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179 Original Articles Extraction of Response Waveforms of Heartbeat and Blood Pressure to Swallowing Using Mixed Signal Processing of Time Domain and Respiratory Phase Domain T. Numata1; Y. Ogawa1; K. Kotani1,2; Y. Jimbo1,2 1Graduate 2School School of Frontier Science, The University of Tokyo. Tokyo, Japan; of Engineering, The University of Tokyo, Tokyo, Japan Keywords Heart rate variability, Hilbert transform, respiratory phase, blood pressure variability, swallowing Summary Background: Evaluating the accurate responses of the cardiovascular system to external stimuli is important for a deeper understanding of cardiovascular homeostasis. However, the responses should be distorted by the conventional time domain analysis when a frequency of the effect of external stimuli matches that of intrinsic fluctuations. Objectives: The purpose of this study is to propose a mixed signal processing of time domain and respiratory phase domain to extract the response waveforms of heartbeat and blood pressure (BP) to external stimuli and to clarify the physiological mechanisms of swallowing effects on the cardiovascular system. Methods: Measurements were conducted on 12 healthy humans in the sitting and Correspondence to: Takashi Numata Graduate School of Frontier Science The University of Tokyo #303, Building 4, RCAST 4-6-1 Komaba, Meguro Tokyo 153-8904 Japan E-mail: [email protected] standing positions, with each subject requested to swallow every 30 s between expiration and inspiration. Waveforms of respiratory sinus arrhythmia (RSA) and respiratoryrelated BP variations were extracted as functions of the respiratory phase. Then, respiratory effects were subtracted from response waveforms with reference to the respiratory phase in the time domain. Results: As a result, swallowing induced tachycardia, which peaked within 3 s and recovered within 8 s. Tachycardia was greater in the sitting position than during standing. Furthermore, systolic BP and pulse pressure immediately decreased and diastolic BP increased coincident with the occurrence of tachycardia. Subsequently, systolic BP and pulse pressure recovered faster than the R-R interval. Conclusions: We conclude that swallowinginduced tachycardia arises largely from the decrease of vagal activity and the baroreflex would yield fast oscillatory responses in recovery. Methods Inf Med 2015; 54: 179–188 http://dx.doi.org/10.3414/ME14-01-0050 received: May 2, 2014 accepted: September 23, 2014 epub ahead of print: November 14, 2014 1. Introduction The autonomic nervous system (ANS) regulates the cardiovascular (CV) system for the purpose of maintenance of physiological homeostasis, taking into account the CV system responses to external stimuli and recovering to its previous state. Therefore, it is effective to extract the CV response induced by external stimuli for understanding the response mechanism of the CV system and the dynamics of ANS control. Human heartbeat and blood pressure (BP) always fluctuate with intrinsic fluctuations such as respiratory sinus arrhythmia (RSA), and Mayer wave, which is the oscillations of arterial pressure, even at rest [1– 7]. Although evaluation of average response waveforms across groups of subjects [8 –10] has been generally used to evaluate response in the time domain, the average response would be distorted when the swallowing effects have a frequency that matches that of intrinsic fluctuations such as RSA and Mayer wave. For the same reason, the frequency domain analyses or time-frequency domain analyses cannot be directly applied for evaluation of the CV responses to swallowing. In addition, the conventional linear parametric model or cross-spectral analysis [11–18] are not appropriate because the timing of respiration and its effects on CV system is complex due to time varying rhythms. Further, nonlinear systems identification tools, which have been applied to investigate the mutual interactions of the CV system [19 –22], are limited when we take higher-order nonlinearity into account due to the drastic © Schattauer 2015 Methods Inf Med 2/2015 Downloaded from www.methods-online.com on 2017-08-12 | IP: 88.99.165.207 For personal or educational use only. No other uses without permission. All rights reserved. 