Cerebral Blood Flow Regulation (Nova Biomedical)

INTRODUCTION Studies of the mechanisms relating blood supply to the brain appeared to be, in some sense, at a deadlock. Despite extensive application of different methodical approaches, no qualitative progress has been observed in these studies at the present time. This is perhaps due to the traditional, but not understandable, separation of neurophysiological and "circulatory" studies. It may seem very paradoxical, but the study of cerebral blood circulation proceeds almost in complete isolation from the knowledge about brain functions and does not take into account the specificity of the working brain as a part of the whole body. It is well known that the brain belongs to the group of organs having a high level of oxygen consumption. According to the data of Artru et al., (1980), oxygen consumption by the brain is an average 4.6 ml per 100 g of tissue per minute. In humans, the level of oxygen consumption by the whole brain attains 46 ml/min (Wade, Bishop, 1962). This makes up approximately 20% of the total oxygen volume consumed by the organism. Consequently, the cerebral tissue is characterized by highly energetic processes. There is evidence indicating that even in functionally resting conditions, 18% of the entire energy expenditure of the body is utilized by the brain (Kinney et al., 1963). Calculations made by Rushmer indicate that the intensity of energy consumption by the human brain appears to be on average 20 Watt (Rushmer, 1981). The data described above account for the major particularity of the cerebral vascular system, for its high functional significance in the metabolic maintenance of the brain functions, and, consequently, for a high reliability of functioning of the mechanisms responsible for the regulation of brain blood supply during a permanent existence of the external and internal disturbing influences of different natures. The history of investigations of these mechanisms is full of dramatic collisions. In the nineteenth century Theodor Meynert (1867-1868), while studying the morphological differentiation of individual structures of the cortex, put forth a hypothesis on partial hyperemia in these areas as an indication of their partial awaking. "The ...same search for the physical basis of mental activity made Hans Berger, one generation later, investigate blood flow (Berger, 1901) and heat production (Berger, 1910) of the `resting' and `working' brain. But he left this line after he had discovered, in the early 1920's, that the electrical potential which could be recorded from the cerebral cortex could be related to restfulness

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(regular 10/sec alpha-waves) and mental activity (predominant beta-activity) (Berger, 1938)..." (Creutzfeldt, 1975, p.21). This put off for a whole century the investigation in the direction of Meynert's hypothesis. Correlation of specific changes in the brain's electrical activity with behavior initiated a new trend in brain studies. It appeared that the cerebral cortex responds by desynchronization to orientation reaction, attention, goal-directed behavior, mental activity, stress, etc., but responds with synchronization to a resting state, lack of attention, inactivation of cerebration, etc. However, great difficulties were faced, trying to correlate the observed electrical event with the functional anatomy of the brain. The degree of complexity of the task to be solved could by no means be co-measured with the degree of changes seen in the EEG. That is why interest in Berger's discoveries eventually has waned while interest in Meynert's idea has increased. Moreover, following Berger's theory instead of Meynert's, researchers lost the brilliant chance of joining the neurophysiological and circulatory investigations for approximately one century. Which theories did investigators of cerebral blood circulation follow in the meantime? In 1890 Roy and Sherrington in their classic work "On the Regulation of the Blood Supply of the Brain" put forth a view that the cerebral blood flow (CBF) value was determined by two factors: a) systemic arterial pressure (SAP) and b) intrinsic mechanisms based on the action of metabolic products and capable of modulating the degree of blood supply of the brain in terms of changes occurring in its functional activity. Six years later, Hill (1896) categorically rejected the possibility of existence in the brain's vascular system of intrinsic regulatory mechanisms and advanced a postulate on the CBF's passive dependence upon SAP changes. This point of view was not refuted until the 1930's. However, since that time an increasing number of evidence has been accumulated indicating the active involvement of the cerebral vessels in the regulation of its blood supply. In 1934 Fog employing "cranial window" method which permits the direct measurement of the pial vessel diameter, demonstrated convincingly that the feline pial arteries constricted when SAP increased. This observation, corroborated in his subsequent studies (Fog, 1938, 1939), prompted him to resort to the concept of intrinsic regulation of CBF which he considered was based on the spontaneous reactions of vessels to changes in transmural pressure. With the development of new methods for CBF measurement, more direct and indirect evidence (both experimental and clinical) accumulated providing support for Fog's conclusion. The most essential qualitative leap in studies of the regulation of cerebral blood circulation followed the appearance of Kety and Schmidt's method in 1948 which made it possible to perform quantitative measurements of CBF. Thanks to a successful application of this method, Lassen in 1959 definitely confirmed that the vascular system of the brain appears to be autonomic and self-regulating. Here is a short description of the structural-anatomical organization of this system. The brain of humans and animals is supplied with blood by a system of parallel major arteries comprised of two internal carotid and two vertebral arteries. The degree of involvement of these arteries varies in different human and animal species (Klosovski, 1951; Gannushkina et

Introduction

3

al., 1977). The internal carotid arteries branching off from the common carotid pass in most animals and in humans through the cavernous sinus and reach the brain base outside the visual chiasma. The vertebral arteries by-passing the medulla oblongata are unified and form the basilar artery. Characteristic of all representatives of the feline, artiodactyla, and cetacean orders, is a poor development of the vertebrate arteries, a reduction of the internal carotids, and the presence of so-called rete mirabile in the cranial base (Yakovleva, 1948; Gannushkina et al., 1977). It is supposed also, that there is an analog of the rete mirabile in human in the form of tiny anastomoses binding the branches of the external and internal carotid arteries (Gillian, 1974). Functional implications of the rete mirabile remain still obscure. It is thought to be involved in the dampening of pulse oscillations, in thermal exchange, and in neurohumoral regulation of cerebral blood circulation. From the rete mirabile there originate vessels which are referred to as the cerebral carotid arteries (Akaevskii, 1975). At the brain base, the major arteries and their branches form an anastomising ring, the circle of Willis. Here, like to a common collector, blood is delivered from the internal carotids and vertebral arteries, which play an exclusively important role in the formation of collateral blood flow in the case of pathology in any major artery. From the circle of Willis originate the anterior, medial, and posterior cerebral arteries, which, by ramifying extensively on the brain surface, form the anastomising network of the pial arteries. The degree of density of the latter depends on the degree of evolvement of the animal. Compared to the system of the carotid arteries, the vascular reservoir of the vertebral arteries is thought to be organized in a more complex way. From the pial arteries originate the intracerebral arteries, which penetrate brain tissue and, by ramifying therein form a continuous capillary network. The higher the density of such a network is, the more intensive is the metabolism of the given brain region (Scarrer, 1940, 1944). As distinct as the major and pial arteries are, the intracerebral arteries are not associated with each other by anastomoses (Klosovski, 1951). In contrast to other organs, the capillaries are believed to be a single communication between the arteries and veins of the brain, and there are no arteriovenous anastomoses (Schneider, 1953; Kiss, Tarjan, 1959; Rowbotham, Little, 1965; Kennedy, Taplin, 1967; Ponte, Purves, 1974; Hasegawa, Ravens, Toole, 1976; Marcus et al., 1976; Tada, 1978). Outflow of venous blood from the capillaries occurs, on the one hand, along the pial veins located on the brain surface, and on the other hand, along the deep veins running from the subcortial ganglia and vascular plexuses in the thick layer of brain tissue. From the pial veins blood is delivered to the venous sinuses, and then to the jugular veins. The deep veins uniting form the large Hallen's vein which also enters the venous sinuses of the brain. In spite of intensive study of the role and contribution of the vascular regions mentioned above in the regulation of cerebral blood circulation, there is no universal view yet concerning this question. That is not surprising as wonder a detailed study of the finite parameter of the regulation of local CBF was not started until the 1960's. Since that time, investigations became more complex and started developing in three basic directions: 1. The study of the hemodynamic aspect proper of cerebral blood flow regulation, functioning of its mechanisms and executive links. 2. The study of the correlation of the blood supply of individual brain structures and regions with metabolism and the level of functional activity

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and 3. The use of local CBF dynamics as a neurophysiological test for determining the extent of involvement of various brain structures in the organization of a complex functional act. According to the viewpoints contained in the work by Moskalenko, Orlov and Beketov (1988) one may speak about the structural, functional, systemic and comparativephysiological approaches to study the problem of cerebral blood circulation. The first, the structural, provides for the analysis of the texture of the cerebral vascular system, the second, the functional, gives the processes observed in this system during a variety of influences, the third, the systemic, synthesizes the experimental data by using the theory of control and regulation, while the last one generalizes the rest of the approaches in a comparativephysiological manner. The most indisputable data have been obtained from the structural approach, but its potential is unfortunately finite (in view of the boundaries of the cerebral vascular system itself) and is limited, because on the basis of data obtained by using the structural approach, it is impossible to conceive what the functioning of the CBF regulatory system is. The largest body of evidence, and the most conflicting was gathered by using a functional approach. Its possibilities appear to be as infinite as the number of putative influences (simple and compound) on the cerebral circulatory system. Its approach observes the processes in the cerebral vascular system, during different influence on the system. This method served as an impetus for the development of a wide variety of methods giving an objective recording in a definite time interval. In view of the controversy of data obtained by using this approach in a complex situation, it appears to be a systemic approach to derive material from the results of a functional approach. As far as the comparative-physiological approach is concerned, it inevitably sums up all the errors, the outcome of the pitfalls and limitations of the other approaches. The overwhelming majority of studies devoted to displaying the CBF regulation mechanism are based on obtaining static characteristics of the regulating system. As a rule, only the steady state value of the parameter, which in each particular case is utilized for the evaluation of the process of regulation (be it CBF, for example, or the value of the vascular lumen) is recorded and analyzed. This approach is extremely important for the establishment of the final results of the process of regulation, but it furnishes nothing concerning the dynamics of this process. In terms of the theory of automatic regulation and control, it is well known that it is principally impossible to describe the functioning of the regulating system on the basis of only static characteristics. It is also required to obtain the so-called dynamic characteristics yielding a description of transient processes. It is known that at the exposure of the system's input to a disturbing influence, the parameter to be regulated does not immediately come to its new level, but comes only after the lapse of a certain time interval. The processes developing in the regulating system from the moment of application of the influence until the establishment of a new steady state are termed transient. They, as a matter of fact, throw light on the principles by which the regulating mechanisms function. To obtain the indicated characteristics is the most typical task of an expert in the theory of automatic control and regulation, and the methods to solve this are sufficiently and strictly defined (especially for linear systems). Unfortunately, physiologists often unaware of the basic principles of this theory (though for this purpose there are classical books by Grodinz (1966) and by Milsum (1968), about the analysis of this or another process of regulation), employ a

Introduction

5

priori an incorrect methodical approach. Naturally, a complex, living system exceeds the most complex technical devices, but that is an extra argument in favour of the necessity to use a more adequate tool for analysis. There are, we think, major reasons which give rise to a large number of controversial experimental data on CBF regulation, and they, to a considerable extent, lead to discussions about the nature of the mechanism or mechanisms underlying it. What are the most valid, or at least thought to be such to-date, experimental facts by which current viewpoints are formulated on cardinal issues in the field of the physiology of cerebral blood circulation? 1. Cerebrovascular smooth muscles have characteristics which differ from those of other organs (Bevan et al., 1982). 2. There is relative steadiness of the total CBF during alteration (within certain limits) of systemic arterial pressure (SAP) (the so-called "autoregulation" of blood supply to the brain (Lassen, 1959; Rapella, Green, 1964; Harper, 1966; Hagendal, Johamsson, 1968; Ekstrom-Jodal et al., 1970; Smith et al., 1970). 3. Blood supply also varies during variation of the brain structures functional activity (Antoshkina, Naumenko, 1960; Ingvar, 1961; Ingvar et al., 1962; Benua, Lesnjak, 1967a,b; Baldey-Moulinier, Ingvar, 1968; Freeman,Ingvar, 1968; Klosovski, Kosmarskaja, 1969; Meyer, Gotoh, 1969; Reivich et al., 1969; Risberg, Ingvar, 1971; Bicher et al., 1973; Moskalemko et al., 1075; Leniger-Follert, Lubbers, 1976; Demchenko, 1983; Mitagvaria, 1983). 4. In smooth muscles of the brain vessels, there is both electromechanic and pharmacomechanic coupling of influences with active reactions (Hirsh, Korner, 1964; Kogure et al., 1970; Orlov et al., 1971; Edvinsson et al., 1975; Gabrieljan, 1976; Kuschinsky, Wahl, 1978; Tada, 1978; Balueva et al., 1980; Bevan et al., 1982). 5. Cerebral vessels are well innervated with adrenergic and cholinergic nerve fibers (Nielsen, Owman, 1967; Edvinsson, 1975; Motavkin, Markina-Palashchenko, Bojko, 1981) whose specific receptors are distributed along the cerebrovascular bed (Edvinsson, McKenzie, 1977). These are the most reliable findings that served as a basis for building up various theories about the regulation of the cerebral blood supply. For example, the finding about the augmentation of bioelectric spike activity of the smooth muscle vessels during stretch and deformation is a vigorous basis for the theory of myogenic regulation of vascular tone and appears to be an impetus for the development of its idea. No less an intriguing finding is also the pharmacological mechanism of the smooth muscle activation nourishing the development of the idea of both neurogenic and metabolic theories about the regulation of the cerebral blood supply. However, the utmost attention of investigators was attracted by the finding concerning abundant innervation of cerebral vessels up to arteriols 15-20 mcm in diameter which served as a basis for the emergence and development of an idea about the neurogenic mechanisms of the regulation of the cerebral blood circulation, but has not been properly explained so far.

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At any rate, debate between adherents of various points of views concerning the role of each of the mechanisms indicated above in the regulation of the brain blood supply has not been terminated over the decades, though at present, it has been going on possibly qualitatively on a level different from earlier ones. The present treatise is an attempt to furnish fundamental findings reported in the literature and the results of our own investigations relative to the problem of the mechanisms of the regulation of cerebral blood circulation and the physiological and morhological effects of local hyperthermia undertaken for recent years in the Department of Regulatory Mechanisms of Metabolic Maintenance of Brain Functions at the I.Beritashvili Institute of Physiology, Georgian Academy of Sciences (Tbilisi, Georgia) and in the Valley Cancer Institute (Los Angeles, California. USA). It deals with the question of the regulation of local CBF during the most essential external and internal disturbing influences, such as: the variation of systemic arterial pressure (SAP), oxygen insufficiency, the alteration of metabolic demands of brain tissue, and the influence of a hyperthermia factor, induced by microwave radiation (employed, in particular, in oncological clinics). In the treatise several hypotheses are put forth; their critical evaluation by experts in the field will be gratefully acknowledged. The present work could not have been undertaken and the treatise written without everyday efforts and a great deal of our co-workers. Among them (from the Beritashvili Institute of Physiology, Tbilisi, Georgia): Drs - T.Adamia, V.Begiashvili, M.Devdariani, L.Gobechia, L.Gumberidze, G.Kvrivishvili, V.Meladze, M.Nebieridze, and L.Nicolaishvili (from the Valley Cancer Institute, Los Anjeles, CA): Drs - Ralph Woolfstein, Silvia Carter, Carlos Caridad, Duane Brulley, Roxana Dan. Included in the book are also the results of studies pursued by one of the author in the Max Planck Institute of Physiological Systems together with Professor D.Lubbers and Professor E.Leniger-Follert (Dortmund, Germany). We wish to express our sincere gratitude to all of them. Our special thanks are due to Miss Ninel Skhirtladze for the translation of the several parts of the book into English. The authors also give their special appreciation to Dr. Betty Ciuchta for the many hours devoted to the editing and organization of this book.

