1710 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 54, NO.
9, SEPTEMBER 2007
detector followed by a single classifier. The detection errors are intro-
duced in these new definitions, providing more coherent statistics for
the clinician. These new statistics increase safety since they now pro-
vide reliably lower limits for the performance values. We experimen-
tally tested these new tools on the MIT/BIH database with a dedicated
real-time hardware and software architecture.
The proposed tools can be applied considering other kinds of algo-
rithms and architectures. The comparison between various implemen-
tation configurations therefore becomes objective.
Even if an exhaustive comparative study is not presented in this
communication, the results obtained are quite significant. Indeed, the
MIT/BIH database presents a great diversity of pathologies, exhibiting
a good panel of QRS waveforms morphologies. The results show that
the detection stage has a reduced influence concerning the sensitivity
for normal beats and the positive predictivity for normal/abnormal
beats. This suggests that the classification system may be improved by
investigating the classification stage. Nevertheless, care must be taken
with the detector stage that may deteriorate the total classification
error rate by about 50%, considering a drop of a 1.78% error rate in
the detection quality. In conclusion, the higher the performance of the
classifier is, the greater the impact of the detector will be.
ACKNOWLEDGMENT
The authors would like to thank CRESITT Industrie for the
design and realization of the digital signal processor–field-
programmable gate-array (DSP–FPGA) hybrid electronic board
(http://www.cresitt.com).
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formatik.uni-tuebingen.de/SNNS/, 1998.
Phase Resetting in One-Dimensional
Model of the Sinoatrial Node
D. G. Tsalikakis, D. I. Fotiadis*, L. K. Michalis, and
G. P. Kremmydas
Abstract—In this paper, we use a one-dimensional model of the rabbit
sinoatrial node (SAN), and we investigate the response of the model to
hyperpolarizing and depolarizing stimulus. Depending on the stimulus
timing, either a delay or an advance in the occurrence of next action
potential is produced. This resetting behavior of the model is quantified
in terms of phase transition curves (PTCs) for short electrical current
pulses of varying amplitude which span the whole period. The main
focus of this paper is to compare the dynamic properties of the spatially
extended system and the single cell model. The detailed analysis of the
results provides new insights in the understanding of the transition from
the theoretical single cell models to the spatially extended systems.
Index Terms—Cardiac models, phase resetting, phase transition curves,
sinoatrial node.
I. INTRODUCTION
The sinoatrial node (SAN), the pacemaker of the heart, is subjected
to external stimuli under both physiological and clinical conditions as
well as accidental situations. Cardiac muscle defibrillation and acci-
dental electrocution are typical examples of such external stimulation
[1]. The application of short current pulses to cardiac pacemaker cells
results in transient alterations of the cells’ cycle length depending on
both the phase and the amplitude of the stimulus [2]–[5]. The phase
Manuscript received May 12, 2006; revised December 30, 2006. Asterisk in-
dicates corresponding author.
D. G. Tsalikakis is with the Unit of Medical Technology and Intelligent Infor-
mation Systems, Department of Computer Science, University of Ioannina, GR
45110 Ioannina, Greece, and also with the Department of Cardiology, Medical
School, University of Ioannina, GR 45110 Ioannina, Greece.
*D. I. Fotiadis is with the Unit of Medical Technology and Intelligent In-
formation Systems, Department of Computer Science, University of Ioannina,
GR 45110 Ioannina, Greece, and also with the Biomedical Research Institute-
FORTH, GR 45110 Ioannina, Greece (e-mail: fotiadis@cs.uoi.gr).
L. K. Michalis is with the Department of Cardiology, Medical School, Uni-
versity of Ioannina, GR 45110 Ioannina, Greece, and also with the Michaelidion
Cardiology Center, GR 45110 Ioannina, Greece.
G. P. Kremmydas is with the Unit of Medical Technology and Intelligent
Information Systems, Department of Computer Science, University of Ioannina,
GR 45110 Ioannina, Greece, and also with the RTD Department, LUMC-KI,
Argostoli, GR281 00, Kefalonia, Greece.
Digital Object Identifier 10.1109/TBME.2007.902606
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 54, NO. 9, SEPTEMBER 2007 1711

shift resulting from the transient alteration of the beat-to-beat interval

depends on the timing as well as the total charge injected into the cell.