180 T. Numata et al.: Response Waveforms of Heartbeat and BP to Swallowing increase of the parameters required for identification, and the original timedependent dynamics are obscured. Recently, a respiratory-phase domain approach has been developed that successfully extracted the accurate waveform of RSA [5, 23 –26]. In particular, respiratory phase domain analysis has also been extended to extract the accurate waveforms of not only RSA but also respiratory effects on BP [25]. In addition, circadian changes of swallowing effects on RSA in the respiratory-phase domain analysis, which circadian rhythms on the CV system should be regulated by the ANS, was reported in our previous study [27]. Although the previous study [27] would be able to evaluate the relationship between swallowing effects on the CV system and the ANS, this method does not allow the evaluation of response waveforms in the time domain. Neither, the method cannot evaluate the interactions between heartbeat and BP. As pertains to the external stimuli, it is known that the CV system is strongly influenced by some external stimuli. In particular, swallowing has a strong effects on the CV system, reflecting the control of the ANS [9, 10, 28, 29]. Since fatal disease presentations such as atrial tachyarrhythmia, atrial fibrillation, and syncope are sometimes induced by swallowing [30, 31], it is important in the fields of clinical medicine and physiology to clarify the swallowing effects on CV system. However, swallowing effects and relationship between swallowing effects and the ANS are conflicting. Sheroziya et al. [28] reported that body position changed the swallowing-induced tachycardia, while Nitta et al. [9] reported that it did not. In order to resolve this conflict on the mechanism responsible for CV changes that accompany swallowing, the method for accurate evaluation of the response waveforms to swallowing from the CV system with different body positions in the time domain is necessary. In this study, we developed a method that extracts the response waveforms of heartbeat and BP during swallowing from the intrinsic fluctuations in the time domain. We then evaluated the physiological mechanisms underlying swallowing effects on the CV system. 2. Methods 2.1 Experimental Procedures The subjects consisted of 12 young healthy males without CV and respiratory diseases with mean age of 23.0 ± 1.3 y who were tested in experimental sessions in sitting and standing positions with the resting state. These experiments were approved by the Ethics Committee of the Graduate School of Frontier Sciences (The University of Tokyo). Subsequent to being given a full description of the study, informed consents were got by all subjects. In both experiments, swallowing were performed 12 times purposely at intervals of 30 s between expiration and inspiration. There are two reasons to set these artificial setting. One is that we expected the enhanced information to evaluate the signal-processing algorithm with CV time series before swallowing. Since swallows were performed between expiration and inspiration, the CV fluctuations induced by respiratory activity should be enhanced just before swallowing, it is effective to evaluate the signal-processing algorithm with data before swallowing. The other is to obtain enough rest time between swallows for extracting response waveforms. Since swallowing were always performed between expiration and inspiration under the free-timing experiment [24], and the previous studies show that the response waveform of heartbeat to swallowing with artificial setting (swallowing every 30 s) [27] seems to be same as the response with natural setting (free timing) [24] and fast recovery such as one respiration after swallowing [24], there would be little impact to the CV system with the artificial setting in this study. In addition, since paced respiration might result in unnatural hyperventilation or an alteration in the autonomic balance [32], the experiments were made under free-breathing conditions. Six subjects performed in standing position first, followed by sitting, while the others performed in sitting position first to offset the effect of order. Data were recorded for 410s in each session. Measurements of electrocardiographic R-R intervals (RRI) (AC-601G, Nihon-Koden); radial artery BP, by means of a tonometric device (BP-608EV, Colin Medical Technology); instantaneous lung volume (ILV), by means of inductive plethysmograph (standard type Respitrace, A.M.I); and the motion of the laryngeal prominence, by means of two accelerometers (8305A2M4 and 8305B2M4, Kistler) were performed. Accelerometers were positioned on the top and the bottom of the laryngeal prominence. Since swallowing in normal individuals gave rise