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A between-subjects comparison of respiratory sinus arrhythmia and baroreceptor cardiac reflex sensitivity as non-invasive measures of tonic parasympathetic cardiac control
INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY
ELSEVIER
International
Journal of Psychophysiology
22 (1996) 163-171
A between-subjects comparison of respiratory sinus arrhythmia and baroreceptor cardiac reflex sensitivity as non-invasive measures of tonic parasympathetic cardiac control Gustav0 A. Reyes de1 Paso a3*, Wolf Langewitz b, Humbelina Robles ‘, Nieves PCrez ’ a Departamento de Psicologia, Facultad de Humanidades, Uniuersidad de Jab, 23071 Jae’n, Spain b Departament Innere Medizin, Kantonsspital Basel, CH-4031 Basel, Switzerland ’ Departamento de Personalidad, Evaluacidn y Tratamiento Psicol&ico, Facultad de Psicologia, Unitiersidad de Granada, 18071 Granada, Spain Received 5 April 1995; accepted 30 January
1996
Abstract Respiratory sinus arrhythmia (RSA) has been used as an index of parasympathetic cardiac control. However, recent psychophysiological research casts serious doubts upon the usefulness of RSA as an index of vagal influences upon the heart in psychophysiological as well as in clinical studies. It suggests the need to look for another measure. In this exploratory study we investigated whether the baroreflex sensitivity (BRS) could serve as an alternative tool to investigate between-subject tonic parasympathetic influences on the heart. In nine healthy subjects we examined the effects of intravenous atropine (0.03 mg/kg i.v.), intravenous metoprolol (lo-15 mg i.v.), and of saline as a placebo condition upon RSA, BRS, and related cardiovascular and respiratory variables, both under resting and under mental task conditions. After parasympathetic blockade, RSA and BRS display values near zero, showing their vagal origin. After beta-adrenergic blockade, when heart period is predominantly under vagal control, RSA fails to predict heart period variability. Using BRS, however, it is possible to predict more than 97% of heart period variance during beta-blockade. Finally, both the vagal and beta-adrenergic
blockade show that BRS is a better predictor of parasympathetic cardiac control during blood pressure increases than during blood pressure decreases. Keywords: Baroreceptor Vagal cardiac blockade
cardiac reflex sensitivity:
Respiratory
sinus arrhythmia;
1. Introduction The development of a non-invasive measure for the quantitative assessment of cardiac parasympa-
* Corresponding
author.
0167-8760/96/$15.00 Copyright PII SO1 67.8760(96)00020-7
Parasympathetic
cardiac control; Beta-adrenergic
blockade;
thetic activity is an important goal in psychophysiology. In basic research it will help the understanding of autonomic mechanisms affecting cardiac activity under various types of psychological stress and mental states; in clinical research it will help evaluate the protective function of vagal influence on the heart. For a long time, respiratory sinus arrhythmia (RSA) has been used to measure parasympathetic
0 1996 Elsevier Science B.V. All rights reserved.
cardiac control. RSA refers to cyclical fluctuations in heart rate corresponding to alternating respiratory phases: increases in heart rate during inspiration and decreases during expiration. The cyclical pattern in heart rate depends on respiratory characteristics: low respiratory rates and high respiratory volumes increase RSA, whereas a respiratory pattern of high respiratory rate and low amplitude reduces RSA drastically (Eckberg, 1983). Although the physiological mechanisms responsible for RSA imply complex interactions among different physiological processes, both in the periphery and in the central nervous system, the final generators for RSA are cyclical vagal discharges due to the inhibition of vagal efferent activity during inspiration (Katona et al., 1970). Administration of atropine or vagotomy eliminates RSA, and variations in heart rate related to respiratory patterns can be predicted from directly measured efferent cardiac vagal activity (Katona et al., 1970). Given this vagal modulation of RSA, its amplitude has been proposed as a non-invasive index of parasympathetic cardiac control (Fouad et al., 1984; Katona and Jih, 1975; Lipson and Katona, 1979; McCabe et al., 1984, 1985; Raczkowska et al., 1983; Yongue et al., 198 1, 1982). Most of these validation studies have employed a within-subjects design. Studies employing between-subjects designs have produced more mixed results (Kollai and Miszei, 1990). Recent research however (Grossman et al., 1991; Grossman and Kollai, 1993; Kollai and Miszei, 1990), has found some problems using RSA to predict parasympathetic cardiac control. Firstly, differences in respiratory pattern can influence RSA to such an extent that parasympathetic cardiac control cannot be assessed reliably (Grossman et al., 1991). Specifically, changes in cardiac vagal tone do not necessarily coincide with respiratory mediated alterations in RSA. The physiological basis for these results may be that the inspiratory inhibition of vagal cardiac efferent activity is far from complete. Substantial vagal cardiac control persists during inspiration. The amount of inspiratory vagal activity varies depending on the respiratory pattern, decreasing when respiratory period and tidal volume increase and increasing when respiration is quicker and shallower (Grossman and Kollai, 1993). Under these circumstances, RSA amplitude as a measure of tonic vagal
control would underestimate actual vagal influences upon the heart, which should actually be the sum of and not the difference between inspiratory and expiratory vagal traffic (Grossman et al., 1991). In this way, comparison of RSA amplitudes under circumstances when breathing patterns differ significantly will produce errors in the estimation of parasympathetic cardiac control. To reliably predict cardiac vagal tone from RSA amplitude it would be necessary to control breathing, maintaining constant respiration rate and tidal volume. However, this control is neither possible nor desirable in most psychophysiological applications where subjects are actively engaged in mental tasks. Secondly, RSA, even under controlled respiratory conditions, does not accurately predict individual differences in parasympathetic cardiac control (Grossman and Kollai, 1993). The relationship of RSA to intersubject differences in cardiac vagal tone remains questionable. These results raise serious doubts about the usefulness of RSA to predict cardiac vagal efferent activity in psychophysiological research. Another measure which might be used as an indicator of cardiac vagal influences is the activity of the baroreceptor reflex. The baroreceptor reflex is one of the most important physiological mechanisms affecting efferent cardiac vagal activity and RSA (Davidson et al., 1976; Davis et al., 1977; Eckberg et al., 1980, 1984, 1985; Gilbey et al., 1984; McAllen and Spyer, 1978a,b; Raczkowska et al., 1983). With the availability of equipment which allows for the continuous and non-invasive measurement of blood pressure (Settels and Wesseling, 1985) it is now possible to assess baroreceptor cardiac reflex function non-invasively from the analysis of spontaneous patterns of blood pressure and heart period, using both frequency domain measures (Robbe et al., 1987) and time domain techniques (Bertinieri et al., 1985; Reyes de1 Paso, 1994; Steptoe and Sawada, 1989). The aim of the present research is to evaluate the usefulness of baroreceptor cardiac reflex sensitivity (BRS) - expressed as the change in heart period per unit change in systolic blood pressure - as a non-invasive measure of between-subject tonic parasympathetic cardiac control compared to RSA amplitude. We address this issue examining the following points: 1. Assessment of the effects of pharmacological blockade with a p,-selective beta-blocking agent
G.A. Reyes de1 Paso et al. /International Journal of Psychophysiology 22 (1996) 163-171
(metoprolol - without intrinsic sympathetic activity) and atropine on both measures. 2. Study of the relationship between both measures and heart period before and after pharmacological blockade. 3. Investigation of the relationship between RSA amplitude and BRS both during rest and mental load conditions. Furthermore, we shall report on other relevant psychophysiological measures namely respiratory activity and blood pressure changes in response to mental load.