Experimental work on phase response behavior involved both single
cell and spatially extended (tissue preparation, whole heart and ECG)
studies [6]–[8]. On the other hand, theoretical studies have exclusively
focused on single cell models. To the best of our knowledge, there is not
a single study in the literature combining spatially extended simulation
of cardiac excitation with the analysis of phase response characteristics
of the simulated system. Given the fact that the heart is a spatially ex-
tended system giving rise to a semiperiodic electrical signal (the ECG),
it is the phase response behavior of the extended system that is more
relevant to clinical practice. If the behavior of the heart as a whole is
in focus and the interest lies in the generation and dynamics of cardiac
arrhythmias, then the phase response behavior of the cardiac muscle as
an extended system should be analyzed.
In this paper, we use a one-dimensional model [9] of the rabbit sinoa-
trial node incorporating detailed description of regional differences in
excitation dynamics (central and peripheral cells). This one-dimen-
sional model is used as a simplified spatially extended representation
of sinoatrial node dynamics of which phase response characteristics
[3] are sought to be analyzed. The assumption behind this approach is
that the phase response behavior of the simplified (1-D) spatially ex- Fig. 1. General situation of phase resetting in an oscillation. The application
tended system is a better approximation of the real dynamic responses of an external stimuli in the rhythmic activity of a biological oscillator (like
SAN) may cause an advance (or delay) on the onset of the oscillator after the
to external stimuli on the real heart than that of the single cell studies.
The main focus of the present paper is to compare the key dynamic
1 1 = 10
perturbation. The phase shift  of the oscillator is calculated as  .
Further calculations are cited in the text.
properties of the spatially extended (1-D) system and the constituent
single cell models and evaluate the phase response results as a mean
to studying more complicated spatially extended systems (2-D, 3-D,
anatomic models, etc.). is accompanied by a set of partial differential equations which describe
the kinetics of the gating variables of the ionic components of Itot ,
as well as ion concentration changes. The equations are given in our
II. METHODS previous work [13].
SAN is a heterogeneous structure. The accurate mapping of spatial An explicit Euler method is used for the integration of the partial
differences in elecrophysiological patterns of individual SAN cells is differential equations describing the excitation kinetics of our medium.
important for elucidating its functional role. Given the limitations of The space step for the method was set to x 1 = 100 m, which is
experimental data the model reconstruction of spatial heterogeneity is sufficiently small for the stability of the numerical solution [14], [15],
a difficult task. This has been achieved in the 1-D model of the rabbit 1=
and the time step was set to t 0.01 s. Initially, space steps between
SAN developed by Zhang et al. [9], which we use in this paper. Our dis- 10 and 500 m were used and results show that a convergence was
cretized medium consists of 15 nodes creating a one-dimensional fiber achieved for space steps of 200 m or less. The chosen x and t 1 1
(five nodes representing central and ten nodes representing peripheral always had to satisfy the (1 ) (1 )
t = x2  (1) (2 )
= D . Two boundary
=
sinoatrial node cells). The length of the fiber is L 1.05 mm and both conditions were taken into account. The cut-end of the fiber, where the
the intracellular conductivities and the cellular dimensions are based potential is abolished and the nonflux, representing the sealed end of the
on [9]. Information about intracellular coupling derived from published fiber. Recordings from single nodes at both the central and peripheral
experimental data [10], where the mean values reported in these studies regions are used to determine the time of stimulus application as well
are 7.5 nS for SAN cell pairs. Further studies show that the density of as the construction of the phase transition curves.
gap junction increases towards the periphery of the SAN [11]. This is
included in the model by assuming a conductivity ratio of 1:10 between A. Phase Resetting Technique
the center and the periphery of the node. Effects of conductivities be- Spontaneous active cardiac cells, like other nonlinear oscillators, re-
tween central and peripheral cells have been extensively studied in [12]. spond to discrete perturbation by transient change in the cycle length.
The one-dimensional excitable medium model of the SAN tissue Fig. 1 illustrates the general situation of a perturbation in a repetitive
represented by the partial differential equation of the reaction diffusion activity of an oscillator. It is common to associate the oscillation with
@V
@t
= 0 ICtot + r(DrV )
m
(1)
the stable limit cycle in the phase space. Stable limit cycle is the peri-
odic solution of a differential equation in the limit t ! 1. The period
of the physiological rhythm is To and after the perturbation at tstimulus
where V is the membrane potential, t is the time, Cm is the SAN mem- the new period is T . Also the new period T is as
brane capacitance, D is the effective diffusion coefficient (mm2 ms01 )
and
Itot = (INa + ICa L + ICa T
; ;
T =+ (2)

+ Ito + Isus + IK r + IK s + If
; ; where  is the time period between the onset of the oscillator and the
+ Ib Na + Ib Ca + Ib K + INaCa + Ip ):
; ; ; occurrence of the stimulus, and  is the time interval until the next onset
of the oscillator. Dividing (2) with the old period To , the normalized T
The diffusion coefficient D describes the spread of the voltage and denoted by  becomes
scales the conduction velocity of a solitary traveling wave. It depends
on the membrane capacitance Cm and conductance [9]. Equation (1)  =+ (3)
1712 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 54, NO. 9, SEPTEMBER 2007
Fig. 2. Normal electrical activity in (a) central and (b) peripheral sinoatrial
node cells connected into a one-dimensional fiber. The membrane potential V
is plotted versus time t for a total duration of 1 s.
