New measures for noninvasive and real time monitoring of the autonomic balance: an explorative study

J. De Poorter Zara T., VZW e-mail: john.depoorter@arteveldehs.be

Contents
Abstract ................................................................................................................................................... 2 Introduction............................................................................................................................................. 3 Methods .................................................................................................................................................. 6 1. New measures for the autonomic system ...................................................................................... 6 2. Feedback in the autonomic model ................................................................................................ 14 3. Phase relations in the autonomic model ...................................................................................... 16 Procedure .............................................................................................................................................. 20 Data Analysis ......................................................................................................................................... 20 Results ................................................................................................................................................... 23 Discussion .............................................................................................................................................. 25 Conclusions............................................................................................................................................ 30 Tables .................................................................................................................................................... 31 Figures ................................................................................................................................................... 34 References ............................................................................................................................................. 41

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Abstract
Good measures for the autonomic system to investigate the functioning of diverse relaxation and breathing techniques are still missing. Commonly used measures of parasympathetic activity like HF are based on the heart rate variability but have a low time resolution (several minutes) and are not applicable for experiments where people are breathing slowly (with frequencies lower than 0.15 Hz). The sympathetic activity can be monitored using peroneal microneurography but this technique has the disadvantage of being complex and invasive. We designed an approximated mathematical model with new measures for the autonomic system. These measures allow the monitoring of the autonomic system on the time scale of the heartbeat and are based on parameters that can be extracted from one signal, namely the time evolution of the arterial blood pressure. The parasympathetic signal can be monitored by the psys signal with which it has a positive correlation. The Windkessel relaxation time v can be used as a monitoring measure for the sympathetic signal, with which v has either a positive or negative correlation. We also developed a method based on phase differences between the psys, v and the HR signals to determine the sign of this correlation. This phase method compares the phase relations over the different breathing frequencies. This approach has the potential to give insight in the numerous processes that are interacting with the autonomic signal during breathing. We found a great variability of these phase relations over the five volunteers reflecting the different ways people are breathing. For some special cases we could indicate the dominant processes that are determining the HR. If psys and v signals are not phase locked at 0 or 180, we could calculate which characterizes the sympathovagal balance of the heart signal. Although, the accuracy of this method is not high, we get consistent results for this explorative study with five volunteers. More extensive experiments with people trained in breathing techniques are necessary for more general conclusions about the breathing mechanisms involved.

Internal report about the autonomic nerve system Key words: autonomic nerve system, heart rate variability, arterial blood pressure, parasympathetic activity, sympathetic activity, sympathovagal balance

version 1.0 12/9/2011

Introduction
The dynamics of the parasympathetic and sympathetic activity is a key focus of many research fields. In clinical setups the autonomic signals have a diagnostic value for cardiovascular diseases and the functioning of the autonomic nerve system itself (Phillip A, 2004). Besides physiological applications, autonomic signals are also investigated for psychological interests. The sympathetic signal correlates with arousal (Dawson, Schell, & Filion, 2007) and the parasympathetic signal with relaxation (Berntson, Cacioppo, & Quigley, 1993) which makes the autonomic signals popular in psychophysiology studies (Stern, Ray, & Quigley, 2001), for stress reduction methods and biofeedback (Blase, 2005; Edmonds, Tenenbaum, Mann, Johnson, & Kamata, 2008; Fortney & Taylor, 2010; Healey & Picard, 2005; Kumar, Weippert, Vilbrandt, Kreuzfeld, & Stoll, 2007; Park et al., 2008). However, the popularity of these research topics is not reflected in transparent and reliable noninvasive measuring techniques. The autonomous signals themselves cannot be measured noninvasively and most of what we know about the dynamics of the nerve signals was found out of indirect observations and animal experiments (Brack, 2004). An exception to this is the research field around the muscle sympathetic nerve activity (MSNA) because the invasiveness is limited to some needle pricks around the knee. The dynamics of the MSNA signals are well documented (Karemaker & Wesseling, 2008; Wallin & Charkoudian, 2007) and also useful for physiological research (Wallin, 2007) but the measuring technique is not suitable for field studies around stress and relaxation techniques. Non-invasive measuring techniques are using the known impact of the autonomous signals on organs like the skin, the heart, the eyes, (Stern, et al., 2001). The measurement of electrodermal activity, i.e. the conductivity of the skin, is well standardized and widely used in arousal studies (Fowles et al.,

Internal report about the autonomic nerve system

version 1.0 12/9/2011

1981). The technique can detect arousal pulses on the time scale of 1 second, but the relation to the skin sympathetic activity (SSNA) is rather complex. Skin sympathetic nerve signals induce a combination of vasoconstrictor, vasodilator, sudomotor and pilomotor effects (Wallin & Charkoudian, 2007) resulting in a temperature dependence of the electrodermal signals (Dawson, et al., 2007; Wallin, 1981) and a complex correlation between the electrodermal signals and the sympathetic signals (Kettunen, Ravaja, Naatanen, Keskivaara, & Keltikangas-Jarvinen, 1998; Vissing, Scherrer, & Victor, 1991; Wallin & Charkoudian, 2007). The situation for the parasympathetic signal (the vagal tone) is even worse. Most popular measures are related to the Variations of the Heart Rhythm (HRV) (Cohen & Taylor, 2002). But the heart is fundamentally driven by both the sympathetic and parasympathetic system, so a spectral analysis of the HRV signals is necessary to distinguish the effect of both parts in the HRV signal. This distinction is still under debate and dependent on the breathing frequency (Cohen & Taylor, 2002). To calculate the strength of the vagal tone variations one has to subtract the High Frequency (HF) component of the spectrum (0.15 Hz < f < 0.4 Hz) on the condition that the breathing was also in this HF range. Because most people have a natural breathing rhythm in this range, this condition is almost never mentioned explicitly. HRV studies are often used in a context of biofeedback, and most relaxation techniques advice to lower the breathing frequency (Song & Lehrer, 2003). Slower breathing stimulates Mayer waves increasing the overall HRV but making it harder to distinguish the effect of the vagal tone from the sympathetic signals because the HF component is not relevant anymore. Another drawback of the HRV technique is that the spectral calculation increases the time of a measurement to at least 1-2 minutes resulting in a technique with a poor time resolution. The drawbacks of the existing techniques inspired us to search for new non-invasively measures for both the sympathetic and parasympathetic signals that could be used in a context of meditation and relaxation techniques, preferable with a small time resolution. A first idea was to use existing mathematical models that relates the heart rate to both branches of the autonomic activity

Internal report about the autonomic nerve system

version 1.0 12/9/2011

(Karemaker & Wesseling, 2008; Olufsen, Alston, Tran, Ottesen, & Novak, 2008; Seidel & Herzel, 1998; Ursino & Magosso, 2003). These models describe the many interactions in the autonomic system. They mostly starts from the arterial pressure profiles exciting the baroreceptors and invoking both parasympathetic and sympathetic signals. Because the arterial pressure profiles can be monitored using tonometry or infrared measurements it must be possible to calculate the autonomous signals out of the measured arterial pressure signal on a time scale of the heartbeat. Although this idea is found back in literature (Olufsen et al., 2006) it is limited by the fact that the number of person dependent physiological constants in most models is rather big (at least 10) and these constants are not easy to determine. Another problem is that there is still debate between physiologists on the principle working mechanisms of the autonomous system (Karemaker, 2009). For this study we summarized the complex network of dynamical interactions that regulate the autonomous system and defined some basic physical measures of which the relation with the autonomic signals can be expressed using approximated but linear mathematical relations. Inspired by different phase techniques that are used to analyze the interactions between complex systems (Cimponeriu, Rosenblum, Patzak, Mrowka, & Bezerianos, 2002; Mrowka, Cimponeriu, Patzak, & Rosenblum, 2003), we also investigated the phase relations between different subsystems. The advantage of phase related techniques is that they are less sensitive to saturation effects which occur very frequently in anatomical systems (Seidel & Herzel, 1998).