2. Materials and methods 2.1. Subjects Subjects were nine healthy and physically fit male students of medicine aged between 23 and 25. The study protocol was approved by the Ethical Committee of the University of Bonn. Participants had given their informed consent and were given DM 400 for their collaboration. None of the subjects were on psychotropic medications; history, physical examination and baseline ECG did not show any abnormalities. 2.2. Apparatus Heart rate was recorded from lead II of the ECG by a Gould amplifier. Respiratory activity was measured from a Respitrace belt around the chest at the level of the xiphoid process. Blood pressure was recorded continuously with the non-invasive FIN.A.PRES device (Settels and Wesseling, 1985) from the middle phalanx of the third finger of the left hand. The hand was positioned at the level of the tricuspid heart valve. 2.3. Design Six subjects were investigated twice: They received either atropine (0.03 mg/kg body weight i.v.) on day 1 and metoprolol (up to 3 X 5 mg i.v.) on day 2 or the reverse order of drugs. Three subjects were investigated only once, receiving 3 X 5 ml of saline as a placebo condition. The latter individuals were
165
informed that they received a drug influencing the regulatory characteristics of the cardiovascular systern with no noticeable side effects. A similar experimental design has previously been used by Akselrod et al. (1981, 1985) Stephenson et al. (1981), and Pomeranz et al. (1985). 2.4. Mental load task A memory search and counting task was used for the mental load condition. Subjects had to memorize four letters presented on a computer screen (memory set). Then, single letters appeared on the screen at 3-s intervals, the subjects having to decide whether or not the letter belonged to the memory set. If the decision was affirmative the subject had to press a button with his right hand. At the same time, subjects were told to count the number of occurrences of the correct letter from the memory set on the screen. 2.5. Procedure One hour prior to the examination subjects were provided with a peripheral intravenous line. In the laboratory, subjects sat in a comfortable armchair in a semirecumbent position. After having attached and checked electrodes and the measuring apparatus, an initial baseline of IO-min duration ensued (baseline 1) followed by the first mental load task period of 5-min duration (task 1). Then, drugs were injected over a period of 5 min (atropine) or during a maximum of 3 X 5 min (metoprolol and saline). The dose of the beta-blocking agent was calculated according to the reduction in heart rate: If heart rate was reduced 2 25%, the injection was stopped. This goal was achieved in all subjects with doses between 10 and 15 mg of metoprolol i.v. Two minutes after the injection of drugs, when physiological variables reach a steady state to avoid possible measurement error (Byrne and Porges, 1993), another baseline was recorded over a lo-min sampling period (baseline 2). Then, another task phase of 5-min duration followed (task 2). 2.6. Data reduction and analysis Analysis of all measures was carried computer programs previously developed.
out using RSA am-
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de1 Paso et al./Intemationcrl
plitude was assessed on a breath-by-breath basis through the peak-to-valley method (Grossman and Svebak, 1987) quantifying the difference in milliseconds between the shortest heart period found during inspiration and the longest heart period found during expiration, and adjusting the temporal phase relation between respiratory and cardiac activity according to Eckberg (1983). When the minimum heart period during inspiration is longer than the maximum heart period during expiration a value of zero is assigned to the RSA amplitude of this respiratory cycle (Reyes de1 Paso, 1992). Baroreceptor cardiac reflex function was assessed by analysing sequences of 3 to 7 consecutive cardiac cycles (most sequences, about 80%, were of three cycles’ duration), during which systolic blood pressure increased (by at least 1 mmHg in each beat) in combination with an increase in heart period (by at least 2 ms in each beat) or sequences of equal length in which the decrease of systolic blood pressure was accompanied by a decrease in heart period, following the same rules for minimum changes. When one of these sequences was detected, the corresponding line of regression was computed. The slope or sensitivity of the reflex is expressed as change in heart period (in ms> per mmHg change in systolic blood pressure (Reyes de1 Paso, 1994). The program also obtained the proportion (in percent) of cardiac cycles that form part of the sequences with respect to the total number of cycles during the analysis period. This parameter has been interpreted as an index of the relative power of the baroreflex to regulate cardiac activity (Bertinieri et al., 1985; Steptoe and Sawada, 1989). The validity of this method to assess baroreceptor cardiac reflex function has been tested against spectral analysis techniques (Reyes de1 Paso, 1994). For the last 200 s of the baseline periods and for the first 200 s of the task periods, mean values of the following variables were computed: heart period, RSA amplitude, baroreceptor sensitivity both when systolic blood pressure increased (‘up’ sequences) and when systolic blood pressure decreased (‘down’ sequences), baroreceptor power (BRP) (i.e. percentage of cardiac cycles that contributing to sequences in an analysis period with respect to the total number of cycles) both when systolic blood pressure increased (‘up’ sequences) and when systolic blood pressure decreased (‘down’ sequences), systolic, diastolic, and
Jourml
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mean blood pressure, systolic blood pressure variability (as the successive difference mean square), breathing amplitude as the difference in analog-todigital units between the two samples which signalled the starting and finishing points of inspiration, and respiratory rate, defined as the number of respiratory cycles within each period of analysis in cycles per minute. Respiratory amplitudes were expressed in terms of percentage of change with respect to the amplitude obtained during baseline. Statistical analyses of the effects of drug and task conditions were performed using planned comparisons through an ANOVA of repeated measures. The effect of the pharmacological blockade was analyzed comparing baseline and task periods before and after drug administration (baseline l/baseline 2 or task 1/task 2). The effect of the task was analyzed comparing baseline with task periods before drug administration (baseline 1/task 1). Relationships between variables were assessed through Pearson’s Product Moment correlations.
3. Results 3. I. Effect of pharmacological
blockade
Table 1 shows the average levels of heart period, RSA, and baroreceptor sensitivity and power before and after drug administration according to the different drugs used. 3.1.1. Heart period During baseline periods (F( 1,5) = 50.66, p < 0.0001) as well as under mental load conditions (F(1,5) = 33.67, p < 0.0001) atropine administration produced significant decreases in heart period. After the administration of metoprolol heart period increased, the comparison of baseline periods (F( 1,5) = 305.33, p < 0.0001) and mental load tasks (F(1,5) = 385, p < 0.0001) being highly significant. 3. I .2. RSA amplitude Atropine administration produced a large decrease in RSA amplitude, the comparison of the baseline periods (F(1,5) = 30,82, p < 0.0001) and mental load task (F( 1,5) = 177.17, p < 0.0001) being highly
G.A. Reyes de1 Paso et al./International
Journal of Psychophysiology 22 (19%) 163-171
Table 1 Average levels and standard deviations (in parentheses) for heart period (HP), RSA amplitude, baroreceptor power (BRP) before and after drug administration as a function of the drug No drug TKl
BL2
HP
Betablock Atropine Placebo
888 956 917
RSA
Betablock Atropine Placebo
99.4 117.5 138.9
(14) (39) (53)
65.5 68.4 83.2
(10) (8) (10)
115.6 6.5 142.7
Betablock Atropine Placebo
17.3 23.9 33.8
(7) (13) (18)
14.1 16.8 19.5
(1) (5) (9)
Betablock Atropine Placebo
16.9 15.3 21.2
(10) (3) (12)
16.4 11.9 17.4
Betablock Atropine Placebo
19 18 18
(6) (7) (9)
10.5 11.5 10
Betablock Atropine Placebo
20.8 23 21
(6) (11) (13)
(up)
BRS (down)
BRP
(up)
BRP (down)
baroreceptor
sensitivity
(BRS)
and
Drug
BLl
BRS
167
(142) (130) (222)
851 875 912
(140) (124) (220)
12 12 9
1146 564 975
TK2 (155) (30) (149)
1116 550 887
(163) (39) (129)
(41) (2) (25)
81.9 4.6 87.3
(30) (2) (4)
28.4 1.2 26.8
(17) (0.3) (14)
20.8 1.2 19.3
(7) (0.3) (11)
(8) (3) (8)
19.5 1.3 26.9
(5) (0.4) (13)
20.4 1.6 20.9
(10) (0.6) (10)
(5) (5) (5)
14 2.8 15.7
(9) (2) (6)
9.1 3 10.7
(6) (3) (6)
(8) (8) (10)
15.6 8.8 17
(8) (11) (13)
7 6 10.6
(4) (7) (6)
BL = baseline; TK = task.
