Annotation of the results obtained in 2017
In this stage of the project we carried out theoretical analysis of the video-capillarascopy data, which allowed us introduce important details into understanding of light interaction with blood vessels. We have experimentally proved that visible light acquires modulation at the heartbeat frequency exclusively in the cutaneous capillary bed. Considering the revealed features of light interaction with capillaries, we developed new advanced algorithm of photoplethysmographic (PPG) data processing recorded synchronously with an electrocardiogram (ECG). This algorithm allowed us significantly increase accuracy and fidelity of measuring the blood-flow parameters in the capillary bed. Advanced system of the camera based PPG is capable to measure spatial distribution of the blood-flow parameters on the face or other part of the body for every subject including patients with essential hypertension and migraine. The advanced camera-based PPG system was used for studying influence of the body-position change on the parameters of blood supply to the head. This study was carried out with the extended group of subjects (80 volunteers). It was found that the pulse wave propagates through the vascular system from the heard to the head with the lower speed in the sedentary position compare to the recumbent. Statistically significant difference of the mean pulsation amplitude was also found between the positions: in sedentary higher than in recumbent. In addition, the pulse frequency was lower in the recumbent position suggesting decrease in activity of the sympathetic nervous system in the recumbent position. Notably, we found significant asynchronicity in blood pulsations in the cheeks when the subject was in the recumbent position on the side: the pulse transit time was longer in the upper cheek than in the lower. These experiments demonstrated the effectiveness of using the developed camera-based PPG system for the analysis and diagnosis of the functioning of the cardiovascular system. In searching of an effective marker for migraine diagnosis, we developed and tested the procedure of estimation the vascular system reaction on the application of a patch containing 8% of the capsaicin. Procedure testing was carried out using the advanced camera-based PPG system with 24 subjects, a half was patients with migraine and another half was a healthy control group. Both groups were comparable in age, main constitutional and hemodynamic parameters. We found that the capillary blood flow starts to be increased not immediately after patch application but with certain delay personal for each subject. Moreover, it was found that the skin redness as a reaction on the capsaicin application is not common. Therefore, it could not serve as a parameter for characterization the body reaction on the capsaicin. In contrast, increasing of the capillary blood flow manifested as the growth of the blood pulsation amplitude (BPA) was observed in all studied subjects without exception. Statistical analysis showed that the coefficient of variability of the speed of BPA changes was significantly higher in the group of patients with migraine than in the control group. Moreover, the delay time of the reaction on the capsaicin had a tendency to be lower in the migraine group. Joint dispersion of both these parameters can be used as an objective biomarker of migraine. The developed camera-based PPG system was also used for measuring the blood flow in facial capillaries of 8 patients with scleroderma. Data analysis of the spatial distribution of the pulse transit time (PTT) in the face of the seek persons revealed significant increase of PTT variability as compared to the control group. This finding opens up the prospects of applications of the camera-based PPG in clinical rheumathology suggesting the parameter of PTT variability to be a biomarker of the disease allowing estimation of the grade of morphological disorders and more reliable diagnosis of the scleroderma. Study of BPA mapping in the facial area of 59 patients with essential hypertension and 45 healthy subjects was carried out with our advanced camera-based PPG system. Increase of the mean BPA in facial capillaries was found in patients with the second stage of disease, which is characterized by clinical signs of the target organs affection. It was found that mean BPA is further increasing in patients with associated clinical conditions as the disease progresses. The revealed continuum of the capillary blood flow changes during progression of essential hypertension confirms nonrandom nature of changes. We found that the observed features of capillary blood flow in patients with hypertensive disease resemble the changes shown in patients with migraine, which indicates a common pathogenesis of these diseases. In the frame of the project we carried out the study of vasomotor and cardiochronicotropic regulation in patients with arterial hypertension and migraine. It was found that in patients with essential hypertension and accompanying migraine, there are some features that are characteristic for patients with isolated hypertension. However, these patients possess a marked reactivity in response to multiple stimuli, which are absent in patients with migraine. The revealed features are consistent with researches that announce a more severe prognosis of the combined pathology. This requires the correction of risk prognosis and the selection of adequate antihypertensive therapy. Therefore, our study shows that a group of patients with a combination of hypertension and migraine can be identified in a target group to which approaches to treatment and monitoring the disease should be modified. High accuracy and fidelity of the capillary blood flow measuring in the advanced camera-based PPG system were achieved due to synchronized recording of video-frames and ECG. Aiming further simplification of the system hardware and convenience of its operation, we started development of a next version in which the information needed for correlation data processing was supplied by an alternative sensor, which is a pulse-oxymeter attached to a distant phalange of subject’s finger. A new software for data processing was developed to achieve the goal of the laboratory setup fabrication. Testing of the fabricated setup showed that we were able to measure both the spatial distributions of BPA and relative changes in PTT maps caused by physiological or drug tests. Therefore, feasibility of using more simple PPG system for estimations of the capillary blood flow parameters was demonstrated. In this stage of the project, we introduced significant modifications in both hardware and software of the laboratory setup for non-contact estimation of the blood flow, which was developed last year using 4-cameras PPG system. The modernized system was used for comparison the response of the optical PPG system and standard contact plethysmograph on the act of venous occlusion. It was found that the moments of the beginning and end of venous occlusion were synchronously registered by both systems. Signals from both systems showed a linear growth probably related with linear increase of the blood volume accumulated in veins after their occlusion. In addition, we carried out pilot study of how the blood flow parameters measured by both systems are affected by the global hypothermia. The experiment showed that the relative decrease of the speed of the signal growth as a response to the cold stress is the same for both systems. Therefore, non-contact system based on imaging photoplethysmography has good prospects for measuring dynamics of musculocutaneous blood flow in the extremities. Please, visit the website of the ITMO University for further information: http://irc.ifmo.ru/en/87797/res_dir/17393/issledovaniya_osobennostey_krovosnabzheniya_na_osnove_metoda_dvumernoy_otrazhatelnoy_fotopletizmografii.htm

