Biomedical Signal Processing and Control 6 (2011) 251–260

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Biomedical Signal Processing and Control

journal homepage: www.elsevier.com/locate/bspc

Mathematical model-based markers of autonomic nervous activity during the

Valsalva Maneuver and comparison to heart rate variability
Michel Kana a,∗ , Jiri Holcik b,c
a
Department of Biomedical Informatics, Czech Technical University in Prague, Nam. Sitna 3105, 27201 Kladno, Czech Republic
b
Institute of Biostatistics and Analyses, Masaryk University Brno, Kamenice 3, 62500 Brno, Czech Republic
c
Institute of Measurement Science, Slovak Academy of Sciences, Dubravska cesta 9, 841 04 Bratislava, Slovakia

a r t i c l e i n f o a b s t r a c t

Article history: This work exhibits limitations of some time–frequency markers of heart rate variability (SDNN: standard
Received 29 March 2010 deviation of normal-to-normal intervals, RMSSD: root mean square successive difference of normal-to-
Received in revised form 22 March 2011 normal intervals, LF: power of low frequency components 0.015–0.15 Hz, HF: power of high frequency
Accepted 5 May 2011
components 0.15–0.4 Hz) as tool for assessing autonomic nervous activity on the cardiovascular system
Available online 2 June 2011
during the Valsalva Maneuver (VM) and proposes a new approach based on a physiologically based
mathematical model.
Keywords:
Our mathematical model fits measured heart rate and galvanic skin response during intra-thoracic
Markers of autonomic nervous activity
Parasympathetic tone
and intra-abdominal pressure elevation, simulates the baroreflex and estimates parameters that should
Sympathetic tone quantify mean autonomic tone of parasympathetic activity (MATpar ), maximal autonomic tone of
Valsalva Maneuver parasympathetic activity (MATpar , total autonomic tone of sympathetic activity (TATsym ) and autonomic
Heart rate variability tone balance (ATB) on 5 healthy subjects.
Mathematical modeling An extended statistical analysis including multivariable linear regression analysis and correlation anal-
ysis was performed in order to study patterns of variation of our model-based estimates and possible
relationships with time–frequency markers of heart rate variability during the tachycardia phase 2 and
bradycardia phase 4 of the VM. It was found that, MATpar significantly decreased by 32 ± 8% (p < 0.001)
from 0.87 ± 0.02 n.u. (normalized unit) in phase 1 to 0.58 ± 0.05 n.u. in phase 2 and was found to be signif-
icantly correlated to HF (R = 0.87, p < 0.05) that decreased from 0.5 ± 0.21 n.u. to 0.1 ± 0.01 n.u. Meanwhile
TATsym increased by 2135 ± 711% (p < 0.001) from 0.14 ± 0.05 n.u. to 2.89 ± 0.7 n.u. and was significantly
correlated to LF (R = 0.95, p < 0.05) that increased from 0.49 ± 0.21 n.u. to 0.89 ± 0.01. MATpar significantly
increased by 87 ± 63% (p < 0.001) from 0.53 ± 0.18 n.u. in phase 3 to 0.89 ± 0.02 n.u. in phase 4 and was
found to be significantly correlated to RMSSD (R = 0.91, p < 0.05) that increased from 18.61 ± 5.23 ms
to 36.31 ± 7.02 ms. Meanwhile TATsym significantly decreased by 82 ± 13% (p < 0.01) from 1.46 ± 1.4 n.u.
to 0.14 ± 0.05 n.u. and was significantly correlated to SDNN (R = 0.91, p < 0.05) that decreased from
28.79 ± 8.17 ms to 22.62 ± 9.63 ms.
An additional Wilcoxon sign test suggested the following markers that might provide the most signif-
icant assessment of autonomic nervous activity in a given phase of VM: SDNN in phases 0 & 5, TATsym in
phases 1 & 2 and ATB in phases 3 & 4 for sympathetic activity assessment; RMSSD in phases 0 & 5, MATpar
in phases 1 & 2, MATpar in phases 3 & 4 for parasympathetic activity assessment.
Results suggest that statistical quantities derived from mathematical models of cardiovascular control
provide useful information for assessing the distinct contribution of sympathetic and parasympathetic
branches on heart rate variability during the Valsalva Maneuver.
© 2011 Elsevier Ltd. All rights reserved.

1. Introduction (1677–1723), which consists of an abrupt transient increase of

The Valsalva Maneuver (VM) is a cardiac autonomic test,
named after the physician and anatomist Antonio Maria Valsalva
∗ Corresponding author. Tel.: +420 312 608 207; fax: +420 312 608 204.
E-mail address: kana@fbmi.cvut.cz (M. Kana).
intra-thoracic and intra-abdominal pressure provoked by blowing
into a resistance of approx. 40 mmHg for about 15 s. The VM is suit-
able for assessing the integrity of autonomic nervous control on the
cardiovascular system [1]. The VM consists of several phases which
are graphically depicted in Fig. 1. During phase 1 a brief increase
in arterial blood pressure and decrease in heart rate is observed. In
phase 2 sustained high intra-thoracic and intra-abdominal pressure

