Effect of Alterations in Mental Activity on the Breathing Pattern in Healthy Subjects 1- 3

M. JEFFERY MADaR and MARTIN J. TOBIN

Introduction

Breathing is regulated by an automatic metabolic control system located in the brainstem and a behavioral or voluntary control system located in supramedullary and cortical structures (1). Although the metabolic control system exerts the predominant control during resting breathing, the mean output of the respiratory control system can be overridden by behavioral factors in certain circumstances (2). However, it is not known how behavioral stimuli influence the constancy of respiratory center output, which is also important when considering the overall function of a control system. Information on the constancy of respiratory center output can be obtained by measuring the breath-to-breath variability in breathing pattern (3). During wakefulness, studies of breathing pattern have revealed marked breath-to-breath variability (4-7), but the factors responsible for this variability are unknown. However, it is known that the variability of breathing pattern is decreased during deep non-rapid eyemovement (NREM) sleep (8-12), a time when the level of mental activity is considered reduced (13). We (14) and others (15-18) have shown that the mean values of breathing pattern components are altered by performing mental arithmetic, a task that increases attention and cognitiveactivity. However, the effect of mental activity on the variability of breathing pattern has not been formally assessed. Accordingly, we tested the hypothesis that different forms of mental activity can alter the variability of breathing pattern. To test this hypothesis, we measured breathing pattern during a carefully defined state of "resting wakefulness": the eyes were closed, a blindfold was applied, headphones were worn to exclude auditory stimuli, and the electroencephalogram (EEG) was monitored continuously to verify that the subject had not fallen asleep. We compared the variability 0 f the breathing pattern during this state of resting wakefulness

SUMMARY The overall output from the respiratory centers is regulated by an automatic metabolic control system in the brainstem and by higher neural centers under direct voluntary control. An understanding of the constancy with which respiration is controlled can be obtained by measuring the breath-to-breath variability in breathing pattern. Wehypothesized that different forms of mental activity would alter the variability of breathing pattern. Totest this hypothesis, we measured breathing pattern on a breath-by-breath basis during resting wakefulness and during four conditions of altered mental activity. Measurements were obtained with a calibrated respiratory inductive plethysmograph, and variability was assessed by calculations of the coefficients of variation. We also examined the effect of the altered states of mental activity on the mean values of the breathing pattern components. We found that noxious stimulation increased the variability of all the breathing pattern indices, audiovisual stimulation tended to Increase the variability of tidal volume (VT), and mental arithmetic had no effect. In addition,the variability of breathing pattern was increased during rapid eye movement sleep and decreased during Stage IV sleep. The variability of VTand expiratory time were greater than that of Inspiratory time (TI) across the different states of mental activity. Significant correlations were observed between VTand 11and between VT and frequency (f) during Stage IV sleep. With regards to the mean values, mental arithmetic, audiovisual stimulation, and noxious stimulation all Increased minute ventilation and mean Inspiratory flow. The Increase In minute ventilation was achieved solely by an increase in f during mental arithmetic and audiovisual stimulation and by an increase in both f and VT during noxious stimulation. These results demonstrate that higher centers affect the breath-to-breath variability of the breathing pattern and that they exerted a greater influence on the variability of respiratory volume than on that of respiratory timing. AM REV RESPIR DIS 1991; 144:481-487

with four conditions of altered mental activity: watching television (increased auditory and visual stimulation); performing mental arithmetic (increased cognitive activity); staring at a bright light (noxious stimulation); and various stages of sleep. We were interested not only in overall changes in variability but also in the relative variability of indices of respiratory volume and timing because in a previous study, performed during wakefulness, we found that measurements of respiratory volume were more variable than those of respiratory timing (7). A number of investigators (4,6, 19-22) have shown that certain breathing pattern components are significantly correlated with each other. Newsom-Davis and Stagg (21)have speculated that these interrelationships are wakefulness dependent as the strength of the correlations appeared to deteriorate at sleep onset. To determine whether this was in fact the case, we examined the interrelationships between breathing pattern components during Stage IV sleep. Finally, we examined the effects of alterations in mental