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Methods
1. New measures for the autonomic system
New measures for the autonomous system should have a clear correlation (positive or negative) with the autonomic signals. They should be strongly coupled and preferably phase locked with these signals in a wide frequency range. Several mathematical models describing the relations between the different autonomic signals are proposed in literature (Karemaker & Wesseling, 2008; Olufsen, Alston, Tran, Ottesen, & Novak, 2008; Seidel & Herzel, 1998; Ursino & Magosso, 2003). There are significant differences between them, not only are there differences in the basic mechanisms describing the process but also the mathematical expressions describing the different relations are differing from model to model. The model proposed in Figure 1 summarizes the known relationships between the autonomic nervous system, the hemodynamic system, the central nervous system, the lung system and the skeletal muscles. Most of these relations are incorporated in the Seidel (Seidel & Herzel, 1998) and Ursino model (Ursino & Magosso, 2003), but there are some exceptions like relations (12-7 and 1310) that are more recent results of the MSNA research and related to the influence of muscle activity to the sympathetic system (Dempsey, Sheel, St Croix, & Morgan, 2002; Derchak, Sheel, Morgan, & Dempsey, 2002). In the forthcoming discussion, simplified mathematical descriptions of the most important relations of Figure 1 are derived allowing a better insight in the relative importance of the different relations. We limit ourselves to breathing frequencies that are lower than 0.25 Hz and cover the spectrum of normal and slow breathing frequencies. 1.1. Parasympathetic measures : psys and HRV All mathematical models have the baroreflex as a basic mechanism behind parasympathetic activity. The main idea is that arterial pressure excites the baroreceptors in the sinus aorticus and the arteria 6

Internal report about the autonomic nerve system

version 1.0 12/9/2011

carotis communis (see Fig. 1, part baroreceptors and pressure signal). These afferent signals are processed in the central nerve system and are inducing both parasympathetic and sympathetic activity. The parasympathetic signal Tp correlates positively with the baroreceptor signals and takes over the pulsatile nature of the blood pressure. Signal dynamics can be seen in the time scale of a single heartbeat. The systemic pressure is raised from the diastolic pressure pdia of the last heart beat to the systolic pressure psys of the new heartbeat. After the beat the pressure relaxes to pdia with a relaxation time constant v. This pressure signal (also seen in Fig. 1) induces a high barosignal during the systolic period and the beginning of the diastole, lowering to a minimum value at the end of the diastole. So for every heartbeat a high parasympathetic signal is expected near the systolic period. There exists different mathematical description of the sensitivity of the baroreceptors. Ottesen and Olufsen propose a nonlinear model with short pulses in the systolic period but also describing adaptation effects of the baroreceptors when they are extended to high arterial pressure over a longer period of time (Ottesen & Olufsen, 2011). The model of Seidel and Herzel ignore these long time effects and define a linear model consisting of a weighted sum of the systemic pressure and the derivative of the systemic pressure (Seidel & Herzel, 1998). Because we are only interested in slow variations (<0.25 Hz), we limit our model to parameters averaged over one heartbeat. <Tp>i is the parasympathetic signal averaged over RRi the period of heartbeat i. The complex baroreceptor models is replaced by a more pragmatic and approximated model described by ( ), (1)

with psys the systolic pressure corresponding with heart beat I and po,p a threshold pressure above which the systolic pressure gives rise to parasympathetic signal. It is interesting to notice that the parasympathetic signal is 0.1-0.5 s delayed relative to the barosignal (Karemaker & Wesseling, 2008). Because this is mostly within one heartbeat both parts of equation (1) can be seen as almost simultaneous.

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Eq. (1) is a simplified model ignoring the nonlinearity of the baroreceptors, saturation effects, sinus node phase dependency and the exponential decay of the pressure curve. But even more important, it considers only the systemic pressure as source for the parasympathetic signals (see relation 1 in Fig. 1). There is however no consensus about that. Only the models of both Olufsen (Olufsen, et al., 2006) and Karemaker (Karemaker & Wesseling, 2008) work with this presumption. The Ursino model (Ursino & Magosso, 2003) also incorporates the signal of stretch receptors in the lungs (relation 3, Fig. 1). The Seidel model (Seidel & Herzel, 1998) doesnt use the lung stretch receptors but add a term to Tp due to respiratory neurons (relation 4, Fig. 1). Without taking a real point of view, we take the practical approach of simplicity ignoring other parasympathetic sources. Even if these relations are important, it is likely that due to feedback mechanisms (like relations 18-17, Fig. 1) and the coupling between the lung pressure and the systemic pressure system (relation 21, Fig 1), psys will ultimately also coupled with other sources of Tp. A decisive experiment is not easy to develop and will need more detailed models taking in to account the whole picture. In our approach, Eq. (1) is only used to monitor and quantify the systemic pressure contribution to the parasympathetic system. As can be seen in the experimental results we applied this approach to a series of breathing experiments. There are indications that extra sources are probably relevant but our study is too limited to make more general statements. The effects of the autonomic signals are mediated by the neurotransmitters acethylcholine for the parasympathetic signals and noradrenaline for the sympathetic measures. The concentrations of these chemicals can be calculated out of the nerve activity using first order equations with one time constant (Brack, 2004; Olufsen, et al., 2008). The time constants are both for the parasympathetic and sympathetic process in the order of magnitude of 1 s (Olufsen, et al., 2006). Even for slow breathing there can be measurable effects especially if we focus on the phase difference between the autonomic signals and the corresponding concentrations (see further). Therefore, the variables Cp and Cs are introduced which correspond to the concentrations of respectively acethylcholine and noradrenaline at the synapses of the autonomic efferent nerves. 8

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Parasympathetic activity is an important measure in stress studies (Kumar, et al., 2007). Not the absolute value of the parasympathetic signal is of interest but the variations of the parasympathetic activity. Often this measure is derived out of HRV calculating the standard deviation of the HRi or RRi intervals over the time period of interest. But HR is also influenced by the sympathetic signal Ts. Ignoring saturation effects HRi can be approximated out of the autonomous signals using (2) with <Cs>I is the concentration of noradrenaline at the sinus averaged over beat i, and HO, Ms and Mp person dependent constants. Eq. (2) is a linearization of more accurate integrate and fire descriptions integrating the heart rate potential (Olufsen, et al., 2006). The HR will phase lock with Cp if Mp is big compared to Ms and vice versa. Despite of the sympathetic component, the standard deviation of HRi is often used as measure of parasympathetic activity. The rationale behind this is the chronotropic effect of the acethylcholine on the noradrenaline (Brack, 2004; Zhang, Holden, Noble, & Boyett, 2002). If the mean concentration of acethylcholine is sufficiently high the effect of noradrenaline is reduced significantly (Ms becomes small in comparison to Mp), so in situations where people are in rest we can expect that the sympathetic influence on HRV can be neglected. We will discuss this assumption using our breathing data set. Another approach is to separate the parasympathetic from the sympathetic influence on the HR is to use the HF component of the HR spectrum (0.15-0.4 Hz) where the slower sympathetic influences are assumed to be filtered out. Also this assumption will be discussed using our dataset. This HF approach is of course only relevant if the breathing frequencies are in the HF band (normal breathing). For slow breathing most of the power of the spectrum is situated in the LF band, so the HF value has no direct relevance to the subject of the study, namely the influence of breathing.

Internal report about the autonomic nerve system 1.2 Sympathetic measures : pdia and RC

version 1.0 12/9/2011

Good sympathetic measures are even more difficult to find than parasympathetic measures. Some authors use the VLF spectral band of the HR as a measure of the sympathetic activity but this approach is often criticized (Berntson, et al., 1993). Sympathetic signals give rise to muscle and skin sympathetic nerve activity (MSNA and SSNA) (Wallin & Charkoudian, 2007). The MSNA has an immediate feedback effect on the arterial pressure and is therefore integrated in Fig. 1. The MSNA research has given a good insight in the mechanisms inducing the sympathetic signals. The basic mechanism is related to the systemic pressure and baroreceptor signals (Karemaker & Wesseling, 2008). During the heart beat cycle, the sympathetic signals are inhibited by high signals of the baroreceptors. Only at low pressure values MSNA activity are found with a delay s of 1 to 2 s. The diastolic pressure is therefore a straight forward choice as a measure for Ts. The lower this pressure, the higher the MSNA activity should be, but this relation is only indicative due to presence of a stochastic gate controlling the sympathetic bursts (Karemaker & Wesseling, 2008). So the diastolic pressure doesnt give a good prediction for every heartbeat, often there is even no sympathetic activity at all even at low pressures. Only if the signals are averaged over different heartbeats the diastolic pressure dependency works. MSNA values are mostly averaged over 100 beats. Taking the stochastic character into account the mean sympathetic signal <Ts>I is defined by ( ( )) (3)

with ti the time of beat i, po,s the threshold value under which the arterial pressure gives rise to sympathetic activity and (x) a statistical function with x as a mean value. Averaging the <Ts>I values over different heartbeats will give rise to a value proportional with MSNA. In the MSNA literature, evidence for Eq. (3) can be found (Sundlof & Wallin, 1978). In the work of Wallin, the measured correlation between the MSNA and max(po,s-pdia, ,0) for single persons is high, namely 0.95,