1746-8094/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bspc.2011.05.001
252 M. Kana, J. Holcik / Biomedical Signal Processing and Control 6 (2011) 251–260
Fig. 1. Mean arterial pressure (plain line) and heart rate (dashed line) changes dur-
ing the VM. The maneuver covers the timeline from the 15th to the 30th second.
Phase 1 goes from 15th to 16th second, phase 2 ends at 30th second, followed by
phase 3. The last phase 4 runs from 31st to 38th second.
hinders venous return, leading to a rapid decrease in arterial blood
pressure and increased heart rate. During phase 3, the forced expi-
ration is released resulting in a sudden decrease in arterial blood
pressure. During phase 4, the accumulated venous blood returns
to heart and is pumped into the constricted arteries causing an
“overshoot” of arterial pressure.
There are signal analysis methods to evaluate cardiovascular
response during the Valsalva Maneuver including T-wave width
alteration [2], QT-RR regression lines [3] and baroreflex open-
loop gain [4]. Although such methods provide insight information,
the contribution of neural pathways involved is not covered. An
attempt using frequency domain analysis of heart rate variability
(HRV) with Fast Fourier Transform (FFT) was made in [5,6]. FFT
analysis of autonomic balance during the VM can held erroneous
results because of the very short duration of the test (15–30 s).
Recording of approximately 1 min is needed to access the high
frequency (HF) components of HRV; while 2 min are needed to
evaluate the low frequency (LF) components. Very low frequency
(VLF) assessment from short-term recordings (less than 5 min) is a
dubious measurement and should be avoided [7]. Discrete Wavelet
Transform (DWT) has been suggested to provide a more accurate
frequency analysis of very short signals. DWT has been applied in
[8] to decompose the non stationary heart rate signals obtained
during VM over time, yielding both frequency and time resolu-
tion. Disadvantages of DWT method include its limitation to clearly
demonstrate the distinct contribution of LF (0.067–0.125 Hz) and
HF (0.125–0.25 Hz) components between phase 2 and phase 3 of
VM. Furthermore the reported increase to 30% in LF band dur-
ing phase 4, is contradictory with the observed bradycardia in
that phase. It appears that both FFT and DWT methods are not
able to delineate the contributions of parasympathetic and sympa-
thetic activities in the LF band. Physiologically based mathematical
models look as a promising tool for distinctly evaluating sympa-
thetic and parasympathetic activity during each single phase of
the VM. Authors of [9,10] proposed such integrated cardiovascu-
lar and respiratory models aiming to quantify the response to VM.
Both models include multiplicity of mechanisms for simulating
hemodynamic response; atrial, ventricular and lung mechanics.
Because of the lack of direct experimental evidence, the authors
acknowledge that their equations for autonomic nervous con-
trol are largely empirical in nature and not readily applicable to
other studies without modification. It is not clear how to interpret
the simulated firing rates of efferent neurons, since a quantita-
tive comparison with common methods such as HRV was not
included.
Our objective is to develop a simpler mathematical model of
cardiovascular control during VM and to derive model-based esti-
mates that aim to quantify sympathetic and parasympathetic tone
on the cardiovascular system. A comparison with HRV should
bring evidences for validity and eventually superiority of this
method.
2. Materials
Three healthy women (age 15, 21 and 46 years) and 2 men
(both age 23 years) underwent the Valsalva Maneuver. Each sub-
ject performed the maneuver several times until a typical heart rate
response was visible, which characterizes the VM. We selected 10
datasets, corresponding to 2 measurements per subject.
A Biopac MP35 [11] system was used for data acquisition. Three
leads electrocardiogram (ECG) was recorded using SS2L electrodes
placed on the left and right wrists and on the left part of the
abdomen just above the belt. Two electrodes SS57L were fixed
around the index (ground) and middle finger (+) for galvanic skin
response (GSR) measurement. Baseline measurements were per-
formed during 15 s prior to the maneuver. After taking a breath the
subject expired against a resistance during 15 s while signals were
recorded. After the forced expiration was released, measurements
were resumed for another 30 s. Thus we obtained 60 s ECG and
GSR records for each subject. The signals were sampled at 500 Hz
using the Biopac Student Lab PRO acquisition software. They were
exported in time series ASCII files for further processing in Matlab.
R-peaks were detected from the ECG signal using an implemen-
tation of the non-syntactic QRS detection algorithm [12]. For this
purpose the ECG signal was sampled down to 400 Hz and filtered
to get rid of shifting baseline and 60 Hz noise using a Butterworth
band pass filter. RR intervals durations were calculated as dif-
ferences of timestamps of consecutive R-peaks. The obtained RR
time series was de-trended, sampled down to 10 Hz and stored
in a vector RRmeas for further analysis. The activity of the sweat
glands in response to sympathetic nervous stimulation results in
an increase in the level of skin conductance. The measured gal-
vanic skin response signal was sampled down to 10 Hz and stored
in a vector GSRmeas for further analysis.
3. Limitations of heart rate variability
Heart rate variability presents one of the most promising mark-
ers of quantitative assessment of autonomic activity. Variables can
be measured in frequency domain of NN intervals (normal-to-
normal interval between adjacent QRS complexes in the ECG). The
spectral values for heart rate variability can be calculated for low
(LF: 0.04–0.15 Hz) and high (HF: 0.15–0.5 Hz) frequency bands. Low
frequency heart rate oscillations are considered to be mediated by
combined sympathetic and parasympathetic activity while there
is a predominance of sympathetic tone during stressful conditions.
High frequency heart rate oscillations are associated with respi-
ratory sinus arrhythmia and reflect parasympathetic activity. The
physiological background of very low frequency (VLF) components
is still under discussion. The spectrum of the HRV signal is usu-
ally calculated using non-parametric methods based on Fast Fourier
Transforms or other methods such as Lomb periodogram, which is
a method of spectral analysis for unevenly sampled series [13]. A
rigorous evaluation requires at least 60 s ECG. This basic condition
is not met by the Valsalva Maneuver, which is usually performed
for less than 30 s. Therefore time-domain analysis is more suitable
in the evaluation of HRV during VM, for example the standard devi-
ation of NN intervals (SDNN) which reflects the overall variability,
but strongly depends on the duration of the signal. SDNN increases
with the length of recording. The square root of the mean square
successive differences of NN intervals (RMSSD) estimates high fre-
quency variations of heart rate and is proposed as a measure of
parasympathetic activity.
Time-domain and frequency-domain estimates of HRV were
estimated for the 10 data sets and values are presented in Fig. 2 (top
panels). The SDNN and RMSSD for each single phase were calculated
on the portion of NN intervals of that phase. Changes in SDNN are
 M. Kana, J. Holcik / Biomedical Signal Processing and Control 6 (2011) 251–260
Fig. 2. Time-domain parameters (SDNN – top left, RMSSD – top right) and normalized frequency-domain parameters (LF – bottom left, HF – bottom right) of HRV during
each phase of the VM for 10 data sets and their mean values (dashed line).
visible from one phase to the next phase of the maneuver. Greatest
heart rate variability occurs in the phase 2, where average SDNN
equals 38.66 ± 3.67 ms compare to 21.27 ± 5.78 ms before the
maneuver. Phase 2 is also characterized by a decreased RMSSD from
30.14 ± 8.11 ms before the maneuver to 23.81 ± 6.66 ms, which
suggests a withdrawal of vagal activity and increased sympathetic
activity as response to the transient decrease in blood pressure.
Phase 4 bradycardia is characterized by an increase of RMSSD from
18.61 ± 5.22 ms in phase 3 to 36.31 ± 7.02 ms in phase 4.
Frequency-domain estimates of HRV were calculated for each
phase of the VM using the Lomb periodogram. The power of low
frequency components (LF band 0.015–0.15 Hz) and high frequency
components (HF band 0.15–0.4 Hz) are depicted in normalized
units in Fig. 2 (bottom panels). They represent the relative value
of each power component centered at the frequency of interest
(LF or HF) and divided by total power. At baseline, on average
22.54 ± 11.02% of the energy corresponds to LF components. Their
activity increases by 49.46 ± 21.74% and 89.03 ± 1.2% of the total
energy of phases 1 and 2, respectively, suggesting an increase
in sympathetic activity. A similar increase was obtained in [8]
using wavelets transform. Phase 4 is characterized by predominant
energy in HF components, 61.52 ± 6.4% what supports the observed
bradycardia.
Although LF, HF, RMSSD and SDNN provide a measure of the
degree of autonomic modulation, they do not indicate the level of
autonomic tone regulating heart rate for each single phase of the
VM [14]. They can also provide contradictory results, for exam-
ple in Fig. 2, LF increases in phase 1 while a decreased SDNN is
observed. RMSSD surprisingly increases from 17.24 ± 10.18 ms in
phase 1 to 23.81 ± 6.66 ms in phase 2 although phase 2 should be
characterized by a decrease of parasympathetic activity. Phase 3 is
characterized by an increase of HF by 80% while RMSSD is reporting
a decrease by 20%. Such inconsistency motivated us to investigate
the usage of estimates of autonomic tone based on mathematical
models.
253
4. Model development
4.1. Circulatory component
A block diagram of our model is depicted in Fig. 3. The circulatory
component includes four compartments following the approach
suggested in [15]. Large arteries (e.g. aorta) are lumped together
in an arterial systemic compartment, characterized by the pres-
sure Pas in mmHg. The aorta branches into smaller arteries and a
network of capillaries which form the peripheral systemic com-
partment, characterized by the resistance PR in mmHg min/l. After
leaving the capillaries blood flows into veins, then into both vena
cavae, which join together to form the venous systemic compart-
ment, characterized by the pressure Pvs in mmHg. From there blood
enters the atria, lungs and ventricles, which we lump together into
a heart compartment, characterized by the stroke volume Vstr in
liter and the heart rate HR in beats/min.
The volume of blood ejected by the heart per beat (stroke vol-
ume in liter) depends on the pressure in both venous and arterial
systemic compartments. We capture the effect of contractility and
compliance of the ventricles using a weighting factor Kstr in liter:
pvs
Vstr = kstr · (1)
pas
The blood flow generated by the heart, the cardiac output in
l/min, is given by:
Qin = HR · Vstr (2)
The blood flow in l/min through the peripheral systemic com-
partment can be modeled as:
1
Qout = · (Pas − Pvs ) (3)
PR
If we assume that the arterial systemic compartment is charac-
terized by a compliance Cas in l/mmHg, then we can partly use the
254 M. Kana, J. Holcik / Biomedical Signal Processing and Control 6 (2011) 251–260