activity on the mean values of the various breathing pattern components because many previous studies have not included a rigorously defined resting state. Indeed, there is considerable conflict among studies about the effect of sleep on breathing pattern (10-12, 23, 24). A failure to adequately control the external environment during wakefulness could be at least partly responsible for some of the discrepancies among previous studies. (Receivedin originalform December 29, 1989 and in revised form August 17, 1990) 1 From the Division of Pulmonary Medicine, State University of New York at Buffalo, Veterans Administration Medical Center, Buffalo, New York, and the Division of Pulmonary and Critical Care Medicine, Edward Hines Jr. Veterans Administration Hospital, Loyola University of Chicago, Stritch School of Medicine, Hines, Illinois. 2 Supported by Veterans Administration Medical Research Funds. 3 Correspondence and requests for reprints should be addressed to M. Jeffery Mador, Division of Pulmonary Disease, State University of New York at Buffalo-VAMC, 3495 Bailey Avenue, Buffalo, NY 14215.

481

482

MADOR AND TOBIN

Methods

Subjects Nine healthy subjects, seven men and two women, aged 26 to 35 (mean 29.5) yr, volunteered for this study. The study was approved by the committee for the protection of human subjects of the health science center, and informed consent was obtained from all subjects.

Respiratory Inductive Plethysmograph A detailed description of the de-coupled respiratory inductive plethysmograph (RIP) (Respitrace'"; Non-Invasive Monitoring Systems, Miami Beach, FL) has been published (25). Calibration against simultaneous spirometry was accomplished by the two-position least-squares method (25). Validation was checked against simultaneous spirometry during tidal breathing in the horizontal, semirecumbent, and lateral decubitus positions and the percentage difference (mean ± standard deviation [SD]) from spirometry, ignoring the algebraic sign, was calculated. Data were considered unacceptable if the validation procedure indicated that RIP measurements displayed a greater than lOOJo difference from spirometry in any posture. The signals from the RIP were recorded using a Z-80A-based microprocessor system (Respicomps; Non-Invasive Monitoring Systems), which sampled the data at 20 points/s. On a breath-by-breath basis, it continuously calculated minute ventilation (VI), f, tidal volume (VT), inspiratory time (TI), expiratory time (IE), fractional inspiratory time (TIl Ttot), mean inspiratory flow rate (VT/TI), and the percentage contribution of the rib cage (RC)-to-VT (OJoRC/VT). The degree of asynchronous or paradoxical motion of the RC and abdominal (AB) compartments also were measured (26, 27). The amount of RC and AB paradox was computed by taking the derivatives of the RC, AB, and sum signals (VT) and comparing their algebraic signs. If a compartmental signal was negative (downgoing) when the sum (VT) signal was positive (upgoing during inspiration), the motion of that compartment was considered paradoxical at that moment. The paradoxical volume excursion was calculated by volume integration over the time span of the paradoxical motion. The inspiratory AB paradox was computed as the

ratio (expressed as a percentage) of the paradoxical volume of the AB to the total volume excursion of the AB, both in phase and out of phase with the sum signals. The inspiratory RC paradox was computed similarly. Calculation of the degree of asynchronous motion of the RC and AB was based on the analysis of sinusoidal phase shifts according to the equation e = sin:' MIS, where e is the phase angle, M is the distance between the intercepts of the RC-AB loop on a line drawn parallel to the x axis, which is placed at onehalf the distance between the maximum and minimum RC excursion, and S is the maximal AB excursion (28).

protocol. Each problem had six to seven steps to the final solution, and the subject was allowed approximately 3 s at each step. The subject was informed that the final solution would be an integer between 1 and 9, thus allowing the answer to be signaled by a show of fingers without requiring speech. At the end of each problem the subject was informed of whether the answer was correct. Breathing pattern measurements were obtained for lOmin during baseline, mental arithmetic, and audiovisual stimulation but only for 2 min during noxious stimulation because the retina rapidly adapts to bright lights (29). After collection of the data during the various wakeful states, the lights were switched off and the subjects were allowed to sleep. Sleep records were scored according to the standard criteria of Rechtschaffen and Kales (30). Sleep efficiency was defined as the time asleep divided by the total time of the study after switching off the lights, expressed as a percentage. Breathing pattern measurements were obtained for 5-min periods during Stage II, Stage IV, and REM sleep. The sleep stage was stable for at least 2 min before the breathing pattern measurements, and no change in sleep state, however brief, occurred while the breathing pattern was being measured. The first 5-min period meeting these criteria was chosen for analysis for each sleep stage. Rather than lO-min time periods, 5-min periods were selected because 10 consecutive min of "pure" REM or Stage IV sleep was not available in many subjects. Validation of the RIP was checked against simultaneous spirometry in the supine, lateral decubitus, and semirecumbent positions after the subject had passed through all sleep stages. The subject was then encouraged to go back to sleep, and the validation of the RIP was again checked upon termination of the study at 6 A.M.