SECTION 1: REGULATION OF LOCAL CEREBRAL BLOOD FLOW DURING SYSTEMIC ARTERIAL PRESSURE CHANGES

Chapter I

SOME THEORETICAL PREREQUISITES 1.1. HISTORICAL BACKGROUND Over a hundred years ago A.A.Ostroumoff (1876) determined an indirect way (according to temperature variation) of blood flow measurement through the skin of a dog's extremities and found that during the elevation of the systemic arterial blood pressure (by stimulating the peripheral end of the celiac nerve) the blood flow value does not increase in the normal nor in the denervated limb. Because this could be due only to the vessel's constrictory response to the intravascular pressure elevation, Ostroumoff postulated that the vascular walls possess the capacity to react actively to an abrupt rise in blood pressure by increasing their tension. Though analogous observation had been made even earlier (Ludwig, Schmidt, 1869), it was since the work of Ostroumoff that the study of this problem was pursued, a problem which has acquired a paramount importance for the interpretation of the questions dealing with the genesis, alteration and regulation of vascular tone in general. The problem in question deals with the physiological mechanisms, underlying the vascular responses, providing a relatively steady organ blood flow during arterial pressure level changes. Some 25 years later since the investigations of Ostroumoff, same problem was addressed in 1902 by Bayliss who, by the use of the plethysmographic method, showed the vascular constriction during a rise in blood pressure (either by way of short-lasting asphyxia or by stimulation of the celiac nerve) and their dilation rises during a fall of the intravascular pressure achieved by the occlusion of the abdominal aorta. This reaction of vessels to the intravascular pressure changes has been termed "the Ostroumoff-Bayliss phenomenon." However, the question of the significance of vascular reactions to stretching remained for a long time in the dark because of the predominance at that time of the theory of that vascular tone depended exclusively upon impulses from the vasoconstricting nerves, a theory that compelled physiologists to consider this reaction merely as a striking manifestation of the general features of muscular tone, but not so important as the role of the nervous regulation of the vascular tone. Therefore, before the early 1940's the number of investigations concerned with the Ostroumoff-Bayliss phenomenon appeared to be relatively negligible. Among them one can single out works where some first conjectures were made on the nature

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of vascular responses to the intravascular pressure changes, works whose topic still remains a subject to discussion (Anrep, 1912; Bayliss, 1923; Fog, 1937, 1938, 1939). When the existence of the peripheral tone of vessels and its significance were firmly established, then the next stage in the development of the physiology of blood circulation studied the problem of dealing with the regulation of the blood flow to the organs. Therefore, the major trends in studying the significance of intravascular pressure changes were the investigations made in various regional beds of the system of blood circulation. A considerable majority of studies on the effect of intravascular pressure upon the vascular tone was then based on the comparison of the pressure levels with the blood flow values in individual vascular areas. This was just the same method of investigation led by Ostroumoff and Bayliss as well, but in order to study the vascular responses to intravascular pressure changes, the most diverse methods for blood flow value measurements were being applied. At the same time, the approach to studying these responses was also somewhat modified. If Bayliss associated the reaction of vascular musculature to stretch with the mechanism of vascular tone organization, then in the majority of current works dealing with the vascular responses to intravascular pressure variation, emphasis is made not so much on the characteristics of vascular smooth muscle features but on the study of the finite result of their activity, i.e. changes in the vascular bed resistance to the blood stream. Such an approach to the question namely led to the fact that the vascular reaction to intravascular pressure changes was, as a rule, designated not as the response to stretch, but as the autoregulation of the blood flow as the property of the vascular bed under study (Johnson, 1964). The latter term does not imply the nature of the agent inducing the vascular response, but nevertheless, it emphasizes the eventual result, a tendency to maintain a relatively steady level of blood flow during intravascular pressure variation. It is clear that the notion of "autoregulation" per se appears to have wider meaning and embraces a large class of regulatory processes, but in the world's physiological literature, this term has been established and has become commonly accepted namely in this narrow sense. We will, later on, employ this most currently used term. Further extension of the problem of vascular responses to intravascular pressure alteration was greatly enhanced by works of Selkurt in 1946 on the kidney and by Folkow in 1949 on extremity, which proved to be an effective and well documented evidence for the vessels' active response to intravascular pressure changes. Though similar evidence since Ostroumoff and Bayliss had been obtained earlier (Winton, 1931; Glaser, Laszlo, Schurmeyer, 1932; Hartmann, Orskov, Rein, 1936; Unna, 1935; Malmejac, 1939), neither Selkurt nor Folkow found anything that was principally new, but in their experiments qualitative estimation of changes in blood flow was replaced by quantitative recording, and what is more, their papers were published when the regulation of organ blood flow became the subject of numerous investigations and the existence of the vascular peripheral tone was proven. Early in the 1940's, a large number of investigations showing the ratio between blood flow values and arterial pressure in different regions of the vascular bed were considered. Methods of these investigations boiled down to the fact that they modulate the pressure under which blood flows along the isolated artery and that they monitor by some means the insuing thereat changes in blood flow values in the vascular bed of the organ by measuring, in

Some Theoretical Prerequisites

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particular, the amount of blood passing through the organ, artery, or vein. If the effect of the intravascular pressure fall within arteries is considered, then the latter can be achieved by applying pressure to the vessel of a screw cuff: the more the artery is occluded, the more pressure decreases distally from the place of occlusion, where it is recorded. In order to elevate the pressure above the original level, either a perfusion pump is used or a systemic arterial pressure is increased (for instance, occlusion of the carotid arteries). Similar investigations have convincingly shown the existence of autoregulatory vascular responses in quite various organs: the kidney, skeletal muscle vessels, and the vessels of abdominal organs, the coronary and cerebral vessels. The most comprehensive study was made on the autoregulatory responses, namely of the cerebral vessels, both of the entire vascular bed and of its different regions up to individual vessels (Forbes, Wolff, 1928; Fog, 1937, 1938; Carlyle, Grayson, 1956; Kety, 1958; Lassen,1959, 1964; Haggendal, Johansson, 1965; Harper, 1966; Konrady, Parolla, 1966; Mchedlishvili, 1968; Konrady et al., 1969; Mchedlishvili, Mitagvaria, Ormotsadze, 1971, 1972). It should be pointed out that during direct measurement of the global cerebral blood flow that is necessary for flow-pressure curves plotting, the results obtained by different studies are rather controversial. Some of them in such experiments found autoregulation of cerebral blood flow (Carlyle, Grayson, 1956; Lassen, 1959; Held et al., 1972), some rejected its existence (Hirsch, Korner, 1961), while others observed autoregulation in some experiments and no autoregulation in others. Yet, to-date the majority of investigators consider the existence of autoregulation of the cerebral circulation as a firmly established fact. It has also been established that it is restricted to definite pressure ranges. In a very general mode this range appears to be between the "low" and "high" levels of perfusion pressure (see Figure 1 according to Lassen and Skinhoj, 1975). In view of wide individual differences, the range of autoregulation has not been distinctly established so far. Depending on the statistical readout (experimental or clinical data) which the investigator has, there appear in the literature both rather narrow and sufficiently wide ranges tending toward low as well as high pressures. Thus, for example, Fazio (1970), observing autoregulation at systemic arterial pressure (SAP) equal to 300 mm Hg, suggests that the upper limit is not known yet. The limits of autoregulation, reported by Van Aken (1976) are: lower limit being 60-80, while upper, 150-200 mm Hg. Beyond the indicated limits, CBF passively follows SAP changes. In acordance with Greisen the lower threshold for cerebral autoregulation can be assumed to be 30 mm HG or below. When blood pressure falls below this threshold, CBF decreases more than in proportion to pressure due to elastic reduction in vascular diameter, but significant blood flow can be assumed to continue untill the blood pressure is well below 20 mm Hg (Greisen, 2007). In the category of firmly established facts is attributed a disturbance in the CBF autoregulation process (up to its abolishment altogether) during brain lesions (Reivich, Marshall, Kassel, 1969; Sakuma, 1977; Mascia et al., 2000; Czosnyka et al., 2001; Hlatky et al., 2002; Steiner et al., 2003), anaesthesia (Moskalenko, Zelikson, 1973; Tibble et al., 2001), sustained hypoxia (Freeman, Ingvar, 1968; Haggendal, 1968; Kogure et al., 1970) ischemia (Agnoli et al., 1966; Hong et al.,2001; Sundgreen et al., 2001), hypercapnia (Harper, 1966; Haggendal, Johansson, 1968; Parolla, Beer, 1975; Lu et al., 2004; Aksa et al., 2006; Rozet et al., 2006), hemorrhagy (Dernbach et al., 1988; Soehle et al., 2004) and trumatic brain injury (Engelborghs et al., 2000; Tibble et al., 2001; Steiner et al., 2003). Impairement of CBF

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autoregulation has also been demonstrated in a rat model of Streptococcus pneumoniae meningitis (Pedersen et al., 2007). Hence, autoregulation of CBF is believed to be a process ultimately susceptible to disturbances of various genesis that are likely to occur within the brain, though the results of our studies (Mitagvaria, 1983, 1985) differ, as will be shown further in this study in some details.

Figure 1. General mode of regional cerebral blood flow (rCBF) autoregulation (Lassen, Skinhoj, 1975).

Although the very fact of the existence of CBF autoregulation has been universally adopted and causes no doubts in investigators, that is not the case with the explanation of the mechanisms underlying it. A vast number of studies which deal with this topic adhere largely to three theories summarized as follows: 1. The myogenic theory asserts that the stretch of the walls of the small arteries leads to changes in the activity of the smooth muscles of these walls. Myogenic activity enhances with a rise of pressure, and, as a result, there develops vasoconstriction bringing about an increase in the resistance to blood flow. 2. The metabolic theory postulates that the level of CBF is mediated by the concentration of one or another substance within the tissue, which is either utilized or produced by metabolism. During perfusion pressure falls that do not entail changes in metabolism, a decrease in CBF attenuates the tissue oxygen tension and enhances CO2 tension. Both factors result in the reduction of the tone of resistance in vessels and in the increase of blood flow. During perfusion pressure rise, the reverse is observed. 3. In the neurogenic theory, a disruption of blood supply to the cerebral tissue is perceived by the receptor zone and, depending on the direction of changes in perfusion pressure, the corresponding commands are sent along the dilatory or constrictory effector fibres, which innervate the cerebral vessels. Each of these theories will be described in details later on, but here it is necessary to mention also another, less popular theory appealing to tissue pressure. This theory denies the active change of the vascular smooth muscle tone and explains autoregulation as induced by mechanical factors. According to this theory the arterial pressure elevation leads to the increase of transmural pressure and infiltration fluid pressures on the capillary level. If rigid

Some Theoretical Prerequisites

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walls exist in the organ, tissue pressure inside it enhances, which result in vessel compression. During the pressure fall, the opposite will likely happen (Johnson, 1964). Over the decades, at almost all symposia and conferences, devoted to topics of CBF regulation, debates have been going on among the adherents of the above mentioned first three theories. Statistical analysis of popularity of one or another theory could yield an interesting picture of crises and revivals of each of them. As a matter of fact, each of the three theories, or, in other words, each of the three hypothetical mechanisms, are theoretically in a position to describe the process of autoregulation, either independently, or in conjunction with others. However, detalization of concrete loops of regulation, localization and characteristics of functioning of separate links of these loops, determination of the feedback channels are to day still impossible. Consequently, the question as to the mechanism or mechanisms of CBF autoregulation still remains open.

1.2. POSSIBLE REASONS FOR CONTROVERSIAL INTERPRETATIONS OF THE RESULTS IN THE STUDY OF AUTOREGULATION The above survey of the basic theories of local CBF autoregulation clearly indicates that controversies exist even in interpretating the homogeneous experimental data. So how can one expect to find a universal theory (or hypothesis) on the functioning of a system of CBF autoregulation? Lets look at how such a situation came to exist. I.There are various methods used in measuring and thus altering arterial pressure (input disturbing factor). Let us briefly analyze the most frequently utilized methods.

Input Disturbing Factor Survey of reported data in the literature indicates that conventional methods used in alteration of systemic arterial pressure are: For induction of hypotension: a). Exanguination. During time there is a relatively slow reduction of SAP whose velocity appears to not be controllable. When hypotension persists long enough, acidosis develops. This view is quite justified (Kontos et al., 1978) that this method can barely be considered as pressor influence that is certainly necessary in autoregulation studies. b). Pharmacochemical hypotension, (develops, for example, by injection of bromide hexametonin). This enables control, to certain extent, of the level of SAP. Yet, the velocity of SAP falls and its duration appears to be uncontrollable.

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Nodar P. Mitagvaria and Hiam I. Bicher c). Electrical stimulation of the peripheral end of right vagus nerve causes bradycardia and a subsequent abrupt fall in SAP. The level of hypotension is virtually impossible to regulate. Cardiac rhythm is soon released from the influence of the vagus and SAP recovers. d). Occlusion of larger arteries which supply the brain with blood leads to a sharp decrease of perfusion pressure. The level of hypotension is poorly controlled, while collateral pathways of blood supply are not able to regulate its duration. The responsiveness of cerebral vessels are lost by repeated occlusions. e). Occlusion of the inferior cava vena, results in the attenuation of the venous inflow of blood to the heart with a subsequent hypotension. The speed at which the pressure falls and the level of hypotension and its duration are controlled, in case there is a need to regulate the velocity and degree of the venous occlusion.

Induction of Hypertension: a). a). Elevation of SAP is accomplished by means of infusion of blood or blood substitutes in the arterial system. The level and duration of hypertension are well controlled, while the velocity of elevating pressure is not. b). b). Pharmacological hypertension (can be induced, for example, by injection of noradrenaline or angiotensin). The velocity, level and duration of SAP increases and they appear to be virtually uncontrollable. c). c). Occlusion of larger arteries (for example, abdominal aorta) disrupts blood supply to an extensive area of the body and thus causes an increase in SAP. This method is the same method described above for the occlusion of the vena cava. The level of cerebral perfusion pressure can be easily varied and controlled by the use of a perfusion pump. Complex surgical interventions, that are usually required to facilitate perfusion, may disturb or even completely abolish autoregulation of CBF, (Zwetnow et al., 1968), thus offering incorrect results (Siesjo et al., 1980). There is a wide spectrum of methodical procedures used to induce hypo- and hypertension. There is still a wider spectrum of possible pitfalls relating to the purity of the pressure effect obtained. Each of them will introduce its correction toward the ultimate result of the experiment. Evaluation of the above methods in relation to input disturbance has shown occlusion of the inferior vena cava (hypotension) and occlusion of the abdominal aorta (hypertension) to be the most acceptable methods. (Apart from the highest "purity" from the point of view of the pressure effect, these impacts provide for, manageable in relation to the level and duration, a sharp saccadic variation of SAP toward increase or decrease.) The method most frequently employed, that of exanguination is found to be the least acceptable. II.Incomparability of the methods employed for the evaluation of the CBF autoregulation process (output parameter of the regulating system). Below, in Table 1 an assortment of the methods being utilized most frequently for experimental and clinical studies of the CBF autoregulation is presented. Advantages and disadvantages from the point of view of studying CBF autoregulation are briefly discussed.

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As seen in this table, direct and indirect, quantitative and qualitative, continuous and discrete (including a single measurement) methods were employed. (They possess various resolving capacity encompassing different levels of vascular reservoir of the brain.) Table 1. Advantages and disadvantages of different methods, using for study of the Cerebral Blood Flow autoregulation Methods Direct pial vessels visualization (“transparent” skull)

Advantages in vivo observation; vessel diameter continuous recording; exact localization of observed vessels; no inertial

Micropuncture of cerebral vessels

- direct measurement of pressure gradients along vessel

Fixation and histological observation of cerebral vessels Autoradiography

- permits study of vessels in deep cerebral tissue;

Impedance plethismography

Thermoelectric methods

Thermal clearance Clearance of diffusible indicators Clearance of non diffusible indicators Electrochemical generation of hydrogen

Transcranial doplerography .

Single photon emission tomography and Functional MRI Laser Doppler-flow metering

- quantitative measurement of cerebral blood flow dynamically; usable in chronic experiments; no inertial - continuous recording in acute and chronic experiments - quantitative cerebral blood flow measurements - quantitative measurement of local blood flow in different brain areas simultaneously - qualitative determination of local blood flow in different brain areas simultaneously - quantitative and qualitative recording of local cerebral blood flow in microareas of tissue under acute or chronic conditions noninvasive technique; evaluation of blood linear velocity in cerebral vessels.

Disadvantages not usable in chronic experiments only surface vessels accessible; no information of blood flow rate; difficult to maintain continuous recording for long time periods not usable in chronic experiments only surface vessels accessible; no direct information of blood flow rate; technique very difficult; data tends to be inhomogeneous - discrete measurements; - no blood flow determination; - errors related to fixation technique; - not dynamically; - not usable in chronic experiments not quantitative; not suited for blood flow measurements; low degree of area localisation - errors due to brain tissue heat production; - low resolution; - high inertia - same as previous - discrete measurement; - big volume of tissue flow averaging; - errors due to diffusion - same as previous

- quantitative errors possible

does not allow to estimate volumetric parameters of a blood-flow; "operator-dependence" (an essential role the angle of an inclination of the probe)

- dynamical evaluation of local blood flow

- not quantitative measurements; - high cost

- noninvasive

- not quantitative measurements; - "operator-dependence" (essential role of mechanical shift of the probe)

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Of course, the more methods that are employed for studying a given problem, the greater the chance for its comprehensive analysis and successful resolution. However, contradictions naturally occur when comparisons are attempted based on results only, omitting to take into account the peculiarities of experimental conditions as well as proper evaluation the technique employed. The state of the experimental animal is also variable.

Choice of the Parameter to be Regulated Continuous recording of the diameter of blood vessels appear to be the best method for studying the dynamics of autoregulation of blood vessels. Several difficulties are inherent in this procedure. According to available evidence, regulation of the vascular lumen throughout the entire vascular bed is affected in a diffuse and hierarchical way (Jones, Berne, 1964; Mchedlishvili, 1968). That is to say that the vascular bed is to be considered a system with distributed parameters. In such a structure, autoregulation reactions of a subsequent part of the vascular bed may result from both an inability to compensate from the preceding bed, (Mchedlishvili, Mitagvaria, Ormotsadze, 1972) as well as its surplus (Mchedlishvili et al., 1969). This heterogeneity of reactions and the coupling of individual vessels along the entire vascular bed make the observation of a particular vessel of little use. Attempts at studying a particular vessel at a given point in the vascular bed requires the measurement of pressure directly inside of it or at its input. This is next to impossible to accomplish. While attempting to study an isolated vessel, it is well known that it looses its capacity to autoregulate reactions (Burnstock, Prosser, 1960; Uchida et al., 1967). While recording the changes in vascular diameter, how can one begin to speak of the interaction during the course of observed reaction, when the mechanisms are of such a diverse nature? The effect of the latter ought to be judged by the blood flow volume velocity change which occurs in the vessel. How can data be evaluated by vascular diameter value and then to the value of blood flow volume, when precise intravascular pressure is unknown? Its value will be determined by inaccurate measurements of intravascular pressure and its inherent methodical errors. These errors become apparent during measurement of blood vessel diameter, since it is dependent on the type of the vessel under study (Chernukh, Aleksandrov, 1976). Keep in mind that in our studies of autoregulatory vascular responses advantage was given to local blood flow recording in different microareas of the cerebral cortex. From the point of view of local blood flow, changes in the vascular bed may be considered as a system with lumped parameters, since it is of no importance in which part of the vascular lumen regulatory changes occur. Local blood flow will reflect these changes unequivocally. In addition, recording of blood flow should be continuous, for it is only in this way the adequate dynamic characteristics of the functioning of the local CBF regulation system can be evaluated. Significance can occur in a fraction of a second while studying this system (Moskalenko et al., 1975). Note that the larger the volume of "measurable" tissue region is, the greater the number of parallel connected regulating vessels would be involved in the regulation of blood flow. Any variations in blood flow can be accounted for by the superpositioning of the reactions of the numerous regulatory vessels. These apparently, impede the possibility of judging the

Some Theoretical Prerequisites

17

responses of individual vessels. Therefore, a limited tissue volume region should be urged to study. In doing so, reduction in the probability of CBF changes of a multicomponent nature, will be reduced. That is to say that the probability for their induction by a joint action of a number of parallel connected regulating vessels will be reduced. In measuring it is of no importance in which site the regulatory changes of the vascular diameter are observed. It should be kept in mind that with such a minimal volume of the examined tissue region extrapolating to typical vascular responses presents a challenge. Therefore, it is suggested that the local blood flow measurements be taken concomitantly in several tissue regions and each study as many of regions as possible, ultimately treating the whole statistical analysis. There were two basic requirements needed to be met in choosing technique for local CBF measurements. 1. Possibility of continuous measurement of blood flow and 2. Least volume of measurement tissue for region. All of other requirements did not differ from an accepted experimental procedure (Moskalenko, Khilko, 1984). Analysing the possibilities of the methods represented in Table 1, as well as taking into account data provided by Demchenko (1976) in methodical work, we have arrived at the conclusion that it is the method of local CBF measurement based on the principle of electrochemical generation of hydrogen which occurs directly in cerebral tissue (Stosseck, Lubbers, 1970; Stosseck, Lubbers, Cottin, 1974) that most completely meets the above indicated requirements. Experience in application of this method of local CBF measurement and the study of microcirculation has revealed a broad scope of possibilities (Moskalenko et al., 1975; Mitagvaria et al., 1976; Meladze et al., 1977; Koshu et al., 1982; Mitagvaria, 1983).