significant. Metoprolol non-significant increase
administration produced in RSA amplitude.
a
3.1.3. Baroreceptor sensitivity Atropine administration produced a decrease in BRS, the comparison of the baseline periods (F(lS) = 11.20, p < 0.05 in the ‘up’ sequences and F(1,5) = 32.40, p < 0.0001 in the ‘down’ sequences) and mental load tasks (F(1,5) = 525.67, p < 0.0001 in the ‘up’ sequences and F(1,5) = 54.77, p < 0.0001 in the ‘down’ sequences) being significant. After the administration of metoprolol BRS increased without reaching a statistically significant level. 3.1.4. Baroreceptor power The administration of the three substances produced a decrease in this parameter in the baseline periods, both in the ‘up’ sequences (F( 1,14) = 9.47, p < 0.01) and ‘down’ sequences (F(1,14) = 4.71, p < 0.05). The decrease appeared greater after atropine administration, but there was no significant interaction of drug X comparison.
3.2. Effect of the memory search and counting task Table 2 summarizes the mean levels of the physiological parameters during the first baseline and task
Table 2 Average values and standard deviations different parameters during the baseline drug administration Baseline Heart period RSA Systolic blood pressure Diastolic blood pressure Mean blood pressure Systolic blood pressure variability Baroreflex sensitivity (up) Baroreflex sensitivity (down) Baroreflex power (up) Baroreflex power (down) Respiratory rate Change in respiratory amplitude
(in parentheses) of the and task periods before
Task
940 (153) 875 (149) 114 (32) 1:: (Z 123 (11) 68 (8) 73 (9) 85 92 (10) (9) 9.4 (6) 6.7 (3) 23 (11) 16 (3.5) 18.5 (6) 15 (6) 18.2 (7) 10.6 (5) 21.7 (9) 10.8 (8) 15.5 (2.7) 20.2 (2.5) - 12% (12)
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periods. The planned comparison showed significant main effects of the task for heart period (F( 1,14) = 20.12, p < O.Ol), RSA amplitude (F(1.14) = 19.22, p < O.Ol), systolic blood pressure (F(1,14) = 15.3, p < O.Ol), diastolic blood pressure (F(1,14) = 10.37, p < O.Ol), mean blood pressure (F(l,l4) = 12.25, p < O.Ol), systolic blood pressure variability (F(l,14) = 6.02, p < 0.05>, BRS both in the ‘up’ sequences (F(l,14) = 12.12, p < 0.01) and in the ‘down’ sequences (F( 1,14) = 18.80, p < 0.0 I ), BRP both in the ‘up’ sequences (F( 1,14) = 20.93, p < 0.01) and in the ‘down’ sequences (F( 1,14) = 15.90, p < O.Ol), respiratory rate (F(l,l4) = 25.78, p < O.Ol), and respiratory amplitude (F( 1,14) = 5.54, p < 0.05). As can be seen in Table 2, the mental load task produced decreases in heart period, RSA amplitude, BRS, BRP, systolic blood pressure variability and respiratory amplitude and increases in blood pressure and respiratory rate. 3.3. Correlational tion
analysis
before drug adrninistru-
The correlations between RSA amplitude and heart period was 0.433 (n.s.) during the baseline and 0.622 (p < 0.05) during the task. As regards baroreceptor reflex, we continually report BRS in ‘up’ as well as in ‘down’ sequences because this might reflect differences in the physiological control mechanisms (Eckberg, 1980; Miyajima et al., 1986; Pickering et al., 1972). In our study, BRS was greater in the ‘up’ sequences than in the ‘down’ sequences (see Table 2), confirming research in cats by Bertinieri et al. (1985). These differences were significant for the first baseline period (F(l) 14) = 5.12, p < 0.05). BRS showed a somewhat closer association with heart period than RSA amplitude, the correlations being higher for the ‘up’ sequences (0.826, p < 0.01, during the baseline and 0.743, p < 0.01, during the task) than for ‘down’ sequences (0.574, p < 0.05, during the baseline and 0.46, n.s., during the task). 3.4. Correlation
coejj%ients
after vagal blockade
The percentage of change in heart period induced by atropine administration might be used as an invasive measure of the amount of parasympathetic cardiac control before the blockade. The correlations of
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the percentage of change in heart period (between task 1 and baseline 2) with BRS during the ‘up’ sequences (0.952, p < 0.01) was somewhat greater than for RSA (0.865, p < 0.05). BRS during ‘down’ sequences presented no significant correlation (0. I). 3.5. Correlation blockade
coefficients
after
beta-adrenergic
After administration of beta-blocker, where we can assume that heart period changes are predominantly under vagal control, correlations between RSA amplitude and heart period were low (0.007 during the baseline and 0.052 during the task). To see whether these low correlations were due to differences in respiratory rate we controlled for respiratory rate as well. This procedure improved the correlation between RSA amplitude and heart period but the correlation coefficients remained non-significant (0.219 during the baseline and 0.527 during the task). BRS yielded a larger association with heart period, but the correlation coefficients were significant only for the ‘up’ sequences (0.8 16, p < 0.05, during the baseline and 0.858, p < 0.05, during the task) and not for the ‘down’ sequences (0.423 during the baseline and 0.457 during the task). The multiple correlation between BRS in both the ‘up’ and ‘down’ sequences as predictor variables and heart period as dependent variable was 0.985 (p < 0.01) during the baseline and 0.987 (p < 0.01) during the task, accounting for more than 97% of heart period variance. 3.6. Correlation measures
between
RSA amplitude
and BRS
Table 3 shows the correlations between RSA amplitude and BRS in the different experimental Table 3 Correlations of RSA and baroreceptor four experimental periods
BRS (up) BRS (down) R (up-down)
sensitivity (BRS) during the
LB1
TKl
LB2
TK2
0.598 + 0.601 + 0.856 *
0.644 ’ 0.638 * 0.839 *
0.647 * 0.756 * 0.734 *
0.828 0.844 0.863
* * *
R (up-down) = multiple correlation of BRS in the ‘up’ and ‘down’ sequences as predictor variables of RSA amplitude; BL = baseline: TK = task. * p
GA. Reyes de1 Paso et al./International
periods. RSA amplitude correlates positively with the BRS both in the ‘up’ and ‘down’ sequences. The multiple correlation between RSA amplitude as dependent variables and BRS in the ‘up’ and ‘down’ sequences as predictor variables accounted on average for about 70% of the RSA amplitude variance.