Fig. 3. Block diagram describing the model of heart rate, blood pressure and peripheral vascular resistance control during the Valsalva Maneuver. Intra-thoracic pressure
change is communicated to venous systemic and peripheral systemic compartments via pressure variables Ps , P1 and P3 . Change in venous pressure Pvs affects stroke volume
Vstr , which has a direct influence on arterial pressure Pas . Baroreceptors firing rate N signalizes pressure fluctuations to autonomic nervous centers for cardiovascular control.
Response is communicated via efferent sympathetic and parasympathetic outflows Tsym and Tpar ; this has the effect of modulating heart rate HR, cardiac output Qin , blood
flow through the peripheral systemic compartment Qout and peripheral vascular resistance PR.

Grodins model of the mechanical part of the cardiovascular system 4.3. Intra-thoracic pressure component
[16] and write the differential equation:
During the phase 1, the gradual increase in intra-thoracic and
dPas 1 intra-abdominal pressure will cause aortic and peripheral vessels
= · (Qin − Qout ) (4)
dt Cas compression. This results in slight increased peripheral resistance
that is modeled using a Gaussian function P1 :
4.2. Autonomic nervous control component (t−dPtime −(P1dur /8))2
2(P1dur /8)2
P1 = P1amp · e (10)
The change in arterial blood pressure is sensed by the carotid and
aortal baroreceptors, which adjust their firing rate accordingly. We where P1amp is the amplitude of pressure increase in mmHg,
adapt the non-linear mathematical model for baroreflex regulation dPtime is the timestamp in seconds when the VM starts with con-
proposed in [17] as follows, stant value 15 s, P1dur is the duration of the phase 1.
Therefore Eq. (9) can be rewritten as:
dPas M−N
= (Pas − Pasmean ) · N · − N0 (5)
dt (M/2)2 PR = PR0 · (1 + Kpr · Tsym ) + P1 (11)

