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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
2 Nodar P. Mitagvaria and Hiam I. Bicher
(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 arterio-
venous 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
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 comparative-
physiological 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 comparative-
physiological 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.
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
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 11
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
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
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.
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.
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 Advantages Disadvantages

Direct pial vessels in vivo observation; not usable in chronic experiments
visualization (“transparent” vessel diameter continuous recording; only surface vessels accessible;
skull) exact localization of observed vessels; no information of blood flow rate;
no inertial difficult to maintain continuous recording
for long time periods
Micropuncture of cerebral - direct measurement of pressure not usable in chronic experiments
vessels gradients along vessel only surface vessels accessible;
no direct information of blood flow rate;
technique very difficult;
data tends to be inhomogeneous
Fixation and histological - permits study of vessels in deep - discrete measurements;
observation of cerebral cerebral tissue; - no blood flow determination;
vessels - errors related to fixation technique;
Autoradiography - quantitative measurement of cerebral - not dynamically;
blood flow - not usable in chronic experiments
Impedance plethismography dynamically; not quantitative;
usable in chronic experiments; not suited for blood flow measurements;
no inertial low degree of area localisation
Thermoelectric methods - continuous recording in acute and - errors due to brain tissue heat production;
chronic experiments - low resolution;
- high inertia
Thermal clearance - quantitative cerebral blood flow - same as previous
measurements
Clearance of diffusible - quantitative measurement of local - discrete measurement;
indicators blood flow in different brain areas - big volume of tissue flow averaging;
simultaneously - errors due to diffusion
Clearance of non diffusible - qualitative determination of local - same as previous
indicators blood flow in different brain areas
simultaneously
Electrochemical generation - quantitative and qualitative recording - quantitative errors possible
of hydrogen of local cerebral blood flow in
microareas of tissue under acute or
chronic conditions
Transcranial doplerography noninvasive technique; does not allow to estimate volumetric
. evaluation of blood linear velocity in parameters of a blood-flow;
cerebral vessels. "operator-dependence" (an essential role
the angle of an inclination of the probe)
Single photon emission - dynamical evaluation of local blood - not quantitative measurements;
tomography and Functional flow - high cost
MRI
Laser Doppler-flow metering - noninvasive - not quantitative measurements;
- "operator-dependence" (essential role of
mechanical shift of the probe)
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
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 near-
lying 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
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.
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
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
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 2-
AMP 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 two-
fold, 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
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
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%
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.
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).
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
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
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 purin-
histamine-, 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.
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 blood-
brain 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
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.
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 adreno-
or 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
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.
arterial pressure (2) alteration. Responses type 2 (A,B) and type 3 (C,D).
Analysis of Dynamic Characteristics of Local CBF Autoregulation 37
arterial pressure (2) alteration. Responses type 4 (A,B,C) and type 5 (D).
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 5A-
C).
5. When local CBF passively follows both the increase and decrease of SAP occurs
(Figure 5D).
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<1 and depends, in particular, on the caliber of
the examined blood vessel.
Statistical processing of data has revealed that the probability of observation in the given
tissues microregion of the cerebral cortex on the autoregulatory responses of one or another
type is distributed among individual types of responses in the following way (see Table 2).
It becomes evident from the presented table, that there exists a relatively smooth
gradation in the autoregulatory capacity of the vessels - from overtly pronounced to overtly
weak. At the same time, we failed to detect any correlation between the degree of expression
of autoregulatory vascular reactions and the initial level of SAP in animals, therefore the
probability of observing reactions is not dependent on the initial level of SAP.
Table 2. Distribution of the individual types of autoregulatory responses
Type of vascular responses Probability of its observation (P<0.01)

1 0.209±0.034
2 0.213±0.035
3 0.187±0.030
4 0.248±0.030
5 0.143±0.027
Reproducibility of reactions of any type under repeated influence makes up 100%. This
implies of course the reproducibility of the type of reaction and not its concrete pattern.
Thus, the studies described above have demonstrated equivocality of vascular reactions
in response to the same type pressor influence, under almost constant experimental
conditions. Such nonhomogeneity of the vascular responses may be due, for example, to the
difference in the mechanism responsible for them or else the difference in some initial
conditions determining functioning of one and the same mechanism subserving the vascular
responses. In the first case the indicated reactions would be described to be quite different
from each others equations in terms of the principles of functioning of different mechanisms
in the vascular activity. While in the other case, there should be only one equation (or a
system of equations) describing the functioning of one basic mechanism of vascular
responses, which, depending on some initial conditions, is capable of providing the
development of any of the above inumerated types of autoregulatory reactions.
With a view to construct such a mathematical model we have made a preliminary
generalized analysis of the data found in the literature concerning the autoregulatory
processes during alterations in the values of blood pressure and the properties of individual
blood vessels. The net result is formulated as follows:
1. The majority of vessels, which are generally capable of active vasomotor reactions,
are affected during variations in the IVP value (Johnson, 1964; Konradi, 1973;
Mchedlishvili, 1980).
2. Active autoregulatory reactions appear to be particularly clear-cut when there is a
sufficiently rapid variation of blood pressure, while during slow changes in pressure,
the onset of autoregulation is delayed or does not manifest itself at all (Johansson,
Mellander, 1975; Mellander, 1977; Smiesko et al.,1978; Richard et al., 2001).
3. During the first stage of the process of autoregulation the operation is controlled by
the myogenic mechanism, when the vascular response is determined by a direct
reaction of the smooth muscle elements of the vascular wall to IVP changes
(Johnson, 1964; Zelikson, 1973; Baez, 1977; Lombard, Duling, 1977; Tada, 1978;
Purves, 1978; Mitagvaria, 1983).
4. Magnitude of the myogenic vascular tone is directly proportional to the value of IVP
(Johnson, 1964; Johansson, Bohr, 1966; Uchida, Bohr, 1969; Baez, 1977; Mellander,
1977; Grande, Mellander, 1978), and is altered in accordance with the change of the
latter, the velocity of change in the myogenic tension of the vascular wall being
directly proportional to the velocity of IVP change (Sigurdsson, Johansson,
Mellander, 1977; Grande, Mellander, 1978, Mitagvaria, 1983).
5. Effectiveness of the myogenic mechanism of autoregulation is likely to be limited by
quite a definite value of myogenic tension, finite for each particular vessel (Johnson,
1964; Uchida, Bohr, 1969; Herzmeyer, 1973; Johansson, Mellander, 1975).
6. In the case where the capacity of blood vessel for active reactions are not taken into
account, its wall behaves as a visco-elastic body, that is, it has the property of
elasticity and viscosity (Bergel, 1961; Fung, 1967; Hoffman, Bassett, Bartelstone,
1968).
These statements are by no means exhaustive of all the details of the process of
autoregulation. Only those findings which are concrete and experimentally substantiated are
presented here. They are the prerequisites upon which the underlying equations are based and
upon which the model of blood vessel was constructed (Begiashvili, Meladze, Mitagvaria,
1979a, 1979b, 1980).
Description of a Mathematical Model of a Blood Vessel
A comprehensive analysis of all cumulative characteristics of local CBF autoregulation,