4. Discussion Our results concerning RSA seem to corroborate previous findings questioning the validity of RSA amplitude predicting individual differences in tonic parasympathetic cardiac control (Grossman et al., 1991; Grossman and Kollai, 1993; Kollai and Miszei, 1990). The most relevant finding has been obtained after beta-adrenergic blockade, when heart period is predominantly under vagal control. Under this condition correlations between RSA amplitude and heart period are very low. Even though the statistical control for respiratory rate improves this relation to some extent, the correlations still remain non-significant. As far as baroreceptor sensitivity is concerned, the correlations after beta-blockade with heart period are higher than those obtained for the RSA amplitude, but were significant only for the ‘up’ sequences. Using both parameters of baroreceptor sensitivity it is possible to predict more than 97% of heart period variance in the beta-blocking condition. The data show that the use of ‘up’ and ‘down’ sequences for the calculation of baroreceptor sensitivity yield different results. First of all, we find that the baroreceptor sensitivity is greater when blood pressure rises than when it falls. A similar finding has been reported by Mancia et al. (1983) and Bertinieri et al. (1985). Other authors systematically varied blood pressure levels and registered concomitant heart rate changes over a wide range of blood pressure values: they report a clear hysteresis pattern of the baroreceptor activity (Coleridge et al., 19811, showing a higher baroreflex gain with increasing blood pressure and lower gain with falling blood pressure. The different relation between baroreflex sensitivity calculated during ‘up’ versus ‘down’ sequences and heart period or RSA has not been reported directly by other authors. However, there have been reports indicating that the relative or differential sympathetic and vagal determinants of
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heart rate regulation are different when blood pressure rises compared to falling blood pressure. The slowing of heart rate in response to rising blood pressure is primarily a vagal response (Scher and Young, 1970; Thames and Kontos, 1970; Miyajima et al., 1986; McCabe et al., 1985). In our study, before drug administration, baroreceptor sensitivity during ‘up’ sequences shows a closer relationship with heart period (mainly under vagal control under resting conditions and during low levels of arousal) than ‘down’ sequences. After drug administration, both the vagal and beta-adrenergic blockade conditions show higher correlations of baroreceptor sensitivity with the invasive vagal measures during ‘up’ sequences. These results suggests that the ‘up’ sequences might be a better predictor of parasympathetic cardiac control than the ‘down’ sequences. This may be explained by the larger relative contribution of the vagal influences on the ‘up’ sequences in comparison with the ‘down’ sequences. Apart from that, we have to take into account that these sequences reflect different dynamics. The ‘up’ sequences reflect vagal activation and the ‘down’ sequences, vagal withdrawal. The validity of the pharmacological blockade is evident in the significant effects on heart period. The administration of metoprolol increased heart period by 29% and the administration of atropine decreased it by 41%. Atropine administration reduces RSA amplitude and baroreceptor sensitivity to values near zero, confirming their vagal origin. The administration of the beta-blocking agent produced a non-significant increase in RSA amplitude and baroreceptor sensitivity. Such an observation has also been made by others (Coker et al., 1984; Eckberg et al., 1976; Fouad et al., 1984; Grossman and Svebak, 1987; Grossman and Kollai, 1993). The memory search and counting task produced a significant decrease in the RSA amplitude levels. Several physiological mechanisms have been implicated to explain the observed reduction: an increase in respiratory rate, a small decrease in the respiratory amplitude, and decrease in blood pressure variability, which in turn would lead to a diminished heart rate variability mediated by the baroreceptor reflex. A fundamental factor seems to be the decrease in BRS. This last factor predicts about 70% of the variability in the RSA amplitude. This figure is in line with
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other physiological studies on the relationship between RSA amplitude and carotid baroreceptor reflex responses (Bennett et al., 1978; Raczkowska et al., 1983). A reduction in RSA amplitude has also been reported by Grossman and Svebak (1987) using a video game with or without threat of shock. On the other hand, the decrease in baroreceptor sensitivity during the memory search and counting task is supported by the findings of Steptoe and Sawada (1989), who had used a mental arithmetic task. Given the preliminary nature of this study and the small number of subjects used, our results should be viewed with caution. They do indicate, however, that useful information about vagal cardiac tone can be obtained non-invasively from the analysis of baroreceptor cardiac reflex function, especially during the ‘up’ sequences. The availability of technical devices al!owing for a non-invasive registration of continuous blood pressure values allows for the easy assessment of baroreceptor cardiac reflex function.
Acknowledgements This research was supported by a Grant from the Commission of the European Communities Medical and Health Research Programme. Concerted Action: Quantification of Parameters for the Study of Breakdown in Human Adaptation. We would also like to thank L.J.M. Mulder and his colleagues from the University of Groningen for their support and collaboration in carrying out this research.
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dotti, A. and Mancia, G. (1985) A new approach to analysis of the arterial baroreflex. J. Hypert., 3: S79-S81. Byrne, E.A. and Porges, S.W. (1993) Data-dependent filter characteristics of peak-walley respiratory sinus arrhythmia estimation: A cautionary note. Psychophysiology, 30: 397-404. Coker, R., Koziell, A., Olivier, C. and Smith, S.E. (1984) Does the sympathetic nervous system influence sinus arrhythmia in man? Evidence from combined autonomic blockade. J. Physiol., 356: 459-464. Coleridge, J.C.G., Kauafman, M.P. and Dangel, A. (I 98 I) Operational sensitivity and acute resetting of aortic baroreceptors in dogs. Circ. Res., 48: 676-684. Davidson, N.S., Golner, S. and McCloskey, D.I. (1976) Respiratory modulation of baroreceptor and chemoreceptor reflexes affecting heart rate and cardiac vagal efferent nerve activity. J. Physiol., 259: 523-530. Davis, A.L., McCloskey, D.I. and Potter, E.K. (1977) Respiratory modulation of baroreceptor and chemoreceptor reflexes affecting heart rate through the sympathetic nervous system. J. Physiol., 272: 691-703. Eckberg, D.L. (1980) Nonlinearities of the human carotid baroreceptor-cardiac reflex. Circ. Res., 47: 208-216. Eckberg, D.L. (1983) Human sinus arrhythmia as an index of vagal cardiac outflow. J. Appl. Physiol., 54: 961-966. Eckberg, D.L.. Abboud, F.M. and Mark, A.L. (1976) Modulation of carotid baroreflex responsiveness in man: Effects of posture and propanolol. J. Appl. Physiol., 41: 383-387. Eckberg, D.L., Kifle, Y.T. and Roberts, V.L. (1980) Phase relationship between normal human respiration and baroreflex responsiveness. J. Physiol., 304: 489-502. Eckberg, D.L., Mohanty, S.K. and Raczkowska, M. (1984) Trigeminal-baroreceptor reflex interactions modulate human cardiac vagal activity. J. Physiol., 347: 75-83. Eckberg, D.L., Nerhed, C. and Wallin, G. (1985) Respiratory modulation of muscle sympathetic and vagal cardiac outflow in man. J. Physiol., 365: 181-196. Fouad, F.M. Tarazi, R.C., Ferrario, C.M., Fighaly, S. and Alicandro, C. (1984) Assessment of parasympathetic control of the heart by a noninvasive method. Am. J. Physiol., 246: H838H842. Gilbey, M.P., Jordan, D., Richter, D.W. and Spyer, K.M. (1984) Synaptic mechanisms involved in the inspiratory modulation of vagal cardio-inhibitory neurones in the cat. J. Physiol., 356: 65-78. Grossman, P. and Kollai, M. (I 993) Respiratory sinus arrhythmia, cardiac vagal tone, and respiration: Within- and between-individual relations. Psychophysiology, 30: 486-495. Grossman, P. and Svebak, S. (1987) Respiratory sinus arrhythmia as an index of parasympathetic cardiac control during active coping. Psychophysiology, 24: 228-235. Grossman, P., Karemaker, J. and Wieling, W. (1991) Prediction of tonic parasympathetic cardiac control using respiratory sinus arrhythmia: the need for respiratory control. Psychophysiology, 28: 201-216. Katona, P.G. and Jih, R. (1975) Respiratory sinus arrhythmia: A noninvasive measure of parasympathetic cardiac control. J. Appl. Physiol., 218: 1030-1037.
