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OPEN Fractal Based Analysis of the
Influence of Odorants on Heart
Activity
received: 20 July 2016 Hamidreza Namazi & Vladimir V. Kulish
accepted: 09 November 2016
Published: 08 December 2016
An important challenge in heart research is to make the relation between the features of external
stimuli and heart activity. Olfactory stimulation is an important type of stimulation that affects the
heart activity, which is mapped on Electrocardiogram (ECG) signal. Yet, no one has discovered any
relation between the structures of olfactory stimuli and the ECG signal. This study investigates the
relation between the structures of heart rate and the olfactory stimulus (odorant). We show that the
complexity of the heart rate is coupled with the molecular complexity of the odorant, where more
structurally complex odorant causes less fractal heart rate. Also, odorant having higher entropy causes
the heart rate having lower approximate entropy. The method discussed here can be applied and
investigated in case of patients with heart diseases as the rehabilitation purpose.

Electrocardiography (ECG or EKG) is the process of recording the electrical activity of the heart over a period of
time using electrodes placed on the skin. ECG has been used widely by scientists for monitoring heart activity.
Besides analyzing the nature of ECG signal, many scientists have tried to analyze the influence of different kinds
of external stimulation on heart activity. The works reported on analyzing the influence of auditory1–3, visual4–6
and olfactory stimuli7–9 are noteworthy to mention.
One useful method to study different types of biological signals is fractal method. A fractal is a natural phe-
nomenon or a mathematical set that exhibits a repeating pattern displaying at every scale (self-similar). The
scaling rules are characterized by “scaling exponents” (dimension). “Simple” regular fractals have integer scal-
ing dimensions. Complex self-similar objects have non-integer dimension. Fractals can be defined as geometric
objects whose scaling exponent (dimension) satisfies the Szpilrajn inequality10:
ℵ ≥ DT (1)
where ℵ is the scaling exponent (dimension) of the object and DT is its topological dimension, that is, Euclidean
dimension of units from which the fractal object is built. In fact, Fractal and Euclidean geometries are conjugate
approaches. Fractal geometry builds complex objects by applying simple processes to complex building blocks;
Euclidean geometry uses simpler building blocks but frequently requires complex building processes10. Fractal
time series shows the long-range correlations, meaning that each fluctuation in the time series is correlated with
last fluctuations (memory concept), where the correlations change based on power law11. Fractal theory has been
used widely in biology and medicine for various cases such as DNA12, eye movement13, EEG signal14, bone structure15,
respiration signal16, human stride time series17 and face18.
In case of using fractal theory for analysis of ECG signals many works have been reported in literatures.
D’Addio et al.19 performed fractal analysis on cardiac patients during resting, stress, early and late recovery phases
of ECG stress test. They found out a significant change in fractal dimension values from resting to stress phase. In
another work, Bhaduri and Ghosh20 did the fractal analysis on ECG signal of subjects performing Kundalini Yoga
and Chi meditation. The result of their study showed enhancing complexity of the cardiac dynamics during med-
itation. Ghosh et al.21 used fractal analysis for comparison of ECG signal between healthy subjects and subjects
suffering from Intracardiac Atrial Fibrillation. The result of their analysis showed that fractal dimension in case
of Intracardiac Atrial Fibrillation has significant higher values compared to the normal ECG signal. This result
indicates increasing ECG complexity for Intracardiac Atrial Fibrillation. See also22–24.
On the other hand, some researchers have focused on analyzing the entropy of ECG signal. They have
employed different types of entropy for this purpose. For instance Kamath25 examined Renyi and Shannon

School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore. Correspondence
and requests for materials should be addressed to H.N. (email: hnamazi@ntu.edu.sg)

