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Methods of Studies of the Autonomic Nervous System

Human Physiology. Vol. 27, No. 6, 2001. pp. 732-737. Translated from Fiziologiya Cheloveka, Vol. 27, No. 6, 2001, pp. 9S-101. Original Russian Text Copyright © 2001 by Nozdrachev, Shcherbatykh.

REVIEWS

Modern Methods of Functional Studies of the Autonomic Nervous System

A. D. Nozdrachev* and Yu. V. Shcherbatykh**

* St. Petersburg State University, Russia

** Voronezh State Medical Academy, Russia

Abstract—Contemporary methods to assess the functional state of the autonomic nervous system are reviewed. This paper discusses different hypotheses on the nature of the low- and very low-frequency waves (LF and VLF, respectively) that are recorded during the spectral analysis of the heart-rate variability (HRV). Analysis of their own data along with data found in literature enabled the authors to propose the possible parasympathetic nature of the LF-wave generators. The application of the established indices of the absolute power of all the compo­nents of the HRV spectrum led to the hypothesis that emotional stress is related to the attenuation in the regu­latory effects of the higher levels of the central nervous system.

For many years, the sympathetic and parasympa­thetic interactions of the nervous system have been of deep interest to physiologists who study the activity of the autonomic system and to physicians who encounter different manifestations of cardiovascular diseases with the leading role of the autonomic disturbances. For example, the relationship between the increased sym­pathetic activity level and the ventricular fibrillation [1] and the protective role of the vagal activity, which results in the prevention of cardiac fibrillation, have already been proved [2]. Certain parameters of the autonomic activity are reliably correlated with mortal­ity caused by cardiovascular diseases [1,3,4]. The risk of death from myocardial infarction is associated with a decrease in the heart-rate variability [5, 6].

Parasympathetic effects on the heart rate are caused by the release of acetylcholine from the vagal terminals along with an increase in the K+ conductance through the cell membrane [7] and the inhibition of the pace­maker's current [8]. The sympathetic effects on the heart are mediated by the release of epinephrine and norepinephrine, both of which increase the Ca2+ cur­rent. In normal a state, the vagal tone dominates the sym­pathetic tone [9]. At rest, the heart-rate variability depends on the parasympathetic inputs to a greater extent [10] and the efferent vagal activity is tonically inhibited by the afferent cardiac sympathetic activity [11].

Apparently, an adequate assessment of the parame­ters cardiac activity and, moreover, this control process requires exact information on the current state of the autonomic nervous system. Previously, this purpose was achieved by the use of the following parameters: the heart rate, the arterial pressure value, the respiration rate, the Kerdo's autonomic index, the Hildebrand's coefficient, and also the clinical indices of the integral autonomic activity [12-16]. However, these methods

do not allow for discrimination between the sympa­thetic and parasympathetic inputs; their effects are not simply antagonistic but are complex reciprocal interac­tions, which vary depending on the exact type of the adaptive activity of the body [17, 18].

A new method, the mathematical analysis of the heart rate variability (HRV), was created during the search for more effective methods to differentiate between the activities of the sympathetic and parasym­pathetic autonomic nervous systems. This method is more precise than the traditional functional tests. How­ever, there are still some unresolved questions concern­ing the correctness of the comparison of the results of the old and new methods of evaluation. The nature of certain HRV parameters, in particular, the long-wave com­ponent of the spectrum, still remains unclear [19-21]. These questions will be considered in this review.

Heart-rate changes are known to be a universal part of the body's response to the influences of the external and internal medium and reflects the numerous regula­tory effects on the cardiovascular system. The hierar- -chy of the regulatory levels comprises the nervous apparatus of the heart, the subcortical nervous centers, the higher autonomic centers, and, perhaps, the cere­bral cortex.