where N is the firing rate of the baroreceptors in Hz corresponding The sustained high intra-thoracic and intra-abdominal pressure
to the deviation of the arterial pressure from its mean value Pasmean ; is modeled using a logistic function Ps :
M is the maximum firing rate with constant value 120 Hz. N0 is the
⎧
⎨ Psmax · 10−1 · edPrate ·t
baseline firing rate with constant value 100 Hz. if 0 ≤ t ≤ dPtime + dPdur
Ps = −1
· (edPrate ·t + 1) (12)
The baroreceptors firing rate information is integrated in ⎩ 0Psmax + 10 if t > dPtime + dPdur
the cardiovascular autonomic nervous centers, which generate a
parasympathetic and sympathetic response. The level of parasym-
where Psmax is the maximum intra-thoracic pressure with
pathetic tone is given by Tpar . It is assumed to follow the direct
constant value 40 mmHg, dPrate is the growing rate of pressure
law, thus it is linearly dependent on the baroreceptors firing rate
development at the beginning of the expiration and dPdur is the
N. The sympathetic tone is modeled by Tsym . The inhibitory effect
duration of the forced expiration with constant value 15 s.
of parasympathetic tone on the sympathetic response is taken into
We assume that this intra-thoracic pressure has a linear effect
account using a dampening factor ˇ. The following equations were
on the pressure Pvs in the venous systemic compartment, thus we
proposed by Ottesen et al. [17]:
can write the following:
N + N0 Pvs = Pvs0 + kvs · Ps (13)
Tpar = (6)
M
where Pvs0 is the mean venous pressure in mmHg prior to VM
1 − ((N + N0 )/M) and kvs is a weighting factor.
Tsym = (7)
1 + ˇ · Tpar During the phase 2, the sustained intra-thoracic and intra-
abdominal pressure hinders venous return. We can rewrite (1) and
The heart rate HR deviation from its mean value HR0 depends
include the resulting decrease of transmural pressure in the venous
on the sympathetic and parasympathetic tone on sinoatrial node.
systemic compartment, as follow:
We model this response using scaling factors Ms and Mp :
Pvs0 − kvs · Ps
HR = HR0 · (1 + Ms · Tsym − Mp · Tpar ) (8) Vstr = kstr · (14)
Pas

The sympathetic nervous stimulation additionally results in During the phase 3, the forced expiration is released, resulting
increased peripheral vascular resistance PR. We assume local con- in a decrease in venous pressure. We model this marked decrease
trol and hormone control of arteriolar resistance to be negligible using a negative Gaussian function:
and model the modulation of peripheral resistance by sympathetic (t−dPtime −dPdur −(P3dur /4))2
outflow Tsym using the scaling factor Kpr with PR0 being the baseline z·(P3dur /8)2
P3 = −P3amp · e (15)
peripheral resistance:
where P3amp is the amplitude of pressure drop in mmHg, P3dur
PR = PR0 · (1 + Kpr · Tsym ) (9) is the duration of the phase 3 in seconds.
 M. Kana, J. Holcik / Biomedical Signal Processing and Control 6 (2011) 251–260 255

Therefore, Eq. (14) can be rewritten as sympathetic tone over total parasympathetic tone for a given phase
using the following formulas.
Pvs0 − kvs · Ps + P3
Vstr = kstr · (16)
Pas TATsym (i)
ATB(i) = (27)
During phase 4, the accumulated venous blood returns to heart TATpar (i)
and is pumped into the constricted arteries causing an overshoot
of stroke volume above the normal level. We can rewrite (16) and 4.5. Sensitivity analysis
include the overshoot effect, as follows:
⎧ We study how sensitive the model outputs are to small per-
⎪ Pvs0 − kvs · Ps + P3
⎪
⎪ Vstr = kstr · turbation of parameters values. The sensitivity of model output
⎪
⎪ Pas
⎪
⎪
HR is obtained by partial differentiation of Eq. (8) with respect to
⎪ if 0 ≤ t < dPtime + dPdur
⎪ model parameters. For example this will held following sensitivity
⎨ Pvs0 − kvs · Ps + P3 + P4amp
Vstr = kstr · functions for parameters HR0 , Ms and Mp :
P (17)
⎪
⎪
as
if dPtime + dPdur ≤ t < dPtime + dPdur + P3dur + P4dur
⎪
⎪ ∂
⎪
⎪ Pvs0 − kvs · Ps + P3 + (P4amp /5) S1 = HR = 1 + Ms · Tsym − Mp · Tpar (28)
⎪
⎪ Vstr = kstr · ∂HR0
⎪
⎩ Pas
if t ≥ dPtime + dPdur + P3dur + P4dur ∂
S2 = HR = HR0 · Tsym (29)
∂Ms
where P4amp is a weighting factor to quantify the overshoot effect
on the stroke volume, P4amp is the duration of phase 4. ∂
S3 = HR = −HR0 · Tpar (30)
∂Mp
4.4. Model-based estimates of autonomic tone
The sensitivity of model output PR is obtained by partial differ-
entiation of Eq. (11) with respect to model parameters. For example
As an alternative to heart rate variability we extend the mathe-
this will held following sensitivity functions for parameters PR0 and
matical model previously developed with markers of autonomic
Kpr :
activity during the Valsalva Maneuver. For this purpose we use
model equations (6) and (7) to calculate the trajectory of parasym- ∂
pathetic tone Tpar and sympathetic tone Tsym on a normalized scale S4 = PR = 1 + Kpr · Tsym (31)
∂PR0
of 0–1.
The first class of model-based estimate is the so-called mean ∂
S5 = PR = PR0 · Tsym (32)
autonomic tone (MAT) which is calculated as the average ∂Kpr
parasympathetic or sympathetic tone for a given phase of the Val-
Sensitivity Eqs. (28)–(32) were resolved together with models
salva Maneuver using the formulas below. The index i represents
equations in Matlab. A sensitivity ranking of the parameters using
the phase of the maneuver which can be baseline (i.e. before the
the maximum absolute value of the sensitivity function as criterion
maneuver), phase 1, phase 2, phase 3, phase 4 and post VM (i.e. after
shows that sensitive parameters can be ranked from the most to the
the maneuver). Tpar {i} is the portion of the parasympathetic signal
less sensitive as follows: Mp , Ms , HR0 , Kpr , PR0 . The remaining 13
corresponding to the phase i. Tsym is the portion of the sympathetic
model parameters are more or less sensitive and have been ranked
signal corresponding to the phase i. MATpar and MATsym are the
closed to the middle of the ranking scale. This suggests performing
average parasympathetic tone and average sympathetic tone in the
mean arterial blood pressure measurement in order to be able to
phase i, respectively.
identify those parameters more efficiently.
MATpar (i) = mean(Tpar {i}) (18)
5. Results
MATsym (i) = mean(Tsym {i}) (19)