Measurement of Local CBF by means of Electrochemical Generation of Hydrogen The technique, as a matter of fact, is a modification of commonly known method of hydrogen clearance based on polarographic measurement of hydrogen tension by way of platinum electrodes (Clark, Bargeron, 1959; Hyman, 1961; Aukland et al.,1964; Aukland, 1965, 1968; Fieschi et al.,1965, 1969; Gotoh et al.,1966; Lubbers, 1968). The velocity of hydrogen clearance, preliminarily administered into the brain by means of inhalation or intraarterial injection, is known to be dependent on the blood flow intensity in the site of measurement. It has been, however, demonstrated that in the case of one or the other mode of introduction hydrogen from the small pial arteries diffuses in the surrounding tissue and veins. Diffusion on this level appeared to considerably distort the calculated value of blood flow (Wodick et al.,1969). In this context, a system has been developed which delivers hydrogen directly to tissue and eliminates the problem of diffusional loss and shunting diffusion (Stosseck, 1970a). In this system hydrogen is generated by electric current and is then measured polarographically. Generation and measurement are accomplished in two nearlying points of the tissue surface by means of soldered into glass platinum wires. By the law of Faraday, the amount of generated hydrogen is proportionate to the value and duration of

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current pulse in the generation circuit (Adams, 1969). In electrolytic solution, hydrogen ions are reduced to molecular hydrogen on the platinum electrode, provided it is attached to the negative potential. Consequently, by the passage of a current between the two electrodes, contacting to the brain, one may obtain a stable generation of hydrogen in order to saturate the tissues surrounding the cathode. The other platinum wire measures polarographically the hydrogen partial pressure at the site of the generation. Thanks to the appropriate construction of the electrode, changes in hydrogen partial pressure (in the regimen of continuous generation) after some initial period of tissue saturation are determined by washing out hydrogen from the saturated region with tissue blood flow, i.e. they reflect variation of the latter. Moreover, when tissue volume is equal to 2-0.1 cubic mm (Stosseck, Lubbers, Cottin, 1974; Demchenko, 1983) this method allows both for qualitative and quantitative measurements of blood flow value, and it is considerably more dynamic in the latter case than any other method (Moskalenko et al.,1975). Quantitative measurement is however hampered by such factors as a complex dependence of hydrogen diffusion velocity within tissue on blood flow values through the tissue, (Wodick, 1973). This is especially seen under conditions of permanent and rapid variability of blood flow. Experience shows that even the dynamic character of this method (in quantitative measurements) really lags behind the dynamics of blood flow changes during autoregulatory reactions (Meladze et al., 1977; Mitagvaria et al., 1976, 1978, 1981; Mitagvaria, 1983). Therefore, we have chosen in the majority of cases to restrict our analysis to qualitative assessment of autoregulatory responses of blood vessels to SAP changes.

Figure 2. (A) - a principal scheme of local generation of hydrogen and measurements of its tension in the brain tissue, (B) - construction of the electrode.

Some Theoretical Prerequisites

19

Figure 2A represents a principal scheme of local generation of hydrogen and measurements of its tension on the brain surface. The closing of a circuit leads to the passage of direct current in range 0.3-1.0 mcA (permissible deviation from the selected value is not more than 1%) and accordingly, to the generation of hydrogen in tissue. As in the process of generation impedance of the generating electrode varies, tension in the generation circuit may range from 500 to 800 mV. The reference electrode (platinum wire) is grounded and is connected to the positive pole of the current source. The construction of the electrode which we employed is presented in the same figure (2B). It consists of five platinum wires soldered in glass. The central wire 200 mcm in diameter serves as a generator providing saturation with hydrogen of a tissue microregion with a volume up to 2 cubic mm. Around it, at the distance of 200-300 mcm four measuring wires (with the diameter of 100 mcm each) are placed. Polarographic recordings are made by hydrogen tension concomitantly in four adjacent microregions of cerebral tissue. 3. Inadequacy of the methodological approaches employed for the study of CBF autoregulation process. The problem of using methods that determine static characteristics while attempting to analyze a regulatory system which is dynamic was discussed in the introduction of the book.

Chapter II

MAIN THEORIES OF AUTOREGULATION OF CBF 2.1. MYOGENIC THEORY The author of myogenic theory of autoregulation Bayliss (1906) stated that blood pressure per se with its expansion (stretching) power induces a permanent tonic contraction of the vascular smooth muscles. In Bayliss' view, active responses of vessels are due to direct changes in the stretch rate of their walls, elicited by a variation of intravascular pressure. This idea intrigued many an investigator to pursue the study of the vascular responses to stretch, as the stretch with the power of transmural pressure may be considered as a constant contributor to the formation of the vascular tone. The primary objective of the investigations in question was to prove that the changes occurring in the vascular tone during variation of intravascular pressure are not due to the content of vasoactive metabolites as claimed by the adherents of the metabolic theory of autoregulation. Under natural conditions of blood circulation, it is extremely difficult to obtain direct evidence for the reaction of vascular muscles only to their stretch by intravascular pressure. Since variation of the latter (except the case when it is induced under the influence on veins by means of resistography) will by all means entail also changes in the amount of blood flowing through the tissue and, consequently, change in the amount of products of metabolism and hormones. This is why arguments about the myogenic theory have come to the point where facts often did not agree with the metabolic concept itself. Facts, very frequently are obtained not by the process of autoregulation itself, but by such processes as functional and reactive hyperemia. Thus, a large number of studies that were undertaken provided indirect evidence that reactive hyperemia developed also under the conditions which did not lead to the accumulation of vasoactive metabolites (Malmejac, 1939; Folkow, 1949; Mood, Wilkins, 1956; Haddy, Scott, 1964; Dahn, Lassen, Westling, 1967; Konradi, Levtov, 1970). Furthermore, in terms of the metabolic theory, it is very difficult to explain ischemic effects: ischemia produced by the clamping of veins does not result in reactive hyperemia, or if it does, it is very insignificant (Gaskell, 1878/1879; Bayliss, 1902; Folkow, 1949, 1953a, 1953b, 1962; Levtov, 1967; Kan, Levtov, 1970). Direct studies of reactive hyperemia also did not support the metabolic interpretation (Konradi et al.,1969), but later the multiple

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mechanisms (metabolic, myogenic and passive) has been described (Lombard et al., 1981). Recently, Toth et al. (2007) demonstrated that anaerobic vasodilator metabolites are responsible for the increase in reactive hyperemia with arterial occlusion longer than 45 s. A potent argument in favour of the myogenic theory supports the finding that when the normal pulsatile regimen of arterial pressure is replaced by the nonpulsatile, the vascular tone is altered (Held et al.,1972; Mellander, Arvidsson, 1974). This event can hardly be explained by the metabolic theory. Particular interest should be paid to studies of the isolated vessels and smooth muscle preparations where the investigator is dealing directly with the substrate responsible for the contractile act. Proof of the myogenic theory of autoregulation should be sought after by studying the properties of smooth muscle fibers directly. Therefore, Bayliss in his time made an endeavour to substantiate his conclusions about the nature of autoregulatory vascular responses in experiments on isolated large arteries: by elevating pressure in them he observed (though not in all cases) their constriction (Bayliss, 1923). The results obtained by other investigators also verify the capability of isolated vessels to actively react to changes in intravascular pressure (Muchholder, 1921; Burgi, 1944; Sparks, Bohr, 1962; Davignon, Lorenz, Shepherd, 1965; Plekhanov, 1967; Joyce, Rack, Westbury, 1969). In the course of such experiments spontaneously generated rhythmic biopotentials were observed in the vascular smooth muscles. The rhythmic bursts of electrical activity were as a rule, accompanied by contraction of muscles (Funaki, 1961; Funaki, Bohr, 1964; Axelsson et al.,1967; Nakaijama, Horn, 1967; Gurevich, Bernstein, 1969; Orlov et al.,1971; Brandt, Enzenross, 1976; Baez, 1977; Aubineau, Lusamvuku, Sercombe, 1978), which lead to the origination of the concept of automation of vascular smooth muscles (Konradi, 1973). It was found that in response to the passive stretch of the smooth muscles the frequency of action potentials increased and, accordingly enhanced the contractile activity (Bulbring, Kurijama, 1963; Sparks, 1964; Davignon, Lorenz, Shepherd, 1965; Johansson, Bohr, 1968; Holman et al.,1968). Synthesis of these observations with in vivo studies has resulted in formulation of the myogenic hypothesis (Folkow, 1964), in which a myogenically active smooth muscle of a vessel acts as a mechanoreceptor, whose distension by way of acting on the rhythm driver causes facilitation of impulses bioelectric discharge, spreading over the nearby lying effector cells of the muscle. The net action of this mechanoelectric coupling is evidenced in the variation of generation rate of the rhythm driving spikes in response to deformation and respective active changes of the vascular tone. The role of rhythm drivers in the entire vascular network of each organ is played, in Folkow's view, by the smooth muscles of the precapillary sphincters. As far as the last statement is concerned, it does not seem sufficiently well substantiated, but hypothesis as a whole has become widely spread and supported (Khaijutin, Manveljan, 1963; Bevan, Ljung, 1974; Mellander, Arvidsson, 1974; Johansson, Mellander, 1975). As a result, the question of the myogenic theory of autoregulation has been addressed mainly within the framework of this hypothesis and a number of fairly interesting facts have been revealed. In particular, the existence of a "static" and "dynamic" components of vascular responses to stretch has been established (Johansson, Mellander, 1975; Mellander, Lundvall, Grande, 1976; Grande, Lundvall, Mellander, 1977, Zeidan et al., 2003) and characteristic peculiarities of these components have been displayed (Sigurdsson,

Main Theories of Autoregulation of CBF

23

Johansson, Mellander, 1977, Brookes, Kaufman, 2003; Preisman et al., 2005, Ichinose et al., 2007; Just, 2007). Yet ultimately the question of the significance of myogenic mechanism for the development of autoregulatory vascular responses and of its interaction with neurogenic and metabolic mechanisms remains so far open that is solely due, as Orlov believes (1980), to study the myogenic properties of the finest vessels. Apparently, we have to add here that "...the standard study of autoregulation consists in revealing in fact the static characteristics of organ hemodynamics during step-by-step changes in perfusion pressure. Under these conditions, the initial fast component of autoregulatory responses to shifts in systemic hemodynamics cannot be detected..."(Teplov, 1980, p.13). Though Teplov in the given case under the "fast" component implied the neurogenic mechanism of autoregulation, his words may be even more successfully applied to the myogenic mechanism. In essence, its manifestation must precede manifestation of all other mechanisms.

2.2. METABOLIC THEORY The idea of a regular influence of metabolites on cerebral blood flow was first put forth by Roy and Sherrington (1890) at the end of the XIX century. The authors supposed that the value of cerebral blood flow was determined by two factors: a) Systemic arterial pressure and b) Intrinsic mechanisms based on the action of metabolic products which are capable of modulating the degree of blood supply to the brain in accordance with variation of its functional activity. Still earlier Roy and Brown (1879) revealed the participation of metabolites in reactive hyperemia on the frog's denervated paw. Subsequently, the hypothesis of metabolic regulation of blood flow has ben experimentally confirmed in Gaskell's (1890) studies. Based on the first evidence cited by the author, a number of issues were outlined which later on became the objectives for further studies, thus providing a theoretical prerequisite for the metabolic concept. In terms of the concept, the metabolic mechanism, one of the leading ones in regulation of vascular hemodynamics, provides adequate tissue blood supply in dependence on its functional-metabolic demands. At the start of XX century Anrep (1912a, b) related the concept of metabolic regulation of blood flow to the basis of organ blood supply autoregulation. Increase in blood flow occurred while a decrease in intravascular pressure happened. He explained that by accumulation of metabolites suppressed the contractile activity of the vascular smooth muscles. Indeed, a large number of findings indicate the compatibility of these ideas. Many substances formed in the process of metabolism were found to dilate the blood vessels. At local level the vasodilatory effect is exerted also by CO2, by products of unaerobic glycosis, metabolites of the Crebs cycle, potassium ions, ATP-conversion products and local hormones - acetylcholine, histamine, serotonin, bradykinin, etc. (Sokoloff, 1959, 1977; Bohr, Goulet, 1961; Betz, 1972, 1976, 1977; Carpi, Cartoni, Giardoni, 1972; Olesen, 1972, 1975; Allen et

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al.,1974; Mrwa, Achtig, Ruegg, 1974; Bevan, Ducless, Lee, 1975; Forrester et al.,1975; Cameron, Caronna, 1976; Csornai, 1976; Kuschinsky, Wahl, 1976, 1977; Astrup et al.,1977; Tagashira et al.,1977; Britton et al.,1979; Chung, Detar, 1980; Detar, 1980; Hansen et al.,1984; Henser et al.,1985; Wahl et al.,1986, 1987; Vainshtein et al.,1988). Independent groups of vasoactive factors are formed in the process of metabolism. These are adenine nucleotides which are the by-products of breakdown of ATP: ADP, AMP, adenosine, inosine, hypoxantine, xantin, urea (Halfen, Denisova, 1975; Fetisova, Sokolova, 1979). The presence of these factors was established in the interstitial fluid, liquor and blood (Rubio, Berne, 1969; Berne et al.,1984). Under conditions of functional rest the concentration of adenosine in the liquor of canine cerebral ventricles appears to be within the ranges 6*10-8 - 6*10-7 mol/l (Berne, 1980). In the canine coronary blood in the period of postischemic hyperemia adenosine was found in the concentration 1.3*10-7 M (Rubio, Berne, 1969). Adenosine is one of the products of ATP breakdown, and is accumulated in the extracellular spaces: breakdown of intracellular ATP, mediator adenosine, released from the synaptic clefts of purinergic nerve fibers, an enzymatic formation of 5-adenosylhomocystin (Shartz et al.,1978). Two possible pathways of adenosine formation were identified in the brain: 1) from 5-AMP in the reactions catalysed by 5-nucleotidase, alkalic or acidic phosphatase, 2) from 2AMP catalysed by 2-nucleotidase (Romanenko, 1985, Pedata et al., 2001; Diogenes et al., 2004). An increase in the adenosine content in the brain is observed during hypoxia, hypercapnia, systemic arterial pressure fall, electrical activation of the cortical neurons, enhancement of functional activity of nervous tissue (Rubio et al.,1978). Thus, in rats when systemic arterial pressure reduced to 72 mm Hg, adenosine in the brain tissue increased twofold, whereas the content of nucleotides and phosphocreatine remained unaltered. In the case of pressure decreased up to 45 mm Hg with maintenance of cerebral blood flow autoregulation the adenosine content increased by six times. Lactate concentration increased from 1.02 to 5.25 in proportion with blood pressure attenuation (Winn et al.,1985). Concentration of adenosine in the rat's brain tissue according to Winn et al. (1985) increased 3 fold within a 10 sec period after the arterial pressure fell and attained a maximum which 5 times exceeded the control level per 60 seconds; the content of adenosine coincided with the doses necessary for manifesting pronounced changes in the diameter and resistance of vessels during local application. Consequently, these data indicate that adenosine may exert a considerable influence on regulation of cerebral blood flow. At the same time, Gregory et al. (1970, 1980) expressed doubt regarding the participation of adenosine in dilation of vessels during cerebral ischemia. It was found that only in concentrations 10-5 M adenosine caused dilatation of the pial arteries in cats by 29.2%. Moreover, under conditions of hypoxia, hypercapnia and hypotension the dilatory effect of adenosine is attenuated by 50, 71 and 2.4%, respectively. During hypocapnia (aPCO2 = 25 mm Hg) dilatation response of the cortical arteries to the action of adenosine decreases up to 14.5%. However, in hypercapnia (aPCO2 = 48 mm Hg) inactivity of cerebral vessels to adenosine is maintained (Gregory et al.,1979, 1980). An opinion is expressed that the vasoactive action of adenosine is realized through the activation of specific cytoreceptors in the cerebral vascular smooth muscle cells (Beck et al.,1984; Edvinsson, Jensen, 1986). A marked variability of responses of the isolated cerebral