Scientific Reports | 6:38555 | DOI: 10.1038/srep38555 1

head-up tilt resulted in a significant reduction in sample entropy of R-R intervals and cross-sample entropy. bigger and/or less symmetric molecules have higher molecular complexity. In another step. As another parameter to investigate.24 Diethyl malonate C7H12O4 125 132. ti stands for the total time that the value spends in the i-th bin. log plots of size vs. For a time series.42 Diethyl succinate C8H14O4 135 136. Based on their founding. Joseph et al. For this purpose. For instance in case of a time series with range of variation between Vmax and Vmin. Baumert et al. Scientific Reports | 6:38555 | DOI: 10. Here we define this generalized fractal dimension. The fractal dimension can be determined using some methods that approximate scaling and detail from lim- its estimated from regression lines over log vs. The molecular complexity (C) of an odorant is defined using Bertz formula31: C = Cn + Ce (2) In this equation. entropy for discriminating normal and Ventricular. In order to investigate the influence of odorant’s complexity and entropy on fractality and entropy of heart rate.26 analyzed the effect of reflexological stimulation on heart rate variability.27 explored the influence of head-up tilt and mental arithmetic stress on beat-to-beat variability of heart rate and QT interval.1038/srep38555 2 . we can divide the total range into N bin. we hypothesize that there should be a correlation between odorant’s molecular complexity and the ECG signal fractal dynamics. All these methods can be seen as special cases of a continuous spectrum of generalized fractal dimensions.nature. by computing sample entropy and cross-sample entropy. and T is the total time. no work has been reported that studies the influence of olfactory stimulus (odorant in this research) on fractal dynamics of ECG signal. scale. In general. which indicates that the ECG signal becomes more random with reflexology. In this research. See also28–30.29 Diethyl malate C8H14O5 177 145. their entropy increases. the probability of a value to fall into the i’th bin: Ni w i = lim N→∞ N (4) In Equation (4) Ni is the number of times the value falls into the i-th bin.50 Table 1. the odorant’s complexity should be quantified. we selected five pleasant odorants (look at Table 1) from Fenaroli’s Handbook of Flavor Ingredients35. Method In order to investigate the effect of odorant’s complexity on fractality of heart rate. Besides all the efforts done on the analysis of ECG signal using fractal approach. predic- tively and accuracy. we considered the molecular complexity of odorants.com/scientificreports/ Molecular Name Compound complexity Entropy ( ) cal mol·K Benzyl alcohol C7H8O 55. The result of their study showed the increment of Kolmogorov–Sinai entropy in reflexological stim- ulation compare to relaxed sitting.  Characteristics of odorants. He found out that Renyi entropy outperforms Shannon entropy for this purpose with very high sensitivity. while mental arithmetic stress resulted in a significant reduction in coupling directed from R-R to QT. it can be written as: ti w i = lim T →∞ T (5) In Equation (5). where each bin has the size of δ​  ∈​  : V max − V min N= δ∈ (3) So.4 85. tachycardia or fibrillation (VT-VF) subjects. In another work. information dimension and correlation dimension for computation of fractal dimension32. we analyze the correlation between entropy of odorant and ECG signal. at 0 °K odorants have zero entropy and as the temperature increases.55 Dimethyl succinate C6H10O4 114 118. There are several formal mathematical definitions such as box counting. The fractal exponent is based on the entropy con- cept for a probability distribution33. we study the influence of odorant’s entropy at 25 °C on the entropy of heart rate. Cn and Ce are functions of bond connectivity (n) and element diversity or kinds of atoms respectively. specificity.www. As it is known. The generalized fractal dimensions of order q defined by34: q 1 log ∑ iN=1w i Dq = lim ∈→ 0 q − 1 log ∈ (6) where ∈​ is the scaling factor.