Experimental Protocol Subjects were studied overnight in a sleep laboratory. All studies began at 9 P.M. The bands of the RIP were securely fastened to the chest and abdomen with adhesive tape, and the device was calibrated and validated against simultaneous spirometry. Electrodes werethen attached to the scalp, the skin adjacent to the lateral canthi, and the submental region, providing EEG (C4/A 1 and C 3/A2 ) , electrooculogram, and electromyogram signals, respectively. The signals were recorded on a polygraph (Grass Instruments, Quincy, MA) at a paper speed of lO mm/s. Following successful validation of the RIP, the subjects rested quietly on a bed for 15 min and then the breathing pattern was measured during (1) the resting state (baseline), (2) increased cognitive activity as occurs when performing. mental arithmetic, (3) increased audiovisual stimulation as occurs while watching television, and (4) noxious visual stimulation produced by shining a bright light into the subject's eyes. These experimental interventions were performed in a randomized manner. During baseline measurements, the subjects were asked to remain as relaxed as possible without falling asleep; the EEG was monitored continuously to ensure that the subjects had not fallen asleep. The eyes were closed, a blindfold was applied, and padded headphones were worn to exclude auditory input. Mental arithmetic consisted of 24 problems involving addition, subtraction, multiplication, and division of one to three-digit numbers. These problems were called out in a stereotype fashion from a previously prepared

Data Analysis Mean values of the various breathing pattern parameters were calculated for the different states of mental activity. In addition, breathto-breath variability in breathing pattern within each subject was assessed by calculating the coefficient of variation (SD divided by the mean and expressed as a percentage) for the various breathing pattern parameters. In turn, the group mean coefficient of variation

TABLE 1 EFFECT OF DIFFERENT STATES OF MENTAL ACTIVITY ON THE VARIABILITY OF THE BREATHING PATIERN (COEFFICIENT OF VARIATION) (%)* Resting State VT TI TE VTITI

26.7 19.7 22.8 30.2

± ± ± ±

4.3 2.8 3.2 6.3

Audiovisual Stimulation

Mental Arithmetic

34.7 19.6 25.3 28.3

26.3 19.2 22.2 28.3

± ± ± ±

3.2 1.8 2.2 3.2

± ± ± ±

5.0 3.0 2.7 5.3

Noxious Stimulation

57.5 42.6 42.3 53.8

± ± ± ±

9.5t 5.9t 6.3t 8.1

REM Sleep

35.2 23.6 38.5 34.8

± ± ± ±

3.5 2.6 6.8t 3.0

Stage II Sleep

23.0 16.5 19.0 26.8

± ± ± ±

4.1 1.6 2.1 3.3

Stage IV Sleep

11.0 14.4 13.7 16.0

± ± ± ±

1.9t 1.6 1.2t 3.2

p Value

< 0.0001 < 0.0001 < 0.0001

• V~lues are mean ± SEM, n = 9. The effect of mental activity on the coefficient of variation of the variables was assessed by multivariate analysis of vana~ce:. The differe~t st~tes of mental activity w~re then compared with the resting state using a Bonferroni correction for multiple comparisons. The v.an~~llIty of. mean inspiratory flow (VTNI, a denved variable) is shown for qualitative comparison to the primary variables. t Significant difference from resting state.