to a characteristic acceleration pattern which was quite reproducible, and signal occurred during laryngeal elevation and the magnitude of acceleration correlated well with the laryngeal displacement [33, 34], it is reasonable to determinate the trigger point by the accelerations of laryngeal elevation. The sampling frequency of the electrocardiogram, BP, and motion of the laryngeal prominence were 1,000 Hz, and that of ILV was 100 Hz. 2.2 Signal Processing In this study, we propose a method of extracting the response waveforms of heartbeat and blood pressure to swallowing in the time domain without the effects of RSA and Mayer wave. ▶ Figure 1 shows diagrams of the signal-processing algorithms. First, respiratory induced modulation (RM) is extracted by the same algorithm as a previous study [25] which is shown in ▶ Figure 1A. Then, the effects of intrinsic fluctuations such as RM and Mayer wave are removed and the response waveforms to swallowing are extracted by the newly developed algorithm which is shown in ▶ Figure 1B. The algorithm for extracting RM (▶ Figure 1A) is the same algorithm used in a previous study [25]. First, ILV data was filtered by a band-pass filter of 0.1–10 Hz. The band pass filter was the finite impulse response filter with hamming window and the order of the filter was 4000. The instantaneous phase ϕ (t ) of signal s (t ) was thus uniquely defined by using Hilbert transform [25]. To extract the stable waveform of RSA, RRI data were first converted to an instantaneous heart rate (HR) time series by the inverse of the derivative of cubic spline interpolation (DCSI) method [25]. In addition, systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) were converted to the instantaneous SBP, DBP, and Methods Inf Med 2/2015 © Schattauer 2015 Downloaded from www.methods-online.com on 2017-08-12 | IP: 88.99.165.207 For personal or educational use only. No other uses without permission. All rights reserved. T. Numata et al.: Response Waveforms of Heartbeat and BP to Swallowing Figure 1 Schematic diagrams of the signal processing in this study. (A) Extraction of RM waveforms. BPF, band-pass filtering; RRI, R-R interval; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; DCSI, derivative of cubic spline interpolation; CSI, cubic spline interpolation. (B) Derivation of averaged response waveform. X should be replaced with RRI, SBP, DBP, or PP in actual signal processing. PP by the method of cubic spline interpolation. SBP is the maximum value and DBP is the minimum value of the BP in a cycle of interbeat intervals. PP was obtained as the subtraction of DBP from SBP. Then, instantaneous RRI, SBP, DBP, and PP were extracted at every π/10 of ϕ (t ) to obtain each RM waveform. Thus, CV signals were interpolated and processed together with the timing of respiratory phase which were data from different sampling frequencies. The RRI, SBP, DBP, and PP data for respiration during swallowing and the following two respirations after swallowing were removed, and the remaining data were extracted and averaged as the normal data. The obtained waveforms demonstrated the response of heartbeat and BP to normal respirations, which was expressed as a function of respiratory phase. Finally, the time course of i-th swallowing (RRIi , SBPi , DBPi , PPi ) and RM function (RRIRM , SBPRM , DBPRM , PPRM ) were obtained and used in the following signal processing. ▶ Figure 1B shows the algorithm for extracting the response waveform to swallowing in the time domain. First, the RRI, SBP, DBP, PP, and respiration phase data from 5 s before swallowing to 15 s after swallowing (from –5 s to 15 s) were resampled at a rate of 4 Hz. The waveform before swallowing (from –5 s to –1 s) should be flat at the value 0 when the effects of RSA and Mayer wave were sufficiently excluded. Thus, it was used to ensure the validity of the signal processing in this study. Then, differences between the data during swallowing and normal respiration were derived in response to the respiratory phase of each period. Here we denote that is a representative expression of the physiological variables as RRI, SBP, DBP, or PP (i.e. X Î {RRI, SBP, DBP, PP}) and ti as the onset of the i-th swallow, Xi (t ) as a time course of the i-th swallow (from –5 s to 15 s), and Xi (t ) as a respiratory modulation waveform extracted in the respiratory phase domain. The relationship © Schattauer 2015 Methods Inf Med 2/2015 Downloaded from www.methods-online.com on 2017-08-12 | IP: 88.99.165.207 For personal or educational use only. No other uses without permission. All rights reserved. 