Then. We have noninvasively recorded ECG signal (cardioscope Oli Monitor 432. and we did our study based on the approved guidelines. the breathing of subjects was paced (breathing rate was 0.5 ±​ 13. and we recorded the ECG signal for 3 minutes.  The experiments were conducted on forty healthy students (look at Table 2).nature. So.25 Hz) with a sound signal. the allowable level that heart rate can be increased/decreased in the experiments and also task difficulty. the odorants have entropy in the range of 85. As it is shown Table 1. In the second day.5 years old Height 172 ±​ 10.www. bigger and/or less symmetric molecules have higher molecular complexity. We found the most effective concentration for each odorant by considering the pleasantness level of odorant sensed by subjects. We have explained the study to subjects and then collected the informed consent from them.1038/srep38555 3 .55 (Benzyl alcohol) to 145. The values of odorants’ entropies in 25 °C were collected from (http://realtime.4 (Benzyl alcohol) and 177 (Diethyl malate). for our main experiments. Subjects did not drink beverages which contain alcohol/caffeine within 48 hours before the experiments. as it is shown in Table 1. The selected odorants showed the similar level for the most effective concentration. and subject sniffed the odorants. So. and analog-to-digitally converted with a sampling rate of 200 Hz. we repeated the data collection where in total two trials were collected from each subject for each stimulus.  After data collection. It was mentioned that in general. Subjects were lying down on the bed comfortably (supine position) during the data collection and instructed to focus on their breathing without doing any other job.  Molecular structure of selected odorants. Since the recorded ECG signal is noisy. Data collection. we did the preliminary experiments which analyze the effect of changing of odorants’ concentrations (by dilution) on the fractal dimension and approximate entropy of heart rate. The molecular structures of selected odorants are shown in Fig. As un-wanted external stimuli can affect the data recording. During measurement. A physician examined subjects before the experiment to ensure that subjects are healthy. Also. 1. we presented different odorants in separate experiments to the subject’ nose using a 10 ml vial. It is noteworthy we considered inter-stimulus time of 15 minutes between different odorants’ presentations.50 (Diethyl malate). All data were normal. the physician checked all recorded heart rate data to ensure they are nor- mal.5 ±​ 0. we diluted odorants in mineral oil in order to equalize their concentrations in the observed most effective level and achieved an approximate gas-phase partial pressure of 1 Pa.molinstincts. Kone Instrument Division) from the left middle finger. In order to find out the most effective concentration for each odorant.3 kg Race Indian Ethnicity Singaporean Table 2. We also measured the con- centrations of odorants using an olfactometer which was connected to a gas analyzer. A physician controlled all experiments. We found out that odorant concentration in the range of “detection threshold” did not cause any significant change in heart rate. but odorant concentration over “recognition threshold” affected the heart rate. The presentation of each odorant to gas analyzer was done 5 times (each time for 3 seconds) with inter-stimulus interval of 2 minutes. in order to find heart rate (expressed in terms of R-R interval time series) we needed to filter the ECG Scientific Reports | 6:38555 | DOI: 10. Characteristic Description Sex 20 male and 20 females Age 22. we didn’t exclude any recorded data from analysis.2 cm Weight 71.com/scientificreports/ Figure 1. com/). to ensure that the resulting vapor concentrations did not differ. the odorants have molecular complexities in the range of 55. Data acquisition was ini- tiated 15 min after the start of experiment to have stabilized hemodynamics. we did the experiments in an isolated room from external stimuli. At first. The Internal Review Board of Nanyang Technological University approved all procedures (including experimentation on human subjects).  Subjects characteristics. the data collection was done free of any stimulus. Data analysis.

Approximate entropy is indicator of randomness of time series where lower value of approximate entropy stands for less randomness. Also. Low-pass filters were set at 40. The variations of fractal dimension for R-R interval time series due to different odorants and the odorants’ molecular complexities are shown in Fig.1038/srep38555 4 . In fact.05) was conducted to test the sphericity. Results Mauchly’s test indicated that the assumption of sphericity had not been violated in case of outcomes (fractal expo- nent and approximate entropy of R-R interval time series). Mauchly’s test (α =​ 0. Scientific Reports | 6:38555 | DOI: 10.www. After filtering of the signal. The generated R-R interval time series were processed for computing of fractal dimension and entropy using other code. Error bars indicate standard deviations. The statistical analyses were performed using SPSS (ver. 3. Trend analysis was conducted based on the odorants’ properties.  Mean values of fractal exponent and approximate entropy for the R-R interval time series were compared between different conditions using one-way repeated measures ANOVA.  A schematic of QRS complex. another algorithm detects QRS complex (look at Fig. Effect size.05 and 0. the embedded time delay of 1 was chosen. Statistical analysis. Omega squared (ω2) was used for a repeated measures design. 100. 2) followed by interpolation of R peaks. signal. The R-R intervals36 were detected with a temporal resolution of 2 ms and then the R-R interval time series was generated. Mauchly’s sphericity test is a statistical test used to vali- date a repeated measures analysis of variance (ANOVA). It is noteworthy that size of 11 was chosen for boxes based on literatures39–41. The results stand for the mean values.nature.0). r was employed for pairwise comparisons. and the odorants’ molecular complexities (right side).  Fractal dimension for R-R interval time series due to different odorants (left side).com/scientificreports/ Figure 2. For this purpose we wrote a set of codes to do filtering. All of these analyses were done in MATLAB. and 150 Hz (high-frequency cutoff). The written code computed the fractal dimension and entropy of R-R interval time series based on Box counting method37 and approximate entropy techniques38 respectively. Figure 3. 16. The low-frequency cutoff (high-pass filter) was set at 0.5 Hz.