483

EFFECT OF MENTAL ACTIVITY ON BREATHING PATTERN

was calculated for each parameter for the different states of mental activity. As recommended for statistical analysis of coefficients of variation, the data were logarithmically transformed before statistical analysis (31). Least-squares linear regression analysis was used to analyze the relationships between VT and TI, between VTand f, and between Tt and IE during Stage IV sleep. The number of breaths utilized in the determination of the correlation coefficients varied from 62 to 233 breaths depending on the number of minutes analyzed and the subject's f. The significance of changes in the mean values of the breathing pattern indices betweenthe different states of mental activity was assessed by two-way analysis of variance (subjects, Factor 1;states of mental activity, Factor 2). If this overall comparison of factor 2, that is, states of mental activity, was significant, each state was compared with resting wakefulness by analysis of variance using a Bonferroni correction for multiple comparisons. Changes in breathing pattern variability were assessed by multivariate analysis of variance to allow comparison of the relativevariability of the different breathing pattern parameters. Tolimit the number of potential comparisons only the primary respiratory variables (VT, TI, and IE) were statistically analyzed. First, weexamined whether the overall variability of the breathing pattern was affected by the different states of mental activity (Hotelling-Lawley trace statistic). If this overall comparison was significant, we next determined which breathing pattern indices were responsible for this change. For those breathing pattern indices that significantly contributed to the overall effect, the individual states of mental activity were compared with resting wakefulness within the multivariate analysis of variance using a Bonferroni correction for multiple comparisons. Finally, the relative variability of VT, Tt, and IE were compared across the different states of mental activity.

tematic difference between RIP and spirometric measurements.

Sleep Stage The total study time after switching off the lights was 6.6 ± 0.3 h (standard error of the mean [SEM)). Despite the experimental equipment and unfamiliar environment, none of our subjects had difficulty in sleeping (sleep efficiency, 82.8 ± 2.5070). REM sleep occurred in all subjects, and Stage IV sleep was present in eight of the nine subjects. The subjects spent 6.7 ± 0.7% in Stage 1,31.8 ± 1.7% in Stage II, 10.1 ± 0.5% in Stage III, 12.5 ± 2.0% in Stage IV, and 21.7 ± 1.6% in REM sleep. Variability of Breathing Pattern Alterations in the state of mental activity had a highly significant effect on the variability of the breathing pattern (table 1) (p < 0.0001,Hotelling-Lawleytrace statistic). VT, n, and 1£ all significantly contributed to this effect (p < O~OOOI in each instance). Comparing each state of mental activity with resting wakefulness (baseline), noxious stimulation resulted in a global increase in the variability of the breathing pattern. Mental arithmetic had no effect on the variability of the breathing pattern, whereas audiovisual stimulation tended to increase the variability of VT, although this change did not reach statistical significance (p < 0.05). The duration of sampling during noxious stimulation was shorter (2 min)

Breathing Pattern (Mean Values) Compared with the baseline state of resting wakefulness, VIwas significantly in-

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Results

Validation of the Respiratory Inductive Plethysmography Validation of the respiratory inductive plethysmograph against simultaneous spirometry in the horizontal, semirecumbent, and lateral decubitus positions revealed differences (ignoring the algebraic sign) at the start of the study of 3.4 ± 1.2, 3.0 ± 1.0, and 5.4 ± 1.1%, respectively. Repeat validation after the subject had passed through all sleep stages revealed differences of 5.6 ± 1.1, 6.7 ± 1.7, and 5.4 ± 0.8070, respectively. Repeat validation upon completion ofthe study revealed differences of 6.3 ± 0.8, 5.5 ± 1.2, and 3.4 ± 0.9%, respectively. Taking the algebraic sign into account, there was no significant difference between RIP and spirometry in any posture at any time, indicating that there was no sys-

than at baseline (10min), but this factor was not responsible for the increase in variability since equivalent results were obtained when noxious stimulation was compared with the first 2 min of baseline. Frequency histogram analysis indicated that there was greater scatter during noxious stimulation compared with baseline for both nand VT. Histograms from a representative subject are shown in figure lA. The variability of breathing pattern during sleep depended on the sleep stage: it was more variable than baseline during REM sleep, less variable during Stage IV sleep, and of similar variability during Stage II sleep. Frequency histograms displayed less scatter during Stage IV sleep compared with baseline for both nand VT. Histograms from Stage IV sleep compared with baseline (for the same subject as in figure lA) are displayed in figure lB. Tt was significantly less variable than VT across the different states of mental activity (p < 0.0001) (table 1 and figure 2). However, during Stage IV sleep, this relationship was reversed in that Tt was significantly more variable than VT (p < 0.001). Tt was also significantly less variable than Th across the different states of mental activity (p < 0.002), but the variability of VT and Th were not significantly different.