which was obtained by taking into account the above statements, generalizing data available
in the literature, thus permitted us to formulate a number of conclusions:
1. The reaction of blood vessels to IVP alteration is determined by a passive (elastic
stretch of the vessel wall), Pe, and active (tension developed by contraction of smooth muscle
cells), Pa, components of tension developed by the vessel wall, Pv, that is:
Pv(t) = Pe(t) + Pa(t) = kR(t) + Pa(t) (2)
where R(t) is the vessel radius; k is the modulus of the vascular wall elasticity; t is time.
2. Active tension of the vascular wall occurs at any increase in IVP (P), if the velocity of
the latter exceeds some threshold value V or is equal to it. While any decrease in IVP with
the velocity exceeding the threshold or being equal to it results in suppression of active
tension of the vascular wall. That is, variation of active tension occurs only in the intervals of
time (ti) when:
|dP(ti)/dt| >= V (3)
3. Velocity of active tension alteration of the vascular wall is directly proportional to the
velocity inducing their variation in IVP:
dPa(t)/dt = bdP(t)/dt (4)
where b is a coefficient of proportionality, determined apparently by the current state of

contractile apparatus of the vascular wall.
4. Velocity of active tension variation of the vascular wall has some limit, B, that is:
|dPa(t)/dt| <= B (5)
This deduction was reached by common physiological viewpoints about the ultimate
velocity of paired mechanoelectric processes in smooth muscle cells.
5. The value of active tension developed by the vascular wall may vary from zero up to a
maximal value (let us designate it as P*), defined, apparently, by the properties of the
contractile smooth muscle apparatus of the vascular wall and its current functional state:
0 <= Pa(t) <= P* (6)
6. A vessel behaves as a visco-elastic body with fixed parameters - elasticity coefficient k

and viscosity coefficient ρ, obeying the following equation:
c . ρ . dR(t)/dt + k*R(t) + Pa(t) = P(t) (7)
where c is a coefficient determined apparently by the vessel geometry.