GA Reyes del Paso et al. /International Journal of Psychophysiology 22 (19961 163- I71 Katona. P.G., Poitras J.W.. Bamett, GO. and Terry, B.S. (1970) Cardiac vagal efferent activity and heart period in the carotid sinus reflex. Am. J. Physiol., 218: 1030-1037. Kollai, M. and Miszei, G. (1990) Respiratory sinus arrhythmia is a limited measure of parasympathetic cardiac control in man. J. Physiol., 424: 329-342. Lipson, D. and Katona, P.G. (1979) Respiratory sinus arrhythmia: A noninvasive assessment of parasympathetic chronotropic cardiac control in the conscious dog. Fed. Proceed., 38: 990. Mancia, G., Ferrari, A., Gregorini, L., Parati, G., Pomidossi, G., Bertinieri, G., Grassi, G., di Rienzo, M., Pedotti, A. and Zanchetti. A. (1983) Blood pressure and heart rate variabilities in normnensive and hypertensive human beings. Cir. Res., 53: 966IL ,. McAllen, R.M. and Spyer, K.M. (1978a) The baroreceptor input to cardiac vagal motoneurones. J. Physiol., 282: 365-374. McAllen, R.M. and Spyer, K.M. (1978b) Two types of vagal preganglionic motoneurones projecting to the heart and lungs. J. Physiol., 282: 353-364. McCabe, P.M., Yongue, B.G., Porges, S.W. and Ackles, P.K. (1984) Changes in heart period, heart period variability, and a spectral analysis estimate of respiratory sinus arrhythmia during aortic nerve/stimulation in rabbits. Psychophysiology, 21: 149-158. McCabe. P.M.. Yongue, B.G., Ackles, P.K. and Porges, S.W. (1985) Changes in heart period, heart period variability, and a spectral analysis estimate of respiratory sinus arrhythmia in response to pharmacological manipulations of the baroreceptor reflex in cats. Psychophysiology, 21: 195-203. Miyajima, E., Matsukawa, T., Yamada, Y., Tochikubo, 0. and Kanedo, Y. (1986) Differential baroreflex changes in sympathetic and parasympathetic nerve activities in patients with essential hypertension. I. Hype& 4: S219-S221. Pickering, T.G., Gribbing, B. and Sleight, P. (1972) Comparison of the reflex heart rate response to rising and falling arterial pressure in man. Cardiovasc. Res., 6: 277-283. Pomeranz, B., Macaulay, R.J.B., Caudill, M.A., Kutz, I., Adam, D., Gordon, D., Kilbom, K.M., Barger, A.C., Shannon, D.C., Cohen, R.J. and Benson, H. (1985) Assessment of autonomic
171
function in humans by heart rate spectral analysis. Am. J. Physiol., 248: H151-H153. Raczkowska, M., Eckberg, D.L. and Ebert, T.J. (1983) Muscarinic cholinergic receptor modulates vagal cardiac responses in man. J. Auton. Nerv. Syst.. 7: 271-278. Reyes de1 Paso, G.A. (1992) An on-line program to calculate respiratory sinus arrhythmia amplitude. Behav. Res. Meth. Instr. Comput., 24: 466-466. Reyes de1 Paso, G.A. (1994) A program to assess baroreceptor cardiac reflex function. Behav. Res. Meth. Instr. Comput., 26: 62-64. Robbe, H.W.J., Mulder, L.J.M., Riiddel, H., Veldman, J.B.P., Langewitz, W.A. and Mulder, G. (1987) Assessment of baroreflex sensitivity by means of spectral analysis. Hypertension, 10: 538-543. Scher, A.M. and Young, A.C. (1970) Reflex control of heart rate in the unanesthetized dog. Am. J. Physiol., 218: 780-789. Settels, J.J. and Wesseling, K.H. (1985) FinAPres.: Noninvasive finger arterial pressure waveform registration, In: J. Orlebeke, G. Mulder and L. Doomen (Eds.). Psychophysiology of Cardiovascular Control, Plenum Press, New York. pp. 267-283. Stephenson, R.B., Smith, O.A. and Scher, A.M. (1981) Barorecep tor regulation of heart rate in baboons during different behavioral states. Am. J. Physiol., 241: R277-R285. Steptoe, A. and Sawada, Y. (1989) Assessment of baroreceptor reflex function during mental stress and relaxation. Psychophysiology, 26: 140-147. Thames, M.D. and Kontos, H.A. (1970) Mechanisms of baroreceptor-induced changes in heart rate. Am. J. Physiol.. 218: 25 l-256. Yongue, B.G., McCabe, P.M., Kelley, S.L., Rivera, P. and Porges, S.W. (1981) Changes in a respiration-modulated component of heart period variability as a result of pharmacological manipulations of vagal tone in rats. Psychophysiology, 18: 137. Yongue, B.G., McCabe, P.M., Porges, S.W., Rivera, M., Kelley, S.L. and Ackles, P.K. (1982) The effects of pharmacological manipulations that influence vagal control of the heart on heart period, heart period variability and respiration in rats. Psychophysiology, 19: 426-432.
ELSEVIER
International
Journal of Psychophysiology
22 (1996) 163-171
A between-subjects comparison of respiratory sinus arrhythmia and baroreceptor cardiac reflex sensitivity as non-invasive measures of tonic parasympathetic cardiac control Gustav0 A. Reyes de1 Paso a3*, Wolf Langewitz b, Humbelina Robles ‘, Nieves PCrez ’ a Departamento de Psicologia, Facultad de Humanidades, Uniuersidad de Jab, 23071 Jae’n, Spain b Departament Innere Medizin, Kantonsspital Basel, CH-4031 Basel, Switzerland ’ Departamento de Personalidad, Evaluacidn y Tratamiento Psicol&ico, Facultad de Psicologia, Unitiersidad de Granada, 18071 Granada, Spain Received 5 April 1995; accepted 30 January
1996
Abstract Respiratory sinus arrhythmia (RSA) has been used as an index of parasympathetic cardiac control. However, recent psychophysiological research casts serious doubts upon the usefulness of RSA as an index of vagal influences upon the heart in psychophysiological as well as in clinical studies. It suggests the need to look for another measure. In this exploratory study we investigated whether the baroreflex sensitivity (BRS) could serve as an alternative tool to investigate between-subject tonic parasympathetic influences on the heart. In nine healthy subjects we examined the effects of intravenous atropine (0.03 mg/kg i.v.), intravenous metoprolol (lo-15 mg i.v.), and of saline as a placebo condition upon RSA, BRS, and related cardiovascular and respiratory variables, both under resting and under mental task conditions. After parasympathetic blockade, RSA and BRS display values near zero, showing their vagal origin. After beta-adrenergic blockade, when heart period is predominantly under vagal control, RSA fails to predict heart period variability. Using BRS, however, it is possible to predict more than 97% of heart period variance during beta-blockade. Finally, both the vagal and beta-adrenergic
blockade show that BRS is a better predictor of parasympathetic cardiac control during blood pressure increases than during blood pressure decreases. Keywords: Baroreceptor Vagal cardiac blockade
cardiac reflex sensitivity:
Respiratory
sinus arrhythmia;
1. Introduction The development of a non-invasive measure for the quantitative assessment of cardiac parasympa-
* Corresponding
author.
0167-8760/96/$15.00 Copyright PII SO1 67.8760(96)00020-7
Parasympathetic
cardiac control; Beta-adrenergic
blockade;
thetic activity is an important goal in psychophysiology. In basic research it will help the understanding of autonomic mechanisms affecting cardiac activity under various types of psychological stress and mental states; in clinical research it will help evaluate the protective function of vagal influence on the heart. For a long time, respiratory sinus arrhythmia (RSA) has been used to measure parasympathetic
0 1996 Elsevier Science B.V. All rights reserved.