181 182 T. Numata et al.: Response Waveforms of Heartbeat and BP to Swallowing between respiratory phase ϕ and time t is denoted as ϕ = f (t ), which is derived by Hilbert transform of ILV. Then, the subtraction of respiratory influence is calculated as (1) where Xisub(t ) is the time domain waveform with respiratory modulation subtracted. Finally, response waveforms of swallowing Xave(s) from –5 s to 15 s were obtained by averaging the data at the same time with reference to the onset time of swallowing, which eliminated the influence of Mayer Figure 2 (A) Time course of accelerometers around the onset of swallowing. (B – E) Waveforms of SBP as an example of the signal processing in this study. (B) Waveform around a single swallow at t = 0. (C) Waveform of respiratory modulation. (D) Response waveform in the time domain where respiratory modulation is subtracted from (B). (E) Averaged response waveform in the time domain. Vertical bars represent SE. Methods Inf Med 2/2015 © Schattauer 2015 Downloaded from www.methods-online.com on 2017-08-12 | IP: 88.99.165.207 For personal or educational use only. No other uses without permission. All rights reserved. T. Numata et al.: Response Waveforms of Heartbeat and BP to Swallowing wave and low frequency fluctuations, using the equation (2) n describes the trial number in the experiment. Since each subject performed swallowing 12 times, n set at 12 in this study. The trial number was decided based on the previous studies [24, 27], which is enough to evaluate the external effects on the CV system, and it should be decided appropriately with the application to other external stimuli or experimental situations. ▶ Figure 2 shows a representative example to illustrate how the signal processing works. ▶ Figure 2A shows the time course of accelerometers around the onset of swallowing. ▶ Figures 2B –E show SBP waveforms as an example of the signal processing in this study. First, the time of swallowing was identified by the waveform of the accelerometer (▶ Figure 2A). Second, the SBP data during swallowing and during two breaths after swallowing was extracted as “swallowing” data ( ▶ Figure 2B), while the average of the rest of the data was regarded as “normal” (▶ Figure 2C). Then, the swallowing and normal data were restored in the time domain, and the difference between the swallowing and normal data was calculated (▶ Figure 2D). This subtraction removed the effect of RM. Finally, the effect of the Mayer wave was removed by averaging the SBP data from different swallowing events. Thus, the SBP response waveform was extracted. Also, RRI, DBP and PP response waveforms were extracted with subtracting each normal data from each swallowing data. Whereas the sampling frequency of accelerations were 1,000 Hz, the CV responses were resampled 4 Hz and the differences of peak time of each CV response waveforms were much longer than the sampling frequency. Therefore, the effect of sampling frequency was small enough to evaluate the CV response waveforms to swallowing accurately. 2.3 Statistical Analysis To evaluate the influence of swallowing, waveforms of RRI, SBP, DBP, and PP were extracted, and the mean of each waveform was calculated. Then, we employed the comparison between data at the time of swallowing and data before swallowing to evaluate the validity of the proposed method as well as the comparison between data at the time of swallowing and data after swallowing to evaluate the effect of swallowing. Whereas CV indices to be compared are not normally distributed, the indices in this study are different from merely heart rate or blood pressure because of subtraction of CV fluctuations from raw CV signals. In addition, the non-normality of the indices were not apparent because the p values of all data of indices were no less than 0.05 (p > 0.05) by Shapiro-Wilk normality test. Therefore, we assumed that the indices were normally distributed and applied the t test as well as the recent studies [35, 36]. Since time variation of CV responses would be expected to clarify with high accuracy by the proposed method, statistical differences between data at the time of swallowing and data at every second before swallowing (from –5 s to –1 s) and after swallowing (from 1s to 15s) were tested by paired t test with a post-hoc Bonferroni correction. In addition, the peak decrease and/or increase of data of each waveform and the elapsed time of peaks from swallowing were set as indices of heartbeat and BP based on the results of statistical analysis, and statistical differences between the data collected during standing and sitting were tested by paired t test. Furthermore, the elapsed times of RRI, SBP, DBP, and PP in the same position were compared by 2-way analysis of variance (ANOVA) with the assumption that different time-variant CV responses might be induced by postural differences. We derived parameters of each index in each data set and compared them by the two-tailed multiple t test with Bonferroni correction following ANOVA. Detailed explanation of each parameter is provided in the “Results” section and ▶ Figure 3. 