Strictly speaking, positions 2-6 are applicable in full measure only to myogenically
active vessels, though data available in the literature on the myogenic activity is a common
property of all regulatory vessels (Brandt, Enzenross, 1976; Baez, 1977; Aubineau,
Lusamvuku, Sercombe, 1978; Orlov, 1980) provide definite grounds for applying these
contentments if not to all, at least to the majority of blood vessels actively contributing to the
process of regulation of tissue blood flow.
Thus, the system of equations offered by us which describes the autoregulatory
capabilities of blood vessels reactions to IVP changes looks like this:
c . ρ . dR(t)/dt + kR(t) + Pa(t) = P(t)
Pa(t) = Pa(t1, t2,..., ti,...tn-1) + b*$tn dP(tn)/dt dt
0 <= Pa(t) <= P*
dP(ti) >= V, i = 1, 2,..., n
dPa(t) <= B (8)
where ti is integration time for i-th change in IVP; (n-1) is the number of preceding
changes in IVP; n is the ordinal of the IVP change under consideration.
In order to obtain the solution to the system of equations (8) it is usually impeded
because of the necessity to reflect in this solution the cumulative IVP changes, preceding the
change to be considered. Though one may obtain, in an analytical way, a number of solutions
for definite initial conditions and for the simplest changes in pressure (leap, sinusoid, etc).
Then, by presenting voluntary change in IVP as the sum of its simplest changes, we can
obtain in the sum of separate solutions the expression described under the given initial
conditions a vascular reaction to this voluntary pressure change.
Results of Modeling
The system of equations (8) described above was realized on a computer that enabled us
to obtain solutions for any IVP variation under any initial conditions (Begiashvili, Meladze,
Mitagvaria, 1979b, 1980). Investigations on the model have demonstrated the following:
1. Any variation of IVP mean level, superimposed on its pulsatile variations, will exert
an influence on the value of active vascular tension Pa. In reality, this is not the case. It
would be more accurate to speak not of the velocity limitation inherent in the mechanism of
autoregulation, but of its limited susceptibility.
2. Characteristics of autoregulatory vascular reactions are to a great extent conditioned
by the value of its original vascular tone: at low tone, vascular capacity for dilation is
attenuated, while during constriction it is facilitated; while at high initial tone, facilitation is
the reaction of dilation and attenuated is the vascular capacity for constriction. This
conclusion is supported by experimental findings of other investigators as well. They have
demonstrated that during reduction of initial tone (usually achieved by administration of
pharmacological agents) vascular capacity for dilatory reactions sharply falls or disappears,
whereas its capacity for constriction is invariable or is even enhanced (Levtov, 1967; Levtov,
Parolla, 1969; Konradi, 1973). At the same time, enhancement of initial tone brings about an
opposite effect (Pugachev, 1947; Haddy, Scott, 1965; Parolla, Mikhailova, 1967; Meyers,
Honig, 1969). Variation in the limits of autoregulation during sympathectomy may also be
considered as proof of the role played by the initial vascular tone in the development of the
process of autoregulation (Ponte, Purves, 1974; Fitch, MacKenzie, Harper, 1975; Hernandez-
Perez, Raichle, Stone, 1975).
3. In order to consider the initial values of active tension of vessels, Table 2 is
reconstructed in the following way (see Table 3).
Table 3. Distribution of the initial value of the vascular walls active tension
Initial value of ative tension of vascular wall Percentage of vessels possessing given value
(Pa) of Pa (P<0.001)
Minimal or close to it (type 2 reaction) 21.3±0.035
Mean or close to it (type 1 or 4 reaction) 45.7±0.034
Maximal or close to it (type 3 reaction) 18.7±0.030
Lack of vascular activity (type 5 reaction) 14.3±0.027
Judging from the presented results of statistical analysis, we found that in our
experiments there is a relatively smooth gradation of values of vascular tone from the
minimal to maximal depending on the predominance of its mean value. This inference is
indirectly corroborated by data on spatial distribution of local blood flow in the brain
(Morgalev, Demchenko, 1979), indicating that this distribution is uneven. According to these
findings, blood flow value in separate microregions of the cerebral cortex varies from 0.2
ml/g/min (what apparently corresponds to a high value of vascular tone) to 2.30 ml/g/min (a
low level of vascular tone) with a marked predominance of mean values (0.4-1.2 ml/g/min). It
should be emphasized that "specific weight" of maximal and minimal values of blood flow is
quite in line with the evidence presented in Table 3, supporting the inferences made by us
concerning the uneven distribution of the initial value of vascular tone within the cortical
vessels. It is very clear that such distributions determine efficacious autoregulation of total
cerebral blood flow both during elevation and reduction of IVP, with some tendency toward
"preference" to the elevated pressure, which is evidenced by the presence of a greater number
of vessels with minimal or close to minimal value of tone than with maximal.
4. Autoregulatory reactions in the vascular bed must occur step-by-step. Each subsequent
part of the vessel must come into the process of autoregulation when the amplitude of
disturbance cannot be compensated for by virtue of the preceding part of the vessel. This is
corroborated by data which according to the augmentation of the amplitude of pressure
change in autoregulation are involved successively the major, the pial (Mchedlishvili, 1968;
Mchedlishvili, Mitagvaria, Ormotsadze, 1972) and, perhaps, the intracerebral arteries
(Mchedlishvili, Mitagvaria, Ormotsadze, 1980). Such hierarchy in the process of
autoregulation is likely to lead to cases when excess reaction to pressure influence of one
section of the vascular tree elicits an opposite reaction in another section. Such cases have
been described in the literature in detail (Carlyle, Grayson, 1955; Mchedlishvili, 1960, 1968,
Toyoda et al., 1996).
Proceeding from the fact that in our experiments the induced changes in the system of
blood circulation were merely related to pressure and they appeared to be too short-standing
to lead to any considerable shifts in chemical composition of the vascular environment, we
thought that direct participation of a metabolic factor needed to be ruled out in the observed
autoregulation. This is clearly evidenced by the course of typical dynamic characteristics - we
have never observed blood flow increases (wash-out of dilatory factors) which were not first
preceded by vessel constriction, or by its decrease (accumulation of dilatory factors)
forewarning the dilation of vessels. We can conceive of an indirect influence of a metabolic
factor on these reactions via metabolic parameters of the environment on the functional
characteristics of the described mechanism - such as values of P*, coefficient b and, most
likely, the level of the original vascular tone Pa(0). In this case the metabolic factor is not
directly involved in autoregulation, but helps to identify the degree of its pronouncement.
This area involves short pressure variations as we used in our sets of experiments
described above. It is more likely that under a longer disturbed change in the metabolic
content of the environment they actively interfere with the course of autoregulation (but this
question will be dealt with below).
In addition, under our experimental conditions, autoregulatory events started to develop
simultaneously with the onset of pressure effect and were over as soon as IVP attained a
stable level. Numerous experimental findings testifying to the existence of myogenic vascular
tone (Johnson, 1964; Johansson, Bohr, 1966; Uchida, Bohr, 1969; Brandt, Enzenross, 1976;
Baez, 1977; Aubineau et al.,1978; Tada, 1978; Smiesko et al.,1978; Vinall, Simeone, 1982,
Lam et al., 1998; Kaley, 2000; Ahn et al., 2007) and, the dependence of its value on the
mechanical effect on the vascular wall (Sparks, 1964; Johansson, Bohr, 1966; Johansson,
Mellander, 1975; Mellander, 1977; Vinall, Simeone, 1982) suggest namely such a pattern of
myogenic vascular responses to IVP variation, since these responses were shown to be related
primarily to the velocity of pressure changes (Mellander, 1977; Sigurdsson, Johansson,
Mellander, 1977; Grande, Mellander, 1979). Myogenic vascular responses in relation to
pressure velocity changes are many times greater than those occurring at a gradual smooth
pressure elevation, or at a stable pressure (Mellander, 1977). Therefore, we believe that the
predominant role of the myogenic factor in the formation of the mechanism of autoregulation
described is apparent. In the above findings which the mechanism describes the vascular
active contraction appears to be in many ways similar for both the vessels in vitro and the
isolated vessels when all mechanisms except for the myogenic mechanism is ruled out.
However, such "instant" action of the myogenic mechanism, during which time of
development of the vascular responses is restricted to the time of IVP velocity changes,
accounts, apparently, for the sufficient effectiveness of this mechanism only under conditions
of comparatively rapid and brief "impulses" of pressure similar to those used in our
experiments. And if changes in pressure can be compensated for by the myogenic vascular
responses, then under conditions of slow pressure changes and also under sustained elevation
or fall of pressure, a possible insufficiency of the level of active myogenic tension could
develop during the pressure elevation. Therefore, it is more than likely that the myogenic
"dynamic" reaction to IVP changes are accompanied and reinforced by functions of other
mechanisms as well, which assume special value after the stabilization of pressure on a new
level, and when the activity of the myogenic mechanism is attenuated (Mellander, 1977).
3.2. DYNAMIC CHARACTERISTICS OF AUTOREGULATION OF