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Fig. 1. Frequency histograms of inspiratory time (TI)and tidal volume (VT) in a representative subject. Baseline (resting wakefulness) (solid line) is compared with noxious stimulation (interrupted line) in A and with Stage IV sleep (interrupted line) in B. Compared with baseline, the frequency histograms displayed greater scatter during noxious stimulation (p < 0.01 for both Ti and VT, MannWhitney U test of variability) and less scatter during Stage IV sleep (p < 0.002 for both Ti and VT).

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MADaR AND TOBIN

484 Fig. 2. Coefficients of variation of tidal volume (VT) (solid bars) and of inspiratory time (Ti) (stippled bars) at baseline (resting wakefulness, BL), while watching television (audiovisual stimulation [AVSj), during mental arithmetic (MA), during noxious stimulation (NS), and during REM, Stage II, and Stage IV sleep. VTwas significantly more variable than Ti across the different states of mental activity (p < 0.0001). However, during Stage IV sleep this relationship was reversed in that Tl was significantly more variable than VT.

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creased during mental arithmetic (15.8%) and noxious stimulation (36.10/0), a tendency toward an increase in VI was observed during audiovisual stimulation, and a significant decrease in VI was observed during Stage IV sleep (6.2%) (table 2). During audiovisual stimulation and mental arithmetic, the rise in VIwas achieved entirely by an increase in f, and in fact there was a slight but insignificant decrease in VT. In contrast, the rise in VI during noxious stimulation was mediated by both f and VT, but the reduction in VI during Stage IV sleep was mediated solely by VT. The changes in f with the various states of mental activity were predominantly due to alterations in 11, and Ts was less consistently affected. Likewise, there were no consistent alterations in Tr/Ttot (p = NS, two-way analysis of variance). Increases in VT/1I were observed during audiovisual stimulation (12.1 0/0), mental arithmetic (24.3%), and noxious stimulation (37.70/0); the values of VT/1I during sleep were similar to those at baseline. Compared with a baseline value of 38.5 ± 5.4%, the RC to VT ratio increased during Stage II and IV sleep to 53.3 ± 5.40/0 (p < 0.01) and 52.1 ± 5.5% (p < 0.01), respectively, and remained unchanged during REM sleep (31.8 ± 6.90/0), audiovisual stimulation (35.5 ± 6.70/0), mental arithmetic (39.1 ± 6.3%), and noxious stimulation (36.4 ± 5.1 %).

STII

STIV

There were no significant differences in the degree of asynchronous or paradoxical breathing between baseline and NREM sleep. In contrast, during REM sleep, there was a significant increase in the phase angle (a measure of asynchronous breathing) and in the degree of RC paradox compared with both baseline (p < 0.05 and p < 0.03, respectively) and NREM sleep (p < 0.04 in each instance), but the degree of AB paradox was not significantly different (figure 3).

Interrelationships between Breathing Pattern Indices During Stage IV sleep, a state in which breathing pattern is expected to display stationary properties, VT and 11 were

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Discussion

This study showed that alterations in mental activity have a number of effects on breathing pattern, both in terms of changes in the mean values of different components and in their breath-to-breath variability. The alterations in particular indices are specific to the nature of the mental stimulus.

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positively and significantly correlated in six of eight subjects (there was no Stage IV sleep in one subject). The mean r for all subjects was 0.42 ± 0.09, range 0.15 to 0.79. Because a few outlying values can significantly influence the strength of a correlation, the data were reanalyzed after eliminating all breaths whose VT or 11 was above or below 2SD from the mean. The mean r improved slightly to 0.46 ± 0.08, range 0.25 to 0.79, and the correlation was then significant in all eight subjects. VT and f also were significantly correlated in six subjects, although the strength ofthis correlation was slightly weaker than that between VT and TI: mean r - 0.39 ± 0.09, range -0.06 to -0.78. In contrast, 11 and Ts were significantly (positively) correlated in only one subject. The mean r was only 0.09 ± 0.05, range -0.11 to 0.24.