10

Internal report about the autonomic nerve system

version 1.0 12/9/2011

corresponding to our prediction in equation (3) and even confirming its linear aspects. Also the threshold pressure po,s can be predicted out of the performed measurements (around 90 mmHg). Eq. (3) is only applicable in the static case where we can average the unknown statistical function (x) over different heartbeats. During dynamic changes the predictability of Eq. (3) is limited because of (x). Also, this equation assumes the baroreflex as the only source of sympathetic activity which is certainly not the case. Important other sympathetic sources are signals from the vestibular otoliths giving rise to a vestibulosympathetic reflex controlling blood pressure (Dyckman, Kearney, & Ray, 2006; Dyckman, Monahan, & Ray, 2007) and muscle activity invoking an ergoreflex (Swenne, 2002) and controlling the blood flow to the working muscles (Dempsey, et al., 2002). Because breathing is also a consequence of muscle activity, the last one is the most relevant in within this context. Generally, one can state that contraction of muscles induces extra sympathetic pulses, increasing the sympathetic outflow to the blood vessels of the systemic system (relations 7-20-8 in Fig. 1). This gives rise to the paradox that working muscles seems to get lesser blood supply because the vascular resistance is increased by the sympathetic pulses. However, this sympathetic effect is a whole body effect. There is an accumulation of powerful local vasodilator metabolites in the working muscles, reducing the vascular resistance locally. The contrast between the resistance of the working and non-working muscles increases the blood supply to the working muscles even more and decreases the blood supply to other muscles. Similar, the movement of the diaphragm during breathing is also changing the MSNA and there is a MSNA variation over a single breath. During normal breathing (frequencies around 0.2 Hz) MSNA bursting declines during inspiration, reaching its nadir at endinspiration/early-expiration, and then rises, reaching its peak at end-expiration (Seals, 2001). This principle may not be extrapolated to lower breathing rates due of the existence of Mayer pressure waves as will be shown in the discussion about our dataset. Because of this muscular dependency of <Ts>I other measures than <pdia >i are worthwhile looking for. Direct measurement of MSNA using peroneal microneurography is of course the most 11

Internal report about the autonomic nerve system

version 1.0 12/9/2011

appropriate but problematic because of its invasive nature. We suggest a noninvasive parameter that can be easily derived out of the arterial pressure dataset, namely the Windkessel relaxation time constant v (see relation 8 in Fig. 1). This parameter characterizes the time it takes for the systolic pressure to relax to its diastolic value. The higher v, the slower the relaxation is and vice versa. v can easily be derived out of the decaying pressure profile and is equal to the product of the total peripheral resistance R and the total arterial compliance C in a two-element Windkessel description of the relaxation process (v = RC) (Z. R. Liu, Brin, & Yin, 1986). An interesting property of v is that it is changes because of sympathetic activity but not of parasympathetic activity. Only problem is that the sign of the correlation is not fixed because the sympathetically induced vasodilator effects make the blood vessels smaller and stiffer. If the sympathetic dependency of R dominates the RC product, a sympathetic pulse will increase the value of v. But If the sympathetic dependency of C (the compliance of stiffer vessels is smaller) dominates the RC product, v will diminish after a sympathetic pulse. We will derive our formulas assuming the C dominance that is mostly used in mathematical models (Seidel & Herzel, 1998), but being aware that this is not necessary the case. So ignoring saturation effects, <Ts>I for heartbeat i can be calculated out of v using the following approximated equation (4) with o the value of v in the absence of sympathetic activity, and M a positive constant when the sympathetic dependency of C is dominant in v, M is negative in the case of R dominancy. All autonomous measures are summarized in Tabel 1. We distinguish between the classically used measures and newly proposed measures. For the parasympathetic activity one normally takes the standard deviation of the heart rate (SD(HR)) or the high frequency power density value of the heart rate spectrum (HF(HR)). The new measure is psys, which has a linear relationship with <Tp>i as long that the systolic pressure stays above a threshold pressure and no other that the systemic sources for Tp are dominant. The sympathetic activity is normally derived out of Muscle Sympathetic Nerve 12

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Activity (MSNA). Our non-invasively alternative is the relaxation time v mostly with a negative correlation with Ts. From the new measures MEAN values and Standard Deviations (SD) can be calculated over the time interval of interested corresponding with both the absolute level of the autonomous signal as their changing activity. Another practical consequence of this approach is that the whole autonomous system can be monitored using only one sensor measuring the arterial pressure. Although, nowadays this is not yet an easy parameter to measure and expensive equipment is still necessary, we believe that recent developments around piezo film technology will make cheap and motion insensitive sensors available in the near future opening a wide variety of possibilities for monitoring more complex situations (Matthys et al., 2008).

13

Internal report about the autonomic nerve system

version 1.0 12/9/2011

2. Feedback in the autonomic model

Because the autonomic system is a complex mixture of feed forward and feed backward effects it is very difficult to distinguish between cause and effect. For instance the HRVs are often seen as a consequence of parasympathetic activity (1-19-2 Fig.1) but in the dynamics of the system the HRVs themselves induce blood pressure variations (18) that have direct influence on the parasympathetic (17-1) and the sympathetic signals (11). The autonomic signals play an important role in stabilizing the systemic pressure. This is done by several feedback mechanisms. The best known is the parasympathetic loop that runs over the heart rate and can be visualized in the next equation:

(5)

Where the numbers above the arrow refer to the relations of Fig. 1, the upward arrows refer to an increase of the parameter and the downward arrows to an decrease. Of course, all the arrows can be reversed, reflecting the feedback mechanism balancing a pressure drops. There is a similar feedback loop using the impact of the sympathetic signal on the heart rate, i.e.

(6)

However, for the sympathetic signals there are more loops possible. Another stabilizing loop (i.e. negative feedback) is using the sympathetic outflow to the blood vessels and its effect on the resistivity of the vessels, i.e.:

(7)

But, there also destabilizing sympathetic loops (positive feedback). One is running over the pulse pressure

(8)

and another one is running over the relaxation time v:

14

Internal report about the autonomic nerve system

version 1.0 12/9/2011

(9)

The last one is interesting because it is based on the compliance dominance in the sympathetic sensitivity of v. If the dominance changes to the resistivity, the feedback loop becomes stabilizing again. Normally, these destabilizing loops arent dominant and compensated by the stabilizing loops (especially by the fast parasympathetic loop), but for low frequencies these positive feedback loops can have a significant influence, giving rise to the so called Mayer waves, which are spontaneous pressure variations around a frequency of 0.1 Hz (Cohen & Taylor, 2002). The feedback mechanisms of the parasympathetic and sympathetic systems are also coupled which each other. Because pdia and psys are closely related, sympathetic feedback will influence parasympathetic feedback and vice versa. The only fundamental difference between both is the difference in delay time between the parasympathetic and the sympathetic system. The sympathetic barofeedback has a significant delay time of around 2 s. Besides the baroreflex mechanisms (Eq. (6) to (9), the sympathetic system is also loaded with activity related to muscle and breathing activity. This activity can be more dominant overriding the baroreflex signals.