CEREBRAL BLOOD SUPPLY IN RESPONSE TO PROLONGED
VARIATIONS IN SYSTEMIC ARTERIAL PRESSURE
In order to evaluate the function of the autoregulatory neurogenic mechanism of cerebral

blood flow, we have carried out series of several experiments on cats during prolonged
stepwise changes in SAP. In contrast to the above described data obtained during short-
lasting SAP changes, it appears that during prolonged SAP changes (Table 4) two more
components become involved in the process of autoregulation. The reason for their
emergence is determined by conditions of the experiment itself (whether the animal is
anesthetized or not, what the length of disturbance is, whether adren- and cholinergic
blocking agents are used or not). Various latent periods manifested different components of
autoregulation and served as a basis to distinguish them from each other with more than
0.999 reliability. Let us consider reasonableness of this differentiation.
Table 4. Parameters of prolonged changes of the Mean Systemic Arterial Pressure
Parameters of mean systemic The state of the animal

arterial pressure Preliminary ether anesthesia, Nembutal anesthesia
local anesthesia (40mg/kg)
Initial level (mm Hg) 116±2.2 102±1.5
Elevated level (mm Hg) 150±2.0 163±2.5
Lowered level (mm Hg) 70±2.1 57±1.3
Length of exposure (seconds) 124±13.5 265±14.3
Figure 7. Local cerebral blood flow (lCBF) variations with "splashes", counterphase to the direction of
systemic arterial pressure (SAP) alterations.
Figure 8. Local cerebral blood flow deviation from the original level and its short latent period
regulation during decrease (A) and increase (B) in systemic arterial pressure.
In the first series of experiments (with no anesthesia) two components of autoregulation

were distinctly delineated: 1) operating concomitantly with the onset of pressure influences
(described by us in the previous chapter), whose characteristics appear to be in close
correlation with the dynamic phase of SAP fluctuation and for which the most characteristic
is the pattern of local CBF variation with "splashes", counterphase to the direction of SAP
fluctuation (Figure 7), and 2) manifesting itself only in the case when as a result of SAP
change local CBF deviates from the original level and characterized by a short latent period
and comparatively rapid completion of the reactions mediated by it (Figure 8). Mean values
of latencies and times of reaction completion are given in Table 5. Both components are
displayed with equal probability, both during increase and decrease in SAP, frequency of
their manifestation is high enough - on an average 60% (see Table 6). At the same time, in a
number of cases (Figure 9) CBF pattern in response to stepwise changes in SAP verified the
third component which was latent in its time of completed reaction and its involvement of the
autoregulatory process. (see Table 5). The frequency in observing this component in the
series of experiments without anesthesia is 8.5% which is insufficient to be excluded from
consideration. Of course, one could assume that for one or another reason a modified
manifestation of the second component may occur. Yet, there are cases of joint occurrence of
both components (Figure 10). In addition, the difference in temporal characteristics of the
second and third components under one and the same conditions appear to be statistically
significant, p < 0.002 (see Table 5).
Figure 9. Manifestation of the first and third components of local cerebral blood flow autoregulation in
two adjacent microareas of the brain during decrease in SAP.
Table 5. Mean temporal characteristics of components of the local CBF autoregulation
Conditions of the Component 1 Component 2 Component 3

experiment Latent Time of Latent Time of Latent Time of
period (s) reaction period (s) reaction period (s) reaction
termination termination termination
Increase With 0 Coincides 11.2±1.7 32.5±3.7 81.2±7.0 94.5±10.0
of SAP anesthesia with
Without 0 duration of 31.0±2.5 54.0±2.6 92.0±6.6 113.0±7.8
anesthesia dynamic
Decrease With 0 phase of 6.0±0.7 13.6±0.7 49.0±3.3 72.0±3.6
of SAP anesthesia SAP
Without 0 alteration 24.0±2.1 43.0±4.5 57.0±2.2 80.0±3.1
anesthesia
Figure 10. Manifestation of the second and third components of lCBF autoregulation during decrease in
SAP.
In the results of our second series of experiments, with the use of anesthesia, the
existence of the third, slow component of autoregulation is proven.
In these experiments, frequency in observation of the third component is dramatically
increased (from 8.5 to 55.2% - see Table 6). What is most important, is its temporal
characteristics which appear not to differ from those obtained in the first series of
experiments: the level of reliability makes up 0.2 < p < 0.5 for latent period and 0.1 < p < 0.2
for the time of reaction completion. Consequently, it may be concluded that in both cases we
are dealing with the manifestation of the very same component of the local CBF
autoregulation process.
Table 6. Frequency of manifestatition of the autoregulatory components in anethetised

an unanesthetised animals
Mode of influence Frequency of Manifestation (%)