cardiac control. RSA refers to cyclical fluctuations in heart rate corresponding to alternating respiratory phases: increases in heart rate during inspiration and decreases during expiration. The cyclical pattern in heart rate depends on respiratory characteristics: low respiratory rates and high respiratory volumes increase RSA, whereas a respiratory pattern of high respiratory rate and low amplitude reduces RSA drastically (Eckberg, 1983). Although the physiological mechanisms responsible for RSA imply complex interactions among different physiological processes, both in the periphery and in the central nervous system, the final generators for RSA are cyclical vagal discharges due to the inhibition of vagal efferent activity during inspiration (Katona et al., 1970). Administration of atropine or vagotomy eliminates RSA, and variations in heart rate related to respiratory patterns can be predicted from directly measured efferent cardiac vagal activity (Katona et al., 1970). Given this vagal modulation of RSA, its amplitude has been proposed as a non-invasive index of parasympathetic cardiac control (Fouad et al., 1984; Katona and Jih, 1975; Lipson and Katona, 1979; McCabe et al., 1984, 1985; Raczkowska et al., 1983; Yongue et al., 198 1, 1982). Most of these validation studies have employed a within-subjects design. Studies employing between-subjects designs have produced more mixed results (Kollai and Miszei, 1990). Recent research however (Grossman et al., 1991; Grossman and Kollai, 1993; Kollai and Miszei, 1990), has found some problems using RSA to predict parasympathetic cardiac control. Firstly, differences in respiratory pattern can influence RSA to such an extent that parasympathetic cardiac control cannot be assessed reliably (Grossman et al., 1991). Specifically, changes in cardiac vagal tone do not necessarily coincide with respiratory mediated alterations in RSA. The physiological basis for these results may be that the inspiratory inhibition of vagal cardiac efferent activity is far from complete. Substantial vagal cardiac control persists during inspiration. The amount of inspiratory vagal activity varies depending on the respiratory pattern, decreasing when respiratory period and tidal volume increase and increasing when respiration is quicker and shallower (Grossman and Kollai, 1993). Under these circumstances, RSA amplitude as a measure of tonic vagal
control would underestimate actual vagal influences upon the heart, which should actually be the sum of and not the difference between inspiratory and expiratory vagal traffic (Grossman et al., 1991). In this way, comparison of RSA amplitudes under circumstances when breathing patterns differ significantly will produce errors in the estimation of parasympathetic cardiac control. To reliably predict cardiac vagal tone from RSA amplitude it would be necessary to control breathing, maintaining constant respiration rate and tidal volume. However, this control is neither possible nor desirable in most psychophysiological applications where subjects are actively engaged in mental tasks. Secondly, RSA, even under controlled respiratory conditions, does not accurately predict individual differences in parasympathetic cardiac control (Grossman and Kollai, 1993). The relationship of RSA to intersubject differences in cardiac vagal tone remains questionable. These results raise serious doubts about the usefulness of RSA to predict cardiac vagal efferent activity in psychophysiological research. Another measure which might be used as an indicator of cardiac vagal influences is the activity of the baroreceptor reflex. The baroreceptor reflex is one of the most important physiological mechanisms affecting efferent cardiac vagal activity and RSA (Davidson et al., 1976; Davis et al., 1977; Eckberg et al., 1980, 1984, 1985; Gilbey et al., 1984; McAllen and Spyer, 1978a,b; Raczkowska et al., 1983). With the availability of equipment which allows for the continuous and non-invasive measurement of blood pressure (Settels and Wesseling, 1985) it is now possible to assess baroreceptor cardiac reflex function non-invasively from the analysis of spontaneous patterns of blood pressure and heart period, using both frequency domain measures (Robbe et al., 1987) and time domain techniques (Bertinieri et al., 1985; Reyes de1 Paso, 1994; Steptoe and Sawada, 1989). The aim of the present research is to evaluate the usefulness of baroreceptor cardiac reflex sensitivity (BRS) - expressed as the change in heart period per unit change in systolic blood pressure - as a non-invasive measure of between-subject tonic parasympathetic cardiac control compared to RSA amplitude. We address this issue examining the following points: 1. Assessment of the effects of pharmacological blockade with a p,-selective beta-blocking agent
G.A. Reyes de1 Paso et al. /International Journal of Psychophysiology 22 (1996) 163-171
(metoprolol - without intrinsic sympathetic activity) and atropine on both measures. 2. Study of the relationship between both measures and heart period before and after pharmacological blockade. 3. Investigation of the relationship between RSA amplitude and BRS both during rest and mental load conditions. Furthermore, we shall report on other relevant psychophysiological measures namely respiratory activity and blood pressure changes in response to mental load.
2. Materials and methods 2.1. Subjects Subjects were nine healthy and physically fit male students of medicine aged between 23 and 25. The study protocol was approved by the Ethical Committee of the University of Bonn. Participants had given their informed consent and were given DM 400 for their collaboration. None of the subjects were on psychotropic medications; history, physical examination and baseline ECG did not show any abnormalities. 2.2. Apparatus Heart rate was recorded from lead II of the ECG by a Gould amplifier. Respiratory activity was measured from a Respitrace belt around the chest at the level of the xiphoid process. Blood pressure was recorded continuously with the non-invasive FIN.A.PRES device (Settels and Wesseling, 1985) from the middle phalanx of the third finger of the left hand. The hand was positioned at the level of the tricuspid heart valve. 2.3. Design Six subjects were investigated twice: They received either atropine (0.03 mg/kg body weight i.v.) on day 1 and metoprolol (up to 3 X 5 mg i.v.) on day 2 or the reverse order of drugs. Three subjects were investigated only once, receiving 3 X 5 ml of saline as a placebo condition. The latter individuals were
165
informed that they received a drug influencing the regulatory characteristics of the cardiovascular systern with no noticeable side effects. A similar experimental design has previously been used by Akselrod et al. (1981, 1985) Stephenson et al. (1981), and Pomeranz et al. (1985). 2.4. Mental load task A memory search and counting task was used for the mental load condition. Subjects had to memorize four letters presented on a computer screen (memory set). Then, single letters appeared on the screen at 3-s intervals, the subjects having to decide whether or not the letter belonged to the memory set. If the decision was affirmative the subject had to press a button with his right hand. At the same time, subjects were told to count the number of occurrences of the correct letter from the memory set on the screen. 2.5. Procedure One hour prior to the examination subjects were provided with a peripheral intravenous line. In the laboratory, subjects sat in a comfortable armchair in a semirecumbent position. After having attached and checked electrodes and the measuring apparatus, an initial baseline of IO-min duration ensued (baseline 1) followed by the first mental load task period of 5-min duration (task 1). Then, drugs were injected over a period of 5 min (atropine) or during a maximum of 3 X 5 min (metoprolol and saline). The dose of the beta-blocking agent was calculated according to the reduction in heart rate: If heart rate was reduced 2 25%, the injection was stopped. This goal was achieved in all subjects with doses between 10 and 15 mg of metoprolol i.v. Two minutes after the injection of drugs, when physiological variables reach a steady state to avoid possible measurement error (Byrne and Porges, 1993), another baseline was recorded over a lo-min sampling period (baseline 2). Then, another task phase of 5-min duration followed (task 2). 2.6. Data reduction and analysis Analysis of all measures was carried computer programs previously developed.
