation and hyperventilation pupil fluctuations were absent although the cat was ventilated, i.e., although there were lung movements. This result suggests that lung movements by themselves do not induce pupil fluctuations. It is possible, however, that the influence of the lungs was obscured by “overstretching” of the lungs during hyperventilation or by reduction of the parasympathetic tone due to baroreceptor denervation (2). We therefore repeated the experiment eliminating central respiratory activity by means of a Tris infusion only and abolishing blood pressure waves by use of an external air chamber (windkessel) connected to the carotids, in combination with


RESPIRATORY

PUPIL

1099

FLUCTUATIONS

bilateral aortic baroreceptor denervation (Fig. 14). Pneumothorax was not used because it did not abolish blood pressure fluctuations sufficiently.) In this way, too, lung movements did not evoke pupil fluctuations. However, weak electrical stimulation of the cut central end of the pulmonary division of the vagus trunk, just above the lung roots and below the cardiac fibers, produced a pupil dilatation. This dilatation varied from 0.2 to 1 mm, depending on stimulus strength (0.3-1.5 V, 50 H z, 1 ms), and persisted as long as stimulation continued. The latency time varied from 600 to 1,200 ms, depending on stimulus strength as well. Periodic stimulation of the pulmonary vagus branches, approxi-

blood press.

y&m

4 1windkesse pupi

1

;

1

HI3

1 opened 5.5

11

5.1

m

1

50 pv

phren. $~1111111111

I

Ill1

1

Ill

l

J’

set

FIG. 14. Effect of lung movements (art. resp.) on pupil size before and during connection to external air chamber (arrow). Blood pressure was measured via a connection to T junction in common carotid artery. Before connection there is synchronism between lung movements, blood pressure fluctuations, and pupil fluctuations. During connection both blood pressure and pupil fluctuations disappear.

TABLE 3. Origin Number of cats

of resfiratory

Experimental

arrest

14

of

DISCUSSION

It is remarkable that so few investigators make any mention of respiratory pupil fluctuations, since they are visible to the naked eye both in the cat and the dog. This is probably due to the depth of anesthesia used by others. As shown above, fluctuations only occur in animals under tranquilization and under light anesthesia (halothane or pentobarbital), but not in the alert animal or those under ether or deep halothane or pentobarbital anesthesia. The investigation into the nervous pathways yielded the following: pupil fluctuations proved to be independent of sympathetic innervation but related to variations in parasympathetic outflow. The minor role of the sympathetics in the genesis of pupil fluctuations could be a direct conse-

puPi/ Lfluctuations Procedure Central activity

14

mately in the rhythm of respiration, caused pupil fluctuations resembling those occurring in the intact animal. In addition to the pupil enlargements heart rate rose when the stimulus strength was 0.3-0.5 V, but the very reverse occurred when the stimulus strength amounted to 0.6 V or more. Arterial blood pressure remained unchanged; blood pressure decreased only with a stimulus strength of 1 V or more. The stimulation experiments were carried out after the respiratory center activity had been blocked by a Tris infusion and blood pressure fluctuations had been eliminated by arrest of ventilation. A summary of the experimental results concerning the origin of the respiratory pupil fluctuations is given in Table 3.

ventilation

Factors studied resp. Blood pressure fluctuations

Lung movements

Respiratory fluctuations

present

none

none

continue

arrest of ventilation after hyperventilation or THAMinfusion

none

none

none

abolished

7

artificial variation during

none

present

none

appear

7

the same procedure after baroreceptor denervation

none

ineffective

none

7

artificial hypervent. denervation

none

ineffective

none

7

artificial vent. after blood pressure stabilized air chamber

none

none

none

4

electrical stimulation lung afferents during and arrest of ventilation

none

none

blood pressure after hypervent., arrest of ventilation

ventilation after and baroreceptor

TRAM, by of TRAM

none

pupil

appear


P. BORGDORFF

1100 quence of anesthesia. a) Elimination of parasympathetic activity by application of homatropine caused pupil dilatation up to an average of 7.3 mm; in unanesthetized cats, however, homatropine evokes maximum dilatation, that is, up to 13-14 mm (unpublished experiments on 7 quiet cats). b) In our experiments sympathectomy reduced pupil width by only 0.5 mm; in unanesthetized cats with Horner’s syndrome this reduction proves to be much greater (41). Both facts indicate that in this investigation sympathetic activity was very slight.