3. Results ▶ Figure 3 shows the average waveforms (n = 12) of RRI, SBP, DBP, and PP in the standing and sitting positions and the result of paired t test with Bonferroni correc- tion of the values from –5 s to –1 s before swallowing and from 1s to 15s after swallowing (every second) relative to the value at time of swallowing (0 s). In regards to the time before swallowing, there are no significant differences between the data at the time of swallowing and the data before swallowing. In contrast, in regards to the time after swallowing less than 10s, the RRI values from 1 s to 6 s after swallowing in the standing position and from 1 s to 5 s in the sitting position were smaller than that of swallowing. We confirmed the presence of P-waves prior to R-waves in the electrocardiogram in all subjects during swallowing, which means that the tachycardia in this study was not induced by atrial premature contractions as in previous studies [4, 30]. The decrease in RRI recovered at approximately 7 s (▶ Figure 3A, ▶ Figure 3B). The SBP value at 2 s after swallowing was smaller than that of swallowing, and the values of DBP at 1 s and 2 s after swallowing were larger than that of swallowing in the sitting position. The values of PP from 1 s to 3 s after swallowing in the standing and sitting positions were smaller than that of swallowing. In addition, more than 10 s after swallowing, the RRI values in both positions were smaller than that of swallowing, and the SBP values in the standing position were smaller than that of swallowing. The DBP values in both positions were also smaller than that of swallowing. We compared the magnitude and the time of peak of response waveforms between the standing and sitting positions by referring to the total averaged response waveforms of RRI, SBP, DBP, and PP (▶ Figure 3). With regard to RRI, we compared the peak value of tachycardia (N-RRI) and the peak time of tachycardia (tN-RRI). For SBP and PP, we compared the peak value of decrease (N-SBP and N-PP) and the peak time of decrease (tNSBP and tN-PP). For DBP, we compared the peak value of increase (P-DBP) and the peak time of increase (tP-DBP). We compared the magnitude of the four peak values between the standing and sitting positions using the paired t test (n = 12), and ▶Table 1 and ▶Table 2 show the results of comparison. N-RRI was significantly larger in the standing position than during sit- © Schattauer 2015 Methods Inf Med 2/2015 Downloaded from www.methods-online.com on 2017-08-12 | IP: 88.99.165.207 For personal or educational use only. No other uses without permission. All rights reserved. 183 184 T. Numata et al.: Response Waveforms of Heartbeat and BP to Swallowing Figure 3 (A, C, E, G) Averaged response waveforms of the heart rate and blood pressure indices induced by swallowing in the standing position. (B, D, F, H) Averaged response waveforms of the heart rate and blood pressure indices induced by swallowing in the sitting position. (A, B) RRI; (C, D) SBP; (E, F) DBP; (G, H) PP (PP calculated as SBP minus DBP). Vertical bars represent SE. *P < 0.01, †P < 0.05 Methods Inf Med 2/2015 © Schattauer 2015 Downloaded from www.methods-online.com on 2017-08-12 | IP: 88.99.165.207 For personal or educational use only. No other uses without permission. All rights reserved. T. Numata et al.: Response Waveforms of Heartbeat and BP to Swallowing ting, and the other three values demonstrated no statistically significant differences between positions. In addition, twoway analysis of variance indicated no interaction between position and peak time. tNSBP was earlier than tN-RRI and tP-DBP, and tN-PP was earlier than tP-DBP. 4. Discussion Table 1 Values of the heart rate and blood pressure indices induced by swallowing and results of statistical comparison. Values represent estimated mean values ± SD. N-RRI, the peak value of decrease in R-R