Olfactory stimuli conditions had a significant linear trend (p =​ 0.001] stands for the sig- nificant influence of odorants on the fractal dimension of R-R interval time series. with the effect size ω2 =​  0.48 0.234) =​  61. which indicates that Diethyl malate caused a greater variation in the fractality of R-R interval time series than Diethyl succinate.com/scientificreports/ Fractal dimension Approximate entropy Condition Effect size (r) Effect size (r) No odorant vs. Benzyl alcohol 0.84 0. The effect sizes in Table 3 show that Diethyl malate caused the greatest change in the fractality of R-R interval time series.62 Benzyl alcohol vs. the statistical analysis result [F(5. Figure 4.46 0. 4. Olfactory stimuli conditions had a significant linear trend (p =​ 0.55 Benzyl alcohol vs.87 Benzyl alcohol vs.  Approximate entropy for R-R interval time series due to different odorants (left side).54 0. Diethyl malonate 0. reflecting the trend of molecular complexity of the odorants. with the effect size ω2 =​  0.026). p  =​ 0.20 0. followed by Diethyl malonate. reflecting the trend of entropy of the odor- ants. Diethyl succinate 0.234) =​  2.83 0.38 0. Since Fcrit(5. Diethyl malate 0.  Effect sizes for pairwise comparisons. Diethyl succinate 0. Generally. the statistical analysis result [F(5.25 0. Diethyl malonate 0.85 No odorant vs.61 Diethyl malonate vs. Diethyl succinate 0.82 0.84 No odorant vs.46 0.5.35 0.74 0.05.39 0. the correlation between the characteristics of odorants and the ECG signal was observed. Diethyl malonate 0. Diethyl malate 0. The variations of approximate entropy for R-R interval time series due to different odorants and the odorants’ entropy are shown in Fig. Dimethyl succinate 0.19 Table 3. followed by the Diethyl malonate.001] stands for the significant influence of odorants on approximate entropy of R-R interval time series.05. Diethyl malate 0. p  =​ 0. Dimethyl succinate 0. the application of the odorant reduced the fractal dimension of R-R interval time series.21 0.25 at α =​ 0.007).234) =​  2. Error bars indicate standard deviations. In overall. Dimethyl succinate and Benzyl alcohol respectively.48.21 Diethyl malonate vs. Generally.56. the application of the odorant reduced the approximate entropy of R-R interval time series. The effect sizes in Table 3 show that Diethyl malate caused the greatest change in the approximate entropy of R-R interval time series. Since Fcrit(5. Diethyl malate 0.75 No odorant vs.70 Dimethyl succinate vs. Dimethyl succinate and Benzyl alcohol respectively. Scientific Reports | 6:38555 | DOI: 10. which indicates that Diethyl malate caused a greater variation in the approximate entropy of R-R interval time series than the Diethyl succinate.1038/srep38555 5 .31 Benzyl alcohol vs.51 No odorant vs.35 Dimethyl succinate vs.48 Dimethyl succinate vs.40 Diethyl succinate vs.www.234) =​  50. Diethyl malate 0. The results stand for the mean values.nature.20 0. and the odorants’ entropies (right side). where the odorant having higher complexity and entropy causes the greater change in fractality and entropy of R-R interval time series. Diethyl succinate 0.25 at α =​ 0.

250–5 (2013). V. doi: 10. in order to write the observed correlation in the mathematical form. J. & Jacob. The works on analysis of the influence of lavender51. in further investigation. olfac- tory neurons (as receptor cells) detect odor molecules and transmit information about the odor to the brain in a process called sensory transduction which yields to perception46. Namazi. V. H. When human smells an odorant. T. doi: 10. Scientific Reports | 6:38555 | DOI: 10. et al. Sci. S. Psychophysiol. C.. Barry. Kyung-Hoe.1038/srep38555 6 . 156. For instance.. V. Psychophysiol. Kulish.1038/srep13583 (2015). where more structurally complex odorants have greater effect on the EEG signal. Smith. Roque. reduced heart rate and reduced negative affect. Cha. Health. G. In further attempts. The Analysis of the Influence of Odorant’s Complexity on Fractal Dynamics of Human Respiration.1186/s13030-016-0063-7 (2016). 342–350. A. 2. they will have stronger effect on the brain. et al. 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