Main Theories of Autoregulation of CBF

25

arteries to adenosine was found in different species of animals, that seems to be associated with the species-specific distribution of adenosine receptors in the cerebral vessels. The most potent response to adenosine is shown by the arteries of rabbits, dogs and cats (the vessel diameter increases by 80-100%). In the human pial arteries adenosine reaction appears less pronounced - 43%. The basillary artery of guinea pigs shows an intensive reaction, but with a high index of concentration during which there occurs a 50% effect (Edvinsson, Jensen, 1986). During perivascular administration of adenosine in the concentration ranging from 10-17 to 10-3 M directly into the artery of the feline dura mater a vasodilatory effect which was in direct proportion to the value of the used dose is observed. Administration of a solution of adenosine to the pial arteries of various diameters resulted in their dilatation by similar values. At the 10-7 M concentration of adenosine arteries dilated by 8%, while at 10-3 M concentration by 30%. The degree of vasodilation was not dependent on the external diameter of the vessels ranging from 47 to 260 mcm (Wahl, Kuschinsky, 1976). However, upon intraarterial administration of adenosine (in the canine vertebral artery in the concentration 0.3-0.5 mg/kg/min) cerebral blood flow remained unaltered for 40 minutes (Boarini et al.,1984). Nevertheless, studies (Le Mey, Vanhoutte, 1981; Beck et al.,1983; Stephanovich, 1983; Mistry, Drummond, 1986) suggest the existence of a nucleotide transport system, in relationship to the endothelium of the cerebral capillaries. This somewhat modulates the idea of the interrelationship between adenosine and the blood-brain barrier. Kalaria et al. (1985) also assumed the existence of the adenosine transport system through the vascular endothelium and discussed participation of the nucleotide in question in the regulation of macro- and micromolecules transported through the blood-brain barrier. According to data of Mistry and Drummond (1986), endothelial cells of the heart and brain microvessels are capable of eliciting adenosine breakdown. This may be of some significance for local regulation of blood flow. It is likely that adenosine is incorporated in the realisation of hyperemia in conjunction with other nonoxidative products of metabolism in parallel with shifts in pH in the intracellular fluid, since the time of adenosine accumulation in brain tissue coincides with the formation of lactic acid (Mistry, Drummond, 1986). A correlation was found between the dilatory action of adenosine, pH medium and the content of some inorganic ions in cerebrospinal fluid (CSF). When the pH in CSF shifts toward acidosis and potassium ions concentration increases, the attenuation of dilatory effect of adenosine on the smooth muscles of the feline pial arteries is observed (Wahl, Kuschinsky, 1977). Despite a large number of works which are concerned with the study of the mechanism of adenosine action on vascular smooth muscles, much remains unresolved. There is a lack of data relating to the influence of adenosine on the activity of Na,K-ATPase of the smooth muscle cellular membrane in cerebral arteries. Dependence of the adenosine effect on the smooth muscles of the coronary and femoral arteries upon the activity of Na-K pump of all membranes has been already demonstrated. The role of adenosine in the performance of vasoconstrictor response of vessels remains obscure. It was studied in the rabbit's kidney and canine hypodermic lipid tissue in response to sympathetic nerves stimulation with the introduction of noradrenaline. In these experiments the mechanism of adenosine action on the vasomotor reaction is explained by the authors not to be by its direct action on smooth muscles, but it is mediated through suppression of noradrenaline released from nerve

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terminals and the enhancement of the postsynaptic reaction to noradrenaline (Hedqvist, Predholm, 1976). There is a discrepancy in the data on the mechanisms of dilatation induced by adenosine and calcium. There is evidence indicating that in the mechanism of adenosine action the systems of calcium transmembrane transport to a smooth muscle cell are not involved (Kovach, Dora, 1982; Dutta et al.,1984). However the results of experiments with the large pial arteries reveal that a direct action of adenosine is realized by the superficial membrane of a smooth muscle cell (Gokina, Gurkovskaja, 1981) through the suppression of input extracellular calcium in the smooth muscle cell and direct decrease of intracellular concentration of calcium ions (Gokina et al.,1983; Nikitina, Shuba, 1983). Carbonic acid is capable of affecting the smooth muscle tone (Mchedlishvili et al.,1975; Azin, 1981; Harder, Madden, 1986). A large volume of evidence is available in the literature about the CBF increase when CO2 partial pressure is increased in the arterial blood (Kobari et al.,1987; Vainshtein et al.,1988). Threshold values of PCO2 have been determined, then a realization of vasodilatory effect in cerebral arteries begins. The initial rise of CBF manifests itself at CO2 tension in the arterial blood equal to 45-50 mm Hg (Patterson et al.,1955). Further increase in PCO2 in the arterial blood defines a linear increase of CBF intensity. The highest sensitivity of cerebral vessels to CO2 appears to be from 20 to 60 mm Hg in the arterial blood.(Reivich, 1964). Evidence exists for the interrelationship between PCO2 in the arterial blood and in brain tissue - when PCO2 increases in the blood there is a proportional increase of PCO2 in brain tissue also (Plum, Duffy, 1975; Seylaz et al.,1977). On the brain surface (Meyer, Gotoh, 1961) CO2 tension is measured at 8-10 mm Hg higher than in the arterial blood. The activation of the cortical neurons is also known to result in a definite increase in CO2 content in nerve tissue. Thus, while recording PCO2 on the surface of the cat's visual cortex by means of conductometry PCO2 increase by 2.5-4 mm Hg (Moskalenko et al.,1975) was obtained during activation of neurons in this area in response to photic stimulation. According to data of Demchenko (1983), blood flow in the cat's cerebral cortex increased by 0.03 ml/g/min in hypercapnia. At mean intensity of cortical blood flow in cats 0.9 ml/g/min this makes up 20%, whereas at electrical stimulation of the cortical neurons local blood flow increase makes up 80%, and at seizure activity 300%. So, the opinion that CO2 is a dilatator in the system of cerebral arteries appears to be a fairly well known fact. Nevertheless, the possibility of direct influence of CO2 on the smooth muscles of cerebral vessels and putative mechanisms of action of hypercapnia remains an open issue so far. There are two versions of postulates concerning this matter: neurogenic and humoral. Neurogenic hypothesis is supported by equivocal experimental data whose interpretation provides no distinct knowledge of the role the reflex nervous mechanisms play in the realization of hypercapnic effect. Mchedlishvili et al. (1975) bring up evidence for the responses of pial arteries occurring independently of PCO2 direct influence and intravascular pressure. The vascular responses are present due to the reflex feedback mechanism, which is initiated by nervous impulses from the pressoreceptor wall of the vessel or brain tissue. Additional data by Demchenko and Krivchenko (1980) has demonstrated that following the transaction of connections between the cortex and subcortical structures in cats, blood flow in the isolated hemisphere increases two times less than in the intact hemisphere during inhalation of 5-7%

Main Theories of Autoregulation of CBF

27

of CO2. At the same time there is opposing information. A lesion in the nuclei of the solitary tract in rats did not result in any changes in regional blood flow in the cortex, abolished autoregulation and the cerebral vascular responses to hyper- or hypocapnia did not alter thereat (Ishitsuka, 1986). In the experiments of Iadecola et al. (1986) rise in blood PCO2 was followed by CBF increase in all the areas under study including atropine treated cortical regions. Thus, there are fairly discrepant data on the role played by the reflex mechanism in mediation of CO2 vasomotor effects. There is also evidence on the humoral nature of the mechanism of action of CO2 on the smooth muscles of cerebral arteries. The vasoactive action of CO2 is supposed to be mediated through the increase in blood and liquid of the vasoactive substances (such as choline, potassium, adenosine, etc). A key role in the instalment of this mechanism in hypercapnia has been assigned to changes in pH of extracellular medium (Meyer, Gotoh, 1960; Meyer et al.,1961; Laptook, 1985; Adams et al.,1986). Indeed, reactivity of cerebral arteries to CO2 depends in a definite measure to pH of medium. Thus, CO2 effects were shown to be enhanced during an increase in the pH of the medium and somewhat attenuated when it decreased (Azin, 1981). It is known that pH does have an independent vasoactive action (Kuschinsky, Wahl, 1978: Harder et al.,1985) and, consequently, may exert a modulating influence on CO2 effects. In preparing the internal carotid arteries, Azin (1980) demonstrated that there are relatively independent effects of the CO2 and of the pH medium during the action on the smooth muscles of cerebral arteries. The results of these studies verify that CO2 actually acts on the smooth muscles of major cerebral arteries at a stable pH medium. Studying the effect of CO2 on the smooth muscle membrane and its role in realization of CO2 effects remains scant. Fragments of the feline middle cerebral artery show that PCO2 attenuation below the physiological value and at a pH = 7.4 lead to depolarization of the smooth muscle cell membrane. Alteration in the membrane resting potential is underlied by calcium permeability (Harder et al.,1985). Understanding the calcium mechanism which relaxes smooth muscles under the action of hypercapnia is still incomplete. An important role in the regulation of local CBF, apart from adenosine nucleotides and CO2, are inorganic ions, primarily ions of potassium. Variations in the K+ ion concentration in the solution may lead to diverse reactions of the cerebral arteries. Upon administration of an artificial liquid devoid of K+ ions to the brain surface of cats constriction of pial arteries, occurred while application of the identical solution, with K+ ions from 5 to 12 mcM/l resulted in vasodilation and enhancement of cortical blood flow by 40% (Moskalenko et al.,1975). Within the extracellular spaces under normal shifts in functional activity of nervous cells, changes in K+ concentration occur (Demchenko, Krivchenko, 1980). The process of K+ release from the cell during activation of neurons has a considerable velocity (Demchenko et al.,1975; Lin, 1985), high diffusion capability and a potent vasoactive action. This supports the assumption that K+ ions in conjunction with the neurogenic loop of regulation create a component of local CBF regulation. (Moskalenko et al.,1975). There are findings that indicate that K+ ions act directly on the smooth muscles of large cerebral arteries and that this effect does not depend on the pH of extracellular spaces. (Demchenko et al.,1975; Moskalenko, 1984). However, for this to occur definite concentrations of Ca++ ions in perivascular fluid have to be present.

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Direct action of K+ on the smooth muscle cells of cerebral arteries have been studied only on the isolated preparations of large vessels (Orlov et al.,1972; Azin et al.,1977). Utilizing preparations of the bovine middle cerebral artery with low K+ concentration (10 mM) resulted in a marked relaxation of smooth muscles. In the same work it was reported that in higher concentrations, K+ causes a contractile reaction. Similar findings were obtained by Picard et al. (1976). The distinct reactions with K+ concentration is explained by the fact that low concentration elicits hyperpolarization of the smooth muscle cell membrane along with relaxation, while a high concentration causes depolarization along with contraction (Winn et al.,1980). Substances formed in the process of metabolism, particularly under conditions of oxygen deficit, accumulate in the tissues which will lead to the dilatation of the vessels. However, in order to confirm the metabolic theory of autoregulation it is still necessary to prove that in tissues whose organs are at rest the phenomenon of autoregulation is permanently in a concentration of substances having a vasodilatory action that would be counteracting to the action of an agent, thus tending to constrict the vessels. Support for such a statement has been observed by a number of investigators who initiated the inflowing blood into the organ by artificially forcing venous blood from another organ (Anrep, Blalock, Saaman, 1934; Anrep, Saalfeld, 1935; Ross, Kaiser, Klocke, 1964). No correlation was found between the action on the vessels of the replacement of arterial blood by venous blood and the effect of blood flow attenuation (Daugherty et al.,1967; Guyton, 1977), Autoregulatory events occurring during short-lasting limitation of blood flow, need to be explained by the metabolic theory of autoregulation. During the process of autoregulation one can observe constriction of blood vessels in response to a rise in arterial pressure. Therefore, the metabolic theory of autoregulation has to agree that concentration in tissues with vasodilatory substances are always in direct proportion to the value of blood flow. If this is the case then it must also follow that during elevation in pressure blood flow will first increase while the concentration of the dilatator attenuates, predetermining enhancement of the vascular tone and therefore return of blood flow to the original value. Indeed, there are observations indicating that the period of artificial blood flow increase is occasionally followed by constriction of vessels designated as reactive ischemia (Hyman, Paldino, Zimmerman, 1963; Levtov, 1967), though in other studies it has been shown that the constrictory reaction of the vessels to pressure rise is not at all necessarily prestalled by blood flow increase (Held et al.,1972; Meladze et al.,1977; Mitagvaria, 1983). Another explanation for the autoregulatory vascular reactions to intravascular pressure rise is the idea that the vascular tone is determined by concentration of some substance toning up the elements of vascular wall. This substance should be carried in the blood. First, we are unaware of products of tissue metabolism to which a permanent stimulating action on the vascular smooth muscles could be ascribed, and, second, if this is the case the amount of this substance should increase as blood flow increases. There are studies in which such an idea has been justified. To the Krebs' solution a 2% blood plasma of the same animal to produce or enhance contraction of the embedded in the solution strip of isolated artery from dogs, rabbits or rats (Hysell, Bohr, 1970). The nature of the active agent is not identified. The pressor acting substance, which is similar to angiotensin, was also found to be in the extract from the walls of large arteries (Laszt, 1969).

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Lastly, one must be careful not to assume that the predominantly vasodilatory action of nonspecific metabolites is a constant. One of the most important statements in general physiology states that the effect of any stimulus depends on its intensity and on the state of the tissue it acts on. Thus for example, as pointed out above, when a specific concentration in the products of tissue metabolism is reached, dilation of the vessels usually occurs, and vasodilation is then replaced by vasoconstriction (Johansson, Bohr, 1966; Konradi, Levtov, 1970). Consequently, under conditions which are not yet understood, the dilatatory action of metabolites may then be converted into a constrictory action. Data accumulated during last decade suggest that Nitric Oxide (NO) is important for hemodynamic control and metabolic regulation (Kingwell, 2000). Although still controversial, NO of endothelial origin may potentiate hyperemia. Mechanisms of NO release include both acetylcholine derived and elevation in vascular shear stress (Kingwell, 2000). Use of phase-contrast magnetic resonance imaging shows that hypoxia-induced cerebral vasodilatation in humans is mediated by NO (Van Mill et al., 2003). In summary it should be noted that at present there is no reliable evidence which would ascribe a crucial role in the autoregulatory process to a permanent vascular effect of a chemical substance formed outside the vascular walls. There is not a specific link in metabolic process in the tissue to a specific hormone, which could be considered as the factor in the regulation of tonic tension of the vascular smooth muscles (Betz, 1972, 1976, 1977; Konradi, 1973; Kuschinsky, Wahl, 1976, 1978; Berne et al.,1981; Wei, Kontos, 1982; Vanhoutte, 1982).

2.3. NEUROGENIC THEORY OF AUTOREGULATION As proposed by neurogenic theory, disturbances in cerebral blood circulation are perceived by the receptive zone. Depending on the direction of changes in perfusion pressure, relevant signals are thus sent along the dilatory or constrictory effectors, innervating the cerebral vessels. This theory of autoregulation of cerebral blood supply is supported by abundant experimental findings, explanation of which is lacking in other theories. Let us consider these experimental data from a structural approach. In the cerebral vascular bed there are baroreceptor zones, which may in principle, be the initial link in the chain of the neurogenic mechanisms of autoregulation. (Madjagaladze, 1960; Mikhailov, 1961, 1965; Kuprijanov, Jitsa, 1975). The presence of the executive link is confirmed both by histological and ultrastructural studies, which testify to the rich adrenergic and cholinergic innervation of cerebral vessels including arterioles up to 15-20 mcm in diameter (Falck, Mchedlishvili, Owman, 1965; Sato, 1966; Nielson, Owman, 1967; Lavrentieva et al., 1968; Iwayama, Furness, Burnstock, 1970; Nelson, Rennels, 1970; Edvinsson, McKenzie, 1977; Gero et al., 1978, Bleyers, Cowen, 2001). A clear-cut uneven distribution of nerve terminals throughout the entire length of the vessel, which was visualized on the example of arteries of the circle of Willis, was established (Pereira, 1979). This brought Moskalenko (1978) to assume that in cerebral vessels there may exist local controlling zone capable of regulating the lumen of arteries in separate regions, thus resulting

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in the origination of the so-called "sausage effect", which is observable during some kind of influences on cerebral vessels (Adamia, 1986). The most richly innervated are the large cerebral arteries, especially those at the cranial base where both the adrenergic and cholinergic nerve terminals are represented. They are located at the adventitium of the vessels and are very near to each other. Thus functional interaction is possible. (Sercombe, Wahl, 1982a). The internal carotid artery has a dense innervation apparatus, particularly at its curvature (Borodulia, Plechkova, 1977). The pial and intracerebral arteries are poorly innervated and are predominantly supplied with adrenergic fibres (Lindvall, Biorklund, 1974), although there is data indicating the presence of serotonin- and peptidergic innervation. This is a common characteristic of the intracerebral arteries and arterioles (Brayden, Bevan, 1985; Yokote et al., 1985). The source of sympathetic adrenergic innervation of cerebral vessels is the superior cervical sympathetic ganglia (Sercombe et al., 1975; Traystman, Rapela, 1975). Evidence is available completely rules out the significance of the stellate ganglion in relation to regulation of cerebral circulation (Peerless, Yasargil, 1971). Some authors are sure that it is namely from this ganglion that the cerebral, major and inferior cerebral arteries are innervated (Nielsen, Owman, 1967; Kajikawa, 1969). Some hold to the understanding that the vessels of the cerebral vertebral reservoir have a double sympathetic innervation (Owman, Edvinsson, Nielsen, 1974; Edvinsson, 1975). The concept has also been set forth concerning the participation in this process of central formations localized namely in locus ceruleus whence the sympathetic fibers run to the vessels in the hypothalamus and the cerebral hemispheres (Mitchel et al.,1975), as well as to the fastigial nucleus of the cerebellum and a region of the dorsal medullary reticular formation (Doba, Reiss, 1972a; McKee et al.,1976; Reiss et al.,1982; Devdariani et al.,1989). Virtually in all studies which dealt with the cerebral vessels' innervation there is an indication that neural fibers terminate on the arterioles and do not spread over the capillaries. More complex in understanding is the matter of the source of parasympathetic cholinergic fibers. As far back as 1933, Finesinger and Putman pointed out that vasodilatory fiber must be found to be contained in the vagus nerve. The most popular hypothesis was that of Chorobski and Penfield (1932) which had been advanced by them a year previous their hypothesis maintained that the vasodilatory pathways are connected with the parasympathetic cholinergic fibers of the facial nerve. The same idea has been developed by Edvinsson et al. (1973). At the same time, in the opinion of Motavkin et al. (1981), parasympathetic vasodilators are present in none of the indicated nerves and this coincides with the viewpoint of Lazarthes (1956) who thinks that there is no authentic data which confirms on the presence of vasodilators in the craniocerebral nerves. Afferent innervation in the brain vessels is as abundant as the efferent innervation. By virtue of pharmacological methods and with the use of electrical stimulation of the cerebral sympathetic nerves the presence of both alpha- and beta-adrenoreceptors have been shown to be throughout the vascular bed and stimulation of alpha-adrenoreceptors has been found to result in constriction, while the beta-adrenoreceptors cause dilation of cerebral arteries. This link of the neurogenic mechanism of regulation of cerebral blood supply appears to be best studied to-date (as compared to the efferent link theory). In the theory, there exist two kinds of sources of afferent signals: baro - and chemoreceptors. The first receptors are found