15

Internal report about the autonomic nerve system

version 1.0 12/9/2011

3. Phase relations in the autonomic model

In the complex model of Fig. 1, each variable (like pL, psys RC, Tp, ) can be interpreted as a oscillator that is coupled to the other oscillators over the relations numbered 1 to 22. If one variable starts oscillating (e.g. pL due to paced breathing), the others will follow this rhythm. The coupling between the variables isnt necessary linear, so different frequencies can occur out of one driving frequency. For instance, some of the input breathing energy can be dissipated to the natural frequency of one of the resonators, like the Mayer waves. Besides these nonlinearities it is interesting to look within one frequency to the phases of the different variables. If a variable is only dependent of one other variable there is a strong coupling between those variables and a fixed phase difference (that can be frequency dependent). Strictly speaking this is only the case for the variable sets Tp Cp, Ts - Cs and Cs-R and Cs-C, so the phases of Cp, Cs, R and C can be seen as fixed for a certain breathing frequency. This not the case of the other variables (like Tp, Ts, v, ). Their phases will depend on the relative strength of all the variables that are connected to them. This makes the phases of these parameters less strict and dependent on the relative strength of the connected parameters. To study this complexity , we characterize every relation from one variable to another variable with a coupling constant expressing how strong the phase of second variable is dominated by the phase of the first variable. In the limit two variables can synchronize and have what is called a phase lock (a fixed phase difference of 0 or 180) (Cimponeriu, et al., 2002). The two variables are oscillating in phase or in counter phase. An interesting example is the time constant v , the variable we have suggested as a measure of the sympathetic activity Ts and for which we expect that both are strongly coupled. This is only the case if v is also strongly coupled to Cs. Because v depends on both R and C, R or C have to be strongly coupled to v, thereby dominating the phase difference between them. We assume that for most people the coupling constant of the C- v relation is the biggest, give rise to a fixed phase difference of around 180 between v and Cs. We can conclude that v and Ts have a fixed (but frequency dependent) phase difference that will be further discussed. 16

Internal report about the autonomic nerve system

version 1.0 12/9/2011

A similar strong coupling we expect between psys and Tp. This is only the case if there are no other sources for Tp (so if relations 3 and 4 are not dominating the phase of Tp). If this is not the case, psys can only be seen as a measure of the systemic contribution to the parasympathetic signal. Examining phase differences can give an idea of the more dominant interactions for a certain breathing frequency. Within this context it is interesting to analyze some important phase relations of Fig. 1, like 19, 20, 1 and 2-5. The autonomic signal versus neurotransmitter relations (19-20) can be described by a first order model with a characteristic time constant s and p for noradrenaline and acethylcholine respectively (Olufsen, et al., 2006). Because we are primarily interested in the influence of breathing at a certain frequency we study the equations in the frequency domain. For instance, the first order relation between C and T can be written as: , with and the amplitude and phase of the varying part of and with (10) and the

amplitude and the phase of the variations of

Dome straight forward mathematics allows to

calculate the frequency dependency of the phase difference between C and T, i.e. . (11)

In Figure 2a the phase-frequency relation is seen for the relevant frequency interval (0.05-0.25 Hz) and this for several values of . Within the frequency interval of interest, the phase difference varies from 20 to 40. Because the accuracy of the measured phase differences is not very high (around 30 and more) most of these phase differences will not be noticed in the experimental results. The phase delays of relation 1 and 11 have a different nature. They are due to time delays between the pressure values and the autonomic signals. As was discussed before, the parasympathetic delay p is around 0.5 s while the sympathetic delay s can exceed 2s. These time delays give rise to a linear

17

Internal report about the autonomic nerve system phase differences equation is:

version 1.0 12/9/2011

between the autonomic signal and the pressure signals. The governing

(12) Figure 2b illustrates this phase relation for values of varying from 0.5 to 2 s. We conclude that time delays of 1 s and bigger should be visible in the experimental results. The phase of a time delay of 1 s varies over more than 70 over the frequency interval of interest (0.05-0.25 Hz). The phase of the HR is also an interesting case because it is coupled to two other resonators, namely Cp and Cs over relations 2 and 5. For slow breathing (0.05-0.15 Hz), we can ignore the difference between Cp and psys and combine Eq. (1),(2) and (4) to , with , and (13)

person dependent constants. If the systolic pressure and the relaxation time

are oscillating on the same breathing frequency Eq. (13) gives rise to a strict phase relation between the different varaibles. This relation can be derived out of the phasor representation of Eq. (13): , with and the amplitude and phase of the varying part of the the amplitude and phase of the varying part of v and and (14) signal, similar is the amplitude and and

phase of the HRV. Because all these variables are measured we can use Eq. (14) to derive

(15)

( (

) )

(16)

18

Internal report about the autonomic nerve system

version 1.0 12/9/2011

So slow breathing data can be used calculate important person dependent constants characterizing the heart system and the sensitivity of the heart to parasympathetic and sympathetic signals. Furthermore, if calculated out of Eq. (16) is positive, the relaxation time dependency of the is negative,

sympathetic signal is dominated by the compliance C, like was a premise of Eq.( 4). If the resistivity will dominate this dependency. Because and

have different dimensions there relative impact to the heart rate is difficult to

extract out of their values. Thats why we define a new dimensionless parameter that compares the relative impact of sympathetic variations to parasympathetic variations to the heart rate. This parameter can be compared to the sympathovagal balance that is often extracted out of HR spectra (LF/HF). It can be calculated as
( )

(17)

quantifies the relative coupling strength of the sympathetic and parasympathetic signals to the heart rate. If is much smaller than 1, the parasympathetic signal is dominating the HR, if it is much bigger than 1 the sympathetic signal is dominant. There is one limitation to this phase approach. In the case of synchronization or phase locking of and v ), the real and

imaginary part of Eq. (14) are not independent anymore and Eq. (15-17) lose their value.

19

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Procedure
We examined the breathing patterns of 5 healthy persons (2 man and 3 women, age varying between 40 and 70). They all went through a breathing sequence starting with a period of 2 minutes of relaxation, followed by periods of paced breathing for the following frequencies: 0.25 Hz, 0.225 Hz, 0.2 Hz, 0.175 Hz, 0.15 Hz, 0.125 Hz, 0.1 Hz, 0.075 Hz, 0.05 Hz. Each period took 2 minutes. The volunteers were sitting in a comfortable chair and were asked to breath like they normally do. The whole procedure took around 30 minutes (with around 20 minutes of breathing). To measure the systemic pressure, we used a tonometry instrument (HDI/Pulsewave Research Cardiovascular Profiling Instrument (model CR-2000)) the signal of which was recorded by a picolog datalogger (at 250 Hz) and transported to a computer for post processing. The pressure sensor of the tonometer was placed at the arteria radialis of the right wrist that was fixated. The positioning of the pressure sensor was done with great care using the immediate feedback of the pressure pulse on the screen. The force put on the sensor was optimized to have the maximum possible signal. The blood pressure (pdia and psys) was measured using the arm cuff provided with the tonometer before and after the breathing protocol. These values were used for calibrating the pressure profile. The breathing pattern and the HR was measured using a Zephyr bioharness. An elastic band measures the chest expansion and contraction, the ECG electrodes are implemented in the same band. ECG was sampled at 250 Hz, the breathing signal at 20 Hz. After moistening the ECG contacts, the band was attached just under breast level of the volunteer. Before each measurement, the clocks of both the bioharness and the central computer were synchronized using the Bioharness software.

Data Analysis
All data was downloaded to a central computer and imported into MATLAB. The tonometer pressure data was rescaled comparing the mean psys and pdia over the first two minutes with the measured pressure psys and pdia before the start of the experiment. The pressure pulse data was imported in a 20

Internal report about the autonomic nerve system

version 1.0 12/9/2011

routine ecgViewer (developed by J. T. Ramshur (E-mail: jramshur@gmail.com ) for ECG data) that was adapted to analyze pressure data instead of ECG. This routine has a beat detection algorithm using template matching after which all the data was visually inspected for bad peaks. The Heart Rate (HR) data obtained from the pressure data was compared to the Zephyr HR data to check for correct synchronization and the good functioning of both measuring equipment. Extra routines were developed to calculate pdia, psys and v for every beat. The calculation of v was done following the technique described in (Z. Liu, Brin, & Yin, 1986 ). Per heartbeat the pressure signal was integrated from the first notch onto the end of the diastole. This integral was divided by the corresponding pressure differences. The RR intervals, psys en v were analyzed using HRV Kubios software (http://kubios.uku.fi). We
calculated: time domain parameters: the mean value (MEAN) and the standard deviation (SD) of the RR intervals,

and frequency domain parameters like the power spectrum density (using the pWelsh algorithm) , the absolute power in the very low frequency band (VLF, 00.04 Hz), the low frequency (LF, 0.040.15 Hz), and high frequency (HF, 0.150.4 Hz).