Component 1 Component 2 Component 3
Increase in SAP Without anesthesia 60.6 60.8 11.7
With anesthesia 65.1 7.3 57.8
Decrease in SAP Without anesthesia 62.7 56.4 7.3
With anesthesia 67.7 5.3 52.6
Frequency (independent of Without anesthesia 61.4 58.6 8.5
direction of SAP changes) With anesthesia 66.4 6.3 55.2
Following the application of anesthesia, frequency of manifestation of the second

component of autoregulation falls from 58.6 to 6.3%. At the same time a statistically
significant alteration in its temporal characteristics are observed, indicating a slow down,
attenuation of the action of this component of autoregulation. Also in this case after
observation of successive manifestations of the all three components (Figure 11) one can not
then assume a disappearance in the given conditions of the first one.
The use of anesthesia does not affect the frequency of manifestation of the first
component.
Figure 11. Manifestation of the all three components of lCBF autoregulation.
Based on this information it is possible to conclude that in the process of local CBF
autoregulation three components may be involved. The first component manifests itself with
equal probability both in anesthetized and unanesthetized animals irrespective of the
direction of SAP changes.
Second, the component of autoregulation is well expressed in unanesthetized animals and
that by administering anesthesia it strongly diminishes the probability of its emergence. There
are rare cases in which observations have been made and a slow-down (retardation) or
impairment of its action occurs. The temporal characteristics of the third, slow component of
autoregulation does not actually depend on the action of anesthesia, but anesthesia markedly
increases the probability of its observation.
Let us attempt to establish which mechanism of the vascular activity (or local CBF
regulation) underlies the manifestation of each of these components of autoregulation.
In investigating the concept of a possible neurogenic nature of the described second

component of autoregulation, sets of experiments with the use of adren- and cholinergic
blocking agents were performed. Blocking agents were chosen: phentolamine,
phenoxybenzamine, propranolol and scopolamine.
The Role of Adrenergic System
Phentolamine is the most commonly used antagonist of alpha-adrenoreceptors. It acts

almost equally effectively on α1- and α2-receptors (Langer, 1981). Although phentolamine
penetrates poorly the blood-brain barrier (Anden, Strombom, 1974), when it is introduced
intraperitoneally or intravenously in high enough doses it inhibits α-adrenergic transmission
in the brain (Langer, 1981).
In our experiments, intravenous injections of 0.5 mg/kg phentolamine against the
background of stable initial level of SAP led to the abolishment of the second component of
autoregulation under SAP elevation (Figure 12, see dynamics of local CBF1 and CBF2 prior
to and 30 min after phentolamine injection). It should be noted that the first component of
autoregulation, that of the manifestation of the myogenic mechanism, was completely
maintained (Figure 12, local CBF3).
Figure 12. Dynamics of local blood flow in three microregions of the brain cortex during SAP elevation
prior to (A) and 30 min after (B) phentolamine injection.
Figure 13. Autoregulatory characteristics obtained in three microregions of the brain cortex by the
phentolamine action in response to both decrease (A) and increase (B) in SAP.
Presented in Figure 13 are the autoregulatory curves which were obtained by the
phentolamine action in response to both decrease and increase in SAP. It is interesting to note
that along all the channels of recording, i.e. in all microregions of the cerebral cortex under
study, the second component of autoregulatory vasodilation persists (Figure 13A), whereas
the component of vasoconstrictive character is abolished altogether (Figure 13B), which
leads to a distinct manifestation of the third, slow component, which at its own expense, is
autoregulatory vasoconstriction.
A similar situation is observed when one uses another α-adrenoblocker -
phenoxybenzamine. This is a potent antagonist of α1-adrenoreceptors. In Figure 14 (a two-
channel recording of local CBF) one can see a gradual replacement of the second component
of autoregulation by the third, following the phenoxybenzamine injection (1-1.5 mg/kg).
While studying the transient processes of autoregulation of the cerebral blood supply Teplov
(1980) also found a fast component (analogous to the second component described above):
Assuming it was neurogenic in nature, he excluded α-adrenoreceptor vessels as the terminal
link of the neurogenic vasomotor reaction of any origin. In observing the action of
dihydroergotamine (1 mg/kg, in the carotid artery) a fast phase of autoregulation under
pressure elevation was not observed. During almost 51 seconds, the CBF was traceable by a
high level of pressure followed by a classic reaction of autoregulation (Teplov, 1980, p.18).
In our opinion, the data described clearly illustrates the neurogenic (α-adrenergic) nature of
the second component of autoregulatory vasoconstriction under elevation of SAP.
Figure 14. Replacement of the second component of autoregulation by the third, following the
phenoxibenzamine injection. (A) - control, (B) - after phenoxibenzamine injection.
The role which the β-adrenergic system plays in regulating the cerebral blood supply is
unclear. Based on indirect data Teplov et al. (1978) suggest that in the β-blockade (1-2 mg/kg
propranolol, i/v) the constrictor effect induced by the vagus stimulation is enhanced.
Therefore the β-receptors may be thought to participate in dilation of the cerebral vessels.
According to Tada's (1978) findings, administration of β-adrenoblocking agents has no effect
on prominence and temporal parameters of autoregulatory reactions.
Studying the role of adrenergic innervation in the regulation of blood flow and energetic
metabolism within the brain of anesthetized rats, Kogure et al.(1979) demonstrated that
propranolol (10 mg/kg) induced blockade of β-adrenoreceptors results in a decrease
utilization rate of highly energetic phosphates by 50% and a negligible decrease in the
vascular resistance. The mentioned auythors believe that central adrenergic neurons play an
important role in exercising a metabolic control over the cerebral blood circulation by means
of its affect on the beta-adrenoreceptor vessels and on tissue cellular membranes.
In an attempt to understand the effect of propranolol induced β-blockade on local CBF
under conditions of normo- and hypercapnia Dahlgren (1981) experimented. Results showed
that intravenous injection of the blocking agent in the dose of 2.5 mg/kg did not appear to
lead to any appreciable alteration of local blood flow in any of the 22 examined structures of
the rat brain. A negative result was obtained also under conditions of hypercapnia. It can be
concluded that if propranolol does have any action on the regulation of cerebral circulation, it
must be rather insignificant.
In observing the conditions in the perfusion technique, the action of the β-blocking
agents (propranolol and anapriline) on the feline and rabbit blood vessels, Gaevji (1980)
contributed to the vasoconstrictive response and therefore considerably reduced the dilatory
autoregulatory response of cerebral vessels to perfusion pressure fall. This is supported by the
data of Fujishima (1971) and Meyer et al.(1971) and partly, with the above indicated findings
of Teplov et al.(1978).
The role of β-adrenergic system can be summed up in two statements: 1) the β-receptors
participate in the dilation of cerebral vessels and their blockade contributes to a constrictor
response, and 2) the β-adrenergic system plays no essential role in the regulation of the
cerebral vascular tone.
But results of our experiments on cats with i/v injection of propranolol (2-2.5 mg/kg) do
not confirm the above statement. Data given in Figures 15 and 16 do not show improvement
in vasoconstrictive autoregulation under SAP elevation. A well-pronounced autoregulatory
response is seen in Figure 16C. Its temporal characteristics are attributable to the third,
slowly acting component and are not considered to have the neurogenic nature.
Figure 15. The local blood flow dynamics in two microregions of cortex (CBF1, CBF2) during
elevation of SAP prior (A) and after (B) propranolol injection.
Figure 16. The local blood flow dynamics in two microregions of cerebral cortex (CBF1, CNF2) during
elevation of SAP. (A)- control, (B) - 3 min and (C) - 30 min after propranolol injection.
Figure 17. Local blood flow autoregulatory responses in 4 microregions of the brain cortex during
reduction in SAP under the action of propranolol.
Presented in Figure 17 are the autoregulatory responses (under the action of propranolol)
which occurred as a reduction in SAP. Also in this case, it is difficult to conclude that beta-
blockade improved the vasodilatory responses. In the third-channel recordings (CBF3) one
can see a well expressed myogenic autoregulation.
In these and other experimental findings obtained in our studies, the beta-adrenergic
system does not seem to play significant role in the autoregulatory vasoconstriction or
vasodilation of the cerebral vascular system.
The Role of the Cholinergic System
In order to properly evaluate the role of the cholinergic system in its formation of the
second component of autoregulatory vasodilation in response to a fall in SAP, we have given
an i/v injection of a potent cholinergic blocking agent, scopolamine (1-1.5 mg/kg). In all
experiments a clear-cut transformation of the second component into the third component
was obtained. In Figure 18 an example of this transformation is given. A - before
scopolamine injection (one can see how in response to a fall in SAP local CBF rapidly
recovers its original level), B - 3 minutes after scopolamine i/v injection (latency of the local
CBF response is approximately the same, but the process of restoration is more prolonged), C
- 30 minutes after scopolamine injection (It is seen that autoregulation of local CBF is
accomplished only by the third, slow component and there is an apparent increase in both the
latency and the time of restoration of the local CBF initial level).
Figure 18. Local cerebral blood flow autoregulatory responses during reduction in SAP: (A) - prior, (B)
- 3 min and (C) - 30 min after scopolamine injection.
Presented in Figure 19 are the results of experiments which allowed us to make a