 

Publications

---

Annotation of the results obtained in 2015
New system of blood pulsation imaging (BPI) was developed and manufactured during the course of the first stage of the project. The basis of the system is imaging photoplethysmography (PPG). BPI system allows noninvasive investigation of blood pulsations in a part of subject’s body. The part under study is illuminated by incoherent light generated by one or more light-emitting diodes (LED) operating at the same or different wavelengths with simultaneous recording of electrocardiogram (ECG). Thereafter, all recorded data are processed digitally to reveal spatial distribution of blood pulsations. Distinguishing feature of the developed system is its capability to visualize spatial distribution of not only the amplitude of blood pulsations but also their relative phase, both with high spatial resolution limited only by the total number of pixels of the used light sensitive matrix. Using the developed BPI system operating at the wavelength of 525 nm (green light), we studied distribution of blood pulsations in the hands of 43 healthy volunteers aging from 18 to 74 years. It was found that in usual conditions (when the palm does not contact anything except air), the correlation between ECG and PPG was significant (p < 0.05) in only 47 of 86 measured hands. However, after the palm contacted the glass plate with small pressure (which in average did not exceed 35 mmHg in the area of the contact), the amplitude of observed PPG signal oscillations was significantly increased. The minimal increase of the PPG-signal amplitude was 1.5x, while the maximal was 8.4x. In average, we observed fourfold increase of the pulsations amplitude after the skin contacted the glass. With the increase of the signal amplitude, PPG-waveform sequence has significant correlation with the ECG in 83 of 86 cases. Notably, that even in three exceptional cases of insignificant correlation (p > 0.05) we observed a classical low-noise shape of the PPG waveform. However, the sequence of systole peaks did not follow that of R peaks of ECG. Observed significant increase of the PPG-signal amplitude in the case of the skin contact with glass cannot be explained in the frames of commonly accepted model of light interaction with biological tissue in-vivo, which is the basis of photoplethysmography since its discovery in 1937. Considering the series of recent experimental observations, we proposed new physiological model for the light interaction with living biological tissue. This model provides reasonable explanation not only of the observed increase of the PPG-signal amplitude but also other known conflicts of the experiments with the classical model. These conflicts are (i) observation of the highest PPG signal at the green light, which did not penetrate deeply in the tissue and cannot efficiently interact with pulsatile blood in arteries, and (ii) observation of time-inverted PPG waveforms simultaneously with normal waveforms in adjacent areas of the tissue. In contrast with the classical model, the proposed one states that it is pulsatile transmural pressure of the arteries, which compresses/decompresses the density of capillaries in the dermis, thus modulating the blood volume in the capillary bed, which in its turn modulates the light absorption and scattering coefficients. These effects provide the light power modulation at the heartbeat frequency. Therefore, arterial pulsations can be indirectly monitored even by using the light, which slightly penetrates into the biological tissue. The proposed physiological model explains the number of observations which have been unclear in the classical model of light interaction with tissue. To estimate applicability of the BPI system for objective assessment of local and systemic mechanisms of vasomotor regulation in patients with migraine we studied neuronic mechanisms of cardiovascular reactivity. Current data on cardiovascular reactivity in migraine, especially severe forms, are essentially contradictory. Therefore, we applied a battery of tests to examine the autonomous regulation of circulation in patients with severe forms of migraine. In our experiments patients underwent a combined investigation of the autonomous regulation of circulation, including: the tilt-table test, a deep-breathing and Valsalva Maneuver, handgrip test, cold pressor test, arterial baroreflex, and blood pressure variability. Our study revealed that in patients with frequent episodic or chronic migraine without hypertension the cardiac reactivity almost did not differ from the control group, whereas the vascular reactivity was largely modified. The most significant differences in the vascular reactivity in patients with migraine were presented as the more significant growth of the blood pressure at the later stage of the second phase of the Valsalva Maneuver and in the response of the blood flow to the cold stress. Obtained data allows us to expect that noninvasive method based on the optical BPI system will be capable to find out differences in vasomotor regulation between patients with cephalalgia and healthy persons. Please, visit the site of the ITMO University for further information: http://irc.ifmo.ru/ru/87797/res_dir/17393/.