out using RSA am-
166
G.A. Rqes
de1 Paso et al./Intemationcrl
plitude was assessed on a breath-by-breath basis through the peak-to-valley method (Grossman and Svebak, 1987) quantifying the difference in milliseconds between the shortest heart period found during inspiration and the longest heart period found during expiration, and adjusting the temporal phase relation between respiratory and cardiac activity according to Eckberg (1983). When the minimum heart period during inspiration is longer than the maximum heart period during expiration a value of zero is assigned to the RSA amplitude of this respiratory cycle (Reyes de1 Paso, 1992). Baroreceptor cardiac reflex function was assessed by analysing sequences of 3 to 7 consecutive cardiac cycles (most sequences, about 80%, were of three cycles’ duration), during which systolic blood pressure increased (by at least 1 mmHg in each beat) in combination with an increase in heart period (by at least 2 ms in each beat) or sequences of equal length in which the decrease of systolic blood pressure was accompanied by a decrease in heart period, following the same rules for minimum changes. When one of these sequences was detected, the corresponding line of regression was computed. The slope or sensitivity of the reflex is expressed as change in heart period (in ms> per mmHg change in systolic blood pressure (Reyes de1 Paso, 1994). The program also obtained the proportion (in percent) of cardiac cycles that form part of the sequences with respect to the total number of cycles during the analysis period. This parameter has been interpreted as an index of the relative power of the baroreflex to regulate cardiac activity (Bertinieri et al., 1985; Steptoe and Sawada, 1989). The validity of this method to assess baroreceptor cardiac reflex function has been tested against spectral analysis techniques (Reyes de1 Paso, 1994). For the last 200 s of the baseline periods and for the first 200 s of the task periods, mean values of the following variables were computed: heart period, RSA amplitude, baroreceptor sensitivity both when systolic blood pressure increased (‘up’ sequences) and when systolic blood pressure decreased (‘down’ sequences), baroreceptor power (BRP) (i.e. percentage of cardiac cycles that contributing to sequences in an analysis period with respect to the total number of cycles) both when systolic blood pressure increased (‘up’ sequences) and when systolic blood pressure decreased (‘down’ sequences), systolic, diastolic, and
Jourml
uf Psychophysiology
22 (19961 163-171
mean blood pressure, systolic blood pressure variability (as the successive difference mean square), breathing amplitude as the difference in analog-todigital units between the two samples which signalled the starting and finishing points of inspiration, and respiratory rate, defined as the number of respiratory cycles within each period of analysis in cycles per minute. Respiratory amplitudes were expressed in terms of percentage of change with respect to the amplitude obtained during baseline. Statistical analyses of the effects of drug and task conditions were performed using planned comparisons through an ANOVA of repeated measures. The effect of the pharmacological blockade was analyzed comparing baseline and task periods before and after drug administration (baseline l/baseline 2 or task 1/task 2). The effect of the task was analyzed comparing baseline with task periods before drug administration (baseline 1/task 1). Relationships between variables were assessed through Pearson’s Product Moment correlations.
3. Results 3. I. Effect of pharmacological
blockade
Table 1 shows the average levels of heart period, RSA, and baroreceptor sensitivity and power before and after drug administration according to the different drugs used. 3.1.1. Heart period During baseline periods (F( 1,5) = 50.66, p < 0.0001) as well as under mental load conditions (F(1,5) = 33.67, p < 0.0001) atropine administration produced significant decreases in heart period. After the administration of metoprolol heart period increased, the comparison of baseline periods (F( 1,5) = 305.33, p < 0.0001) and mental load tasks (F(1,5) = 385, p < 0.0001) being highly significant. 3. I .2. RSA amplitude Atropine administration produced a large decrease in RSA amplitude, the comparison of the baseline periods (F(1,5) = 30,82, p < 0.0001) and mental load task (F( 1,5) = 177.17, p < 0.0001) being highly
G.A. Reyes de1 Paso et al./International
Journal of Psychophysiology 22 (19%) 163-171
Table 1 Average levels and standard deviations (in parentheses) for heart period (HP), RSA amplitude, baroreceptor power (BRP) before and after drug administration as a function of the drug No drug TKl
BL2
HP
Betablock Atropine Placebo
888 956 917
RSA
Betablock Atropine Placebo
99.4 117.5 138.9
(14) (39) (53)
65.5 68.4 83.2
(10) (8) (10)
115.6 6.5 142.7
Betablock Atropine Placebo
17.3 23.9 33.8
(7) (13) (18)
14.1 16.8 19.5
(1) (5) (9)
Betablock Atropine Placebo
16.9 15.3 21.2
(10) (3) (12)
16.4 11.9 17.4
Betablock Atropine Placebo
19 18 18
(6) (7) (9)
10.5 11.5 10
Betablock Atropine Placebo
20.8 23 21
(6) (11) (13)
(up)
BRS (down)
BRP
(up)
BRP (down)
baroreceptor
sensitivity
(BRS)
and
Drug
BLl
BRS
167
(142) (130) (222)
851 875 912
(140) (124) (220)
12 12 9
1146 564 975
TK2 (155) (30) (149)
1116 550 887
(163) (39) (129)
(41) (2) (25)
81.9 4.6 87.3
(30) (2) (4)
28.4 1.2 26.8
(17) (0.3) (14)
20.8 1.2 19.3
(7) (0.3) (11)
(8) (3) (8)
19.5 1.3 26.9
(5) (0.4) (13)
20.4 1.6 20.9
(10) (0.6) (10)
(5) (5) (5)
14 2.8 15.7
(9) (2) (6)
9.1 3 10.7
(6) (3) (6)
(8) (8) (10)
15.6 8.8 17
(8) (11) (13)
7 6 10.6
(4) (7) (6)
BL = baseline; TK = task.
significant. Metoprolol non-significant increase
administration produced in RSA amplitude.
a
3.1.3. Baroreceptor sensitivity Atropine administration produced a decrease in BRS, the comparison of the baseline periods (F(lS) = 11.20, p < 0.05 in the ‘up’ sequences and F(1,5) = 32.40, p < 0.0001 in the ‘down’ sequences) and mental load tasks (F(1,5) = 525.67, p < 0.0001 in the ‘up’ sequences and F(1,5) = 54.77, p < 0.0001 in the ‘down’ sequences) being significant. After the administration of metoprolol BRS increased without reaching a statistically significant level. 3.1.4. Baroreceptor power The administration of the three substances produced a decrease in this parameter in the baseline periods, both in the ‘up’ sequences (F( 1,14) = 9.47, p < 0.01) and ‘down’ sequences (F(1,14) = 4.71, p < 0.05). The decrease appeared greater after atropine administration, but there was no significant interaction of drug X comparison.
3.2. Effect of the memory search and counting task Table 2 summarizes the mean levels of the physiological parameters during the first baseline and task
Table 2 Average values and standard deviations different parameters during the baseline drug administration Baseline Heart period RSA Systolic blood pressure Diastolic blood pressure Mean blood pressure Systolic blood pressure variability Baroreflex sensitivity (up) Baroreflex sensitivity (down) Baroreflex power (up) Baroreflex power (down) Respiratory rate Change in respiratory amplitude
(in parentheses) of the and task periods before
Task
940 (153) 875 (149) 114 (32) 1:: (Z 123 (11) 68 (8) 73 (9) 85 92 (10) (9) 9.4 (6) 6.7 (3) 23 (11) 16 (3.5) 18.5 (6) 15 (6) 18.2 (7) 10.6 (5) 21.7 (9) 10.8 (8) 15.5 (2.7) 20.2 (2.5) - 12% (12)
168
G.A. Re.vrs del Paso et al. /International
periods. The planned comparison showed significant main effects of the task for heart period (F( 1,14) = 20.12, p < O.Ol), RSA amplitude (F(1.14) = 19.22, p < O.Ol), systolic blood pressure (F(1,14) = 15.3, p < O.Ol), diastolic blood pressure (F(1,14) = 10.37, p < O.Ol), mean blood pressure (F(l,l4) = 12.25, p < O.Ol), systolic blood pressure variability (F(l,14) = 6.02, p < 0.05>, BRS both in the ‘up’ sequences (F(l,14) = 12.12, p < 0.01) and in the ‘down’ sequences (F( 1,14) = 18.80, p < 0.0 I ), BRP both in the ‘up’ sequences (F( 1,14) = 20.93, p < 0.01) and in the ‘down’ sequences (F( 1,14) = 15.90, p < O.Ol), respiratory rate (F(l,l4) = 25.78, p < O.Ol), and respiratory amplitude (F( 1,14) = 5.54, p < 0.05). As can be seen in Table 2, the mental load task produced decreases in heart period, RSA amplitude, BRS, BRP, systolic blood pressure variability and respiratory amplitude and increases in blood pressure and respiratory rate. 3.3. Correlational tion
analysis
before drug adrninistru-
The correlations between RSA amplitude and heart period was 0.433 (n.s.) during the baseline and 0.622 (p < 0.05) during the task. As regards baroreceptor reflex, we continually report BRS in ‘up’ as well as in ‘down’ sequences because this might reflect differences in the physiological control mechanisms (Eckberg, 1980; Miyajima et al., 1986; Pickering et al., 1972). In our study, BRS was greater in the ‘up’ sequences than in the ‘down’ sequences (see Table 2), confirming research in cats by Bertinieri et al. (1985). These differences were significant for the first baseline period (F(l) 14) = 5.12, p < 0.05). BRS showed a somewhat closer association with heart period than RSA amplitude, the correlations being higher for the ‘up’ sequences (0.826, p < 0.01, during the baseline and 0.743, p < 0.01, during the task) than for ‘down’ sequences (0.574, p < 0.05, during the baseline and 0.46, n.s., during the task). 3.4. Correlation