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localized in the sinocarotid and aortal zones and at the sites of bifurcation of the large arteries, in the bulb of the jugular vein and in the dura mater. Chemoreceptors, as they are known, are located in the area of the carotid sinuses. It is also believed that afferent signals which influence the vessels originate from special tissue receptor formations in the brain, what has been shown to be the case in other organs (Moskalenko, Beketov, Orlov, 1988). The physiological role of the autonomic innervation of cerebral vessels remains unclear and the question of its involvement in the autoregulatory vascular reactions is controversial. This is so because of possible systemic reactions making it difficult to single out the direct action of adrenergic and cholinergic neurotransmitters on cerebral vessels (Kuschinsky, Wahl, 1978) and secondary effects which may mask the direct action of neurotransmitters on the cerebral vessels. There are other important circumstances that must be considered. When pharmacological agents are administered systemically, they are not certain to reach the smooth muscle cells because of the existence of the blood-brain barrier (Oldendorf, 1971). It is well established that the cerebral capillaries vary in their barrier properties from those of other organs both functionally and morphologically (Rapoport, 1976; Hardebo, Owman, 1980). Due to a particular morpho-functional organization of the endothelium (wherein the barrier is localized), only individual types of neurotransmitters are able to penetrate into it, and choice of one or another type of neurotransmitter may vary from area to area (Owman, Hardebo, 1982). This will account for the fact that only in newborn animals in which the blood-brain barrier has not yet evolved, one may observe the effects of the action of many transmitters (Loizou, 1970). If the barrier is disrupted for one or another reason, there arises quite a novel situation and it then becomes difficult to predict the effect of circulating neurotransmitters on the cerebral vessels. Other than the direct action, they, penetrate into the capillaries, enter the cerebral parenchyma, modulate the functional activity and metabolism of cerebral tissue. Whether the vessels vasodilate or vasoconstric, depends on the balance of forces which act on the vessels (Owman, Hardebo, 1982). One has to agree with the opinions of Moskalenko, Beketov and Orlov (1988) that except for the neural influences on the cerebral vessels of sympathetic and parasympathetic nature, verification of other putative types of innervation to the cerebral vessels such as purinhistamine-, and peptidergic ones, and their effects remains to be proven. Studies are being actively pursued at present. The authors take such a stand because none of the above mentioned types of innervation meet the five basic requirements which determine the presence of the neurogenic principle of regulation. 1) The transmitter should be synthesized and contained in the neural stems; 2) It should be released during stimulation of the nerves originating only in them and not in the surrounding tissues; 3) There should be specific receptors for the given transmitters; 4) There must be a special system of inactivation of this transmitter; 5) There should be found specific chemical agents blocking or potentiating the effect of action of this transmitter during stimulation of the nerves or exogenous administration of the transmitter (Burnstock, 1977). Now let us become more detailed in our analysis of data which has been obtained from the functional approach and which serves as the prerequisite for recognition of neurogenic type of regulation of local CBF.

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In order to study the role of the neurogenic mechanism of regulation of cerebral blood supply, vascular denervation or stimulation of the sympathetic system is employed. In obtaining experimental data diverse interpretations have been made. Bilateral sympathectomy in monkeys led to an increase of blood flow volume velocity in the frontal-temporal area (Harper, 1972). Considerable increase in CBF was noted also in experiments on cats an hour after the removal of the superior cervical ganglion (Teplov, 1980). While vascular denervation resulted in no disturbance of autoregulation, but shifted the course of its curve to the left. This enhances the possibility of cerebral blood supply regulation as arterial pressure falls and impairs it at it elevates. (Teplov, 1980). A large number of studies were undertaken utilizing electrical stimulation of the sympathetic nerves. Basic data is analyzed and summed up in the papers published in the Proceedings of a Symposium held in Iowa in 1981 (Eds.: D.Heistad and M.Marcus). Most of the investigators consider the cerebral vascular responses to electrical stimulation of the sympathetic system to be considerably less pronounced than of other vascular beds. The stimulatory effect manifested itself in diverse ways in various species of animals. For example, under normal conditions, sympathetic stimulation causes decrease in blood flow in primates (Heistad et al., 1978) and rabbits (Sadoshima et al., 1981) up to by 20% of the original value, while in dogs and cats this does not occur. It has been demonstrated that in rabbits and monkeys the sympathetic stimulation reduces CBF at the beginning and within 2-5 min, in spite of the stimulation being continued, blood flow returns to the initial level (Sercombe et al., 1979; Marcus et al., 1979). It is very clear that the method used for recording of CBF is crucial. If the measurement is made by clearance of some inert gases which takes several minutes for each trial, it is quite likely that the stimulation effect will not be detected at all. This seems to be the reason for the controversial interpretations of the effect of sympathetic stimulation on the cerebral blood circulation (James et al., 1969; Harper et al., 1972). In many laboratories it has been shown that electrical stimulation of the sympathetic system suppresses the CBF increase at an abrupt elevation of systemic arterial pressure (Bill, Linder, 1976; Edvinsson et al., 1978). The increase in local CBF (in response to hypertension) is more apparent and clear-cut in the gray matter than in the white, and the same ratio is maintained in regards to the effect of electrical stimulation of sympathetic system (Heistad et al., 1982). The authors believe that during acute hypertension, electrical sympathetic stimulation suppresses the passive drive of blood flow after systemic arterial pressure, which then safeguards the disruption of the bloodbrain barrier. Experiments carried out on cats Auer et al. (1982) have shown that electrical stimulation of the sympathetic nerves lead to constriction of the pial arteries. The large arteries appeared to be considerably more constricted than the small ones. However, under the same stimulation while blocking the alpha-adrenoreceptors which was induced by phenoxybenzamine no constriction occurred. But by blocking the beta-adrenoreceptors the stimulation nevertheless led to constriction of large vessels, although small ones remained virtually unaltered. By evaluating the data on the constriction of the pial arteries in cats which occurs with electrical stimulation of the sympathetic nerves (Wei et al., 1975; Kuschinsky, Wahl, 1975; Auer et al., 1982) Busija et al. (1982) have made reasonably conclusion that such constriction should then lead to a marked decrease in blood flow volume velocity. This

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phenomenon has not as yet been observed (Alm, Bill, 1973; Bosivert et al., 1977; Heistad et al., 1978). Most authors consider that there exist some compensatory mechanisms which support the steadiness of cerebral blood circulation, (Harper et al., 1972). Looking to evaluate such mechanisms, Busija et al. (1982) made a simultaneous recording of the diameter of the pial arteries and CBF linear velocity during electrical stimulation of the sympathetic nerve. Constriction of the pial arteries (at invariable SAP) appeared to be accompanied by an increase in blood flow linear velocity and as a result, volume velocity remained unaltered. The authors arrived at the conclusion that an increase in blood flow linear velocity is due to a decrease in peripheral resistance at the expense of dilation of the smallest arteries. At the end of past century it has been demonstrated that during sympathetic stimulation, constriction of the pial veins is more pronounced than of the pial arteries (Auer, Johansson, 1980; Auer et al.,1981), while at the same time considerable changes occur in the intracranial pressure, shifting the production of the CSF, blood volume and blood flow in the brain (Edvinsson, McKenzie, 1976; Auer et al.,1981, 1982). The existence of cholinergic innervation of the pial arteries, has already been shown. Its proof is found both in histochemical and electron microscopical studies (Lavrentieva et al.,1968; Edvinsson et al., 1972; Denn, Stone, 1976; Motavkin, Vlasov, 1976; Motavkin et al.,1981). It is known that the perivascular cholinergic fibers run in parallel to the sympathetic fibers and it is assumed that both systems do allow for possible interaction. In addition it should be taken into account that the distance between the adrenergic and cholinergic terminals in pial vessels does not exceed 25 nm (Nielsen et al., 1975). Pharmacologically it has been demonstrated that cholinomimetics (acetylcholine and nicotine) may inhibit the release of noradrenaline from the sympathetic terminals. Studies in vivo utilizing intracarotid injection of carbochol succeeded in confirming the inhibitory action of the cholinomimetics on the brain sympathetic vasoconstriction (Aubineau et al., 1980). In a similar study with acetylcholine Alberch and Baguenna (1980) also confirmed this hypothesis. Additional review of these experiments again verified that acetylcholine released from the perivascular cholinergic terminals may inhibit the effect of sympathetically induced cerebral vasoconstriction (Sercombe, Wahl., 1982). Ascribing a dilatory function to the parasympathetic cholinergic innervation of cerebral vessels is the most debatable question in the neurogenic theory of regulation of cerebral blood circulation. As was previously pointed out, parasympathetic innervation of cerebral vessels occurs by way of the facial nerve; but there are other cranial nerves as well, namely the third, ninth and tenth (Vasquez, Purves, 1979). Stimulation of the facial nerve brings about dilation of the pial arteries (Chorobski, Penfield, 1932; D'Alecy, Rose, 1977), although, other authors have failed to obtain such effects by stimulation (Stjernschants, Bill, 1978; Busija, Heistad, 1980). In the studies of Linder (1981) the facial nerve of rabbits were transsected on one side. Experiments were done without electrical stimulation. Transsection appeared not to disturb the vasodilatory tone under conditions of both normotension and hypertension, thus autoregulation was fully maintained. Further electrical stimulation of the facial nerve on the intact side did not lead to any changes in total or local blood flow in the brain. Note that the blood flow intensity was measured by use of injections of microspheres.

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In contrast to Linder's data, in the experiments of Mchedlishvili and Nikolaishvili (1970) a blockade was induced by atropine to the cholinergic receptors which led to a complete disruption of autoregulatory dilatation of the pial arteries. It is from this finding that the authors concluded that the cholinergic nervous mechanism in regulation of cerebral blood supply plays the leading role. The authors understand that to hold this view is quite diametrically opposed to exested theories: "... Cholinergic nerves do not seem to produce dilation by a direct effect on smooth muscle ..." (Duckles, 1982, p..445). Several works could be cited, some proving, others rejecting the role of cholinergic neural mechanism in regulation of cerebral blood circulation (Reynier-Rebuffel et al., 1979; Aubineau et al., 1980; Klugman et al., 1980; Owman et al., 1980; Bevan et al., 1982; Busija, Heistad, 1982, Zhang et al., 2002; Claassen, Jansen, 2006). Such discrepancies in experimental findings in relation to the role of cholinergic mechanism and generally in regards to the neurogenic mechanism in regulation of cerebral blood supply ought to be sought primarily, in the incorrect methodical approach. The majorities of the studies described in this chapter were undertaken with the use of discrete methods for the measurement of blood flow volume velocity (clearance of inert gases, method of microspheres) and utilized the values of the lumen of the pial arteries. Therefore, independent of the mode of influence used, be it pharmacological (administration of adrenoor cholinergic agonists or antagonists) or nonpharmacological (denervation or electrical stimulation of the sympathetic or parasympathetic systems), the experimenter is obliged to record the static characteristics rather than the required dynamic ones. This essential limitation attends the use of the available quantitative methods for blood flow measurement.

Chapter III

ANALYSIS OF DYNAMIC CHARACTERISTICS OF LOCAL CBF AUTOREGULATION In previous chapters we have repeatedly pointed out that for a correct analysis (and later on for synthesis too) of the system of regulation in general and autoregulation of local CBF in particular it is quite necessary to obtain dynamic characteristics of the process under study. In this chapter we will address the basic results that our work has yielded with a goal of obtaining and analyzing the dynamic characteristics of local CBF autoregulation. Electrochemical generation of hydrogen is the method (Stosseck, Lubbers, Cottin, 1974) employed for local CBF recording.

3.1. ANALYSIS OF THE DYNAMIC CHARACTERISTICS OF LOCAL CBF AUTOREGULATION IN CASE OF SHORT-LASTING SAP CHANGES Technique Utilized in Local CBF Autoregulation Studies Experiments were carried out in cats of either sex. The electrode of the construction described above was placed on the surface of the cerebral cortex (its contact pressure was up to 1 g/square cm). Pressor influences caused by ballooning of the inferior vena cava (hypotension) and/or abdominal aorta (hypertension). In each experiment the electrode position for local CBF measurement variated 5-10 times. The number of influences (SAP changes) was determined by the character and pronounceness of the vascular responses and made up from 3 to 12-15. Study on each animal was made by means of 3 different electrodes. Vascular reactivity testing was done by the gas mixture with 8% CO2. The obtained curves in the process of treatment were divided into pairs coupled with local CBF and SAP curves. For the sake of convenience of data processing the SAP curve was approximated to mean systemic arterial pressure (MSAP) curve. In the course of all

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experiments we have done analysis of more than 3000 pairs coupled with MSAP and local CBF curves. The results of the analysis of the data which was generalized for all animals, electrodes and influences have shown that local CBF dynamics and, consequently the vascular responses to SAP variation are not identical. It has been established that saccadic changes in SAP result in the following five types of local CBF changes (Figures 3-6).

Figure 3. Dynamic characteristics of local cerebral blood flow (1) autoregulation during systemic arterial pressure (2) alteration. Responses type 1.

Figure 4. Dynamic characteristics of local cerebral blood flow (1) autoregulation during systemic arterial pressure (2) alteration. Responses type 2 (A,B) and type 3 (C,D).

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Figure 5. Dynamic characteristics of local cerebral blood flow (1) autoregulation during systemic arterial pressure (2) alteration. Responses type 4 (A,B,C) and type 5 (D).

Figure 6. Dynamic characteristics of local cerebral blood flow (1) autoregulation during systemic arterial pressure (2) alteration. Regularities: "a" (A,B); "b" (C) and "c" (D).

1. Fall in local CBF in response to SAP elevation and its rise in response to SAP attenuation (Figure 3). 2. Negligible increase (or invariability) of local CBF during elevation of SAP and a marked decrease in lCBF during SAP attenuation (Figure 4A, B). 3. A marked increase in local CBF during SAP elevation and its insignificant attenuation (or invariability) during a fall in SAP (Figure 4C, D). 4. Almost invariable local CBF both during increase and decrease of SAP (Figure 5AC). 5. When local CBF passively follows both the increase and decrease of SAP occurs (Figure 5D).

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The following regularities appeared to be characteristic of local CBF autoregulation: a) The mode of reaction, as well as its level (within one mode) depends on the amplitude and duration of a disturbing influence of SAP (Figure 6A, B); b) The local CBF is less susceptible to the influence of rapid, high-speed changes in SAP and has the tendency to follow in a passive way its slow changes (Figure 6C); c) Changes in the local CBF get attenuated from influence to influence by the repetition of the latter (Figure 6D). By utilizing purely pressor influences on the system of cerebral circulation no changes in local CBF were observed which could not enter the above mentioned classification. Since all changes that occur in local CBF are apparently influenced by the relevant responses of the regulating blood vessels, then from the point of view of autoregulation of the vascular responses its classification would look like this: Type 1 response: excessive vasoconstricting reaction to an increase in intravascular pressure (IVP) and excessive vasodilatory reaction to a decrease in IVP. Type 2 response: pronounced constricting autoregulatory reaction to an increase in IVP and a weak dilatatory response (or lack of it) to a decrease in IVP. Type 3 response: weak constricting autoregulatory reaction (or lack of it) to an increase in IVP and pronounced dilatory reaction to a decrease in IVP. Type 4 response: equally well pronounced autoregulatory reactions both to an increase and decrease in IVP. Type 5 response: equally poor autoregulatory reactions (or their absence) both to an increase and decrease in IVP. Regularities in the autoregulatory vascular responses: a) Expression of autoregulatory responses depends on both the amplitude and duration of the disturbing changes in IVP; b) Autoregulatory responses develop preferentially in response to rapid changes in IVP, whereas slow changes in IVP are not accompanied by such reactions; c) If the vessel is subject to a sequence of similar types of changes in IVP, then autoregulation is accomplished more effectively during the subsequent events rather than with the first one. It should be pointed out that it is assumed that there is a direct proportional dependence between SAP and the pressure inside some blood vessel (P): P = A x SAP

(1)

where the coefficient of proportionality A Physiol., 1967, 239, 36. Betz E., Pickerodt V., Weidner F. Respiratory alkalosis: effect on cerebral blood flow pO2 and acid-hase relations in cerebral cortex with a note on water content. Scand. J. Lab. A.Clin. Invest., 1968, 102. Bevan J.A., Buga G.M., Jope Ch.A., Jope R.S., Moritoki H. Further evidence for a muscarinic component to the neural vasodilator innervation of cerebral and cranial extracerebral arteries of the cat. Circulat. Res., 1982, 51, 4, 421-429. Bevan J.A., Duckles S., Lee T. Histamine potentiation of nerve- and drug-induced responses of a rabbit cerebral artery. Circulat. Res., 1975, 36, 647-653. Bevan J.A., Ljung B. Longitudinal propagation of myogenic activity in rabbit arteries and in the rat portal vein. Acta Physiol. Scand., 1970, 90, 703-715. Bicher, H. I. The physiological effects of hyperthermia. Radiology; 1980: 511-513. Bicher H. Autoregulation of oxygen supply to brain tissue. In: Oxygen transport to tissue (Eds. H.Bicher, D.Bruley). New York, Plenum Press, 1973, pp.215-222. Bicher H.I. Increase in brain tissue oxygen availability induced by localized microwave hyperthermia. In: Oxygen transport to tissue - III (Eds. I.A.Silver, M.Erecinska, H.I.Bicher). New York, Plenum Publishing Corp., 1978, pp.347-351. Bicher H.I., Bruley D.F., Reneau D.D., Knisely M.H. Brain oxygen supply and neuronal activity under normal and hypoglycemic conditions. Amer. J. Physiol., 1973, 224, 275282. Bicher, H. I., D’Agostino L., Johnson R.J. Changes in tumor tissue oxygenation induced by microwave hyperthermia. Int. J. Radiat Oncol Phys. 1977; S-2:157. Bicher, H. I., Hetzel FW, Sandhu, T.S. Results of phase I/II clinical trial of fractionated hyperthermia in combination with low dose ionizing radiation. Advances in Experimental Medicine and Biology, Vol 157; pg. 87-97, 1983. Bicher H.I., Hunt D.H., Flacke W.E., Bruley D.F. Autoregulatory mechanisms controlling the supply of oxygen to microareas of brain tissue. Biochem. and Exp. Biol., 1974/1975, 11, 2, 155-161. Bicher H.I., Mitagvaria N.P. Circulatory responses of malignant tumors during hyperthermia. Microvasc. Res., 1981, 21, 19-26. Bicher H.I., Mitagvaria N.P., Bruley D.F. Changes in tumor tissue during microwave hyperthermia. Clinical relevance. Proc. of ISOTT meeting, Louisiana, U.S.A., 1983, p.51. Bicher H.I., Mitagvaria N., Hetzel F.W., Sandhu T. Changes in tumor tissue oxygenation induced by microwave hyperthermia. Ann. N.Y. Acad. Sci., 1980, 335, 20-21. Bicher, H. I., Reneau DD, Bruley D.F., Knisely M.H. Effect of microcirculation changes on brain tissue oxygenation. J. Physiol 1971; 217:689. Bicher, H.I., Sandhu T.S., Hertzel F.W. Hyperthermia and radiation in combination. Int. J. Radiat Oncol Biol Phys 1980; 6:867-870.