 

Publications

---

Annotation of the results obtained in 2016
Advanced system of blood pulsations imaging (BPI) was developed and manufactured during the second stage of the project. In addition to all functions provided in the previous version (such as synchronous recording of the electrocardiogram and video frames of a part of subject’s body), it has an option of synchronous recording the data from four different external sensors. Experimental study of the influence of polarization filtration on the performance of the BPI system has shown that such a filtration efficiently reduces motion artifacts compared to the non-polarized illumination while the pulsation amplitude measured at the heartbeat frequency remains unaffected. Thus, parameters of cardiocycles could be measured with higher accuracy and fidelity. At this stage, both geometrical and dynamic characteristics of capillaries were studied by combined use of the video-capillaroscopy, imaging photoplethysmography (PPG), and electrocardiography. It was found that the speed of red blood cells is modulated at the heartbeat frequency. Nevertheless, the geometrical size of capillaries remains unchanged during the time of measurement, which was about 30 s. These findings confirm the proposed at the first stage of the project model of visible (green) light interaction with the capillary bed. According to this model, the light intensity modulation at the heartbeat frequency arises from mechanical change of the capillary density caused by pulsating arteries, not from the arterial blood volume change. Reaction of human body on the local change of the temperature was studied by using developed BPI system. Specifically, measurements of blood-pulsation-amplitude change on the cooling of a finger were carried out by using the imaging PPG system. It was found that the amplitude of blood pulsations increases proportionally to the growth of the skin temperature. The proportionality coefficient varies from one subject to another thus characterizing the vasomotor reactivity of studied person. Our study has shown that the pulsation amplitude significantly depends on the skin temperature. Therefore, the BPI system can be used as a highly sensitive instrument for assessment of the body thermoregulation. An investigation of the factors affecting asymmetry of local blood perfusion was carried out within the cohort of healthy volunteers. We have suggested to classify these factors as internal factors (e.g. dysfunction of autonomic nervous system), and external provocative factors, such as irritation of sensor receptors TRPV1, TRPA1, TRPM8 (by mustard, pepper, acetone, etc.), gravitation, temperature, and others. Experimental study of the gravitation influence on the parameters of facial microcirculation was carried out. Detailed analysis of the observed PPG signals has shown that the signal disturbances originate mainly from the stochastically enhanced dichroic notch caused by endogenous cardiovascular mechanisms. New algorithm of the PPG-data processing resulting in accurate estimation of the borders of cardiac cycles has been developed. As opposed to previous algorithms, which were mainly devoted to assessment of the blood pulsation amplitude, it allows determination of the anacrotic wave beginning with high accuracy. The developed algorithm for the first time allowed us to visualize propagation of the pulse wave in the facial area with high spatial and temporal resolution. It is worth noting that the developed algorithm can be used for measurements of the spatial distribution of the pulse transit time in other parts of the body, as well. To study dynamics of the slowly varying component (DC) of the PPG signal during venous occlusion, a laboratory setup for all-around video recordings of the forearm was designed and constructed. Experiments carried out with 20 healthy volunteers have revealed that the intensity of light remitted from the forearm drops down linearly in time immediately after beginning of the cuff inflation with the restoration to the initial level after the cuff deflation. The shape of the observed DC-component waveform resembles the shape of the signals registered by conventional contact plethysmographs. This finding allows us to suggest that the rate of the linear growth of the PPG signal is directly proportional to the speed of the forearm filling with the venous blood. This suggestion is supported by the physiological model (proposed during the first stage of the project) according to which the visible (green) light is modulated due to deformations of the capillary bed caused by changeable pressure in blood vessels. In contrast with the existing plethysmography techniques for monitoring of venous occlusion, the proposed method is more advantageous because of non-contact nature and easiness in its implementation. Both amplitude and phase parameters of blood pulsations