Every dataset of each volunteer was two times analyzed. The first time all parameters were calculated for the whole data set (i.e. all the breathing frequencies together 0.25 Hz, 0.225 Hz, 0.2 Hz, 0.175 Hz, 0.15 Hz, 0.125 Hz, 0.1 Hz, 0.075 Hz, 0.05 Hz). For the second evaluation we focused on the influence of the breathing frequency on the parameters. We divided the dataset into two groups

one with breathing frequencies in the high frequency band (0.25 Hz, 0.225 Hz, 0.2 Hz, 0.175 Hz) which corresponds to natural breathing frequencies of most people,

and one with low frequency breathing patterns (0.125 Hz, 0.1 Hz, 0.075 Hz, 0.05 Hz) which corresponds to reduced breathing frequencies. For most people these frequencies are only attained during breathing techniques. 21

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Both datasets have the same size and the same parameters were calculated for these two subsests we refer to as the normal breathing subset and the slowl breathing subset. Phase differences were determined out of the variations of two variables (eg. HR, v, psys, ) over the breathing period of interest. First the data were resampled with a frequency of 250 Hz. Then, the mean value was subtracted from each of the data sets and the datasets were rescaled so they had similar amplitude. The time delay between the variables was found calculating the cross correlation between the corresponding datasets and determining the time difference that gave rise to a maximal correlation. The phase difference (in degrees) was calculated out of this time delay multiplying it by 360f, with f the breathing frequency. This was done for every breathing frequency and for the three variables of interest (HR, v, psys). As a reference parameter we used the variations in the lung pressure pL. This pressure was obtained from the breathing data using the assumption that an increase in lung pressure is relative to a decrease in lung volume (Yildiz & Ider, 2006), so the breathing data was multiplied with a factor of -1. We compared , and

over the whole frequency domain. Because the slowest breathing interval (period of 20s) didnt give reliable periodic functions , this point was excluded from the data set. For the slow breathing frequencies (f = 0.1 and 0.125 Hz) (17). An estimation of the measurement errors was calculated using the following formula: , and were calculated using Eq. (15), (16) and

(17)

with

the maximal correlation over the breathing interval.

22

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Results
Table 2 summarizes all the calculated parameters that are related with the RR intervals. For every volunteer, the first line reflects the whole dataset, the second and third line reflect the parameters for a limited dataset, respectively the normal breathing frequencies and the slow breathing frequencies. This division of the dataset gives the opportunity to analyze the influence of breathing frequency on the HRV parameters. The MEAN values do not differ much by the subdivision (the differences between the subsets are small compared to the SD-values). With the exception of volunteer 5 the SD values have a systematic difference between the two subsets. The SD values of the normal breathing subset (with HF band breathing frequencies) are almost half the SD values of the slowly breathing subsets. The HF parameter (corresponding with parasympathetic activity) varies in an opposite way as the SD suggesting that the parasympathetic activity is lowered during the slowly breathing period. The majority of the HRV power is situated in the LF band during slowly breathing. Table 3 gives similar parameters but now calculated out of the psys dataset and corresponding to the parasympathetic signal Tp and Table 4 does the same for the v dataset corresponding to Ts values but in a negative way (increase of v corresponds with a decrease in Ts and vice versa). The MEAN and SD parameters of both the psys and the v dataset have a similar behavior then the corresponding RR parameters. Only the differences between the SD values for normal and slowly breathing are not as big as in the RR-case. The MEAN values are not changing in a systematic way over the two subsets but the SD values systematically show an increase for the slow breathing subset compared to the normal breathing subset (except for volunteer 5). In Figure 3 the spectral power densities (RR, psys and v) of volunteer 1 to 3 are displayed. They corresponds with the whole datasets as can be seen by the different breathing peaks in the spectrum. It can be clearly seen that the peaks in the RR spectrum are most of the time 23

Internal report about the autonomic nerve system

version 1.0 12/9/2011

corresponding with both a parasympathetic and a sympathetic peak. The only exception is the 0.025 Hz peak of volunteer 2. This one is clearly dominated by sympathetic energy. All spectra of all measurements were checked this way. There were no peaks found that couldnt be explained with sympathetic of parasympathetic energy of the systemic system. In Figure 4 we show the time variations during 0.1 Hz breathing of the three measures of interest (HR, psys and v) and the lung pressure signal pL for volunteer 3 (a) and 2 (b) . These figures illustrate the potential of the new measures allowing a real time qualitative monitoring of both the parasympathetic variations (psys) and the sympathetic variationsl (-v). Generally we could say that for most 0.1 Hz breathing data both the parasympathetic (psys) and sympathetic measure (v) are more or less in opposed phase with the HR signal. This corresponds to the general idea that higher heart rates are due to lower parasympathetic and higher sympathetic signals. But a more detailed look shows that significant phase differences of this general idea are present in the data (clearly noticeable with volunteer 2 in Figure 4 (b)) . These phase differences and their evolution over the frequency scale are best studied in Figure 5 where the phase relations for volunteers 1 to 4 are visualized. A wide variety of phase relations is found over the different volunteers. Finally, the parameters and were extracted from the phase data for the 0.075, 0.1 and 0.125

data sets and compared in Table 5.

24

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Discussion
Because we are interested in the influence of breathing techniques on the autonomic balance we developed an experimental setup that scanned the whole breathing spectrum from normal to slow breathing (0.25 Hz to 0.05 Hz). The data summarized in Table 2, 3 and 4 compares the value of the newly proposed parameters with classical parameters. It can be clearly seen that the HF(RR) parameter commonly used as a parasympathetic measure, reduces significantly for slow breathing while the parasympathetic activity is just expected to be high due to the high blood pressure variations induced by slow breathing. We conclude that HF(RR) has only a significant meaning if the breathing rhythm is above 0.15 Hz, a condition that should be checked every time this parameter is used. Another important hypothesis behind the HF parameter is that it separates the parasympathetic activity out of the HR data. The general idea is that the sympathetic system is too slow to follow the HF variations. However the HR and v spectra of Fig. 3 clearly show that there are still significant variations in the sympathetic system in the examined part of the HF band. It is not sure that they contribute to the HR, but there are no reasons to doubt that they do. Further on in the discussion we will use our gamma data to prove that for some of our volunteers (like 2 and 5) they do have a significant impact. The misconception of slow sympathetic signals is probably induced by the longer delay times S of the sympathetic system compared to that of the parasympathetic system p . But of course this delay doesnt prevent the sympathetic system to interact with the heart rhythm. Also the time constant of the noradrenaline is of the same order of magnitude as that of acethylcholine (Olufsen, et al., 2006) which also suggest that parasympathetic activity goes mostly hand in hand with sympathetic activity. Besides, the model of Figure 1 is for a big part composed by interactions between the sympathetic and parasympathetic system. To conclude this discussion, the HF factor can still be used for normal breathing but it should be interpreted as a measure of autonomic activity and not as exclusively parasympathetic activity.

25

Internal report about the autonomic nerve system

version 1.0 12/9/2011

For slow breathing it can be stated that the SD of RR of HR is more indicative for the autonomic activity level than HF. In our approach it is possible to differentiate both parts comparing the SD of psys with the SD of v. SD(psys) is certainly related to parasympathetic changes that corresponds to the baroreflex. Like all measures this parasympathetic measure should be handled with sufficient care. It is possible that other parasympathetic sources that are not related to the baroreflex (like 3 and 4) are only indirectly incorporated in this measure. The SD(v) is more clearly related to real sympathetic activity combining all relevant sources of the sympathetic system. An interesting experimental approach improving the reliability of this parameter should be to correlate MSNA data to v. One should be able to show that v is at least partly composed of MSNA. Figure 4 illustrates the possibilities of psys and v as a real time monitoring technique of the parasympathetic and sympathetic activity. If other parasympathetic sources are not relevant or phase coupled with psys the time evolution should correlate with that of the parasympathetic activity. Only a delay of around 0.5 should be taken into account and the barosensor signal can saturate for high values of psys. The time evolution of v should be interpreted with more care. We do not expect significant time delays anymore but we are not completely sure if the v data correlates positively or negatively with the sympathetic signal. For volunteer 3, this exact sign cannot be determined but a negative correlation is rather probable because it is most often seen. For volunteer 2 our gamma analysis (see further) suggests that the correlation between the sympathetic signal and v is positive. This looks a little counterintuitive at a first glance. Therefore we calculated the red curve out of Eq. (13) using the and values of the gamma analysis. The good correspondence between

measured and calculated curves prove that this positive correlation can explain the breathing induced variations of the HR. It can be seen that there are significant saturation effects for high values of psys and there is a significant noise level on the signals. The frequency dependency of the phases of Fig. 5 proves the complexity of the breathing process even if it is structured in paced breathing. There are significant differences between the phase