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INDEX A abdominal, 9, 11, 14, 35 acceptor, 68 acetylcholine, 23, 29, 33, 190 achievement, 142 acid, 26, 137, 171 acidic, 24, 135, 138, 201 acidification, 140 acidity, 136, 140, 172 acidosis, 13, 25, 67, 72, 139, 180 actin, 205 action potential, 22 activation, 5, 24, 26, 27, 86, 88, 139, 163, 169, 182, 184, 197, 201 active oxygen, 204 activity level, 104 acute, 15, 32, 60, 67, 72, 84, 88, 108, 167, 172, 176, 178, 186, 197, 199, 204 adaptation, 79, 184, 187 adenine, 24, 170 adenosine, 24, 25, 26, 27, 67, 169, 170, 176, 181, 186, 200, 203, 204 administration, 25, 27, 31, 34, 42, 51, 55, 68, 93, 108, 158 ADP, 24, 65, 136 adrenaline, 173 adrenergic neurons, 51 adult, 75, 113, 142 age, 172, 183 agent, 10, 28, 51, 53, 55, 107 agents, 31, 42, 44, 49, 51, 140, 167, 168, 185 aggregation, 141, 158, 159, 169, 174, 184, 193, 201 aging, 180 air, 67, 68, 69, 70, 72, 73

albino, 91, 100, 104, 108, 109 alcohol, 182 alertness, 99 alkalosis, 171 alpha, 2, 30, 32, 49, 55, 109, 175, 184, 189 alters, 88, 95, 162 Alzheimer, 172, 174 amnesia, 108, 109 amplitude, 38, 43, 61, 65, 70, 72, 89, 95, 96, 101, 114, 164 anaerobic, 22, 202 anaesthesia, 11 analog, 3 anastomoses, 3, 181 anatomy, 2, 169 angiogenic, 183 angiotensin, 14, 28, 194 animal studies, 181 animals, 2, 25, 31, 32, 36, 39, 48, 58, 59, 60, 65, 66, 67, 87, 88, 91, 92, 93, 94, 99, 100, 105, 109, 119, 138, 141, 142, 143, 145, 146, 147, 148, 149, 150, 151, 152, 155, 156, 157, 164, 170, 199 anoxia, v, 69, 70, 73, 75, 76, 77, 84, 111, 132, 167, 176, 183 anoxic, 66 antagonist, 49, 50, 108, 109 antagonists, 34, 168, 175 antenna, 189 anticancer, 175 anti-cancer, 136 anticholinergic, 93, 105, 108 antioxidant, 159 antioxidants, 165, 182 antitumor, 186, 204 anti-tumor, 140, 154 anxiety, 89

Index

208

aorta, 9, 14, 35 apnea, 191 apoptosis, 135, 153, 202 application, 1, 2, 4, 17, 24, 27, 48, 55, 58, 59, 89, 124, 126, 135, 136, 137, 140, 201 arginine, 68 argument, 5, 22 arithmetic, 89 arousal, 112, 116, 117, 169 arterial hypertension, 172 arteries, 2, 3, 11, 12, 14, 17, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 43, 75, 108, 109, 126, 163, 168, 171, 174, 178, 179, 183, 186, 187, 193, 202, 203, 204 arterioles, 29, 30, 148, 149, 150, 151, 152, 158, 186, 202, 204 arteriovenous shunt, 196 artery, 3, 10, 25, 27, 28, 30, 50, 72, 109, 169, 171, 173, 181, 182, 189, 198 artificial, 27, 28, 73, 75, 127, 136, 140, 142, 143, 163 asphyxia, v, 9, 72, 73, 75, 76, 77, 78, 184, 200 assessment, 18, 124, 187, 190, 200 assumptions, 111 ATF, 179 ATP, 23, 24, 65, 139, 178, 185 ATPase, 25, 193 atropine, 27, 34, 107, 185 attention, 2, 5, 65, 103, 125, 155 autocorrelation, 113, 114 automation, 22 autonomic, 2, 31 autoradiography, 112 autoregulate, 16 availability, 161, 171 averaging, 15 awareness, 105, 176

B

binding, 3 biochemical, 60, 173, 181 biological, 124, 125, 137, 138, 141, 175, 184 biologically blocks, 107 blood plasma, 28 blood pressure, 9, 11, 21, 24, 39, 172, 177, 178, 179, 181, 187, 201, 204, 205 Blood pressure, 173 blood stream, 10 blood supply, iv, 1, 2, 3, 5, 6, 12, 14, 23, 29, 30, 32, 34, 44, 50, 51, 57, 79, 83, 85, 86, 108, 109, 123, 124, 126, 136, 161, 163, 164, 192, 197 blood vessels, 16, 18, 23, 28, 38, 39, 40, 41, 51, 172, 173, 190, 191, 195, 198, 203 blood-brain barrier, 25, 31, 32, 49, 142 body temperature, 143, 154, 165 body weight, 143, 155 Bohr, 22, 23, 28, 29, 39, 40, 43, 68, 176, 178, 182, 183, 200, 203 boils, 98 bone, 142 bovine, 28, 195, 200 bradycardia, 14 bradykinin, 23 brain damage, 83 brain functions, 1, 65 brain injury, 11, 182, 190 brain stem, 112, 113, 182, 202 brain structure, v, 3, 5, 66, 84, 88, 91, 102, 104, 109, 111, 112, 113, 118, 123, 124, 161, 164 brain tumor, 172 brainstem, 85, 169, 187, 189, 191 branching, 3 brass, 126 breakdown, 24, 25, 140, 142 breathing, 68, 77, 200 by-products, 24

C bacteria, 136 baroreceptor, 29, 202 barrier, 25, 31, 184, 189, 195 basilar artery, 3 BBB, 163, 184 Bcl-2, 136 behavior, 2, 77, 91, 95, 98, 99, 100, 101, 102, 106, 164 beta, 2, 30, 32, 51, 53, 172, 189, 198 bicarbonate, 173, 187 bifurcation, 31

Ca++, 27, 186 calcium, 26, 27, 176, 186, 193 caliber, 38 cancer, 6, 124, 139, 141, 169, 173, 177, 179, 180, 186, 188, 194, 196, 197, 200, 201, 203, 204 cancer treatment, 141, 177 capacity, 9, 15, 16, 38, 40, 42, 58, 60, 136, 196 capillary, 3, 12, 67 carbohydrate, 176 carbohydrate metabolism, 176

Index carbon, 176, 181, 186 carbon dioxide, 176, 181, 186 cardiac output, 196 cardiopulmonary, 167, 189, 196 cardiopulmonary bypass, 167, 196 cardiovascular, 101, 159, 185 cardiovascular disease, 185 cardiovascular risk, 159 cardiovascular system, 101 carotid arteries, 3, 11, 27 carotid sinus, 31, 195 carrier, 113 caspases, 136 catecholamines, 187, 198 catheter, 75, 142, 174 cathode, 18, 175 cats, 24, 25, 26, 27, 32, 35, 44, 52, 55, 67, 75, 86, 87, 89, 112, 113, 120, 141, 167, 169, 173, 175, 176, 178, 180, 184, 187, 196, 202, 203 cell, 26, 27, 28, 68, 84, 136, 137, 138, 140, 141, 145, 146, 147, 151, 159, 174, 178, 180, 188, 191, 192, 200, 201 cell cycle, 137, 201 cell killing, 141 centigrade, 135 central nervous system, 88, 181, 199, 200, 201 cerebellum, 30, 112, 124, 131, 132, 133, 165, 189 cerebral arteries, 3, 25, 26, 27, 28, 30, 167, 168, 186, 187 cerebral cortex, 1, 2, 16, 26, 35, 38, 43, 50, 52, 54, 55, 56, 66, 75, 77, 83, 84, 86, 87, 96, 97, 100, 101, 102, 104, 105, 107, 109, 124, 125, 126, 130, 131, 132, 142, 144, 145, 146, 147, 148, 149, 155, 156, 157, 158, 168, 169, 171, 174, 177, 178, 181, 183, 187, 189,Ű199, 201 cerebral damage, 197 cerebral function, 165, 183 cerebral hemisphere, 30, 92 cerebral hypoxia, 181 cerebral ischemia, 24, 111 cerebral metabolism, 88, 111, 142, 168, 180, 183, 195 cerebrospinal fluid, 25, 142, 143 cerebrovascular, 5, 89, 165, 176, 194, 196, 199, 200 certainty, 60, 132 cervical, 30, 32, 167, 199 channels, 13, 50, 60, 76, 181 charm, 69 chemical, 29, 31, 43, 135, 187 chemical agents, 31

209

chemical composition, 43 chemical reactions, 135 chemoreceptors, 30, 68, 195 chemoresistant, 137 chemotherapy, 135, 136, 138, 141, 153 chiasma, 3 children, 183 cholinergic, 5, 29, 30, 31, 33, 34, 44, 49, 53, 54, 55, 93, 105, 107, 108, 161, 173, 175, 180, 185, 190, 195 cholinergic block, 44, 49, 53, 55 choroid, 176 chronic, 15, 83, 85, 125, 170, 183 circulation, iv, 1, 2, 3, 4, 5, 6, 10, 11, 21, 29, 30, 32, 33, 38, 43, 51, 59, 65, 86, 92, 109, 111, 113, 123, 140, 158, 163, 167, 173, 174, 176, 177, 178, 179, 180, 182, 185, 187, 190, 191, 192, 193, 195, 196, 197, 198, 200, 201, 203 classical, 4, 112 classification, 38 classified, 104 cleavage, 136 clinical, 2, 11, 14, 83, 104, 112, 124, 125, 126, 139, 140, 141, 171, 172, 173, 191 clinical trial, 171 clinics, 6, 85, 125 closure, 120 CNS, 88, 125, 165 CO2, 12, 23, 26, 27, 35, 60, 75, 92, 98, 168, 169, 175, 179, 197 coagulation, 188 cognitive, 99, 101, 165 cognitive activity, 165 cognitive map, 99 collateral, 3, 14, 179 communication, 3, 200 compatibility, 23 compensation, 57, 58, 60, 163, 164 complementary, 198 complexity, 2, 195 compliance, 172 components, 22, 40, 44, 46, 47, 48, 55, 56, 57, 58, 59, 60, 61, 88, 164, 184, 203 composite, 58 composition, 143 compression, 13, 184 computer, 42, 84, 126 concentration, 12, 24, 25, 26, 27, 28, 29, 65, 67, 137, 139, 173, 176, 193, 199 concrete, 13, 39, 40, 70, 120

Index

210

conduction, 173 confidence, 155, 156 configuration, 91, 92, 94, 95, 101 consciousness, 65 consensus, 164 consolidation, 93, 98, 102 construction, 18, 19, 35, 91, 93, 126 consumption, 1, 105, 154 continuing, 99 continuity, 102 contralateral hemisphere, 127, 132 control, 4, 13, 24, 29, 51, 52, 72, 85, 87, 93, 100, 102, 112, 119, 124, 143, 145, 155, 170, 172, 175, 179, 183, 184, 185, 186, 187, 191, 194, 195, 198, 203 control group, 112, 155 controlled, 14, 39, 75, 142, 143, 184 convective, 167 conversion, 23 coronary arteries, 176 correlation, 3, 25, 28, 38, 46, 65, 67, 70, 75, 85, 86, 93, 96, 100, 102, 111, 114, 120, 137, 186 correlation coefficient, 114 correlation function, 100 cortex, 1, 26, 49, 50, 52, 53, 54, 55, 66, 76, 83, 84, 85, 86, 87, 88, 89, 96, 97, 103, 104, 113, 114, 117, 118, 119, 124, 131, 132, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 157, 165, 180, 188, 193 cortical, 24, 26, 27, 43, 83, 84, 85, 86, 88, 91, 93, 98, 100, 103, 104, 147, 150, 151, 178, 183, 186, 198 cortical neurons, 24, 26, 84, 103, 183 coupling, v, 5, 16, 22, 67, 83, 84, 88, 101, 102, 104, 109, 120, 163, 164 cranial nerve, 33 craniotomy, 143 critical analysis, 136 critical points, 165 CSF, 25, 33, 167 culture, 125 cyclic AMP, 201 cytoplasm, 159 cytotoxic, 137, 139 cytotoxic agents, 137

D data analysis, 112 data processing, 35 death, 126, 188 decay, 204

decerebration, 192 deduction, 41, 72 defense, 105, 106, 107 deficiency, 66, 79 deficit, 28, 79, 105 definition, 99 deformability, 141, 159 deformation, 5, 22 degree, 2, 3, 14, 15, 23, 25, 38, 43, 61, 70, 75, 85, 88, 89, 136, 140, 173 delivery, 103, 187 delta, 85 demand, 67, 70, 71, 72, 77, 84 dementia, 83, 183 denaturation, 184 dendrites, 148 denervation, 32, 34, 109, 161, 164 density, 3, 84, 129, 147, 148, 149, 152, 163 depolarization, 27, 28 depression, 84, 176, 190 desire, 143 destruction, 124, 140, 157 desynchronization, 2, 84, 85, 96, 118, 125 detection, 178 deviation, 19, 45, 57, 61, 92, 95 differentiation, 1, 44, 89, 204 diffusion, 15, 17, 27, 137 dilation, 9, 24, 29, 30, 33, 42, 43, 51, 52, 139, 196 dipole, 125 direct action, 25, 26, 31, 120 direct measure, 2, 11, 15 discharges, 68, 125, 178 discomfort, 86 discrimination, 103 diseases, 86 displacement, 72, 77 disposition, 127, 128 distribution, 25, 29, 42, 66, 78, 83, 84, 85, 86, 87, 147, 148, 149, 152, 164, 180, 185, 203 diurnal, 177 division, 135 DNA, 136, 137 dogs, 25, 28, 32, 68, 105, 141, 173, 174, 175, 177, 178, 180, 181, 186, 201, 202 dopamine, 168 Doppler, 15, 174 dreaming, 191 drug addict, 136 drug addiction, 136 drug-induced, 171

Index drugs, 93, 105, 184, 188, 200 ductus arteriosus, 199 dura mater, 25, 31, 142 duration, 13, 14, 17, 38, 47, 72, 76, 89, 95, 99, 114, 115, 117, 128, 135, 136, 137, 140, 144, 153, 154, 202

E ecological, 124 edema, 72, 139 EEG, 2, 65, 70, 85, 105, 112, 125, 169, 178, 183, 195 EEG patterns, 183 efferent nerve, 163 ego, 190, 197 elaboration, 93 elasticity, 40, 41 elderly, 83, 141 electric current, 17 electrical, 1, 2, 22, 24, 26, 30, 32, 33, 34, 67, 68, 69, 84, 85, 86, 111, 112, 113, 116, 117, 118, 123, 124, 125, 132, 161, 163, 168, 169, 172, 175, 176, 181, 183, 184, 188 electrochemical, 17, 75, 92, 126 electrodes, 17, 35, 36, 66, 69, 89, 92, 93, 96, 113, 127, 128, 129, 167 electroencephalogram, 65 electrolysis, 186 electromagnetic, 124, 125 electromagnetic waves, 124, 125 electron, 33, 142, 178 electron paramagnetic resonance, 142, 178 electrons, 68 electrophysiological, 92, 104, 112 elongation, 178 emission, 15, 188 emotional, 89, 90, 100, 101, 102, 104, 105, 106, 108, 109, 111, 164, 165, 170 emotional reactions, 89 emotional state, 90, 109 emotional stimuli, 89, 100, 170 emotions, 89, 100, 101, 105, 164, 165 employment, 125 endogenous, 187 endothelial cell, 25 endothelial cells, 25 endothelium, 25, 31 energy, 1, 67, 68, 69, 84, 85, 101, 112, 126, 137, 139, 182, 185, 186, 189, 191, 200 energy consumption, 1, 84