200 breaths, subpared with a period of silence. In the lat- sequently confirmed these findings and ter experiment, the basic musical rhythm also found that the relationship between appears to have acted as an auditory VT and TIwas stronger than that between pacemaker (zeitgeber), causing entrain- VT and f. They interpreted their findings ment of the breathing pattern. Behavioral as indicating that VT/TIis held constant tasks that increase the level of alertness from breath to breath despite wide varistimulate the reticular activating system ations in individual values of VT and TI. (38). A relatively specific "attention" task However, they examined the relationship like mental arthimetic may produce more between VT and TI and did not obtain pronounced stimulation of the reticular direct measurements of VT/TI on a activating system compared with that breath-to-breath basis. In the present resulting from other forms of mental study, it is apparent that VT/TI was not stimulation. Finally, noxious stimulation held constant on a breath-to-breath baand to a lesser extent mental arithmetic sis, and indeed, the breath-to-breath variactivate the autonomic nervous system, ability of VT/TIfrequently exceeded that leading to release of catecholamines, of VT or TI (table 1). which can alter the pattern of breathing In a single subject, Newsom-Davis and (39). Thus, it is apparent that specific al- Stagg (21) observed a reduction in the VTterations in the breath-to-breath variabil- TI correlation at sleep onset compared ity of the breathing pattern occur with with wakefulness. This observation led different mental stimuli, and the speci- them to speculate that the level of alertficity of this response is probably due, ness may be important in determining the at least in part, to differential activation strength of the VT-TI relationship. Howof cortical and subcortical structures. ever, Daubenspeck and Farnham (20) In a previous investigation of breath- have recently shown that the VT-TI relaing pattern during wakefulness (7), we tionship changes over time during wakefound that subjects displayed greater fulness. This temporal variability raises variability in VT and VT/TI, indices of re- questions about the validity of the obspiratory volume and drive, than in for servations of Newsom-Davis and Stagg Ti/Ttot, indices of respiratory timing. We since differences in the strength of the interpreted this finding to indicate that VT-TI correlation may simply have been the rhythm-generating function ofthe re- a reflection of the underlying temporal spiratory control system is more constant variability. We have measured the VT-TI than the gain of the output signal. In the . relationship during Stage IV sleep, a time present study, we examined the relative when periodicity is known to be minivariability of VT (an index of respiratory mal or absent (41) and thus the breathvolume) compared with TI (a primary ing pattern is likely to be temporally innonderived index of respiratory timing) variant. We found a significant positive across the different states of mental ac- correlation between VT and TI; because tivity (table 1 and figure 2). Similar to influences from the forebrain (mental acour previous study, VT tended to be more tivity) are believed to be minimal or abvariable than TI during all experimental sent during Stage IV sleep, this suggests conditions, with the exception of Stage that the VT-TI relationship is not depenIV sleep (figure 2). During Stage IV sleep dent on forebrain or wakefulness stimuli. breathing is controlled primarily by the Breathing Pattern (Mean Data) metabolic control system located in the brainstem, whereas during wakefulness Employing a baseline period of resting and REM sleep higher neural centers ex- wakefulness for comparison, we found ert a greater influence on breathing (40). that increases in audiovisual stimulation Thus, the greater breath-to-breath vari- (watching television), cognitive activity ability of respiratory volume compared (mental arithmetic), and noxious stimuwith respiratory timing does not appear lation (staring at a bright light) produced to be an intrinsic property of the central increases in VI and VT/TI. Interestingly, pattern generator but, rather, may reflect the increase in VI observed during menthe modulating action of higher neural tal arithmetic and audiovisual stimulacenters on respiratory output. tion was achieved by an increase in f, but Priban (22) was one of the first inves- that observed during noxious stimulation tigators to examine the interrelationships was mediated by both f and VT. Recentbetween breathing pattern parameters in ly, Shea and colleagues (18) also examawake humans. He found short-term ined the effect of audiovisual stimulation recurring changes in VT and f that were on breathing pattern using a strictly de-