fluence of lung movements and blood pressure fluctuations are more important. With our method of ventilation pupil dilatation generally began at the end of exsufflation and therefore could then only be caused by the inspiratory activity of the respiratory center. When phrenic discharges and ventilation were not synchronized, pupil fluctuations followed the rhythm of either one or the other (Figs. 9 and lo), sometimes changing from one to the other during the experiment. Relation to Other Respiratory Fluctuations

Origin It is evident from our investigation that both rhythmic activity of the respiratory center and arterial blood pressure fluctuations can cause fluctuations in pupil diameter. Lung movements were shown not to contribute to pupil fluctuations, but electrical stimulation of the afferent pulmonary nerves in the rhythm of respiration was proved to evoke fluctuations in pupil size. In these last experiments it is not likely that pupil dilatations were only part of a general pain reaction, because dilatation is already induced by very weak stimulation and, like the faster heart rate, persisted as long as stimulation was continued. In addition, arterial blood pressure did not increase in contrast to what happened in experiments with pain stimulation (e.g., 38). In our opinion we are concerned here with the same reflex that Anrep et al. (2) found in the dog when they examined the influence of lung movements on heart rate. They also found that weak stimulation of the afferent pulmonary fibers evoked cardiac acceleration but that stronger stimulation produced cardiac deceleration. This cardiac acceleration is claimed to be based on an inhibition of the vagus center in the medulla (Anrep). It now seems that this inhibition is not confined to the vagus center, but extends among others to the Edinger-Westphal nucleus. It still is not clear why electrical stimulation of the pulmonary vagus elicited a pupil dilatation whereas a lung expansion did not. For the time being we suppose that the explanation should be sought in the different experimental conditions. Interactions of the Three Injluences Now that it is known that respiratory pupil-diameter fluctuations can be produced by three different factors, the question arises as to which factor is the most important and what is the interaction between these factors. During spontaneous breathing inspiratory activity of the respiratory center is accompanied by lung inflation and a decrease in blood pressure. All these changes can bring about pupil dilatation. During expiration the opposite occurs. Which of the three factors then has most influence is not clear. During artificial ventilation the central inspiratory acti.vity occurs during the end of exsufflation and the beginning of insufflation, coinciding with an increase in blood pressure. The various influences therefore are then more or less in conflict and their relative strengths become important. Thus, under hypoventilation the influence of the respiratory center will be dominant, but with hyperventilat,ion the in-

Many other respiratory, fluctuations are reported in the literature. Some of them directly result from intrathoracic pressure changes during respiration, such as pressure and flow oscillations in the venous and arterial system, oscillations in filling of the peripheral vascular bed, and, more indirectly, oscillations in liquor pressure and in intraocular pressure (16). Other respiratory fluctuations are of an autonomic nervous nature, such as sinus arrhythmia (e.g., Z), Traube-Hering waves (e.g., 47), and fluctuations in peripheral resistance (e.g., 43). Furthermore, respiratory fluctuations are found in the latency of the pupillary light reflex (ZZ), in the amplitude of the carotid sinus reflex (35, 37), in the activity of several sympathetic nerves (e.g., l), and in the activity of branches of the cardiac vagus (e.g., 35). Still other respiratory fluctuations are of a somatic nervous nature, such as fluctuations in spontaneous motor activity (40, SO), in proprioceptive reflexes such as the knee jerk and the Achilles reflex (36, 54, 55, 58, 60), as well as in shivering (15, 39). This last group of fluctuations can be ascribed to variations in the fusimotor gamma activity (23). Furthermore, respiratory fluctuations have been observed in the electroencephalogram (27, 32, SO), the activity of the olfactory bulb (57), sensory thresholds (26, 56), “mental pictures” (24), and psychomotor reaction times (5, 30, 51). More reports are mentioned in reference 8. The origin of many of these respiratory fluctuations appears to be unknown, but when they have been investigated one or more of the following possible factors are always mentioned: the rhythmic activity of the respiratory center (2, 11, 13, 46, 59), fluctuations in arterial blood pressure (2, 35, 46, 48, 59, 61), and lung movements (2, 46, 59), which are the same three factors that turned out to be important in originating respiratory pupil movements. It therefore seems possible that all the mentioned respiratory fluctuations have their basis in a general, nonspecific fluctuation in activity within the central nervous system that is generated by one or more of the three factors presented in this paper. This impression is enhanced by the finding that the time relation between the fluctuations examined in the literature and respiration always points in the same direction, i.e., toward a higher activity of the whole organism during inspiration. How can we picture this ? Respiratory activity has been observed in almost the entire caudal reticular formation (4, 12, 32, 44, 62, 63) as well as in the pontine part of the medulla (20, 25). The activity of a number of neurons sometimes seems to be absent for quite a period while