A second class of model-based estimate is the so-called total 5.1. Parameters estimation
autonomic tone (TAT) which is calculated as the sum of all indi-
vidual tones within the portion of parasympathetic or sympathetic Measured heart rate was derived in beats/min from measured
signal for a given phase using the following formulas. RR time series (RRmeas ) using the following formula:

TATpar (i) = sum(Tpar {i}) (20) 60 000

HRmeas = (33)
RRmeas
TATsym (i) = sum(Tsym {i}) (21)
Measured galvanic skin response signal (GSRmeas ) was used to
TAT (i) = TATpar (i) + TATsym (i) (22) approximate measured peripheral vascular resistance as follows:
The third and fourth class of model-based estimates are the so- 1
called minimal autonomic tone (MIAT) and maximal autonomic PRmeas = (34)
GSRmeas
tone (MAAT) which are calculated respectively as the minimum
and maximum tone within the portion of parasympathetic or sym- The model equations (2)–(8), (10)–(15) and (17) were imple-
pathetic signal for a given phase using the following formulas. mented using the Systems Biology Toolbox 2 for Matlab [18]. The
toolbox calls Matlab ode23s solver for resolving the ordinary differ-
MIATpar (i) = min(Tpar {i}) (23) ential Eqs. (4) and (5) with initial conditions Pas (0) = 80 mmHg and
MIATsym (i) = min(Tsym {i}) (24) N(0) = 0 Hz. ode23s is a one-step differential equation solver based
on a modified Rosenbrock formula of order 2 [19].
MAATpar (i) = max(Tpar {i}) (25) In order to estimate the parameter values, a weighted least-
squares formulation minimizing the errors between measured data
MAATsym (i) = max(Tsym {i}) (26)
(HRmeas , PRmeas ) and model outputs (HR, PR) was applied. The corre-
The last class of model-based estimate is the so-called auto- sponding cost function is given in Eq. (35) below. n is the number of
nomic tone balance (ATB) which is calculated as the ratio of total data points in the time series (value is 60 s times 10 Hz, i.e. 600 data
 256
Table 1
Estimated values of model parameters.

Mean ± STD Min Max Data set 1 Data set 2 Data set 3 Data set 4 Data set 5 Data set 6 Data set 7 Data set 8 Data set 9 Data set 10

Pasmean 85.37 ± 11.05 mmHg 70 120 102.50 70.50 82.59 76.62 105.42 77.76 88.70 80.17 85.17 84.32
ˇ 1.5 ± 0.42 1 2 1.66 1.98 1.95 1.05 1.31 1.13 1.04 1.85 1.95 1.03
HR0 82.49 ± 7.61 beats/min 60 100 86.29 86.75 85.78 84.35 61.20 82.96 82.64 83.79 85.79 85.33
Ms 1.74 ± 1.15 0.1 5 1.04 1.06 1.30 1.16 4.86 1.66 1.94 1.80 1.70 0.93
Mp 0.005 ± 0.002 0.001 5 0.006 0.001 0.007 0.004 0.004 0.003 0.006 0.004 0.004 0.006
Kpr 1.5 ± 0.59 1 5 1.03 1.01 1.19 1.04 2.72 1.46 2.26 1.69 1.59 1.01
PR0 12.97 ± 1.12 ␮Mho-1 5 20 13.63 13.79 13.62 13.46 10.03 13.29 12.83 13.34 12.34 13.35
Cas 0.16 ± 0.03 0.1 1 0.19 0.16 0.17 0.18 0.10 0.22 0.11 0.18 0.14 0.17
Kvs 0.28 ± 0.07 0.1 1 0.36 0.26 0.33 0.29 0.12 0.30 0.23 0.26 0.36 0.32
Pvs0 11.1 ± 2.14 mmHg 5 20 15.21 8.61 13.04 11.21 9.57 12.17 9.43 9.58 9.38 12.76

M. Kana, J. Holcik / Biomedical Signal Processing and Control 6 (2011) 251–260

Kstr 0.56 ± 0.12 0.1 1 0.58 0.62 0.46 0.47 0.77 0.49 0.73 0.47 0.57 0.44
P1dur 2.37 ± 0.29 s 2 5 2.30 2.91 2.55 2.22 2.82 2.24 2.21 2.15 2.25 2.09
P1amp 1.14 ± 0.19 ␮Mho-1 1 5 1.05 1.06 1.61 1.36 1.02 1.15 1.08 1.02 1.04 1.03
P3dur 4.05 ± 1.04 s 2 5 2.40 4.52 4.99 4.43 2.92 4.79 2.41 4.90 4.50 4.63
P3amp 2.26 ± 0.3 ␮Mho-1 2 5 2.05 2.01 2.03 2.47 3.00 2.26 2.21 2.06 2.16 2.32
P4dur 3.78 ± 0.92 s 2 5 3.08 4.59 4.73 2.52 2.65 4.67 3.21 4.76 4.36 3.22
P4amp 3.04 ± 0.06 ␮Mho-1 3 5 3.03 3.00 3.02 3.00 3.01 3.05 3.05 3.02 3.22 3.05
dPrate 2.22 ± 0.23 0.5 5 2.29 2.30 2.31 2.25 1.57 2.31 2.35 2.31 2.30 2.24

Table 2
Wilcoxon sign/range test for each time–frequency variables of HRV and model-based estimates. p > 0.05 is considered to be non-significant (NS). p < 0.05 is considered to be significant. Most significant (p < 0.001) differences
between consecutive phases of VM are indicated in bold. Percentage of increase ↑ or decrease ↓ is shown. Values are average over all data sets.