211

environment, 43, 61, 69, 102, 135, 138, 168, 201 environmental, 57, 61, 100, 136, 140, 164, 165, 194 environmental factors, 194 environmental stimuli, 100, 164 enzymatic, 24 enzymes, 184 epilepsy, 83, 183 epileptic seizures, 172 epinephrine, 194 equilibrium, 109, 173 erythrocyte, 158, 174, 193, 201 erythrocytes, 141, 148, 150, 151, 157 erythrocytosis, 141 estimating, 118 evidence, 1, 2, 4, 10, 16, 21, 23, 26, 27, 29, 43, 59, 77, 89, 101, 102, 103, 142, 171, 183, 192, 198 excitability, 113, 125 excitation, 59 exclusion, 55, 60 exercise, 180, 185 exogenous, 31, 187 experimental condition, 16, 39, 43, 56, 61, 88, 91, 92, 93, 99, 102, 105, 117, 118, 152, 162 expert, 4 experts, 6 exponential, 140 exposure, 4, 45, 125, 126, 127, 129, 130, 131, 132, 133, 135, 136, 137, 138, 140, 143, 144, 145, 147, 148, 150, 152, 153, 157, 158, 165 expulsion, 120 extracellular, 24, 26, 27, 67, 68, 172, 186, 194, 199 extrinsic, 183 eye, 83, 88, 112, 117, 119, 172 eye movement, 112, 117, 119, 172

F facial nerve, 30, 33, 188 fear, 105, 106 feedback, 13, 26, 120, 142, 143, 164 fetal, 184 fetuses, 199 fiber, 30, 108 fibers, 22, 30, 33, 68, 107, 193 fibrin, 165 fibrinogen, 141 fixation, 15, 103 flow, 9, 10, 15, 16, 17, 23, 26, 28, 32, 33, 34, 43, 67, 83, 84, 85, 86, 87, 88, 89, 100, 101, 102, 104, 105, 109, 112, 116, 117, 120, 132, 136, 137, 139,

Index

212

140, 141, 153, 159, 164, 168, 174, 177, 178, 182, 183, 184, 187, 191, 195, 204 flow rate, 153 flow value, 9, 10, 18, 43 fluctuations, 107, 113, 137, 182 fluid, 12, 24, 25, 27, 143, 172 food, 93, 99, 103, 104, 197 fragmentation, 136 free radicals, 141, 142, 143, 158, 159, 165, 178, 186 frontal cortex, 102, 103, 104, 105, 203 frontal lobe, 109 functional approach, 4, 31 functional changes, 102, 125

G ganglia, 3, 30 ganglion, 30, 32 gas, 35, 65, 70, 185, 189 gas exchange, 189 gases, 32, 34, 179, 188 general anesthesia, 199 generation, 1, 15, 17, 18, 19, 22, 35, 75, 92, 100, 125, 126, 142, 159 genistein, 182 glass, 17, 19, 126, 144 glial, 72, 113 glucose, 84, 88, 139 glycolysis, 136 goal-directed, 2, 103, 104, 105 goal-directed behavior, 2, 105 gold, 126 government, iv gray matter, 32, 88, 112, 197 groups, 24, 99, 108, 114, 143, 145, 147, 182 gyrus, 88, 89, 100

H H2, 172 haematocrit, 141, 158 harm, 60 harmony, 60 head, 174, 182, 194, 200 head injury, 174, 182 health, 185, 198 heart, 14, 25, 92, 100, 107, 169, 174, 178, 182, 189, 202 heart rate, 100 heat, 1, 15, 125, 132, 136, 137, 138, 139, 140, 141, 142, 158, 159, 169, 173, 182, 183, 188, 192, 202

heating, 125, 132, 135, 136, 137, 138, 139, 140, 143, 144, 156, 157, 158, 180, 181 height, 71, 201 hematocrit, 72, 75 hemisphere, 26, 86, 88, 89, 127, 128, 183, 197 hemodynamic, 3, 29, 84, 109, 183 hemodynamics, 23, 86, 159, 174, 191, 196, 197, 201 hemorrhage, 140 heterogeneity, 16, 137, 164, 190 high pressure, 11 high temperature, 135, 137, 138, 153 high-speed, 38 hippocampal, 85, 113, 115, 117, 193 hippocampus, 85, 89, 113, 114, 115, 116, 117, 118, 119, 124, 165 Hippocampus, 115 histamine, 23, 31, 173 histochemical, 33, 184 histogram, 66 histological, 15, 29, 142, 144, 145, 155, 189, 190 HIV, 136 homeostasis, 57, 60, 67, 69 homocysteine, 198 homogeneous, 13 hormone, 29 hormones, 21, 23 horse, 169 Hsp70, 202 human, 1, 2, 25, 84, 104, 136, 137, 138, 139, 140, 165, 167, 169, 175, 178, 179, 184, 189, 194, 197 human behavior, 165 human brain, 1, 104, 194 human cerebral cortex, 84, 179 human subjects, 178 humans, 1, 2, 29, 68, 89, 100, 104, 180, 189, 197, 203 Hydrate, 142 hydrogen, 15, 17, 18, 19, 35, 75, 88, 92, 126, 131, 139, 168, 174, 175, 177, 186, 201 hydrogen gas, 168, 177, 186 hydrogen peroxide, 175 hydroxyl, 175 hypercapnia, 11, 24, 26, 27, 51, 167, 168, 173, 180, 186, 195, 201 hypercarbia, 168 hyperemia, 1, 21, 23, 24, 25, 29, 68, 70, 71, 72, 75, 83, 84, 86, 129, 132, 172, 189, 197, 202 hyperglycemia, 136 hyperlipoproteinemia, 159 hyperplasia, 146, 147

Index hypertension, 14, 32, 33, 35, 159, 163, 180, 188, 202, 204, 205 hyperthermia, v, vi, 6, 121, 125, 126, 135, 136, 137, 138, 139, 140, 141, 142, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 165, 171, 172, 176, 177, 178, 179, 180, 181, 184, 185, 186, 188, 189, 194, 195, 196, 197, 198, 199, 200, 201, 202, 204 hypocapnia, 24, 27, 67, 87, 180 hypotension, 13, 14, 24, 35, 168, 186, 188 hypotensive, 196 hypothalamic, 67, 173, 186 hypothalamus, 30, 100, 112, 113, 163, 177 hypothesis, 1, 13, 22, 23, 26, 30, 33, 71, 72, 73, 77, 78, 111, 142, 178 hypoxemia, 187, 189, 199 hypoxia, 11, 24, 29, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 84, 88, 154, 174, 176, 178, 180, 181, 184, 186, 187, 189, 195, 199, 202, 203, 205 hypoxic, 67, 69, 72, 73, 76, 136, 137, 173, 180, 189 hypoxic stress, 180

I identification, 113, 151 illumination, 87, 103 image analysis, 174 imaging, 68 immunoglobulin, 141 impotency, 60 in vitro, 44, 138, 168, 198 in vivo, 15, 22, 33, 138, 190, 191, 195, 196, 198 inactivation, 2, 31 inclusion, 136 independence, 75 indication, 1, 30, 199 indicators, 15 indices, 117, 118, 125 indirect measure, 168 individual differences, 11, 72 induction, 13, 17, 125, 126, 179, 185 inert, 32, 34, 92, 185 inertia, 15 infarction, 201 inferences, 43, 85, 124 inferior vena cava, 14, 35 infinite, 4 infrared, 142 inhalation, 17, 26, 67, 68, 69, 72, 73, 88, 188 inherited, 159 inherited disorder, 159

213

inhibition, 103, 137, 140, 168, 181, 194, 203 inhibitor, 68 inhibitors, 205 inhibitory, 33, 103, 179, 185 initial state, 70 initiation, 67, 140 injection, 13, 14, 17, 33, 49, 50, 51, 52, 53, 54, 55, 56, 89, 93, 105, 106, 107, 108, 142, 155, 186 injections, 33, 49, 108 injury, 60, 151 innervation, 5, 29, 30, 31, 33, 51, 107, 108, 161, 163, 171, 176, 182, 184, 193, 195, 198 inorganic, 25, 27 insight, 202 insomnia, 112 instability, 125 integration, 41 intensity, 1, 17, 26, 29, 33, 70, 72, 84, 86, 88, 89, 113, 117, 126, 138, 141, 154 interaction, 16, 23, 30, 33, 59, 125, 165, 170, 187, 191, 204 interactions, 125, 140, 165 interference, 125, 179 international, 167 interpretation, 9, 21, 26, 168, 192 interstitial, 24, 139, 176, 177, 189 interval, 4, 93, 137, 138, 144 intervention, 179 intracerebral, 3, 30, 43, 124, 163, 176, 186 intracranial, 33, 72, 86, 111, 197, 200, 205 intracranial pressure, 33, 72, 111, 197, 200, 205 intravascular, 9, 10, 11, 16, 21, 22, 23, 26, 28, 38, 57, 163, 190 intravenous, 49, 51 intravenously, 49 intrinsic, 2, 124, 196 invasive, 124, 133 investigations, 42, 196 ionic, 168, 171 ionizing radiation, 136, 137, 138, 171, 188 ions, 18, 23, 25, 26, 27, 125, 139, 186 ipsilateral, 131 irradiation, 128, 129, 130, 131, 132, 165, 176, 192 irritation, 163 ischemia, 11, 21, 28, 111, 141, 159, 199 ischemic, 21, 170 isolation, 1, 203

K K+, 27, 28, 67, 186, 187, 203

Index

214 ketamine, 127 kidney, 10, 11, 25, 180 killing, 198 kinetics, 193, 194

L lactic acid, 25, 72 land, 158 laser, 193 latency, 53, 71, 72, 75, 77, 128, 132 latent learning, 99 law, 17, 78, 102, 179 laws, 139 lead, 5, 21, 22, 27, 28, 32, 33, 43, 51, 55, 57, 58, 60, 84, 119, 132, 137 learning, 92, 93, 94, 95, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 129, 164 learning process, 99 lesions, 11, 144, 148, 149, 150, 151, 155, 156 leukemia, 136 leukemia cells, 136 limitation, 28, 34, 42 limitations, 4, 196 linear, 4, 15, 26, 33 linear systems, 4 links, 3, 13, 56, 58, 102, 161, 163 lipid, 25, 204 lipid peroxidation, 204 lipids, 199 liquidation, 61 liquor, 24 literature, 6, 10, 11, 13, 26, 39, 40, 41, 43, 56, 67, 84, 85, 102, 142 local anesthesia, 45 localization, 13, 15, 93, 96, 102, 123, 173, 177 location, 71, 99, 127, 128, 143, 150, 165 locomotion, 100, 102 locus, 30, 163 long-term, 125 loss of consciousness, 65 lumen, 4, 16, 29, 34, 108 luminal, 158 lying, 17, 22

M macrophages, 183 magnetic, 29, 68, 199 magnetic resonance, 29, 68 magnetic resonance imaging, 29, 68

maintenance, 1, 6, 24, 61, 67, 68, 72, 137 malignant, 125, 171, 172, 189 malignant tumors, 171 mammalian brain, 175, 198 mammalian cell, 184, 204 mammalian cells, 204 mammals, 138 mask, 31, 102, 164 mathematical, 39, 40 maze learning, 93, 96, 97, 101 maze tasks, 105 measurement, 2, 9, 15, 16, 17, 32, 34, 35, 66, 69, 111, 112, 119, 126, 127, 128, 131, 132, 144, 156, 168, 170, 173, 183, 186, 193 measures, 18 mechanical, iv, 12, 15, 43, 168, 178, 182, 184 mechanical properties, 182, 184 mediation, 27 medication, 136 medulla, 3, 130, 131, 132, 133, 165, 174 medulla oblongata, 3, 130, 131, 132, 133, 165, 174 membranes, 25, 51, 169 memory, 91, 93, 105 meningitis, 12, 195 mental activity, 1, 2, 88 mental arithmetic, 88, 200 mesencephalon, 112 messages, 67 metabolic, v, 1, 2, 5, 6, 12, 21, 23, 28, 29, 43, 51, 56, 57, 58, 59, 60, 61, 67, 68, 70, 71, 72, 77, 81, 84, 88, 91, 102, 104, 105, 109, 113, 117, 119, 120, 124, 132, 135, 137, 141, 158, 161, 162, 163, 164, 170, 178, 184, 185, 189 metabolic changes, 124, 184 metabolic rate, 68, 141 metabolic shift, 84, 120 metabolism, 3, 12, 21, 23, 24, 25, 28, 29, 31, 51, 61, 65, 67, 84, 86, 87, 88, 101, 102, 104, 105, 109, 112, 113, 119, 120, 123, 124, 163, 164, 174, 178, 180, 182, 183, 184, 186, 188, 189, 190, 191, 195, 199, 200, 201, 202, 204 metabolites, 21, 22, 23, 29 MgSO4, 143 mice, 139, 185, 188 microcirculation, 17, 67, 126, 136, 140, 141, 171, 180, 185, 189, 196, 199, 201 microcirculatory, 67, 159, 190 microelectrodes, 69, 126 microenvironment, 200 micrometer, 144

Index microscope, 144 microspheres, 33, 34, 190 microvascular, 179 microwave, 6, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 153, 165, 171, 177, 189, 191, 192, 200 microwave radiation, v, 6, 123, 124, 125, 126, 127, 128, 130, 131, 132 microwaves, 125, 126, 128, 129, 131, 132, 133, 169, 180 mirror, 102 mitochondria, 66, 68 mnemonic processes, 103 modeling, 42 modulation, 103, 104, 123, 125 modulus, 40 molecular weight, 143, 155, 158 monkeys, 32, 103, 141, 197 monograph, 123, 125 morphological, v, vi, 1, 121, 135, 141 morphology, 172, 174, 194 motivation, 93, 99, 102 motor activity, 87, 95, 100, 101, 103, 106, 108, 168 motor area, 88, 97, 102, 103, 112, 142 mouse, 89, 90, 158, 169, 177, 179, 188 movement, 89, 92, 93, 95, 97, 100, 101, 103, 104, 107, 180 MRI, 15 muscle, 5, 22, 25, 26, 27, 28, 68, 168, 181, 182, 184 muscles, 21, 22, 25, 27, 28, 68

N narcolepsy, 191 National Research Council, 183 natural, 21, 163, 169, 182 necrosis, 135, 140, 141, 153 Nembutal, 45, 58, 75 neocortex, 118 neoplastic, 186 nerve, 5, 9, 24, 25, 26, 29, 30, 33, 58, 65, 69, 84, 113, 119, 126, 129, 161, 163, 171, 189, 202, 204 nerve cells, 84 nerve fibers, 5, 24 nerves, 9, 25, 30, 31, 32, 34, 163, 168, 173, 181, 183, 186, 188, 196, 197, 198 nervous system, 99, 118, 125 network, 3, 22 neural mechanisms, 120 neural systems, 124 neurodegeneration, 172

215

neurogenic, 5, 12, 23, 26, 27, 29, 30, 31, 32, 33, 34, 44, 49, 50, 52, 55, 56, 57, 58, 59, 60, 61, 109, 123, 132, 133, 161, 162, 163, 164, 176, 184, 185, 187, 195, 197, 198, 203 neurons, 26, 27, 84, 102, 103, 104, 146, 147, 148, 149, 150, 151, 157, 172, 177, 189 neurophysiology, 184 neurotransmitter, 31 neurotransmitters, 31, 142, 168, 176, 181, 183, 195, 196, 198 nicotine, 33, 194 Nielsen, 5, 30, 33, 138, 176, 193, 194, 195 nitrogen, 68, 69, 72, 73, 132 nitrous oxide, 185, 202 NO, 29, 68 NO synthase, 68 nociceptive, 86 noise, 89 nonparametric, 97 noradrenaline, 14, 25, 33, 168, 174 norepinephrine, 187, 194, 204 normal, 9, 22, 27, 32, 57, 58, 59, 61, 66, 67, 68, 70, 75, 78, 84, 86, 88, 106, 108, 125, 136, 137, 139, 140, 141, 143, 152, 155, 156, 157, 158, 159, 163, 171, 172, 173, 177, 180, 182, 185, 189, 190, 200, 201, 202 normal conditions, 32, 57, 58, 59, 66, 67, 86, 106, 108, 158, 163 normal development, 61 normocapnia, 201 nuclear, 158, 190 nuclear magnetic resonance, 190 nuclei, 27, 85, 123, 124, 132, 163, 175 nucleolus, 147, 148, 149, 151 nucleons, 183 nucleotides, 24, 27, 170 nucleus, 30, 147, 148, 149, 175 nurse, 89

O observations, 22, 28, 48, 55, 58, 67, 69, 91, 104, 112, 113, 165, 201 occipital cortex, 86 occlusion, 9, 11, 14, 22, 72, 140, 159, 165, 189 oncological, 6, 125 oncology, 136, 178, 203 operator, 15 opposition, 69 optical, 196 organ, 9, 10, 13, 22, 23, 28

Index

216

organic, 183 organism, 1, 60, 70, 102, 105, 135 organization, 2, 4, 6, 10, 31, 59, 60, 85 orientation, 2, 95, 99, 100, 101 oscillation, 60, 61, 115, 118, 125, 182 oscillations, 3, 112, 113, 114, 115, 117, 118 oxidation, 68 oxidative, 142, 178 oxidative stress, 142 oxide, 177, 185, 203 oxygen, v, 1, 6, 12, 28, 63, 65, 66, 67, 68, 69, 70, 72, 73, 79, 84, 85, 88, 100, 105, 111, 113, 114, 119, 121, 126, 128, 131, 137, 141, 142, 154, 167, 171, 173, 174, 175, 176, 180, 181, 183, 184, 186, 187, 188, 189, 191, 195, 197, 199 oxygen consumption, 1, 65, 67, 84, 85, 112, 184, 187, 191 oxygen saturation, 65, 72, 154, 181 oxygenation, 126, 129, 136, 137, 167, 171, 172, 180, 183, 185, 192