RESPIRATORY

PUPIL

1101

FLUCTUATIONS

pupil

respiratory

ten

bloodpressure fluctuations lungmovements

15. Diagram of proposed origins of pupil fluctuations. From respiratory center and baroreceptors and probably receptors in lungs, rhythmic impulses reach the reticular formation (shaded area). Here they induce activity fluctuations that are conveyed to various organs, including the pupils. FIG.

This holds especially true when narbreathing continues. cosis is deepened (32, 62). In these studies the investigators therefore wonder whether all these neurons are involved in breathing. There seems to be an “irradiation” of activity

from the respiratory centers to surrounding areas in the medulla (34). The reticular formation (RF) is a very influential area. The activity level of almost the entire body is regulated from here. If we combine this general influence of the RF with the fact that respiratory activity has been demonstrated in many parts of the RF, it is not surprising that in many of the reticular areas of influence a fluctuation is found that is synchronous with the central respiratory activity. As part of the autonomic system the pupil is no exception to this. In the same way blood pressure fluctuations affect many bodily functions (6, 14, 18, 2 1, 29, 52). Signals from the carotid sinus reach not only the cardiovascular centers, but almost the entire RF, both the medullary and the pontine parts (3 1, 45). Lung movements too seem to modulate the activity of the entire RF (7). How the various respiratory biorhythms might originate is depicted schematically in Fig. 15. If this hypothesis holds true it becomes more comprehensible why the various respiratory fluctuations are generally observed only in a state of relaxation or light anesthesia and why they disappear when narcosis is intensified (as shown in this study) or during higher cortical activity (9, 17, 28, 40, 54, 55). With the deepening of the narcosis the irradiation of respiratory activity in the medulla oblongata decreases (32) and changes in blood pressure have less effect on the activity of the medulla (10). On the other hand it is known that attention diminishes the effect of the baroreceptors on the RF (6). In this respect it would be interesting to know whether or not attention diminishes the irradiation of respiratory activity as well. I thank Dr. W. J. A. Goedhard and Dr. N. Westerhof reading of the manuscript. This work was supported in part by a grant from the Fund. This work was performed as part of a dissertation at the versity of Amsterdam. A preliminary report of this study sented at the 12th Meeting of Medical-Biological Societies dam, 1971. Received

for publication

8 March

for Mrs.

critical Reef

Free Uniwas prein Rotter-

1974.

REFERENCES E. D., B. W. BRONK, AND G. PHILLIPS. Discharges in 1. ADRIAN, mammalian sympathetic nerves. J. Physiol., London 74: 115-l 33, 1932. 2. ANREP, G. V., W. PASCUAL, AND R. R~SSLER. Respiratory variations of the heart rate. Proc. Roy. Sot., London, Ser. 23 119 : 191-232, 1936. hippus. &o Ann. 3. BAGHIJI~, L. C. J., AND H. BOUMA. On pupillary Progr. Refit. 3: 85-89, 1969. 4. BIANCHI, A. L. Localisation et Etude des neurones respiratoires bulbaires. J. Physiol., Paris 63 : 5-30, 197 1. time as 5. BIRREN, J. E., P. V. CARDON, AND S. L. PHILLIPS. Reaction a function of the cardiac cycle in young adults. Science 140: 195196. 1963. M., P. DELL, AND G. HIEBEL. Tonus sympathique et 6. BONVALLET, activite electrique corticale. Electroencephalog. Clin. Neurophysiol. 6: 119-144, 1954. 7. BONVALLET, M., AND B. SIGG. fitude electrophysiologique des afferences vagales au niveau de leur pen&ration dans le bulbe. J. Physiol., Paris 50: 63-74, 1958. 8. BORGDORFF, P. Respiratoire Pupilbewegingen (Dissertation). Amsterdam: Free University, 1973, 122 p.