coejj%ients
after vagal blockade
The percentage of change in heart period induced by atropine administration might be used as an invasive measure of the amount of parasympathetic cardiac control before the blockade. The correlations of
Journal
of Psychophysiology
22 (1996)
163-I
71
the percentage of change in heart period (between task 1 and baseline 2) with BRS during the ‘up’ sequences (0.952, p < 0.01) was somewhat greater than for RSA (0.865, p < 0.05). BRS during ‘down’ sequences presented no significant correlation (0. I). 3.5. Correlation blockade
coefficients
after
beta-adrenergic
After administration of beta-blocker, where we can assume that heart period changes are predominantly under vagal control, correlations between RSA amplitude and heart period were low (0.007 during the baseline and 0.052 during the task). To see whether these low correlations were due to differences in respiratory rate we controlled for respiratory rate as well. This procedure improved the correlation between RSA amplitude and heart period but the correlation coefficients remained non-significant (0.219 during the baseline and 0.527 during the task). BRS yielded a larger association with heart period, but the correlation coefficients were significant only for the ‘up’ sequences (0.8 16, p < 0.05, during the baseline and 0.858, p < 0.05, during the task) and not for the ‘down’ sequences (0.423 during the baseline and 0.457 during the task). The multiple correlation between BRS in both the ‘up’ and ‘down’ sequences as predictor variables and heart period as dependent variable was 0.985 (p < 0.01) during the baseline and 0.987 (p < 0.01) during the task, accounting for more than 97% of heart period variance. 3.6. Correlation measures
between
RSA amplitude
and BRS
Table 3 shows the correlations between RSA amplitude and BRS in the different experimental Table 3 Correlations of RSA and baroreceptor four experimental periods
BRS (up) BRS (down) R (up-down)
sensitivity (BRS) during the
LB1
TKl
LB2
TK2
0.598 + 0.601 + 0.856 *
0.644 ’ 0.638 * 0.839 *
0.647 * 0.756 * 0.734 *
0.828 0.844 0.863
* * *
R (up-down) = multiple correlation of BRS in the ‘up’ and ‘down’ sequences as predictor variables of RSA amplitude; BL = baseline: TK = task. * p
GA. Reyes de1 Paso et al./International
periods. RSA amplitude correlates positively with the BRS both in the ‘up’ and ‘down’ sequences. The multiple correlation between RSA amplitude as dependent variables and BRS in the ‘up’ and ‘down’ sequences as predictor variables accounted on average for about 70% of the RSA amplitude variance.
4. Discussion Our results concerning RSA seem to corroborate previous findings questioning the validity of RSA amplitude predicting individual differences in tonic parasympathetic cardiac control (Grossman et al., 1991; Grossman and Kollai, 1993; Kollai and Miszei, 1990). The most relevant finding has been obtained after beta-adrenergic blockade, when heart period is predominantly under vagal control. Under this condition correlations between RSA amplitude and heart period are very low. Even though the statistical control for respiratory rate improves this relation to some extent, the correlations still remain non-significant. As far as baroreceptor sensitivity is concerned, the correlations after beta-blockade with heart period are higher than those obtained for the RSA amplitude, but were significant only for the ‘up’ sequences. Using both parameters of baroreceptor sensitivity it is possible to predict more than 97% of heart period variance in the beta-blocking condition. The data show that the use of ‘up’ and ‘down’ sequences for the calculation of baroreceptor sensitivity yield different results. First of all, we find that the baroreceptor sensitivity is greater when blood pressure rises than when it falls. A similar finding has been reported by Mancia et al. (1983) and Bertinieri et al. (1985). Other authors systematically varied blood pressure levels and registered concomitant heart rate changes over a wide range of blood pressure values: they report a clear hysteresis pattern of the baroreceptor activity (Coleridge et al., 19811, showing a higher baroreflex gain with increasing blood pressure and lower gain with falling blood pressure. The different relation between baroreflex sensitivity calculated during ‘up’ versus ‘down’ sequences and heart period or RSA has not been reported directly by other authors. However, there have been reports indicating that the relative or differential sympathetic and vagal determinants of
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heart rate regulation are different when blood pressure rises compared to falling blood pressure. The slowing of heart rate in response to rising blood pressure is primarily a vagal response (Scher and Young, 1970; Thames and Kontos, 1970; Miyajima et al., 1986; McCabe et al., 1985). In our study, before drug administration, baroreceptor sensitivity during ‘up’ sequences shows a closer relationship with heart period (mainly under vagal control under resting conditions and during low levels of arousal) than ‘down’ sequences. After drug administration, both the vagal and beta-adrenergic blockade conditions show higher correlations of baroreceptor sensitivity with the invasive vagal measures during ‘up’ sequences. These results suggests that the ‘up’ sequences might be a better predictor of parasympathetic cardiac control than the ‘down’ sequences. This may be explained by the larger relative contribution of the vagal influences on the ‘up’ sequences in comparison with the ‘down’ sequences. Apart from that, we have to take into account that these sequences reflect different dynamics. The ‘up’ sequences reflect vagal activation and the ‘down’ sequences, vagal withdrawal. The validity of the pharmacological blockade is evident in the significant effects on heart period. The administration of metoprolol increased heart period by 29% and the administration of atropine decreased it by 41%. Atropine administration reduces RSA amplitude and baroreceptor sensitivity to values near zero, confirming their vagal origin. The administration of the beta-blocking agent produced a non-significant increase in RSA amplitude and baroreceptor sensitivity. Such an observation has also been made by others (Coker et al., 1984; Eckberg et al., 1976; Fouad et al., 1984; Grossman and Svebak, 1987; Grossman and Kollai, 1993). The memory search and counting task produced a significant decrease in the RSA amplitude levels. Several physiological mechanisms have been implicated to explain the observed reduction: an increase in respiratory rate, a small decrease in the respiratory amplitude, and decrease in blood pressure variability, which in turn would lead to a diminished heart rate variability mediated by the baroreceptor reflex. A fundamental factor seems to be the decrease in BRS. This last factor predicts about 70% of the variability in the RSA amplitude. This figure is in line with
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other physiological studies on the relationship between RSA amplitude and carotid baroreceptor reflex responses (Bennett et al., 1978; Raczkowska et al., 1983). A reduction in RSA amplitude has also been reported by Grossman and Svebak (1987) using a video game with or without threat of shock. On the other hand, the decrease in baroreceptor sensitivity during the memory search and counting task is supported by the findings of Steptoe and Sawada (1989), who had used a mental arithmetic task. Given the preliminary nature of this study and the small number of subjects used, our results should be viewed with caution. They do indicate, however, that useful information about vagal cardiac tone can be obtained non-invasively from the analysis of baroreceptor cardiac reflex function, especially during the ‘up’ sequences. The availability of technical devices al!owing for a non-invasive registration of continuous blood pressure values allows for the easy assessment of baroreceptor cardiac reflex function.
Acknowledgements This research was supported by a Grant from the Commission of the European Communities Medical and Health Research Programme. Concerted Action: Quantification of Parameters for the Study of Breakdown in Human Adaptation. We would also like to thank L.J.M. Mulder and his colleagues from the University of Groningen for their support and collaboration in carrying out this research.
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