26

Internal report about the autonomic nerve system

version 1.0 12/9/2011

relations of the different volunteers. We first focus on the sys and v relations. We see the lung pressure as a kind of input signal to the other signals, so in a first glance, we expected other curves (like sys that is closely coupled to pL ) to be delayed relative to the lung pressure, expressed in a negative phase difference. But this data proves that this causal reasoning isnt a valid way of looking to this complex process. Although sys is mostly delayed relative to the lung pressure for volunteers 1 to 3, for volunteer 4 it is positive over the whole frequency interval suggesting a completely different interaction with pL. sys- pL is also positive for volunteer 3 but only for the slow breathing frequencies where sys is phase locked to v. During this locking the parasympathetic and sympathetic signals are in opposed phase (if we assume that sympathetic dependency of v is dominated by C) increasing their effects on the HR. It is not by accident the HRV of person 3 is the strongest of the whole group. For volunteer 1, the phase difference between sys and v for the slow breathing frequencies remains constant around 60. For volunteer 1 to 3, the phase difference between sys and v is increasing significantly for the higher frequencies. For slow breathing frequencies, HR - pL is most of the time around 180 corresponding with the generally accepted idea that inhalation (low pL) is giving rise to an increase of the HR and vice versa. If the phase is lower than 180 one can say that there is a delay between breathing and HR variations, suggesting that the breathing is coupling to the HR. If HR - pL is positive the HR variations are changing before the breathing is already changed, having a reversed coupling (in Fig. 1 this is possible over relations 18 and 21). We see this phenomenon with volunteer 4 and for very slow breathing (f = 0.075) in volunteers 1 and 3. For the first three persons a more or less linearly decreasing phase delay is seen for HR - pL suggesting a constant time delay that is increasing the phase delay for higher frequencies (see Eq. (12)). If we approximate these parameters we get a time delay of 1.3 s for volunteers 1 and 3 and 2.5 s for volunteer 2. This long delay time for volunteer 2 is suggesting that the sympathetic signal has a significant contribution to the HR. This will also be confirmed by the gamma analysis later on.

27

Internal report about the autonomic nerve system In Table 5 the calculated and

version 1.0 12/9/2011

can be found for the different volunteers. They are only

calculated for the slow breathing case (f = 0.075, 0.1 and 0.125 Hz) because the expressions (15) and (16) are only valid for that frequencies. We first refer to Figure 6 where volunteers. This parameter is crucial because it determines the accuracy of the calculations. The phase lock of volunteer 3 near the low frequencies v ( seen making its and is plot for all and is clearly

values unreliable. This lock indicates that relations 15-17 are dominating

the autonomic process (see Fig.1). We also see that volunteer 4 has a similar problem but know with a phase difference that is around 180. This explains the big variations in the its volunteer 4. This data will also be excluded. For volunteer 1, we have stable results for the 0.1 Hz and the 0.125 frequency. The lowest frequency values (0.075 Hz) are in complete contradiction. The reason for this discrepancy can be found in Fig. 7. There we see the HR, psys and the v signals for the 0.1 Hz signal (first 100 s) immediately followed by the 0.075 Hz data. It can be clearly seen that there is a period of instability during the first 50 s of the 0.075 Hz breathing data making the and values worthless. Notice that the HR signal (that and values of

is also subtracted from the pressure data) remains stable during this period, excluding the fact that this is just a motion artifact. Volunteer 1 has a small gamma factor (0.08-0.23), meaning that the heart signal is dominantly determined by the parasympathetic signal. Because the chaotic behavior of psys is not clearly reflected in the HR signal we have an indication the parasympathetic signal of this person is basically determined by other sources than the systemic source. Perhaps the lung pressure or the respiratory neurons are dominating the parasympathetic signal of volunteer 1. More extensive experiments will be necessary to validate this possibility. The fact that the autonomic measures lose their value for the 0.075 Hz case is also illustrated in the calculated HR signal. Because we used the and values of the 0.1 Hz breathing frequency there is a reasonable agreement for the first

100 s (although a systematic shift is already seen after 75 s) but our calculations are completely besides the real HR during the chaotic period.

28

Internal report about the autonomic nerve system

version 1.0 12/9/2011

For volunteer 2 we also find consistent data for the frequency 0.1 and 0.125 Hz, but not for the lowest frequency 0.075 Hz. This can be explained with figure 6 were we see that around 180, reducing the accuracy of the and is

values for that frequency interval. Notice the

negative gamma value suggesting a positive correlation between Ts and v. Also the absolute value of the gamma factor is around one indicating that the sympathetic signal contributes with the same weight to the HR than the parasympathetic signal. Volunteer 5 has more congruent values over the three intervals. The lowest frequency value looks less reliable but we do not find a good reason for this. These variations are probably just related to the related with which the and and can be calculated.

More experiments are necessary to validate both the phase method and sympathovagal factor. The method seems capable of detecting different ways of breathing and/or different physiological responses to breathing patterns. To get more general results we should reduce the variability between different persons. Therefore we will focus on healthy people that are experienced with breathing techniques. This way we hope to extract more reproducible results that are associated with a certain breathing method.

29

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Conclusions
We designed a monitoring method for the autonomic system on the time scale of the heartbeat and based on parameters that can be extracted from the blood pressure signal. The parasympathetic signal that is related with the systemic pressure is monitored by the psys signal with which it has a positive correlation. The Windkessel relaxation time v can be used as a monitoring measure for the sympathetic signal, with which v has either a positive or negative correlation. We also developed a method based on phase differences between the psys, v and the HR signals to determine the sign of this correlation. This phase method has the potential to give insight in the numerous processes that are interacting with each other during breathing. We found a great variability of these phase relations over the five volunteers reflecting the different ways people are breathing. For some special cases we could indicate the dominant processes that are determining the HR. If psys and v signals are not phase locked at 0 or 180, we could calculate which characterizes the sympathovagal balance of the heart signal. Although, the accuracy of this method is not high, we get consistent results over the five volunteers. More extensive experiments with people trained in breathing techniques are necessary for more general conclusions.

30

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Tables
classical measures Tp Ts Ts/Tp SD(HR) of HF(HR) MSNA (invasive) LF/HF (controversial) ( New measures psys -v )

Table 1 Classical measures and newly proposed measures for the autonomous signals Tp and Ts. SD(HR) = the standard deviation of the heart rate, HF(HR) is the high frequency power density value of the heart rate spectrum. MSNA = Muscle Sympathetic Nerve Activity (MSNA). The systolic pressure psys correlates positively with Tp and the Windkessel relaxation time v has mostly a negative correlation with Ts. The -factor (the sympathovagal balance) can be extracted out of phase differences during slow breathing.

volunteer number 1

breathing interval (Hz) 0.25-0.05 0.25-0.175 0.125-0.05 0.25-0.05 0.25-0.175 0.125-0.05 0.25-0.05 0.25-0.175 0.125-0.05 0.25-0.05 0.25-0.175 0.125-0.05 0.25-0.05 0.25-0.175

VLF
((ms)^2)

LF ((ms)^2) 4780 394 11200 4968 1160 11300 6950 566 15500 1020 99 1560 276 160

HF
((ms)^2)

MEAN
(ms)

SD (ms) 90 62 113 84 53 108 107 54 137 47 31 52 38 42

1160 1570 872 1208 1050 1780 2140 622 1230 765 391 573 955 1420

1650 1630 694 510 301 750 1080 794 612 271 374 209 76 76

970 978 964 1044 1046 1037 874 836 912 744 726 756 806 793

0.125-0.05 500 353 59 815 32 Table 2 Parameters calculated out of the RR datasets. Three sets are compared: the complete dataset containing all the breathing frequencies (0.25-0.05 Hz), a subset containing only the frequencies in the HF band (0.25-0.175 Hz, normal breathing) a subset a subset containing only the frequencies in the LF band (0.125-0.05 Hz, slowly breathing). 31

Internal report about the autonomic nerve system breathing VLF LF HF interval (Hz) ((mmHg)^2) ((mmHg)^2) ((mmHg)^2) 0.25-0.05 0.25-0.175 0.125-0.05 0.25-0.05 0.25-0.175 0.125-0.05 3 0.25-0.05 0.25-0.175 0.125-0.05 4 0.25-0.05 0.25-0.175 0.125-0.05 0.25-0.05 0.25-0.175 33 17 38 4.3 1.5 2.7 40 39 32 18 5.7 26 37 17 27 2.1 56 5.9 1.1 8.7 65 7.8 141 28 1.3 49 40 6.1 14 15 37 2.1 3.0 0.8 26 39 4.1 6.3 15 2.2 32 84

version 1.0 12/9/2011

volunteer number 1

MEAN
(mmHg)