H., AND L. C. J. BAGHUIS. Hippus of the pupil: periods of slow oscillations of unknown origin. Vision Res. 11 : 1345-l 351, 1971. BRISTOW, J. D., P. C. ROBERTS, A. FISCHER, T. G. PICKERING, AND P. SLEIGHT. Effects of anesthesia on baroreflex control of heart rate in man. Anaesthesiology 31 : 422-428, 1969. CHERNIACK, N. S., N. H. EDELMAN, AND A. P. FISCHMAN. Patterns of discharge of respiratory neurons during systemic vasomotor waves. Am. J. Physiol. 217: 1375-l 383, 1969. COHEN, M. I. Discharge patterns of brain-stem respiratory neurons during Hering-Breuer reflex evoked by lung inflation. J. Neurophysiol. 32 : 356-374, 1969. COHEN, M. I., AND P. M. GOOTMAN. Periodicities in efferent discharge of splanchnic nerve of the cat. Am. J. Physiol. 218: 10921101, 1970. &QUERY, J. M., AND J. REQUIN. Influence du cycle cardiaque sur l’excitabilite reflexe medullaire chez l’homme. Communication de Biolopie de Marseille. Compt. Rend. Sot. Riol. 158 : 1887-l 891, 1964. CORT, J. H., AND R. A. MCCANCE. The neural control ofshivering in the pig. J. Physiol., London 120: 115-l 21, 1953.

9. BOUMA,

10.

11.

12.

13.

14.

15.


P. BORGDORFF

1102 H. Physiology of the Oculav and Cerebrospinal Fluids. London : 16. D~vsolv, Churchill, 1956. aspecten van mentale belasting (Dis17. ETTEMA, J. H. Arbeidsfysiologische sertation). Assen : Van Gorcum, 1967, 162 p. R. P. Influence of blood pressure on patterns of volun18. FORSYTH, tary behaviour. Psychophysiology 2 : 98- 102, 1965. 19. GABRIEL, M., AND H. SELLER. Interaction of baroreceptor afferents from carotid sinus and aorta at the nucleus tractus solitarii. P’egers Arch. 318 : 7-20, 1970. 20. GANONG. W. F. Review of Medical Physiology. Oxford : Blackwell, 1965, p. 533. 21. GELLHORN, E. Principtes of Autonomic-Somatic Integrations. Minneapolis: University of Minnesota Press, 1967, p. 24. AND P. PETRANYI. Respiratorische Einfliisse 22. GOLENHOFEN. K., auf die Dynamik des Pupillenlichtreflexes beim Menschen. Kybernetik 4: 55-65, 1967. 23. GRANIT, R., AND B. HOLMGREN. Two pathways from brainstem to gamma ventral horn cells. Acta Physiol. &and. 35: 93-108, 1955. 24. GRIFFITS, C. H., AND E. L. GORDON. The relation between the Traube-Hering and attention rhythms. J. Exptl. Psychol. 7: 117, 1924. of Physiological Psychology. New York : 25. GROSSMAN, S. P. A Textbook Wiley, 1967, p. 511. 26. GUILFORD, ,J. P. Fluctuations of attention with weak visual stimuli.

27.

Am. J. Psychol. 38: 534-583, GUREVICH, B. IS. Cited in:

33.

34.

35.

36. 37.

38. 39. 40.

42. 43.

44. 45.

46. 47. 48.

49.

50.

1927.

researches in by V. S. Rusionov Neurophysiol. Suppl. 8:

51. 52.

53. 54.

55.

56. 57.

263: 462, 1969. AND H. REINWEIN.