486

fined baseline period for comparison, and they also found an increase in f (12 versus 16070 in our study). The alterations in breathing pattern we observed during audiovisual stimulation are similar in direction but smaller in magnitude than those we (14) and others (15-17) have observed during mental arithmetic and during the performance of other types of stereotyped "attention tasks" (42). These results suggest that an increase in the level of arousal per se may lead to a relatively stereotyped breathing pattern response, that is, increases in f and VT/TI. In contrast, noxious visual stimulation resulted in an increase in both VTand f. Clearly, noxious stimulation is quite a different mental stimulus than either mental arithmetic or audiovisual stimulation, and it is expected to produce a different pattern of cerebral activation (see discussion of breath-to-breath variability). In addition, noncerebral factors may be important. For instance, cognitive activity has been shown to produce a 47% increase in plasma epinephrine (39), and the administration of adrenergic drugs is known to increase VI and oxygen consumption. In a recent study investigating the breathing pattern during anticipation of exercise (14), we observed increases in VI and VT/TI compared with baseline. However, these increases in ventilation were totally volume based, in contrast with the time-based changes in ventilation with mental arithmetic. These results suggest that the alterations in respiratory drive with different forms of mental activity may be achieved by different mechanisms. We also examined the breathing pattern during sleep. There was no significant difference in VI between wakefulness and Stage II and REM sleep and only a slight reduction in VI during Stage IV sleep. These results contrast with those of previous studies, in which reduction in VI during all stages of sleep has been more easily demonstrated (8, 10-12,43). At least two factors may account for this discrepancy. First, many of the previous studies employed a mouthpiece or face mask when measuring ventilation. These devices can alter the breathing pattern and lead to an increase in VI (44, 45), an effect that may be most pronounced during wakefulness. Indeed, in a recent review, Krieger (23) pointed out that the change in VI between wakefulness and NREM sleep was much smaller in studies in which ventilation was measured noninvasively with inductive plethysmography or magnetometers (0.46 ± 0.21 L/min),

MADOR AND TOBIN

compared with studies in which ventilatory measurements required the use of a face mask or mouthpiece (0.97 ± 0.50 L/min). The reduction in VIbetween resting wakefulness and Stage IV sleep in the present study (0.39 L/min) is comparable to that observed by other investigators employing noninvasive measuring techniques (12, 46). Second, the measurements of ventilation during wakefulness in most previous studies were not obtained under strictly defined "resting conditions." The state of audiovisual stimulation in our study may be more representative of the state of wakefulness employed in some of the previous studies, and when this state is compared with Stage IV sleep, we find a difference in VI of 0.81 L/min. This suggests that differences in the magnitude of a sleepinduced fall in VI between studies may be partly due to a failure to adequately control the external environment during the state of wakefulness. It is also of interest that if we had used audiovisual stimulation as our wakefulness period, a significant reduction in f would have been observed between wakefulness and all sleep stages. Instead, f was virtually identical during sleep and the state of relaxed wakefulness. Previous studies have reported conflicting data regarding the effect of sleep on f, with some investigators reporting an increase in f (43), others a decrease in f (10, 12), and still others reporting no change (11, 24). Our data suggest that this discrepancy may be due in part to a failure to obtain measurements during a state of true "resting wakefulness." In summary, (1) alterations in mental activity significantly affect not only the average values of breathing pattern components, but also their breath-to-breath variability, (2) significant correlations were observed between VT and TI, and between VTand f during Stage IV sleep, and (3) VT, an index of respiratory volume, was more variable than TI, an index of respiratory timing, during all experimental conditions except Stage IV sleep. These data suggest that the greater variability of indices of respiratory volume compared with timing does not appear to be an intrinsic property of the central pattern generator, but may instead reflect the modulating action of higher centers on respiratory output. Acknowledgment The writers thank Mrs. Diane Poch for preparation of the manuscript and Ms. Susan Guenther for technical assistance.

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Effect of alterations in mental activity on the breathing pattern in healthy subjects.

The overall output from the respiratory centers is regulated by an automatic metabolic control system in the brainstem and by higher neural centers un...
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