The most popular methods for the mathematical analysis of the HRV include statistical analysis, varia­tion pulsometry, and spectral analysis. A group work­ing on heart-rate variability at the European Society of Cardiology and the North American Society of Pacing and Electrophysiology recommended several of the most informative parameters for heart-rate assessment [21]. However, domestic researchers continue using some parameters that are not included in this list but are still informative enough to use in functional tests [22]. Altogether, the optimal selection of the HRV parame-

ters is determined, on the one hand, by the targets and tasks of a specific investigation and, on the other hand, by the technical abilities of the equipment.

The properties of the RR interval distribution in the discrete segments of the heart rate analysis (the 5-min and the 24-h recordings are considered as standard) are calculated by means of statistical analysis: mathemati­cal expectation; mean duration of RR intervals in the massive chosen (M, RRNN); standard deviation of RR intervals (SDNN); coefficient of variation (CV); root-mean-square difference between the duration of the neighboring RR intervals (RMSSD); number of RR intervals that differ by more than 50 ms (pNN50); etc.

The method of the variational pulsometry (the so-called geometrical methods in foreign literature) allows us to reveal the regularity of the RR interval distribution as variables in the investigated range of values, which can be graphically presented as a histogram or a numer­ical (variational) series. The numerical characteristics of the variational pulsograms comprise the mode, the value of the most frequently occurring RR interval (Mo); the amplitude of the mode; the proportion of such RR intervals (AMo); and the range of deviation (AX, MxDMn, TINN). A variety of secondary parame­ters is calculated on the basis of the variational pulsom­etry data. These are the index of regulatory system strain (SI), the index of autonomic balance (IVB), the index of the adequacy of the regulatory processes (IARP), the autonomic index of rhythm (VIR) [23]. Until recently, variational pulsometry was the prevalent method for the mathematical analysis of the heart rate that allowed for the assessment and pictorial presenta­tion of autonomic homeostasis. The analysis of RR interval histograms includes the assessment of the val­ues scattering around the mode. The expansion of a his­togram and its displacement to the right, compared to the normal histogram configuration, reflect an increase in the parasympathetic tone, while its constriction and displacement to the left reflect sympathicotonia. A his­togram with two modes indicates the switching of one system of regulation to another [23]. Altogether, these indices have been confirmed in practice and their corre­lation with the activity of both types of the autonomic nervous system is of no doubt. The majority of investi­gators consider the indices SDNN, RMSSD, and pNN50 to reflect parasympathetic activity [19, 21, 23-29] and the indices AMo and SI to reflect the sympathetic activ­ity [19, 23-26, 30-33].

The index of the regulatory system strain (SI, stress-index) is widely used in the domestic literature and is a sensitive indicator of the general sympathetic activation in the body, which occurs under the conditions of phys­ical activity, emotional stress, and several somatic and mental disorders [19, 23-26, 31, 33, 34]. In healthy people, this index varies from 50 to 100 arbitrary units [19,23,25,26, 32]. According to one classification, the SI is subdivided into three types: normotonic, vagotonic, and sympathicotonic. The SI in the range 68-138 arb. units

was attributed to the normotonic type [32]. In view of the fact that under certain conditions (severe stress, dis­ease, etc.) much higher SI values occur (up to several hundred arb. units) [24], it was more productive to sin­gle out five instead of three ranges of values of this index. These are vagotonic (up to 30 units), normotonic (31-120 units), sympathicotonic (121-300 units), super sympathicotonic (301-600 units), and the extreme range (more than 600 units) [26]. Many inves­tigators found out that SI was a very sensitive indicator of stress caused by different factors, such as the neces­sity of resolving mathematical problems under the con­dition of time deficiency [31, 35], cardiovascular dis­ease [23], and examination stress [19, 25, 26]. SI corre­lates closely with the metabolic activity in stress, in particular, with the index of heat production; the resting metabolic activity per unit body mass is related to the SI value [30].