Zur Behandlung des Respiratory-Distress-Syndrome bei Frtihgeborenen mit Tris(hydroxymethyl)-aminomethan (THAM) und Netzmittel. He& Paediat. Acta 1 : 27-39, 1965. The activity of the medullary JOELS, N., AND M. SAMUELOFF. centres in diffusion respiration. J. Physiol., London 133: 360-372, 1956. KATONA, P. G., J. W. POITRAS, G. 0. BARNETT, AND B. S. TERRY. Cardiac vagal efferent activity and heart period in the carotid sinus reflex. Am. J. Physiol. 218: 1030-1037, 1970. KING, C. E., E. A. BLAIR, AND D. GARREY. The inspiratory augmentation of proprioceptive reflexes. Am. J. Physiol. 97: 329, 1931. KOEPCHEN, H. P., P. H. WAGNER, AND H. D. Lux. Ueber die Zusammenhange zwischen zentraler Erregbarkeit, reflektorischem Tonus und Atemrhythmus bei der nervijsen Steuerung der Herzfrequenz. Pfluegers Arch. 273: 443-465, 1961. KOIZUMI, K., AND I. SUDA. Induced moduIations in autonomic efferent neuron activity. Am. J. Physiol. 205: 738-744, 1963. KUHNKE, E. Kzltetremor und seine Amplitudenperiodik bei der narkotisierten Katze. PJluegers Arch. 254 : 421, 1952. LACEY, J. I., AND B. C. LACEY. The relationship of resting autonomic cyclic activity to motor impulsivity. Res. Publ., Assoc. Res. Nervous Mental Disease 36 : 144-209, 1958.

LOEWENFELD, 1. E. Mechanism of reflex dilatation of the pupil. Cot. Gbhthalmol. 12 : 185-448, 1958. LOWEKSTEIN, O., AND I. E. LOEWENFEI~D. Electronic pupillography. Am. Med. Assoc. Arch. Ophtholmol. 59: 352-363, 1958. MANOACH, M., S. GITTER, I. M. LEVUYGER, AAD S. STRICKER. On the origin of respiratory waves in circulation. I. The role of the

chest

Electroencephalographic of the Soviet Union,

the laboratories and clinics and hl. Y. Rabinovich. Electroenceph. C/in. 1958. K. E., AND A. B. VALLBO. Pulse and respiratory 28. HAGBARTH, grouping of sympathetic impulses in human muscle nerves. Acta Physiol. Stand. 74 : 96-l 08, 1968. 29. HEYMANS, C., AND E. NEIL. ReJlexogenic Areas of the Cardiovascular System. London: Churchill, 1958, p. 98. 30. HILDEBRANDT, G. AND P. ENGEL. Einfluss des Atemrhythmus auf die R eaktionszei t. Pjuegers Arch. 278 : 113- 129, 1963. 31. HICKMAN, C. H., K. E. LIVINGSTON, AND J. TALESNIK. Cerebellar modulation of reflex vagal bradycardia. Brain Res. 23: 101-104, 1970. 32. HIJKUHARA, T., Y. SAJI, N. KUMADAKI, H. KOJIMA, H. TAMAKI, R. TAKEDA, AND F. SAKAI. Die Lokalisation von atemsynchron enladenden Neuronen in der retikulgren Formation des Hirnstammes der Katze unter verschiedene experimentellen Bedingungen. Arch. Exptl. Pathol. Pharmokol. JARRE, W. VON, W. KETTERLE,

41.

58.

59.

60.

61. 62.

63. 64.

influence of inspiration and expiration. 1971. E. G. Observations on the activity of the respiratory neurones in the cat. IEEE Trans. Bio-Med. Eng. 16: 342, 1969. MIIJRA, M., AND D. J. REIS. Termination and secondary projections of carotid sinus nerve in the cat brain stem. Am. J. Physiol. 217: 142-153, 1969. OKADA, H. AND I. J. Fox. Respiratory grouping of abdominal sympathetic activity in the dog. Am. J. Physiol. 213: 48-56, 1967. PEIPER, U. Zur Genese Traube-Heringscher Blutdruckschwankungen. Arch. Kreislaufforsch. 40: 97- 116, 1963. Die efferenten Splanchnicus-entPEIPER, U., AND G. HAUCK. ladungen und ihre zeitliche Beziehung zu Blutdruckanderungen und Phrenicuspotentialen. P’uegers Arch. 273 : 335-344, 1961. PIERAU, F. K., E. ALEXANDRIDIS, G. SPAAN, A. OKSCHE, AND F. W. KLU~~MANN. Der Einfluss von lokalen Temperaturanderungen im pupillomotorischen Kerngebiet der Taube auf die Aktivitat der Irismuskulatur. Pfluegers Arch. 315: 291-307, 1970. POOLE, E. W. Periodic EEG discharges in subacute encephalitis with reference to respiratory and cardiac cycles. Electroencephalog. Clin. Neurophysiol. 12: 759, 1960. P~PPEL, E. Oszillatorische Komponenten in Reaktionszeiten. Naturwissenschof ten 55 : 449-450, 1968. REQUIN, J. Role de la per&licit& cardiaque dans la latence d’une reponse motrice simple. Communication a la So&% Fransaise de Psychologie. Psycho/. Francaise 10 : 155-l 63, 1965. ROBERTSON, N. R. C. Apnoea after THAM administration in the newborn. Arch. Disease Childhood 45 : 206-Z 14, 1970. SCHMIDT-VANDERHEYDEN, W. VON, L. HEINICH, AND H. P. KOEPCHEN. Investigations into the fluctuations of proprioceptive reflexes in man, I and II. PJIuegers Arch. 3 17: 56-71, 72-83, 1970. SCHMIDT-VANDERHEYDEN, W. VON, AND H. P. KOEPCHEN. Rhythmischen Eigenreflexschwankungen beim Menschen und ihre Beziehung zum Atemrhythmus. -P&egers Arch. 291 : R7, 1966. STEEVENS, S. S. Handbook of Experimental Psychology. New York: Wiley, 1966, p. 905. STORM VAN LEEUWEN, W., A. KAMP, M. L. KOK, F. DE QUARTEL, F. H. LOPES DA SILVA, AND A. M. TIELEN. Relations entre les acPJIuegers MIXRRIL,