comparison of the effects of the cholinergic receptors' blockade on the autoregulatory
vasodilation and vasoconstriction. Data was obtained 45 minutes after an i/v injection of
scopolamine. In two microregions of the cerebral cortex (CBF1 and CBF2) one sees the lack
of the second component of autoregulation and functioning of the third, slow component. At
the same time, in response to an abrupt increase of SAP there occurs a remarkable change in
function of the second, fast component. With repetitive action, the described picture is
reproduced in full.
Figure 19. Local blood flow autoregulatory responses in 2 microregions of the brain cortex during SAP
alteration under the action of scopolamine.
Thus, by administration of a muscarinic cholinergic blocking agent, scopolamine, the

most prominent peripheral action results in a complete exclusion of the second, fast
component of autoregulatory vasodilation under a fall in SAP and has no effect whatsoever
on the slow vasodilatory or fast vasoconstrictory components.
Table 7 represents the frequency in manifestation in various components of local CBF
autoregulation after administration of adreno- and cholinolytics.
Table 7. The frequency of manifestation of different components of lCBF autoregulation

after administration of adreno- and cholinolytics
Experimental Components of Frequency of manifestation (%) of the autoregulatory components after

conditions autoregulation injection of:
Phentolamine Phenoxibenzamine Propranolol Scopolamine
Increasing of I 58.1 60.0 55.2 64.1
SAP II 2.2 4.0 49.5 59.2
III 48.0 80.2 14.9 7.5
Deacreasing of I 62.3 61.2 57.1 61.2
SAP II 40.5 67.3 53.2 8.3
III 13.4 13.5 11.8 84.2
In summary, the results which were derived from our experiments utilizing adreno- and
cholinoreceptors blockade are as follows:
1. In experiments on unanesthetized cats the second, fast component of autoregulation
reflects the functioning of the neurogenic mechanism. This mechanism mediates the
autoregulatory vasoconstriction through the alpha-adrenergic system, and
vasodilation - through the M-cholinergic system.
2. Exclusion of the neurogenic mechanism of autoregulation does not lead to the
abolishment of autoregulation altogether.
As pointed out above, in experiments where no anesthesia and no blockers were
employed, the rate of manifestation of third, slow acting component of autoregulation
averaged 8.5%. However, application of anesthesia, as well as the indicated blockers sharply
increased the average frequency of manifestation of the given component up to the 55% (see
Table 6 and 7). Anesthesia reduced the frequency of the manifestation of the second,
neurogenic component from 58.6 to 6.3% (under application of adreno- and cholinoblockers,
the frequency of manifestation of the neurogenic component virtually fell to zero).
In Figure 20 one can well see the transformation of the dynamic characteristics of
vasodilatory autoregulation of lCBF in three adjacent microregions of the cerebral cortex
under nembutal anesthesia (40 mg/kg). Under the invariable position of the measuring
electrode, observations were made. Latency of development in the vasodilatory
autoregulation and time of its completion are presented in Table 5. A similar picture is
observed also in the case of autoregulatory vasoconstriction. Such vasoconstriction presented
in Figure 21 was derived from four adjacent microregions of the cerebral cortex under
conditions of anesthesia.
Figure 20. Transformation of the dynamic characteristics of vasodilatory autoregulation of lCBF in