In an effort to compare the results of the mathemat­ical analysis of the HRV with the traditional parameters of the activity of the autonomic system, the appropriate correlation coefficients were calculated (in the normal state and under the condition of the activation of the sympathetic system by emotional stress) [26]. The authors of this paper established that two HRV param­eters, the SI and the pNN5Q, underwent the most pro­nounced alterations under stress. In students waiting for an examination, SI increased from 72.6 to 161.6 arb. units, whereas the pNN50 parameter, on the contrary, decreased from 29.64 to 8.02%. The correlation of these parameters with the conventional markers of the activity of the autonomic system (the heart rate, HR; the systolic and diastolic arterial pressure, APS and APd, respectively; the Kerdo's autonomic index, KAI; car­diac output, CO; and some other physiological param­eters) confirms the existence of the close relations between the stress index and the activity of the sympa­thetic nervous system and between the pNN50 parame­ter and the activity of the parasympathetic system. Under the condition of the relative rest, the SI value positively correlated with the HR (r = 0.67, p < 0.001); the APS (r = 0.24,p < 0.05); the APd (r = 0.21,p < 0.05); the KAI (r = 0.44, p < 0.001); the CO (r = 0.42, p < 0.001); the Hildebrand's coefficient (r = 0.31, p < 0.01). However, the pNN50 negatively correlated with all these parameters: the HR (r = -0.72, p < 0.001); the APS (r = - 0.29, p < 0.05); the KAI (r = - 0.52, p < 0,001); the CO (r = - 0.6l,p < 0.001); the Hildebrand's coefficient (r = - 0.54, p < 0.001); but it positively correlated with the respiration rate (r = 0.32, p < 0.01). Under the con­dition of emotional stress, the sign direction of these relations and their intensity retained. However, their value was somewhat diminished, which could reflect interference of hormonal mechanisms in the regulation of the cardiovascular system activity. However, under stress the SI correlated significantly with KAI, CO, and the Hildebrand's coefficient [26]. According to the for­mula proposed [23], the index of the regulatory system strain is calculated as the quotient from the division of the amplitude of the RR interval mode by the double product of the mode by the variation range. Thus, the SI reflects not only the increase in the activity of the sym­pathetic system but also the shift of the autonomic homeostasis in the direction of the sympathetic system prevalence over the parasympathetic system.

The third method for HRV investigation, which is becoming more popular, is the spectral analysis of the RR interval series. It shows the frequency distribution of the power in the general spectrum of the heart rate. Spectral analysis opens up new opportunities for the investigation of the higher centers of the autonomous nervous system, because heart-rate fluctuations are caused by the actions of certain brain structures that regulate the heart. In domestic literature, the most com­pletely elaborated model of the hierarchic structure of the brain centers that regulate the cardiac activity is the cybernetic model proposed by Baevskii [23]. This model comprises two regulation circuits, autonomic and central. The working elements of the autonomic regulatory circuit include the sinus node, the vagus nerves, and their nucleus in the medulla oblongata. The central circuit comprises three levels including the cor­tical centers, which provide for the rearrangement of the functional activity of the body in response to envi­ronmental changes; the higher autonomic and subcorti-cal centers, which provide homeostatic interactions of various physiological systems of the body; and the vasomotor centers, which put in equilibrium different hemodynamic parameters inside the system.

Under the condition of the relative physical and mental rest, the high-frequency fluctuations of the heart rate prevail. They are related to the respiration rhythm and are determined by the activity of the vagal center, as recognized by most investigators [19,20, 23, 29, 31, 36-42]. These heart rate fluctuations occur in the 0.15-0.4 Hz range and are designated as HF (high-fre­quency) oscillations.

The next spectral region of the HRV lies in the 0.04-0.15 Hz range and is denoted as LF (low-frequency) oscillations. These waves are supposed to be similar to the slow Traube-Hering waves found in the arterial pressure tracings and the plethysmograms [23].