Phase LF HF SDNN RMSSD MATpar MATsym TATpar TATsym TAT ATB MIATpar MIATsym MAATpar MAATsym

0→1 ↑130 ± 95% ↓36 ± 25% ↓36 ± 25% ↓42 ± 34% NS NS ↓83 ± 2% ↓85 ± 2% ↓84 ± 2% NS ↑6 ± 2% NS NS ↓29 ± 10%
p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.01
1→2 ↑116 ± 97% ↓69 ± 28% ↑237 ± 136% NS ↓32 ± 8% ↑415 ± 280% ↑253 ± 49% ↑2135 ± 711% ↑361 ± 76% ↑536 ± 193% ↓50 ± 14% NS NS ↑599 ± 259%
p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001
2→3 ↓43 ± 15% ↑352 ± 130% ↓25 ± 23% NS ↓22 ± 12% NS ↓83 ± 10% ↓61 ± 17% ↓77 ± 10% ↑268 ± 336% NS ↑464 ± 309% ↓38 ± 23% NS
p < 0.001 p < 0.001 p < 0.01 p < 0.01 p < 0.001 p < 0.001 p < 0.001 p < 0.05 p < 0.001 p < 0.001
3→4 ↓15 ± 40% ↑33 ± 35% NS ↑111 ± 77% ↑83 ± 46% ↓16 ± 102% ↑233 ± 302% ↓63 ± 14% NS ↓82 ± 13% NS ↓78 ± 22% ↑87 ± 63% ↓27 ± 26%
p < 0.05 p < 0.05 p < 0.001 p < 0.001 p < 0.01 p < 0.01 p < 0.001 p < 0.01 p < 0.001 p < 0.001 p < 0.05
4→5 NS NS ↓4 ± 2% ↓13 ± 19% NS ↓35 ± 24% ↑705 ± 201% ↑322 ± 219% ↑647 ± 176% ↓45 ± 29% ↑77 ± 55% ↑80 ± 87% ↓5 ± 6% ↓69 ± 23%
p < 0.05 p < 0.05 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.05 p < 0.05 p < 0.001
 M. Kana, J. Holcik / Biomedical Signal Processing and Control 6 (2011) 251–260 257

Multivariable linear regression analysis (*) considering each model-based estimate (row headers) as dependent variable and time–frequency estimates of HRV (column headers) as independent variables. Coefficient of regression points). HRmeas and PRmeas are mean of values in vectors contain-
ing individual heart rate and peripheral vascular resistance values
MAATsym

1 → 2**
r = 0.67
measured during the experiments on a beat-to-beat basis. HR and
PR are their corresponding simulated values.

NS

NS

NS
1 
n

J = |HRmeas (i) − HR(i)|2

n · HRmeas
i=1

b = −0.12
MAATpar

R = 0.91,


p < 0.05
n

3 → 4*
1
+ |PRmeas (i) − PR(i)|2 (35)
NS

NS

NS
(R), beta coefficients (b) and p-value (p) are reported only if p < 0.05, otherwise a correlation analysis (**) is performed and correlation coefficient (r) is reported only if r > 0.5. NS: non-significant.

n · PRmeas
i=1

In order to find the parameters values that minimize the

cost function (35) the Nelder–Mead algorithm [20] was used for
b = −2.24
R = 0.81,
MIATsym

bound-constrained optimization. It is based on cost functional eval-

p < 0.05

4 → 5**
r = 0.52
3 → 4*

uations of sequences of downhill simplexes. The model includes 18

NS

NS
unknown parameters which were estimated for each data set after
an average of 2983 iterations and 38 468 functions evaluations with
a final optimal cost function value in order of 0.000228002. Mean
parameters values are presented in Table 2 for 12 data sets obtained
from 5 subjects. The table includes parameters constraints in form
R = 0.91,

p < 0.05
b = 0.47
MIATpar

1 → 2*

of a finite range (a minimum and a maximum value). Optimized

NS

NS

NS

starting condition for model state Pas was found to be on aver-

age Pas (0) = 82 mmHg obtained with bounds constraints from 80
to 120 mmHg.
b = −7.14

b = −1.09

5.2. Model validation

R = 0.91,

R = 0.91,

R = 0.91,
R = 0.90,
p < 0.05

p < 0.05

p < 0.05

p < 0.05
b = 1.33

b = 0.31
2 → 3**
r = 0.60
3 → 4*

1 → 2*

3 → 4*

3 → 4*
ATB

NS

Figs. 4 and 5 show a good fit of model outputs to data obtained

from individual measurements on one representative 23 years old
healthy man. 97.16% and 97.44% of residuals for heart rate and
peripheral vascular resistance respectively are within the con-
fidence interval with 95% significance level. The corresponding
0 → 1**
r = 0.60

parameter estimates are included in Table 1 under data set 5. The

TAT

NS

NS

NS

average fit over all 10 datasets was found to be 94.23 ± 4.2%.

During phase 1 of the maneuver, the gradual increase in intra-
thoracic and intra-abdominal pressure causes aortic and peripheral
vessels compression. It follows an increase in peripheral resistance
b = −26.1
b = −5.09

resulting in a mild increase in blood pressure from 15th to 16th

R = 0.95,

R = 0.95,
p < 0.05

p < 0.01

1 → 2**

3 → 4**
r = 0.62

r = 0.69
1 → 2*

1 → 2*
TATsym

second (see Fig. 1).