P pacemaker, 181 PaCO2, 172, 184, 185 pain, 86, 203 paradoxical, 1, 112, 178, 198 paradoxical sleep, 178, 198 paralysis, 191 parameter, 3, 4, 14, 16, 84, 93, 99, 113, 141 parasympathetic, 30, 31, 33, 34 parenchyma, 31 parietal cortex, 95, 100, 101, 106, 108, 109 Paris, 167, 172, 187, 191, 192 passive, 2, 22, 32, 38, 40, 96, 109, 115, 117, 184, 189, 200 pathology, 3, 72, 85, 142, 182 pathophysiological, 137, 140 pathophysiology, 181 pathways, 14, 24, 30, 59, 163 patients, 72, 83, 85, 86, 88, 89, 111, 112, 136, 185, 194, 200, 201 penumbra, 147, 149, 151 perception, 191 performance, v, 25, 91, 102, 103, 104, 109, 164 perfusion, 11, 12, 14, 23, 29, 51, 72, 183, 185, 190, 200, 201, 202, 203, 204, 205 periodic, 83, 104, 114, 115, 117 peripheral, 167 peritoneal, 155 permeability, 27, 139

permit, 85, 120 peroxidation, 199 PET, 172 pH, 25, 27, 67, 75, 119, 120, 135, 136, 137, 139, 140, 143, 154, 169, 176, 178, 179, 182, 184, 190, 193, 194, 195, 200, 203 pharmacological, 5, 30, 31, 34, 42, 105, 161, 181 phosphate, 139 phosphates, 51, 199 phosphocreatine, 24 photon, 15 physiological, 4, 6, 9, 10, 27, 31, 41, 66, 68, 98, 135, 137, 139, 140, 171, 176, 178, 192 physiologists, 4, 9 physiology, iv, 5, 10, 29, 140, 169, 176, 180, 181, 182 physiopathology, iv pig, 173, 199 pigs, 25 plasma, 141, 158, 178, 182 plasticity, 172 platelet, 158, 201 platelet aggregation, 158 platelets, 158 platforms, 91, 92, 99, 105 platinum, 17, 19, 66 play, 3, 26, 51, 53, 57, 61, 120, 123, 159 plethysmography, 111 plexus, 176 poly(ADP-ribose) polymerase, 136 polycythemia, 141 polyethylene, 142 polygraph, 142 polymerase, 136 polymerization, 205 population, 102, 104, 136, 137 portal vein, 68, 168, 171, 184 positron, 178, 180 positron emission tomography, 178, 180 postsynaptic, 26 potassium, 23, 25, 27, 173, 176, 185 power, 21, 68, 86, 129, 174 preconditioning, 138 preference, 43 prefrontal cortex, 88 preoperative, 178 preparation, iv, 161 pressure, 2, 5, 6, 7, 9, 10, 12, 13, 14, 15, 16, 18, 21, 22, 23, 24, 26, 28, 29, 32, 35, 36, 37, 38, 39, 41, 43, 44, 45, 46, 50, 51, 57, 72, 75, 87, 111, 154,

Index 159, 161, 162, 163, 164, 169, 172, 175, 177, 180, 181, 184, 188, 189, 190, 191, 200, 201 preventive, 105, 165 primary visual cortex, 88, 184 primate, 103 primates, 32, 102, 104 probability, 17, 38, 39, 46, 48 probe, 15, 142, 143, 201 procedures, 14, 161, 197 production, 1, 15, 33, 158, 183, 204 progressive, 168 promote, 139 promyelocytic, 136 propagation, 171 property, 10, 40, 41 propofol, 202 proportionality, 38, 40 propranolol, 49, 51, 52, 53, 55, 162, 175, 194 prostaglandin, 194 prostate, 204, 205 protection, 105, 188 protein, 192 protein synthesis, 192 proteins, 158, 184 psychological, 89 pulse, 3, 18, 144, 191 punishment, 93, 99 pycnosis, 146, 147 pyramidal, 146, 147, 148, 177 pyruvate, 199

Q quantitative estimation, 113

R radiation, 124, 125, 126, 127, 128, 136, 137, 171, 172, 184, 191, 198 radiation therapy, 137, 172 radio, 137, 205 radiofrequency, 124 radiotherapy, 136, 141, 155 radius, 40 random, 164 range, 11, 19, 61, 66, 70, 71, 72, 73, 77, 84, 85, 96, 124, 125, 136, 138, 140, 141, 143, 163, 164 rat, 12, 24, 51, 68, 92, 93, 94, 95, 98, 105, 142, 168, 169, 171, 172, 178, 182, 183, 184, 185, 186, 187, 189, 197, 198, 199, 204

217

rats, 24, 27, 28, 51, 91, 93, 95, 97, 99, 100, 101, 104, 107, 108, 109, 112, 124, 125, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 168, 184, 202, 203 reactivity, 27, 35, 175, 179, 184, 185, 186 reading, 86, 88, 183 reality, 42 reasoning, 197 receptors, 5, 25, 30, 31, 34, 49, 51, 52, 54, 69, 105, 168, 169, 184, 189, 193, 194, 198 recognition, 31, 65 recovery, 76, 85, 101, 129, 138, 139, 176 red blood cell, 158 red blood cells, 158 red light, 103 redistribution, 67, 85, 101, 102, 104, 105, 109, 112, 132, 164 redox, 176 reduction, 3, 11, 12, 13, 17, 42, 43, 53, 54, 59, 65, 67, 68, 72, 76, 94, 95, 120, 137, 163 reflection, 102, 103, 118, 139 reflexes, 59, 125, 175 regional, 10, 12, 27, 67, 86, 141, 169, 170, 172, 174, 175, 180, 183, 185, 186, 187, 189, 190, 191, 194, 196, 197, 201, 203 regular, 2, 23 regulation, 1, 2, 3, 4, 5, 6, 9, 10, 13, 16, 23, 24, 25, 27, 29, 30, 31, 32, 33, 34, 35, 41, 45, 48, 51, 52, 59, 60, 61, 65, 68, 71, 73, 75, 79, 87, 91, 93, 105, 108, 109, 119, 123, 124, 126, 161, 163, 164, 165, 167, 170, 171, 173, 178, 180, 182, 183, 184, 185, 186, 187, 188, 192, 197 Reimann, 188 reinforcement, 93, 99, 103, 104 relationship, 25, 84, 90, 100, 102, 141, 178 relaxation, 28 relevance, 171 reliability, 1, 44, 47, 96, 97 REM, 112, 115, 117, 119, 120, 165, 196 renal, 175, 184 repair, 137, 138, 139 reparation, 138 research, 135, 165, 175 researchers, 2, 87 reservoir, 3, 15, 30, 142, 143 resistance, 10, 12, 24, 33, 51, 67, 68, 87, 109, 137, 138, 159, 169, 170, 171, 175, 181, 182, 187, 191, 193, 203 resistence, 109 resolution, 15, 16, 96, 98

Index

218 resources, 69, 101 respiration, 70, 73, 75, 132 responsiveness, 14, 168 resting potential, 27 restoration, 53 retardation, 48 retention, 61 retina, 87 returns, 32, 70, 71, 100, 163 rheological properties, 140, 141, 142, 159, 165 rheology, 188 rhythm, 14, 22, 85, 96, 113, 118 rhythms, 114, 115, 117 ribose, 136 right-handers, 88 RNA, 204 rodents, 138 ROS, 183

S safeguard, 32, 58 safety, 141, 155 saline, 144 SAP, 2, 5, 6, 11, 13, 14, 18, 33, 35, 36, 37, 38, 39, 44, 45, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 60, 61, 75, 78, 93, 111, 112, 120, 126, 132 saturation, 18, 19, 65, 72, 154 scavenger, 143, 158, 159 schizophrenia, 83, 88, 183 schizophrenic patients, 88 school, 98, 99, 135 scientific, 161 scientists, 135 SDH, 137 search, 1, 92, 93, 95, 96, 163 sedimentation, 193 seizure, 26, 84 seizures, 174, 181, 182 selecting, 138 self-regulation, 164 semicircle, 145, 148, 150 semiconductor, 172 sensation, 86 sensations, 99 sensitivity, 26, 136, 137, 138, 140, 142, 155, 165, 167, 173, 190, 191, 195, 205 sensorimotor cortex, 86, 113, 114, 117, 118, 120 separation, 1 septum, 84 sequencing, 198

series, 44, 46, 47, 89, 93, 108, 127, 128, 130, 131, 132, 143, 144, 145, 146, 147, 149, 152, 156, 157 serotonin, 23, 30, 174 serum, 158 severity, 65 sex, 35, 113 shape, 75, 114, 147, 152 shear, 29, 158, 180 shear rates, 158 shock, 192 short-term, 65, 69, 72, 125, 135, 153 short-term memory, 65 shoulder, 87 shunts, 174 sialic acid, 180 sign, 84 signals, 29, 30, 103 signs, 65, 66, 83, 88, 101, 104, 105 silicon, 142, 143 similarity, 175 simulation, 190 sinus, 3, 67, 192 sinuses, 3 sites, 31, 67, 72, 88, 98, 114, 128, 181 skeletal muscle, 11, 168, 184, 197, 202 skin, 9 sleep, 83, 111, 112, 113, 114, 115, 117, 118, 120, 165, 169, 172, 176, 177, 179, 180, 182, 184, 187, 193, 194, 196, 197, 200, 203 sleep deprivation, 112 sleep stage, 112, 120, 165 sleep-wake cycle, 172, 197 smoking, 159 smooth muscle, 5, 10, 12, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 34, 39, 40, 41, 68, 169, 173, 174, 176, 178, 181, 182, 183, 187, 193, 195, 199, 200, 204 smooth muscle cells, 24, 28, 31, 40, 41 sodium, 187 soleus, 184 solid tumors, 139 solutions, 41, 42 somatosensory, 117, 118, 178 spatial, 42, 99, 137 species, 2, 25, 32, 154, 204 specificity, 1, 99 spectroscopy, 190 spectrum, 14 speech, 86, 88, 183 speed, 14, 140 spheres, 101, 104

Index spin, 142, 178 spinal cord, 199 stability, 57, 61 stabilization, 44, 70, 96 stable states, 161 stages, 65, 79, 97, 102, 103, 104, 109, 112, 164, 165 statistical analysis, 17, 42 steady state, 4, 144 stellate cells, 148 stereotype, 95, 100, 101, 164 stimulus, 29, 86, 89, 90, 93, 98, 99, 100, 163 stochastic, 113 strength, 103 stress, 2, 29, 180, 184 stretching, 9, 21 stroke, 182 structuring, 159 subarachnoid hemorrhage, 175, 200 subcortical structures, 26, 118, 177 substances, 23, 27, 28, 182 substitutes, 14, 178 suffering, 83, 86, 88, 112 superposition, 102, 164 supply, 2, 5, 14, 32, 66, 83, 121, 126, 140, 163, 171, 180, 189 suppression, 25, 26, 40, 59, 68, 69, 84, 103, 105, 107, 124, 177 surgery, 174 surgical, 14, 86, 143, 161 surgical intervention, 14, 86 surplus, 16 survival, 137, 138, 141, 142, 188, 200 survival rate, 137 susceptibility, 42 swelling, 158 switching, 73, 104, 128, 129 sympathectomy, 32, 42 sympathetic, 25, 30, 31, 32, 33, 34, 107, 163, 167, 168, 169, 172, 173, 181, 182, 184, 186, 189, 194, 197, 198, 202, 204 sympathetic fibers, 30, 33 sympathetic nervous system, 182 synapses, 59 synaptic clefts, 24 synaptic transmission, 59 synchronization, 2, 96, 105, 107, 119, 125 syndrome, 72, 89, 104, 132 synthesis, 35, 137 systems, 26, 33, 34, 101, 124, 125, 140, 162, 196

219

T tangible, 85, 112 target behavior, 102 temperature, 9, 119, 125, 126, 127, 128, 129, 130, 132, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 153, 154, 155, 156, 157, 158, 159, 165, 178, 184, 197, 204, 205 temporal, 32, 46, 47, 48, 51, 52, 56, 59, 83, 86, 87, 88, 92, 98, 100, 103, 104, 109, 140, 162 temporal lobe, 83 tension, v, 9, 12, 17, 18, 19, 26, 29, 40, 41, 42, 44, 65, 66, 67, 70, 89, 100, 101, 102, 104, 105, 106, 111, 113, 114, 119, 126, 128, 131, 164, 167, 173, 174, 175, 176, 181, 183, 193, 197, 199, 200 terminals, 26, 29, 30, 33, 86, 107, 108 TGF, 204 thalamus, 89, 100, 113, 163 theoretical, 23, 70, 72, 168 theory, 2, 4, 5, 9, 12, 13, 21, 22, 23, 28, 29, 30, 33, 69, 72, 124, 185 therapeutic, 125, 136, 137, 138, 140, 141 therapy, 138, 139, 140, 169, 175, 180, 183, 197, 203, 205 thermal, 3, 89, 125, 131, 132, 133, 135, 136, 137, 138, 139, 142, 143, 144, 182, 188, 205 thermal energy, 133 theta, 85, 96, 113, 115, 118 threat, 105 threshold, 11, 40, 67, 86, 190 threshold level, 67 thromboembolic, 159 thrombosis, vi, 135, 141, 159, 165, 177 thrombus, 158 time, 1, 2, 3, 4, 9, 10, 13, 15, 22, 24, 25, 27, 30, 33, 38, 40, 41, 42, 44, 46, 47, 48, 53, 54, 55, 57, 65, 67, 69, 70, 72, 73, 75, 84, 88, 89, 92, 93, 95, 98, 99, 100, 101, 102, 103, 104, 105, 108, 112, 113, 114, 118, 123, 125, 127, 128, 135, 137, 138, 139, 140, 154 time periods, 15 tissue, vi, 1, 3, 6, 12, 15, 16, 17, 18, 19, 21, 23, 24, 25, 26, 28, 29, 31, 41, 51, 58, 61, 65, 66, 67, 69, 70, 72, 75, 77, 85, 105, 113, 118, 119, 124, 125, 126, 129, 132, 133, 135, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 163, 165, 171, 172, 173, 175, 176, 180, 184, 188, 189, 190, 192, 194, 198, 202, 205 tolerance, 137, 138, 184

Index

220

tonic, 21, 29, 103, 104, 178 training, 185 trajectory, 92, 95, 107 transection, 123 transfer, 95 transformation, 53, 55 transition, 70, 85, 111, 114, 115, 116, 117, 119, 120, 138 transitions, 177 translation, 6 transmembrane, 26 transmission, 49, 59 transparent, 15 transport, 25, 26, 69, 154, 171, 172, 180 transverse section, 126 trauma, 72, 132, 196 traumatic brain injury, 177 trend, 2 trepanation, 128, 129 trial, 32, 92, 93, 94, 95, 96, 97, 98, 99, 100, 102, 193 trial and error, 92, 93, 99, 193 tumor, 125, 126, 135, 136, 137, 138, 139, 140, 141, 153, 155, 171, 175, 194, 196, 202, 203 tumor cells, 125, 126, 135, 136, 137, 139, 175, 194 tumor growth, 139 tumors, 72, 136, 137, 138, 139, 140, 184, 188, 190, 200 tumour, 125, 135, 197 tumours, 125, 185, 189 type II diabetes, 190

U ultrasound, 172 umbilical artery, 175 umbilical cord, 184 unconditioned, 105 uniform, 67 urea, 24 uric acid, 139

V vacuole, 158 vagus, 14, 30, 51 vagus nerve, 14, 30 validation, 200 values, 10, 18, 25, 26, 34, 39, 42, 43, 46, 66, 84, 88, 128, 137, 185, 201 variability, 18, 24, 66, 103, 125 variable, 16, 72

variables, 72 variation, 5, 6, 9, 10, 14, 18, 21, 22, 23, 36, 39, 40, 41, 42, 44, 46, 95, 96, 129, 132 vascular, 1, 2, 3, 4, 5, 9, 10, 12, 15, 16, 17, 21, 22, 23, 24, 25, 26, 28, 29, 30, 31, 32, 35, 36, 38, 39, 40, 41, 42, 43, 48, 51, 52, 53, 57, 58, 60, 68, 83, 87, 108, 111, 123, 125, 138, 139, 140, 158, 159, 163, 164, 165, 167, 168, 169, 170, 174, 175, 176, 178, 179, 181, 182, 184, 186, 187, 188, 189, 191, 193, 195, 198, 199, 200, 203, 204 vascular occlusion, 140, 165 vascular reactions, 9, 28, 31, 39, 42, 168 vascular system, 1, 2, 4, 53, 125, 140 vascular wall, 9, 28, 29, 39, 40, 41, 42, 43, 68, 139, 169 vasculature, 140, 172, 189 vasoactive intestinal polypeptide, 176 vasoconstriction, 12, 29, 33, 50, 53, 54, 55, 109, 163, 164, 167, 168, 175 vasoconstrictor, 25, 87, 194 vasodilatation, 29, 67, 68, 108, 109, 111, 123, 124, 132, 158, 186, 187 vasodilation, 25, 27, 29, 50, 53, 54, 55, 109, 164, 165, 173, 182, 203 vasodilator, 22, 168, 171, 188 vasomotor, 25, 27, 39, 50, 174, 179, 184, 185, 191, 193, 196, 198 vasomotor nerves, 174, 196 vein, 3, 11, 31, 142 velocity, 13, 14, 15, 16, 17, 27, 32, 33, 34, 40, 41, 42, 44, 70, 88, 173, 186, 189 venous pressure, 143, 204 ventilation, 127 ventricles, 24 venules, 158 vertebral artery, 25 vessels, vi, 2, 3, 5, 9, 10, 11, 12, 14, 15, 16, 21, 22, 23, 24, 25, 26, 28, 29, 30, 31, 32, 33, 38, 39, 41, 42, 43, 44, 50, 51, 52, 57, 61, 67, 68, 111, 120, 132, 133, 135, 139, 145, 146, 156, 157, 158, 161, 163, 165, 169, 171, 172, 173, 176, 181, 184, 187, 193, 195, 203 viruses, 136 viscosity, 40, 41, 141, 158, 165, 199, 202 visible, 145, 147 vision, 161 visual, 3, 26, 85, 87, 88, 92, 97, 98, 101, 102, 103, 144, 145 visual area, 85, 87, 97, 98, 101, 102 visual stimuli, 103

Index visualization, 15

W waking, v, 67, 83, 111, 119, 177, 182, 196, 203 walking, 99 water, 86, 99, 171, 185 waveguide, 126 waveguides, 126 white blood cells, 158 white matter, 112 wires, 17, 19 Wistar rats, 142 withdrawal, 59, 60, 129 workability, 92 workers, 6

X x-ray, 188

Y yield, 13

221