where  is the old phase and  is the co-phase of the oscillation. The
stimulus application produces an advance (or delay), calculated as
1 =T T0 0 T )  1 =1 1
0  , where  is the phase shift. The new
phase of the perturbed oscillator is 0  = +1 0 .
A single 0.5-ms depolarizing or hyperpolarizing current stimulus of
a given amplitude is applied to the whole medium. The exact timing
of the stimulus in each experiment is selected as follows: a starting
reference point is selected at the membrane potential level 010 mV
during the depolarization phase of the action potential and at each sub-
sequent run the stimulus timing increases by 1 ms until a whole cycle is
spanned. Thus, the corresponding phase transition curve is calculated
[3]. The same sequence of experiments is repeated for different stimu-
lation amplitudes.
III. RESULTS
Normal electrical activity recorded from single nodes in the medium
is shown in Fig. 2. The plot shows the membrane potential V recorded
at a central sinoatrial cell while the bottom plot shows the membrane
potential V recorded at a peripheral sinoatrial cell in the medium. The
difference in the maximum and minimum membrane potential levels
is due to the differences in the electrophysiological properties of the
corresponding cells [9].
The two plots of Fig. 2 are the top and bottom traces of Fig. 3(a),
respectively, where the electrical recording from the nodes in the one
dimensional medium are stacked together to produce an activation plot.
Fig. 3. Normal electrical activity in the (a) one-dimensional fiber model of the
sinoatrial node and (b) an example of single pulse perturbation protocol, used
in the simulations. The horizontal axis represents a time period of 1 s while
traces represent the membrane potential of each cell in the one-dimensional fiber
model of the sinoatrial node (top: central cells; bottom: peripheral cells). In plot
(b), a single pulse perturbation of 2 nA is applied to every single cell after
300 ms from the beginning of the simulation.
Fig. 3(a) shows the normal activation of the one-dimensional model of
the sinoatrial node for a time period of 1 s.
An example of the stimulation protocol used in the simulations is
shown in Fig. 3(b) where a short (0.5-ms) single pulse perturbation of
2 nA is applied to each node of the medium after 300 ms from the be-
ginning of the simulation. The amplitude of the stimulus is sufficient to
prematurely excite the medium as its timing falls within the excitable
region of the action potential. The normal excitation sequence resumes
soon after the premature beat but now the new phase 0 of the subse-
quent action potentials has been altered. The exact timing of the per-
turbation is varied from 0 to T0 while its amplitude is also varied in
order to obtain a whole set of experiments similar to the one shown
in Fig. 3(b). For each experiment, the phase of the stimulus  as well
as the phase of the perturbed oscillator 0 are calculated. In our nu-
merical experiments, we used both depolarizing and hyperpolarizing
stimuli. The results are presented in Figs. 4 and 5, respectively.
Fig. 4 summarizes the results of experiments in which depolarizing
stimuli were used. In the left column, the phase transition curves were
obtained using recordings from central sinoatrial node cell and in
the right column from peripheral sinoatrial node cell of the medium.
The amplitudes applied are 1.5 nA (top), 2.5 nA (middle), and 3 nA
(bottom). Low amplitude stimuli (Fig. 4—top) produce Type 1 phase
transition curves. In Type 1 phase resetting, the net number of times 0
advances through a cycle is 1 since for sufficiently slight perturbation
0 scarcely differs from . For sufficiently strong perturbation, Type
0 resetting is observed: the net number of times 0 advances through
a cycle is 0. The transition from Type 1 to Type 0 phase resetting is
indicative of the existence of a singularity in the limit cycle. Fig. 5
summarizes the results of experiments in which hyperpolarizing
stimuli were used. The amplitudes applied are 1.5 nA (top), 2.5 nA
(middle), and 3 nA (bottom). As in the case of depolarizing per-
turbations, stronger hyperpolarizing stimuli produced Type 1 phase
transition curves.