According to the most popular standpoint, these waves reflect changes in the sympathetic tone [42-44], although some other investigators do not exclude the role of the parasympathetic components in their genesis [19,20,45], especially since the specific cerebral struc­tures generating these oscillations remain undefined as yet. The heart rate variability in this frequency range is related to the function of the baroreceptors [40], to the feedback loop in the regulation of blood pressure [46], and to the vascular effects [47]. Some domestic physi­ologists admit that these waves reflect the activity of the sympathetic system exclusively and draw important practical conclusions [38,48], though the experts of the European Society of Cardiology warn against the

unreasonable interpretation of the nature of the waves in this range [21].

It is worth mentioning that the power oscillations of the LF-waves during the activation of the body caused by different factors are oppositely directed, which depends on the method of their recording [19, 44, 49]. A special committee from the European Society of Car­diology and the North American Society of Electro-physiology particularly noted this fact [21]. The com­mittee reported that the measuring of the integral power in the absolute units (ms2) and in the standardized units (%) under the condition of the body activation give the opposite results. The absolute power of the LF-oscilla-tions decreases under the conditions of the orthostasis, emotional stress, and the other types of changes in the functional state. However, the relative portion of these oscillations in the integral power of the spectrum increases. This circumstance does not allow concluding unequivocally what parts of the CNS, sympathetic or parasympathetic, are responsible for the generation of these oscillations. An attempt to determine the correla­tions between the low-frequency oscillations and other HRV parameters with the established nature was made [19]. According to this investigation, under conditions of rest or emotional stress, the absolute power of the low-frequency oscillations correlates negatively with the following parameters of the sympathetic activity: HR, KAI, SI, and AMo. It correlates positively with the following parasympathetic activity indices: SDNN, RMSSD, and pNNi0. Calculating the LF-oscillations magnitude with the use of the relative units (percentage in the integral power of the spectrum) gave opposite results.

In order to interpret these data properly, one should bear in mind that in the 5-min-long recordings of the RR intervals, the HF- and the LF-ranges constitute the major part of the integral spectral power. Thus, the stan­dardized assessment reflects the ratio between the activities of the neural centers generating the LF- and the #F-oscillations [21]. That is why the apparent increase in the LF-wave power under the condition of emotional excitation only reflects the weakening of the activity of the vagus nucleus under stress. At the same time, the sufficiently close positive correlation between the absolute power of the LF-oscillations and such indi­ces of the parasympathetic activity as the SDNN, the pNN50, and the RMSSD, and the negative correlation with the index of regulatory system strain, the Kerdo's autonomic index, and the Hildebrand's coefficient rather indicate that the hypothetical LF-generator belongs to the parasympathetic system. Clinical data in foreign investigations support this hypothesis. Thus, the LF-component of the spectrum was not observed in the majority of patients with heart failure in the late stage and with an extremely reduced heart-rate variabil­ity, despite of the clinical signs of the sympathetic acti­vation [50]. The follow-up of patients with tetraplegia as a result of complete spinal-cord blockade at the level of the cervical region revealed a pronounced low-frequency component in the HRV and in the arterial pres­sure fluctuations, which gave evidence in favor of the parasympathetic nature of the LF-oscillations [51].

The next region of the oscillation spectrum of the heart rate with the frequency range from 0.04 to 0.015 Hz can be referred to as the superslow waves and is denoted as VLF-oscillations. There are several assumptions about the nature of these rhythms. These assumptions may be related to the thermoregulation, which is realized via changes in peripheral blood flow [52, 53], or to the vasomotor activity of the higher order than the LF-waves [41, 54]. However, the physiological nature of the superslow waves remains unclear [21]. In postin-farction patients, this range prevails and the majority of the HRV power falls to it as a result of a decrease in the power of the HF- and the LF-components of the heart rate spectrum [55].