pump.

Arch.

II.

325:

The

40-60,

tivitis ilectrigues ct!ribrales du chien, son comportement et sa direction tention. Paris: Masson 1967. p. 178. STRUGHOLD, H. Beitrage zur Kenntnis der Refraktgrphasen

d’ut-

der Eigenreflexe beim gesunden Menschen: 1. Mitteilung: Der Einfluss der Atembewegung auf den Patcllarunf Achillesreflex, 2. Biol. 88: 346, 1929. TANG, P. C., F. W. MAIRE, AND V. E. AMAISSIAN. Respiratory influence on the vasomotor center. Am. J. PhysioZ. 191 : 218-224, 1957. TRAVIS, L., AND W. TUTTLE. Periodic fluctuations in the extent of the knee-jerk and the achilles-jerk. J. Exptl. Psycho/. 11: 252, 1928. TUTTLE, R. S. Preganglionic discharge to the cardiovascular system in the comatose cat. Am. J. Physiol. 205: 754-760, 1963. WALDRON, J. Activity patterns in respiratory muscles and in respiratory neurones of the rostra1 medulla of the cat. J. Physiol., I.ondon 208: WOLDRING,

373-383,

1970.

S., AND M. N. J. DIRKEN. Site and extension of bulbar respiratory centre. J. iVeurophysiol. 15 : 226-24 1, 195 1. Yoss, R. E., N. J. MOYER, AND R. W. HOLLENHORST. Hippus and other spontaneous rhythmic pupillary waves. Am. J. Ophthalmol. 70: 935-941, 1970.


Pupil size and stereoacuity.

The role of pupil size in communication.

Pupil size, eye contact, and instrumental aggression.

The effect of pupil size on accommodation.

Pupil size tracks perceptual content and surprise.

Variation in pupillomotor responsiveness with mean pupil size.

Unequal pupil size in patients with unilateral red eye.

Changes in the objective amplitude of accommodation with pupil size.

A circuit for pupil orienting responses: implications for cognitive modulation of pupil size.

Hyperactivity Disorder.

Normal pupil size and anisocoria in newborn infants.

Relationship between postoperative pupil size and disability glare.

Pupillometry reveals increased pupil size during indirect request comprehension.

Effect of pupil size on biometry measurements using the IOLMaster.

Pupil size reflects the focus of feature-based attention.

Chimpanzees and humans mimic pupil-size of conspecifics.

The influence of drop size on pupil dilatation.

The simultaneous application of positive-end expiratory pressure with the Trendelenburg position minimizes respiratory fluctuations in internal jugular vein size.

Quantitative assessments of arousal by analyzing microsaccade rates and pupil fluctuations prior to slow eye movements.

Universal size-dependent conductance fluctuations in disordered organic semiconductors.

Pupil fluctuations track fast switching of cortical states during quiet wakefulness.

Estimating mental workload through event-related fluctuations of pupil area during a task in a virtual world.

Coupling between pupil fluctuations and resting-state fMRI uncovers a slow build-up of antagonistic responses in the human cortex.

Changes in pupil size following panretinal retinal photocoagulation: conventional laser vs pattern scan laser (PASCAL).