In Fig. 6, phase transition curves obtained from single isolated cell
models (ordinary differential equations) of the sinoatrial node are
shown. Fig. 6(a)–(d) corresponds to low amplitude stimuli (00.3 nA)
while Fig. 6(e)–(h) traces correspond to high amplitude stimuli.
Fig. 6(a) and (e) andFig. 6(d), (h) correspond to central and peripheral
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 54, NO. 9, SEPTEMBER 2007
Fig. 4. Phase transition curves for depolarizing stimuli, obtained using record-
ings for central (left) and peripheral (right) cells of the one-dimensional fiber
model of the sinoatrial node. The amplitudes applied are 1.5 nA (top), 2 nA
(middle), and 2.5 nA (bottom).
cells, respectively, while the Fig. 6(b), (c), (f), and (g) corresponds
to transitional cell configurations [13]. A comparison of Fig. 6 with
Figs. 4 and 5 depicts the differences in the phase response character-
istics of isolated (Fig. 6) sinoatrial cells as opposed to in situ central
(Fig. 4) and peripheral (Fig. 6) cells in our one-dimensional medium.
IV. DISCUSSION
Studies in the past have concentrated on the elucidation of the
phase resetting dynamics of the sinoatrial node using biophysical ionic
models [16]–[18] but did not address the issue of regional differences
between central and peripheral node cells (the corresponding ionic
models described central cell behavior). Regional differences in the
electrophysiology of sinoatrial node cells seem to be important in
its function as the natural pacemaker of the heart [12], [19], [20].
In our recent work [13], using models describing isolated central,
peripheral, and transitional sinoatrial node cells [9], we compared and
contrasted their phase response characteristics. The demonstration
of critical stimuli that could annihilate repetitive activity in central
sinoatrial node cells and the absence of such stimuli in peripheral and
transitional cells, revealed important differences in their response to
external electrical stimuli [7], [21].
1713
Fig. 5. Phase transition curves for hyperpolarizing stimuli, obtained using
recordings for central (left) and peripheral (right) cells of the one dimensional
fiber model of the sinoatrial node. The amplitudes applied are 1.5 nA (top),
2.5 nA (middle), and 3 nA (bottom).
When considered in isolation, all types of cells display both Type 1
and Type 0 phase resetting behavior (Fig. 6), but the stimulus ampli-
tude at which Type 0 phase resetting behavior first appears varies. This
is a result of the regional differences in Itot amplitude, the total ionic
current passing through the membrane during the course of the action
potential: Itot is higher in the periphery of the sinoatrial node (mainly
due to the dominance of sodium current INa ) and thus a higher ampli-
tude of external stimulus is required in order to significantly affect the
normal limit cycle behavior.
In the one-dimensional preparation used, the peripheral sinoatrial
node cells have a dominant effect over the rhythmic activity of the
sinoatrial node. This is due to the lack of electrotonic suppression from
the adjacent atrial cells which in a sinoatrial—atrial node preparation
would be expected to alter the overall behavior of the sinoatrial node.
The phase transition curves obtained for the one dimensional prepa-
ration (see Figs. 4 and 5) also display both Type 0 and Type 1 phase
resetting behavior. We have conducted a set of experiments in which
stimulus amplitude and phase varied with fine steps around the regions
of discontinuities. Our simulations failed to show the existence of a crit-
ical stimulus amplitude—phase combinations that would be capable
1714 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 54, NO. 9, SEPTEMBER 2007
Fig. 6. In the central single cell model, the transition from Type 1 (a) to Type
0 (h) phase resetting behavior reveals the existence of critical stimuli (critical
amplitude—phase combinations) that can annihilate normal rhythmic activity.
Such critical stimuli could not be found in transitional or peripheral cells [13]
as well as in the 1-D model presented here. For plots (f–h) a time step of 0.1 ms
was used to span the apparent discontinuous interval (simulations not shown
here) and showed continuity of resetting curves with winding number 0 (Type
0 resetting) as in the case of plot (e).
of annihilating the electrical activity of the one dimensional sinoatrial
node. Our results are consistent with the findings of our previous work
[13], given the fact that in our one-dimensional preparation, the pe-
ripheral sinoatrial node cells have a dominant effect over the rhythmic
activity of the sinoatrial node as a whole.
For a spatially inhomogeneous, complex structure like the sinoatrial
node, regional differences and spatiotemporal interactions could play
an important role in its pathophysiological response to external pertur-
bations in situ. More realistic models of the sinoatrial node as a spatially
extended medium should incorporate interactions with atrial tissue as
well as two-dimensional effects.
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