NS

During phase 2, the sustained high intra-thoracic and intra-

abdominal pressure hinders venous return, leading to a decrease
in cardiac output and consequently a marked decrease in arterial
systolic pressure from the 16th to the 20th second (see Fig. 1).
This fall in arterial pressure is detected by baroreceptors in the
0 → 1**
r = 0.61

carotid artery sinus and aorta. The autonomic response includes

TATpar

NS

NS

an increase of sympathetic tone (see Fig. 6b) to the heart and ves-
sels as well as a decrease of parasympathetic tone (see Fig. 6a) in
the heart. This causes a reflex tachycardia and peripheral vasocon-
striction (see increased peripheral vascular resistance in Fig. 5). The
sympathetically mediated response results in some rise of arterial
1 → 2**
MATsym

r = 0.68

blood pressure from 20th to 30th second (see Fig. 1), which how-
ever does not overcome the elevated intra-thoracic pressure Since
NS

NS

NS

the blood pressure is still below the normal level, the baroreflex
remains active in the whole phase 2, resulting in a continuous rise
of heart rate [21].
During phase 3, the forced expiration is released, resulting in a
R = 0.87,

p < 0.05
b = 0.02

2 → 3**
r = 0.53
MATpar

decrease in intra-thoracic pressure, thus the pressure around the

1 → 2*

aorta decreases and consequently arterial blood pressure slightly

NS

NS

decreases from 30th to 31st second (see Fig. 1). Meanwhile heart
rate is still elevated.
During phase 4, the accumulated venous blood returns to the
heart and is pumped into the constricted arteries causing an “over-
RMSSD

shoot” of arterial pressure above the normal level from 31st to 38th
SDNN
Table 3

second (Fig. 1). This is detected by the baroreceptors and results in

HF
LF

a reflex bradycardia. Sympathetic discharge to the heart decreases

258 M. Kana, J. Holcik / Biomedical Signal Processing and Control 6 (2011) 251–260

Fig. 4. Heart rate change during VM: (a) predicted value (dashed line) and experimental data set 5 (plain line) shows a 97.16% good fit (b).

Fig. 5. Changes in vascular resistance during VM: (a) predicted value (dashed line) and experimental data set 5 (plain line) shows a 97.44% good fit (b).

I II III IV I II III IV
0.18
0.85 (a) Tpar (b) Tsym

0.16
paraympathetic tone

sympathetic tone

0.8
0.14

0.12
0.75

0.1

0.7
0.08

0.06
0 10 20 30 40 50 60 0 10 20 30 40 50 60
seconds seconds

Fig. 6. Predicted parasympathetic (a) and sympathetic (b) activity during the Valsalva Maneuver for a 23 years old healthy man (data set 5). The maneuver covers the
timeline from the 15th to the 30th second. Phase 1 is characterized by slight increase of parasympathetic activity from 15th to 16th second; there is baroreflex mediated
parasympathetic withdrawal and increased sympathetic tone in phase 2 until 30th second. Bradycardia characterizes phase 4 which runs from 31st to 38th second. Sympathetic
activity is reduced in phase 4 in order to compensate arterial pressure overshot.

(see Fig. 6b) whereas parasympathetic discharge increases (see
Fig. 6a), causing a decrease of heart rate. As result arterial blood
pressure returns to normal level.
5.3. Model-based estimates of autonomic tone and statistical
analysis
Eqs. (18)–(27) were resolved in Matlab using built-in statistical
functions and following model-based estimates of autonomic ner-
vous activity were calculated for each data set and each phase of
the Valsalva Maneuver. We therefore obtained 10 values per phase
for each model-based estimate and for each subject.
In the statistical analysis, variables taken into consideration
were the percentage of increase/decrease of the normalized
power in the frequency bands LF and HF; the percentage of
increase/decrease of time-domain indexes of heart rate variability
SDNN and RMSSD; the percentage of increase/decrease of model-
based estimates of autonomic tones when moving from one phase
of the maneuver to the consecutive one.
In order to determine whether there was some pattern of change
among the ranges of the statistical variables by comparing two
consecutive phases, a Wilcoxon range test was performed. Table 2
shows which variables change significantly (p < 0.05) when tran-
siting from one phase of the VM to the next consecutive one.
The most significant (p < 0.001) variability are highlighted in bold
and suggest which variables are the most suitable for assessing
dynamics of autonomic nervous activity for a given transition.
For example, the gradual increase in intra-thoracic pressure dur-
ing phase 1 significantly decreases the total autonomic tone TAT
by 84 ± 2% (p < 0.001) from its baseline value 13.88 ± 0.22. HF,
SDNN, RMSSD and MAATsym decrease as well, but to a less signifi-
cant extend (p < 0.01). In phase 2, baroreflex activation following
sustained decrease in arterial blood pressure causes a signifi-
cant (p < 0.001) increase of LF (116 ± 97%), SDNN (237 ± 136%),
MATsym (415 ± 280%), TAT (361 ± 76%), ATB (536 ± 193%), MAATsym
(599 ± 259%) from their average values in phase 1 (0.49 ± 0.21 n.u.,
13.26 ± 5 ms, 0.057 ± 0.018 n.u., 2.28 ± 0.23 n.u., 0.066 ± 0.024 n.u.,
0.058 ± 0.018 n.u., respectively). Meanwhile HF, MATpar , MIATpar
significantly decrease by 69 ± 28% (p < 0.001), 32 ± 8% (p < 0.001)
and 50 ± 14% (p < 0.001), respectively. Prevalent parasympathetic
activity in phase 4 is significantly reflected in increasing HF
(33 ± 35%: p < 0.05), RMSSD (111 ± 77%: p < 0.001), MATpar (83 ± 46:
p < 0.001), TATpar (233 ± 302%: p < 0.01) and MAATpar (87 ± 63%:
p < 0.001) meanwhile LF, MATpar , TATsym , ATB and MAATsym signifi-
cantly decrease (p < 0.05).
In order to establish the degree of linear dependency of the
model-based estimates with respect to time–frequency estimates
of HRV, different models of multi-linear regression analysis were
used. For each phase, we took the percentage of change of each
model-based estimate as dependent variable and the percentage of
 M. Kana, J. Holcik / Biomedical Signal Processing and Control 6 (2011) 251–260 259

Fig. 7. Fit between HRV estimates HF & LF and model-based estimates MATpar & TATsym .