SD
(mmHg)

127 131 122 122 120 122 126 125 128 101 101 100 122 117

11 6.8 12 3.9 3.0 4.4 11 9.7 12 7.2 4.8 8.4 11 10

0.125-0.05 27 56 5.0 124 10 Table 3 Parameters calculated out of the psys datasets (positively correlating with the parasympathetic signal). Three sets are compared: the complete dataset containing all the breathing frequencies (0.25-0.05 Hz), a subset containing only the frequencies in the HF band (0.25-0.175 Hz, normal breathing) a subset a subset containing only the frequencies in the LF band (0.125-0.05 Hz, slowly breathing).

volunteer number 1

breathing interval (Hz) 0.25-0.05 0.25-0.175 0.125-0.05 0.25-0.05 0.25-0.175 0.125-0.05 0.25-0.05 0.25-0.175 0.125-0.05 0.25-0.05 0.25-0.175 0.125-0.05 0.25-0.05 0.25-0.175 0.125-0.05

VLF
((ms)^2)

LF ((ms)^2) 11400 1300 22000 13800 3990 25800 8410 1350 17600 2830 214 4470 20794 12700 17800 32

HF
((ms)^2)

MEAN
(ms)

SD (ms) 275 118 380 197 160 214 162 150 170 131 96 107 324 407 247

19300 4570 12100 17300 13400 10600 18000 14600 14300 12400 5610 4240 52700 59700 14700

6260 4370 4040 3850 3440 4070 990 780 740 1700 2751 1590 29800 47300 4970

1230 1190 1240 2500 2420 2550 1240 1210 1290 1156 1260 1090 1430 1490 1390

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Table 4 Parameters calculated out of the v datasets (negatively correlating with the sympathetic signal). Three sets are compared: the complete dataset containing all the breathing frequencies (0.25-0.05 Hz), a subset containing only the frequencies in the HF band (0.25-0.175 Hz, normal breathing) a subset a subset containing only the frequencies in the LF band (0.125-0.05 Hz, slowly breathing).

volunteer number 1

breathing frequency (f) 0.075 0.1 0.125 0.075 0.1 0.125 0.075 0.1 0.125 0.075 0.1 0.125 0.075 0.1 0.125 -0.2 0.92 0.76 4.1 1.9 0.87 3.5 3.7 -2.3 -7.14 1.74 1.54 0.56 0.23 0.25 25 9.7 2.7 46 -23 -18 -202 -262 172 -621 152 113 29 16 21

-4.35 0.23 0.08 0.77 -0.63 -1.00 -0.77 -0.83 -1.27 1.08 0.83 0.71 0.71 1.30 1.39

Table 5 The constants

and calculated from the phase data for the 0.075, 0.1 and 0.125 data

set using Eq. (16), (17) and(18). The grey values are in a first approximation consistent with each other and are used to interpret the data. The data of volunteer number 3 and 4 cannot be used because of a phase locking ( psys. indicating a strong coupling between v and

33

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Figures

Figure 1 Scheme of the complex relationships between neural activity (sympathetic Ts, parasympathetic Tp, ventilator TR, vestibular Tv and locomotor TL), neurotransmitters (acethylcholine Cp and noradrenaline Cs), hemodynamical parameters (heart rate HR, pulse pressure pp, systolic pressure psys, diastolic pressure pdia, relaxation time v, total arterial resistance R and total arterial compliance C) and long pressure pL. For the stabilizing of the arterial pressure 4 feedback loops can be found, one of a parasympathetic nature (19-2-18-17-1) and three of a sympathetic nature (20- 518-11, 20-6-1617-11, 20-8-15-11). Each relation is numbered. The sign besides the numbers refers to a positive or negative correlation between the parameters.

34

Internal report about the autonomic nerve system

version 1.0 12/9/2011

-50

()

= 0.1 s
-100

= 0.5 s =1s =2s

-150

-50

()

-100

= 0.5 s =1s =2s

-150

0.05

0.1 f (Hz)

0.15

0.2

0.25

Figure 2 (a) Upper figure: the phase-frequency relation of a first-order process for several values of the time constant . Because the accuracy of the measured phase relations is around 30-40 these phase variations will not be clearly seen. (b) The phase-frequency relations for a fixed delay time varying from 0.5 to 2 s. This linear phase decay for delay times bigger than 1 s should clearly be seen in phase-frequency relations.

35

Internal report about the autonomic nerve system (a) volunteer 1

A
0.2 0.1 0 1000

version 1.0 12/9/2011

RR

psys

500 0

0.2

A
0.1 0

0.05

0.1 f (Hz)

0.15

0.2

0.25

(b) volunteer 2
0.2 RR

A
0.1 0 200 psys 100

0 0.4 0.3 0.2 0.1 0 0.05 0.1 f (Hz) 0.15 0.2 0.25

(c) volunteer 3
0.3 RR

0 3000 2000 psys

A
1000 0 0.3

0.2 0.1

0.2 0.1 0 0.05 0.1 f (Hz) 0.15 0.2 0.25

Figure 3 Spectral power density of RR, psys and v over all the breathing frequencies for three of the volunteers.

36

Internal report about the autonomic nerve system a. Volunteer 3

HR (bpm) p (a.u.)
90 80 70 60 50 160

version 1.0 12/9/2011

HR pL

(mmHg) p
sys

140 120 100

1.8 1.6

v (s)

1.4 1.2 1 0 10 20 30 t (s) 40 50 60

b. Volunteer 2
HR (bpm) p (a.u.)

70

60 HR pL HRcalc 40 130

50

(mmHg)
sys

125

120

115 3

v (s)

2.5

10

20

30 t (s)

40

50

60

Figure 4 One minute time variations of the three measures of interest (HR, psys and v) and the lung pressure pL for a breathing frequency of 0.1 Hz. These figures illustrate the potential of the new measures allowing real time monitoring of both the parasympathetic variations (psys) and the sympathetic variations (-v).

37

Internal report about the autonomic nerve system

version 1.0 12/9/2011

v - pL HR - pL psys - pL

150 100 50

() ()

0 -50 -100 -150

150 100 50 0 -50 -100 -150 0.05 0.1 0.15 f (Hz) 0.2 0.25 0.05 0.1 0.15 f (Hz) 0.2 0.25

Figure 5 The frequency dependency of phase differences for the four volunteers (a) upper left volunteer 1, (b) upper right volunteer 2, (c) lower left volunteer 3 and (d) lower right volunteer 4. The blue curve gives the phase of the HR curve relative to the lung pressure curve. The black one is the v phase and the green one the psys phase both relative to the lung pressure variations.

38

Internal report about the autonomic nerve system

version 1.0 12/9/2011

250

200

150

1 2 3 4 5

v - sys ()

100

50

-50 0.06

0.08

0.1

0.12

0.14

0.16 f (Hz)

0.18

0.2

0.22

0.24

0.26

Figure 6 Phase differences between the v and psys signals for all the volunteers and for the whole frequency range.

39

Internal report about the autonomic nerve system

version 1.0 12/9/2011

100 90

HR pL HRcalc

HR (bpm) p (a.u.) (mmHg) p

80 70 60 50 160 140 120 100 80 1.8 1.6

v (s)

sys

1.4 1.2 1

25

50

75

100 t (s)

125

150

175

200

Figure 7 Time variations of the three measures of interest (HR, psys and v) and the lung pressure pL of volunteer 1. The first 100 s volunteer 1 is breathing at 0.1 Hz, the next 100 s she is breathing at 0.075 Hz. Although the heart signal remains stable the psys and the v dataset become unstable for around 50 s in the beginning of the 0.075 breathing frequency.