were measured in the facial area by the developed BPI system synchronously with electrocardiogram recording. These data were used for assessment of the pulse transit time (PTT) from the heart to the head in patients suffering from migraine or other headache and in healthy volunteers. These measurements revealed that the mean PTT was significantly lower in the group of sick persons than in the control group. Moreover, it was found that the mean PTT difference between the right and left cheek is larger in migraine patients than in healthy subjects. However, the difference in asynchronicity of blood pulsations became insignificant after normalization of the studied groups to the subjects’ age. This is consequence of the observation that there is asynchronicity of blood pulsations in different cheeks among healthy subjects, as well. Perhaps, observed asynchronicity of blood pulsations is a variant of the norm in certain diapason of age. Nevertheless, our study revealed significant difference in the mean PTT from the heart to the head between the group of patients with migraine and control group. The observed difference seems to be nonrandom, and most probably, it has direct relation with the migraine pathogenesis: in particular, PTT diminishing may be due elasticity losses of blood vessels in persons suffering from cephalgia. During the next stage of the project, we are planning to carry out investigation with the extended groups of sick and healthy persons. In addition, during preliminary research we have found that the skin reaction on the application of small dose of the capsaicin to the forearm is different for patients with migraine compare to the healthy subjects. This difference appears in more pronounced and more prolonged hyperemia after capsaicin application. Developed BPI system could serve as a technique for objective estimation of the local microcirculation reaction on the capsaicin application. It would allow not only objective diagnosis of migraine but also selective adjustment of anti-migraine medicaments. Such kind of study will be carried out at the next, third stage of the project. The autonomic regulation of blood circulation was examined in patients with migraine and compared with that in the control group of healthy volunteers. The study included the tilt-table test, a deep breathing and Valsalva Maneuver, handgrip test, cold-stress vasoconstriction, arterial baroreflex and blood pressure variability. It was found that the increase in diastolic blood pressure in handgrip test, the mean blood pressure in the late stage of the second phase of Valsalva Maneuver, and blood pressure variability were all higher in patients with migraine than in the control group. Similar increase of the forearm blood-flow reactivity was observed after cold-stress vasoconstriction. Notably, that the dynamics of the arterial pressure in the orthostasis was the same in sick and healthy persons. However, analysis of the patients with migraine suffering additionally from the hypertension has revealed higher reaction of these patients on the orthostatic loading. Patients with arterial hypertension possess significantly higher increase of diastolic pressure during the orthostatic loading. This finding allows us to conclude that persons suffering from migraine have increased vasomotor reactivity compare to the healthy subjects, whereas the cardiac regulation remains largely unchanged. The most informative methods for assessment of the vasomotor reactivity are Valsalva Maneuver, dynamometric test, and cold-stress vasoconstriction. Moreover, it was revealed that both heredity of cardiovascular disease and increased neurogenic vasomotor reactivity are more frequent in migraine patients regardless of hypertension. Preliminary analysis of influence of antimigraine medicine (agonist of serotonin 5-HT1 receptors) on the vasomotor reactivity has been carried out. We are planning to carry out additional research in this direction at the third stage of the project. Moreover, we reviewed the literature (1956 – 2016) devoted to the role of the parasympathetic nervous system in various forms of cephalgia. Special attention was given to the role of both cholinergic mediator of acetylcholine and peptide parasympathetic co-transmitters, such as vaso-intestinal and hypophysial peptides activating adenylate cyclase. Both these peptides could regulate local microcirculation, which is very important for understanding the processes revealed by our instruments of the microcirculation study. The results achieved in 2016 were published in 11 peer-reviewed papers and presented at 12 international scientific conferences. Please, visit the website of the ITMO University for further information: http://irc.ifmo.ru/ru/87797/res_dir/17393/issledovaniya_osobennostey_krovosnabzheniya_na_osnove_metoda_dvumernoy_otrazhatelnoy_fotopletizmografii.htm

 

Publications

---