interval; N-SBP, the peak value of decrease in systolic blood pressure; P-DBP, the peak value of increase in diastolic blood pressure; N-PP, the peak value of decrease in pulse pressure. Parameter Sitting (n = 12) P N-RRI (ms) – 98.7 ± 35.4 – 158.7 ± 49.7 < 0.01 N-SBP (mmHg) – 3.10 ± 2.77 – 2.04 ± 4.04 NS P-DBP (mmHg) 5.16 ± 1.79 5.60 ± 2.26 NS – 5.99 ± 2.12 – 6.16 ± 2.01 NS N-PP (mmHg) 4.1 Evaluation of the Signal Processing Algorithm To evaluate the validity of the proposed method, we extracted the waveform for 5 s before swallowing and there are no statistical significant differences between the data at the time of swallowing and the data before swallowing. During that period RRI and PP remained constant at zero, while SBP and DBP were almost constant but drifted slightly. Low-frequency fluctuations in blood pressure are thought to cause these drifts in SBP and DBP [37]. Hence, PP remains constant at zero because the drift in blood pressure is subtracted. Because the drifts in SBP and DBP are sufficiently small compared to those after swallowing (i.e. the response and recovery process), intrinsic fluctuations are well reduced by our proposed method, allowing the response and recovery process of heartbeat and BP to be evaluated in detail. The amplitudes of the BP fluctuations induced by RSA are known to be approximately 3 mmHg [25] and the amplitude of SBP in the standing position in this study was also 4.36 ± 2.33 mmHg; see the Appendix in details. They are almost equal to the BP fluctuations induced by swallowing (e.g., N-SBP is –3.10 ± 2.77 mmHg in the standing position). Therefore, it is necessary to extract the response waveforms by removing RM and it is well performed by the method proposed in this study. It can take physiological nonlinear elements into account with a simple signal processing algorism and allows us to evaluate the differences of the time course of heartbeat and BP with the removal of the effects of intrinsic fluctuations, which cannot be achieved by analyses in the frequency domain or combined time-frequency domain analyses. This ability is highly advantageous for placing the obtained results into a Standing (n = 12) physiological context. Thus, the proposed method demonstrated accurately extraction of the response waveforms to swallowing from the CV system with different body position in the time domain and the physiological relationship between heartbeat and BP in the time domain were accurately extracted. 4.2 Swallowing Effect In this study, we confirmed the presence of P-waves prior to R-waves in the electrocardiogram in all subjects during swallowing. Therefore, this tachycardia was not induced by atrial premature contractions as in previous studies [4, 30] and the paths of swallowing have possibilities to be different from that of swallowing with disease presentations [29, 30, 38 – 42]. Thus, two possible physiological factors would induce tachycardia by swallowing in this experiment: mechanical stimulation due to changes in intrathoracic pressure [8, 10] and changes in autonomic nerve activity as the response of the central nervous system [9, 27–29]. Previous studies reported conflicting findings on whether the tachycardia induced by swallowing depends on the posture or not [9, 28] and it would be partly because the intrinsic fluctuations are not sufficiently reduced. On the contrary, the present study shows a large difference with a statistical significance in the response of tachycardia between the standing and sitting positions. Therefore, our accurate waveform analysis reveals that a change in autonomic nerve activity, particularly vagal activity, largely contributes to swallowinginduced tachycardia, which supports the results of Sheroziya et al. [28, 29]. This is also supported by the results that DBP increased and the change in RRI and PP occurred at the same time, because if mechanical stimulation is the main factor and the change indirectly affects RRI through a change in cardiac output, BP should decrease as the primary effects of swallowing, and tachycardia should be observed subsequently. These findings suggest that swallowing-induced tachycardia arises from the decrease of vagal activity, and the changes in blood pressure are induced by the preceding effect of tachycardia. Therefore, the swallowing effect would be helpful to evaluate cardiac vagal tone and combined evaluation of RSA and swallowing effect could be a better index of cardiac vagal tone than that of RSA alone. In addition, SBP and PP immediately decreased, and they