three adjacent microregions of the cerebral cortex under nembutal anesthesia. (A) - prior, (B) - after
nembutal injection.
It should be particularly pointed out that under all experimental conditions the temporal
characteristics of the slow component appear to be almost similar. This is an additional
confirmation that in all cases we continue to deal with the very same mechanism of
autoregulation.
Figure 21. Local blood flow autoregulatory responses in 4 adjacent microregions of the cerebral cortex
during SAP elevation under the action of nembutal.
Hence, from the dynamic characteristics of the three components of autoregulation we

have singled out the first two as representing the myogenic and neurogenic links. Evaluation
of the available literature presented in section 2.2 shows that the third slow component of the
autoregulatory process may be only metabolic in nature.
Chapter IV
STRUCTURAL ORGANIZATION IN THE BRAIN

BLOOD SUPPLY AUTOREGULATION
After analyzing the dynamic characteristics of autoregulation of the brain blood supply,
clearly three mechanisms of vascular activity are involved in this process. They are: 1)
myogenic, 2) neurogenic and 3) metabolic. Under normal conditions (no anesthesia) they
interact in the following way.
The myogenic mechanism is stage 1 of autoregulation, it provides the development of
compensatory vascular events already in the dynamic phase of the SAP change. The events
occur prior to the local CBF changes, and seem to compensate for changes in homeostatic
sphere. The myogenic component of autoregulation has to act as the protective mechanism,
protecting the vascular bed from damage by intravascular pressure. This is the reason why it
is found only in the dynamic phase of SAP changes, since this stage is the most potentially
damaging for the vessels. However, such a "protective" myogenic reaction, at the same time
also affects the value of local CBF preventing, to some extent, its deviation from the original
level. If this preventation is sufficiently efficient from maintaining the environmental
homeostasis then the task of autoregulation will be fulfilled by acting just its first component
(Figure 7). One must also consider that, the myogenic reaction while serving its protective
function quite effectively can do so without providing stability for the environmental
homeostasis. Consequently, changes in SAP will lead to a respective deviation of local CBF
from the original level. The same will occur if for some reason the myogenic mechanism is
not activated. In such a case, the neurogenic mechanism of autoregulation (which is the
second component) comes into action, effecting the return of local CBF to the initial level.
Thus, the process of autoregulation of local CBF is carried out by the first and second
components (Figure 22) or by the second component only (Figure 8B).
Failure to prevent deviations in local CBF from its original level by both the myogenic
and neurogenic mechanisms call in the metabolic mechanism (the third component). The
metabolic mechanism comes into play when components 1 and 2 are negligible, or when the
second component "comes out of play", or its action appears to be insufficiently effective, or
the joint action of the first and second components fails to provide sufficient compensation
for the disturbance.
Thus, in studies of animals under normal conditions (i.e. no anesthesia) one may observe
an autoregulatory reaction which is a composite manifestation of the three components of the
autoregulatory process. However, the (metabolic) component manifests itself rarely under
these conditions - having a frequency of up to 8.5%. Under normal conditions, the task of
maintaining a stable local CBF in response to the demands of brain tissue during variations of
SAP (autoregulation of local CBF) is taken care of sufficiently by two specific mechanisms.
The mechanisms are: 1) myogenic and 2) neurogenic. It appears that the metabolic
mechanism acts as a safeguard to the other two. Our data indicate that the myogenic
component is effective in autoregulation in 35% of cases, while support from the neurogenic
component increases this value of up to 90.6%, with additional help from the metabolic
component it improves insignificantly this already high index. Describing the structure of
autoregulatory process, commitment to its three intersupplementing links, is corroborated by
investigations of several other authors. They have singled out (generally as a basic one)
myogenic (Rapela, Green, 1964; Boysen et al., 1971; Symon et al., 1972; 1973), neurogenic
(Ekstrom-Jodal et al 1970; Tada, 1978) and metabolic (Hirsch, Korner, 1964) components of
autoregulation. There are some works in which the combination of the three components are
observed (Yoshida et al., 1966; Kogure et al., 1970; Kawamura et al., 1974; Balueva et
al.,1980; Moskalenko, 1980; Teplov, 1980), as well as observations which exclude the
neurogenic component following the application of nerve blocators (Kawamura et al., 1974;
Balueva et al., 1980; Teplow, 1980).
Figure 22. Manifestation of the first and second components of lCBF autoregulation during SAP
elevation.
The above principle which describes the organisation of autoregulatory process seems to
be well justified. It provides sufficient compensation for the SAP changes during conditions
when the normal function of one or even possibly two components of autoregulation is
disrupted. Thus, in our experiments withdrawn of the neurogenic mechanism, what we have
attempted to do in a set of experiments with Nembutal anesthesia, did not lead to
considerable impairment of autoregulatory capacity of the brain vascular bed.
Structural Organization in the Brain Blood Supply Autoregulation 59
It is well known that anesthesia impedes the process of synaptic transmission. It strongly
reduces and in some cases disrupts completely the transmission of excitation to synapses,
which leads to a break in the connection between the afferent and efferent pathways of
nervous reflexes or, at least, to a sharp reduction in these connections (Schmidt, Creutzfeldt,
1968; Creutzfeldt, 1975; Mozgov, 1979). Therefore, use of anesthesia results in suppression
of the neurogenic mechanism of local CBF regulation (Moskalenko, 1974; Moskalenko et al.,