Some domestic authors have suggested that the VLF-waves reflect the cerebral ergotropic effects on the underlying brain levels and are closely related to anxi­ety or to some other types of psychoemotional strain [56, 57]. The latter suggestion has theoretical and prac­tical implications and requires special consideration. It is important to note two methodological aspects that hamper the possibility of associating the VLF-oscilla-tions with the anxiety: the method for measuring the VLF-wave power and the principles of detecting the anxiety, which is a rather subjective matter. Concerning the first aspect, the situation with the power of the VLF-oscillations is similar to that of the vasomotor waves; i.e., with anxiety and stress, there is an increment when the standardized units measure the power and a decre­ment when the absolute power is measured [19]. Con­cerning the second aspect, it should be noted that the existing tests for the assessment of anxiety [58, 59] are unable to reliably differentiate the sympathetic mani­festations of the anxiety from the parasympathetic. The clinical examination gives a qualitative rather than a quantitative assessment, which does not allow perform­ing the correlation analysis.

For example, the Hamilton scale [58] cannot dis­criminate between the sympathetic and the parasympa­thetic anxiety manifestations, because it juxtaposes phenomena with the opposite mechanisms: the redness and paleness of the skin, elevated muscle tone, short­ness of breath, meteorism, etc. The Zung scale [59] for anxiety self-rating attributes similar high scores to sub­jects with an elevated activity of both types of the auto-nomic nervous system, because the statement "I some­times have the feeling of palpitation" (sympathetic sys­tem activity) stands alongside with the statement "I sometimes have episodes of weakness" and "frequent urges to urinate" (parasympathetic system activity).

The Spielberger scale is used to define the level of personal and situational anxiety based on the personal psychological state of the subjects tested. The matching of the VLF-waves with the Spielberger anxiety scale scores revealed the negative correlation between the

absolute power of the superslow oscillations, on the one hand, and the situational anxiety and the Kerdo's auto-nomic index, on the other [26]. Correlation was absent if the power of this spectrum region was measured in the standardized units (percentage of the integral spec­tral power). Under emotional stress, a strong negative correlation (r = -0.61,p < 0.001) was observed between the absolute power of the VLF-oscillations and the mode amplitude values (indicator of the sympathetic activity) and a strong positive correlation (r = +0.76, p < 0.001) between the power of the VLF-oscillations and the SDNN values (indicator of the parasympathetic activity).

There also exists the opinion that the higher levels of the nervous system are deprived of the clear morpho-physiological division of the brain structures into sym­pathetic and parasympathetic. Higher brain structures, particularly the hypothalamus and the limbic system, realize the general regulation of the metabolic pro­cesses in the body [12]. During the development of this idea, it was suggested not to distinguish between the sympathetic and the parasympathetic brain centers, but the ergotropic and the trophotropic centers, which per­tain to the development of the VLF-oscillations of the heart rate [56, 57]. Additional investigations are required for a more precise conjunction of the super-slow oscillations to the specified cerebral structures, including experiments with electrically stimulated ani­mals or animals with switched off tentative generators in the hypothalamic area.

In conclusion, we reviewed the concepts of the role of the central structures regulating the heart rate during the perturbation influences that can be found in the domestic literature.

According to Baevskii, the normal regulation of the heart rate is accomplished with the minimal participa­tion of the higher regulatory levels. The heart rate reg­ulation only overpasses to the superposed centers in the cases of emotional stress or severe functional load [23]. However, many investigators note the decline of the absolute power of all the components of the HRV spec­trum under stress conditions [19,21,26,42], which can witness to the contrary. From a biological point of view, in stress, all the systems of the body work cooperatively to achieve a vitally important goal. On the contrary, the role of the heart is simplified: it should develop to max­imal efficiency. In addition, the sympathetic influence results in the flattening of the heart rate, which is accompanied by the elevation in such parameters as the AMo and the SI. The close positive correlation between the absolute power values of the low-frequency HRV and the markers of the parasympathetic activity (SDNN, RMSSD, and pNN^) observed in stress may suggest that the role of the higher centers generating the LF- and the VLF-waves should consist not in the enhancing the ergotropic effects but, on the contrary, in creating a more economic regimen of the cardiac activity. The latter phenomenon corresponds more to the goals and opportunities of the parasympathetic system.

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