40

Internal report about the autonomic nerve system

version 1.0 12/9/2011

References
Berntson, G. G., Cacioppo, J. T., & Quigley, K. S. (1993). Cardiac psychophysiology and autonomic space in humans: emperical perspectives and conceptual implications. Psychological Bulletin, 114, 296-322. Blase, K. (2005). Heart rate variability biofeedback in Dutch and American schools. Applied Psychophysiology and Biofeedback, 30(2), 155-156. Brack, K. E. (2004). Interaction between direct sympathetic and vagus nerve stimulation on heart rate in the isolated rabbit heart. Experimental Physiology, 89, 128-139. Cimponeriu, L., Rosenblum, M., Patzak, A., Mrowka, R., & Bezerianos, A. (2002). Coupled oscillators approach to identification of directionality in cardiorespiratory interaction. Cohen, M. A., & Taylor, J. A. (2002). Topical review: Short-term cardiovascular oscillations in man: measuring and modelling the physiologies. Journal of Physiology, 542(3), 14. Dawson, R. W., Schell, A. M., & Filion, D. L. (2007). The electrodermal system. In L. G. T. J. T. Cacioppo, G. G. Berntson (Ed.), Handbook of Psychophysiology Cambridge: Cambridge University Press. Dempsey, J. A., Sheel, A. W., St Croix, C. M., & Morgan, B. J. (2002). Respiratory influences on sympathetic vasomotor outflow in humans. Respiratory Physiology & Neurobiology, 130(1), 3-20. Derchak, P. A., Sheel, A. W., Morgan, B. J., & Dempsey, J. A. (2002). Effects of expiratory muscle work on muscle sympathetic nerve activity. Journal of Applied Physiology, 92(4), 1539-1552. Dyckman, D. J., Kearney, M. L., & Ray, C. A. (2006). The vestibulosympathetic reflex is attenuated after prolonged head-down bed rest. Faseb Journal, 20(5), A1251-A1251. Dyckman, D. J., Monahan, K. D., & Ray, C. A. (2007). Effect of baroreflex loading on the responsiveness of the vestibulosympathetic reflex in humans. Journal of Applied Physiology, 103(3), 1001-1006. Edmonds, W. A., Tenenbaum, G., Mann, D. T. Y., Johnson, M., & Kamata, A. (2008). The effect of biofeedback training on affective regulation and simulated car-racing performance: A multiple case study analysis. Journal of Sports Sciences, 26(7), 761-773. Fortney, L., & Taylor, M. (2010). Meditation in Medical Practice: A Review of the Evidence and Practice. Primary Care, 37(1), 81-+. Fowles, D. C., Christie, M. J., Edelberg, R., Grings, W. W., Lykken, D. T., & Venables, P. H. (1981). Publication Recommendations for electrodermal measurements. Psychopsychology(vol 18 (3)), 232-239. Healey, J. A., & Picard, R. W. (2005). Detecting stress during real-world driving tasks using physiological sensors. Ieee Transactions on Intelligent Transportation Systems, 6(2), 156-166. Karemaker, J. M. (2009). Last Word on Point: Counterpoint: Respiratory sinus arrhythmia is due to a central mechanism vs. respiratory sinus arrhythmia is due to the baroreflex mechanism. Journal of Applied Physiology, 106(5), 1750-1750. Karemaker, J. M., & Wesseling, K. H. (2008). Variability in cardiovascular control: The baroreflex reconsidered. Cardiovascular Engineering, 8(1), 23-29. Kettunen, J., Ravaja, N., Naatanen, P., Keskivaara, P., & Keltikangas-Jarvinen, L. (1998). The synchronization of electrodermal activity and heart rate and its relationship to energetic arousal: a time series approach. Biological Psychology, 48(3), 209-225. Kumar, M., Weippert, M., Vilbrandt, R., Kreuzfeld, S., & Stoll, R. (2007). Evaluation of heart rate signals for mental stress assessment. Ieee Transactions on Fuzzy Systems, 15(5), 791-808. Liu, Z., Brin, K. P., & Yin, F. C. (1986 ). Estimation of total arterial compliance: an improved method and evaluation of current methods. Am J Physiol, 251, 588-600. Liu, Z. R., Brin, K. P., & Yin, F. C. P. (1986). ESTIMATION OF TOTAL ARTERIAL COMPLIANCE - AN IMPROVED METHOD AND EVALUATION OF CURRENT METHODS. American Journal of Physiology, 251(3), H588-H600. 41

Internal report about the autonomic nerve system

version 1.0 12/9/2011

Matthys, K., Kalmar, A., Struys, M., Mortier, E., Avolio, A., Segers, P., et al. (2008). Long-term pressure monitoring with arterial applanation tonometry: a non-invasive alternative during clinical intervention? Technol Health Care, 16(3), 183-193. Mrowka, R., Cimponeriu, L., Patzak, A., & Rosenblum, M. G. (2003). Directionality of coupling of physiological subsystems: age-related changes of cardiorespiratory interaction during different sleep stages in babies. American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 285(6), R1395-R1401. Olufsen, M. S., Alston, A. V., Tran, H. T., Ottesen, J. T., & Novak, V. (2008). Modeling heart rate regulation - Part I: Sit-to-stand versus head-up tilt. Cardiovascular Engineering, 8(2), 73-87. Olufsen, M. S., Tran, H. T., Ottesen, J. T., Lipsitz, L. A., Novak, V., & Program, R. E. U. (2006). Modeling baroreflex regulation of heart rate during orthostatic stress. American Journal of PhysiologyRegulatory Integrative and Comparative Physiology, 291(5), R1355-R1368. Ottesen, J. T., & Olufsen, M. S. (2011). Functionality of the baroreceptor nerves in heart rate regulation. Computer Methods and Programs in Biomedicine, 101(2), 208-219. Park, S. K., ONeill, M. S., Vokonas, P. S., Sparrow, D., Wright, R. O., Coull, B., et al. (2008). Air pollution and heart rate variability - Effect modification by chronic lead exposure. Epidemiology, 19(1), 111-120. Phillip A, L. (2004). Chapter 36 Laboratory evaluation of autonomic function. In L. H. P. D. L. S. M. Hallett & J. M. Massey (Eds.), Supplements to Clinical Neurophysiology (Vol. Volume 57, pp. 358-368): Elsevier. Seals, D. R. (2001). Robin Hood for the lungs? A respiratory metaboreflex that 'steals' blood flow from locomotor muscles. Journal of Physiology-London, 537(1), 2-2. Seidel, H., & Herzel, H. (1998). Bifurcations in a nonlinear model of the baroreceptor-cardiac reflex. Physica D, 115(1-2), 145-162. Song, H., & Lehrer, P. M. (2003). The Effects of Specific Respiratory Rates on Heart Rate and Heart Rate Variability. Applied Psychophysiology and Biofeedback, 28(1), 13-23. Stern, R. M., Ray, W. J., & Quigley, K. S. (2001). Psychopsychology recording (second ed.). New York: Oxford university press. Sundlof, G., & Wallin, B. G. (1978). HUMAN MUSCLE NERVE SYMPATHETIC ACTIVITY AT REST RELATIONSHIP TO BLOOD-PRESSURE AND AGE. Journal of Physiology-London, 274(JAN), 621637. Swenne, C. A. (2002). Neurocardiological basis for intraindividual ECG variability. Journal of Electrocardiology, 35, 239-242. Ursino, M., & Magosso, E. (2003). Role of short-term cardiovascular regulation in heart period variability: a modeling study. American Journal of Physiology-Heart and Circulatory Physiology, 284(4), H1479-H1493. Vissing, S. F., Scherrer, U., & Victor, R. G. (1991). STIMULATION OF SKIN SYMPATHETIC-NERVE DISCHARGE BY CENTRAL COMMAND - DIFFERENTIAL CONTROL OF SYMPATHETIC OUTFLOW TO SKIN AND SKELETAL-MUSCLE DURING STATIC EXERCISE. Circulation Research, 69(1), 228238. Wallin, B. G. (1981). Sympathetic nerve activity underlying electrodermal and cardiovascular reactions in man. Psychophysiology, 18, 470-475. Wallin, B. G. (2007). Interindividual differences in muscle sympathetic nerve activity: a key to new insight into cardiovascular regulation? Acta Physiologica, 190(4), 265-275. Wallin, B. G., & Charkoudian, N. (2007). SYMPATHETIC NEURAL CONTROL OF INTEGRATED CARDIOVASCULAR FUNCTION INSIGHTS FROM MEASUREMENT OF HUMAN SYMPATHETIC NERVE ACTIVITY. Musle & nerve, 36, 595-614. Yildiz, M., & Ider, Y. Z. (2006). Model based and experimental investigation of respiratory effect on the HRV power spectrum. Physiological Measurement, 27(10), 973-988. Zhang, H. G., Holden, A. V., Noble, D., & Boyett, M. R. (2002). Analysis of the chronotropic effect of acetylcholine on sinoatrial node cells. Journal of Cardiovascular Electrophysiology, 13(5), 465474. 42

Internal report about the autonomic nerve system

version 1.0 12/9/2011

43