recovered faster than Table 2 Time of each peak induced by swallowing and results of statistical comparison. Values represent estimated mean values ± SD. tN-RRI, the time of N-RRI; tN-SBP, the time of N-SBP; tP-DBP, the time of P-DBP; tN-PP, the time of N-PP. N-RRI, N-SBP, P-DBP, and N-PP are described in Table 1. *P < 0.01, † P < 0.05. Parameter Standing (n =12) Sitting (n = 12) tN-RRI (s) 2.67 ± 0.79 2.40 ± 0.88 tN-SBP (s) 1.71 ± 0.40 1.94 ± 0.83 tP-DBP (s) 4.50 ± 3.23 4.06 ± 2.79 tN-PP (s) 2.02 ± 0.45 2.27 ± 0.51 © Schattauer 2015 Methods Inf Med 2/2015 Downloaded from www.methods-online.com on 2017-08-12 | IP: 88.99.165.207 For personal or educational use only. No other uses without permission. All rights reserved. 185 186 T. Numata et al.: Response Waveforms of Heartbeat and BP to Swallowing Figure 4 (A – D) Averaged RM functions in the standing position and the sitting position. (A) RRI, (B) SBP, (C) DBP, (D) PP. (Bar shows the intraindividual average ± SE.) the RRI. In regard to decreases in SBP and PP, they should be related to the decrease in cardiac output. After the decrease induced by swallowing, SBP increased to exceed pre-swallowing values, while RRI did not. Although there is no significant difference which indicates the increase of SBP, this response is likely considered to be induced by the baroreflex. If the baroreflex protects against a drop in SBP, SBP should increase faster than RRI. In fact, tN-SBP was statistically significantly smaller than tN-RRI (▶ Table 2), supporting the occurrence of the baroreflex. Compared to the waveforms of RRI, SBP, and PP, the DBP waveforms and its physiological considerations are rather complicated. Immediately after swallowing, it increased as a result of shortening of the diastolic phase (i.e. blood pressure descent phase) induced by decreased RRI. Even after RRI began recovering, DBP did not decrease, and this phenomenon may reflect the baroreflex compensating for the decrease in SBP to in- crease cardiac output. We then observed an oscillatory recovery process in SBP, DBP, and PP, which may be caused by ANS regulation via multiple feedbacks with different time constants [43, 44]. Thus, the proposed method was able to evaluate the transitional responses of SBP, DBP, and PP with a unique capability to evaluate the recovery response of heartbeat and BP to swallowing. The previous study [45] reported that there are no significant differences of tachycardia induced by swallowing between young and old subjects. Therefore, in this study, young healthy subjects were tested to extract general physiological mechanism related to swallowing effects on the CV system. However, there is a possibility that a slight differences induced by age, which cannot be detected by the conventional time averaging, might exist and the proposed method would be able to evaluate differences of cardiovascular response waveforms between young and old subjects. In addition, the proposed method would be useful to evaluate the differences of tachycardia between healthy subjects and subjects with disease presentations [38 – 42]. Thus, in the future work, based on data of a larger study population or subjects of different ages and physical condition would be considered desirable to understand the swallowing effects on the CV system in detail. 5. Summary In this study, we proposed a mixed signal processing of time domain and respiratory phase domain to extract the response waveforms of heartbeat and BP to external stimuli in the time domain. As a result, we demonstrated high accuracy extraction of time-variable heartbeat response to swallowing that tachycardia peaked around 2.5 s and recovered within 8s and it was greater in the sitting position than during Methods Inf Med 2/2015 © Schattauer 2015 Downloaded from www.methods-online.com on 2017-08-12 | IP: 88.99.165.207 For personal or educational use only. No other uses without permission. All rights reserved. T. Numata et al.: Response Waveforms of Heartbeat and BP to Swallowing standing. In addition, we extracted response relationship between heartbeat and BP in the time domain that SBP and PP immediately decreased, DBP increased coincident with the occurrence of tachycardia, and SBP and PP recovered faster than the RRI. Appendix To evaluate response waveforms of heartbeat and BP to swallowing, it is necessary to extract RM functions appropriately. ▶ Figure 4 shows the RM functions of RSA, SBP, DBP, and PP in the standing and sitting positions. 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