Fig. 8. Fit between HRV estimates RMSSD & SDNN and model-based estimates MAATpar & ATB.

Fig. 9. Mean values of significant model-based and HRV estimates of autonomic nervous activity in each phase transition of VM.

change of all time–frequency estimates as independent variables.
Coefficient of regression (R), beta coefficients (b) and p-values are
presented in Table 3 for significant regression (p < 0.05). In the cases
where no significant regression (p > 0.05) was found, an additional
correlation analysis was performed. The correlation coefficient (r)
is included in Table 3 for significant correlations (r > 0.50). NS is
reported for non-significant correlations (r < 0.50).
In the transition 0 → 1, from baseline to phase 1, TATpar and
TAT were found to be correlated to RMSSD (r = 0.6). The transition
1 → 2 was characterized by a significant regression between MATpar
and HF (R = 0.87, p < 0.05) as illustrated in the line fit plot in Fig. 7
(left panel). Knowing the percentage of decrease in the power of
high frequency components of heart rate variability HF between
phase 1 and phase 2, we were able to predict the percentage of
decrease of the model-based estimate of mean parasympathetic
tone MATpar with a 87% fit. A significant regression was also found
between LF and TATsym (R = 0.95, p < 0.05) as illustrated by the line
fit plot between their percentage of increase in Fig. 7 (right panel).
The transition 2 → 3 was characterized by a significant correla-
tion between MATpar and RMSSD (r = 0.53); and a more significant
correlation between ATB and SDNN (r = 0.60). The transition 3 → 4
highlighted a significant regression between MAATpar and RMSSD
(R = 0.91, p < 0.05) on one hand and between ATB and SDNN on the
other hand (R = 0.91, p < 0.05). This means that, knowing the per-
centage of increase in RMSSD and the percentage of decrease in
SDNN when transiting from phase 3 to phase 4, we were able to
predict the percentage of decrease in MAATpar and the percentage
of increase in ATB, respectively, with a 91% fit, as depicted in Fig. 8.
Finally a less significant correlation (r = 0.52) was found between
MIATsym and SDNN in the transition 4 → 5, i.e. from phase 4 to post
VM phase.
260 M. Kana, J. Holcik / Biomedical Signal Processing and Control 6 (2011) 251–260
Based on results of the Wilcoxon sign test, linear regression and
correlation analysis above, we were able to select the most signif-
icant estimates of autonomic nervous activity in each single phase
of the VM. Results are shown in Fig. 9. For each transition, the plots
show the mean value and confidence interval of the selected signif-
icant estimates of sympathetic and parasympathetic activity in the
previous and current phase; as well as the percentage of increase
or decrease of those estimates. It was found that SDNN and RMSSD
respectively provide the most significant estimates of sympathetic
and parasympathetic activity in phase 1 compared to phase 0 (base-
line) and in phase 5 (post VM) compared to phase 4. Similarly LF
and HF are the estimates of choice when it respectively comes to
assess sympathetic and parasympathetic activity in phase 3 with
respect to phase 2. However, our model-based estimates TATsym
and ATB were found to provide the most significant estimates of
sympathetic activity in phase 2 and 4, with respect to phases 1
and 3, respectively. MATpar was found to provide the most signifi-
cant estimate of parasympathetic activity in phase 2 with respect
to phase 1, similarly MAATpar was found to assess parasympathetic
activity in phase 4 with respect to phase 3 in a significant way.
6. Conclusion
In this work we proposed markers of autonomic nervous activ-
ity using a mathematical model of regulation processes performed
by the autonomic nervous system on the cardiovascular system
during the Valsalva Maneuver. The model could fit measured beat-
to-beat heart rate and galvanic skin response signals with low
residuals error (average fit 94.23 ± 4.2%). We defined model-based
estimates for quantitative approximation of mean, total, minimal
and maximal autonomic activity, as well as autonomic balance for
each phase of VM. We performed an extended statistical analysis
including Wilcoxon sign test, multivariable linear regression analy-
sis and correlation analysis in order to study patterns of variation of
our model-based estimates and possible relationships with current
time–frequency markers of heart rate variability. Results show that
when it comes to assessing autonomic nervous activity as absolute
quantity within a single phase with disregard to transition to the
next phase, we can select SDNN (standard deviation of NN inter-
vals) in phases 0 & 5, TATsym (total autonomic tone of sympathetic
activity) in phases 1 & 2 and ATB (autonomic tone balance) in phases
3 & 4 for sympathetic activity; RMSSD (mean square successive dif-
ferences of NN intervals) in phases 0 & 5, MATpar (mean autonomic
tone of parasympathetic activity) in phases 1 & 2, MAATpar (max-
imal autonomic tone of parasympathetic activity) in phases 3 & 4
for parasympathetic activity.
The absolute values of model-based estimates presented in this
work do not correspond to the real firing rates. They rather give
means of comparison of the change in efferent neural activity.
Future research includes validating the predicted markers of auto-
nomic tones against data from experiments with sympathetic and
parasympathetic blockades. We expect e.g. the model to return
MATpar closed to zero in the presence of atropine. The proposed
model-based estimates are closely related to the design of the
underlying mathematical model and the experimental setup (Val-
salva Maneuver in our case). The basic principles of our method
could be extended in a future effort to other mathematical models
of cardiovascular control and to other experimental setups such as
active change of posture. Extending the model to study the effect
of gender, age and health status on the value range of model-based
estimates is also part of a future research.
Acknowledgments
The research was partially granted by the research program
No. MSM6840770012 “Transdisciplinary Research in the Field of
Biomedical Engineering II.” and by the project VEGA No.2/0210/10
“Methods and systems for multichannel measurement and evalu-
ation of bioelectric signals of heart and brain”.
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