1975) and it disrupts the normal course of regulatory reactions in the system of brain
circulation (Betz, 1972; Moskalenko, 1974). Although, the overwhelming majority of studies
devoted to the study of autoregulation of CBF were made and continue to be made on the
anesthetized animals (Rapela, Green, 1964; Harper, 1966; Kogure et al., 1970; Symon et
al.,1972, 1973; Tada, 1978), this did not stop the authors from coming to conclusions about
the leading role of certaine mechanism in the process of autoregulation: of myogenic (Symon
et al., 1972, 1973; Tada, 1978), and of metabolic (Hirsch, Korner, 1964; Zwetnow, 1968;
Fujishima, 1971).
However, with the autoregulatory structure described above, application of anesthesia
results in the attenuation or "withdrawal" of the neural component. This must, certainly,
modulate the temporal characteristics of the process of local CBF autoregulation. Thus under
these conditions, only the action of myogenic and metabolic mechanisms are implemented.
But the inference concerning the metabolic (Hirsch, Korner, 1964) or myogeno-metabolic
(Yoshida et al., 1966; Mellander, 1977) nature of the autoregulatory process and complete
refutation of participation in it of the neural mechanism (Kawamura et al., 1974; Sakuma,
1977; Tada, 1978) derived from such experiments can scarcely be considered as correct -
they seem to be applicable in the autoregulatory process, only during the conditions of
anesthesia.
Let us compare and contrast the results of our experiments on unanesthetized animals to
the above mentioned results. As seen from Tables 7, application of anesthesia, as well as
adreno- and cholinolytics (Table 7) has virtually no effect on the frequency of manifestation
of a myogenic component of autoregulation. This was to be expected in the light of available
evidence on the intimate nature of this component and principles of its functioning (Folkow,
1964; Shenderov, 1979; Begiashvili, 1981; Mitagvaria et al., 1981; Mitagvaria, 1983). The
neural (second) component tangibly decreases (from 55.6 to 4.6%) which testifies to an
almost complete withdrawal of the latter from autoregulation. In rare cases when the neural
component does manifest itself, its temporal characteristics appear to be strongly retarded as
compared to those under normal conditions (no anesthesia), reflecting a substantial
impairment of functioning of the respective neural pathways. This picture is consistent with
the statements mentioned above. Thus, a joint action under anesthesia between the myogenic
and neurogenic components provides for the effective autoregulation in 44.8% of cases. No
overall impairment of local CBF autoregulation occurs (by the finite result), since the
efficiency of the metabolic (third) component adequately compensates for the "withdrawal"
of the neurogenic one, thereby providing for the necessary autoregulation of local CBF. This
data appears to be consistent with the principle subserving the organization of autoregulatory
process, which has been formulated above. The interaction and intersubstitution of
neurogenic and metabolic components are observed in experiments in which monitoring of
local CBF changes in response to SAP oscillation is performed from one and the same
position of the measuring electrode (prior to and after application of anesthesia).
It should be mentioned that if we, while studying the principles of local CBF
autoregulation process, had restricted ourselves only to the non-anesthetized animal
experiments then we naturally would have come to the conclusion on the myogeno-
neurogenic nature of this process, or rather, would have ruled out the possibility of the
metabolic mechanism. Restricting our experiments to anesthetized animals, on the contrary,
would have led us to the erroneous conclusion that the nature of autoregulation is myogenic-
metabolic and we would have rejected any role of a neurogenic mechanism. These claims
continue to be made.
In summation it is realistic to conclude that the process of local CBF autoregulation is
determined by the joint action of myogenic, neurogenic and metabolic mechanisms of
vascular activity and is built on the basis of their successive incorporation in this process. In
addition, each subsequent (from the point of view of rapid action) mechanism is implicated in
the regulation only in the case when the mechanism (or mechanisms) fails to compensate for
the damaging effect. Such organization in the autoregulatory process makes the system of
local CBF autoregulation highly flexible. If one takes into account that the intimate
mechanisms of each of the three components are vastly different and that it is rather difficult
to imagine these conditions except for episodes of acute injury to the brain (Lassen, Skinhoj,
1975), which lead to the immediate withdrawal of three if not two of the components. While
exclusion of one of the components leads to enhanced activity of the other, the autoregulatory
capacity of vascular bed as a whole is not disrupted. Thus, apart from the examples
considered above, it may be said with definite certainty that withdrawal of the myogenic
mechanism of autoregulation will be compensated for by enhancement of activity of the
neural and metabolic mechanisms.
Hence, depending on the conditions the autoregulation process of local CBF may
incorporate myogenic, myogenic-neural, myogenic-metabolic, neurogenic, neurogenic-
metabolic or metabolic characteristics that would be shown to exist by observation of the
autoregulatory reactions in the various structures. This would occur in harmony with the
general three component principle of organization of the autoregulatory process.
Let us look into some peculiarities in the course of autoregulation which were seen
during our experiments. From the figures presented above, the local CBF autoregulation
process is not always completed by a full compensation for disturbing effect and by accurate
return of local CBF to the original level. In many instances this return was incomplete, but in
overwhelming majority of cases there was no reason to suggest that the partial return of the
local CBF to the initial level was due to impotency of the regulatory mechanisms itself or to
disruption in their functions. Firstly, this idea is not confirmed by testing influences (8%
CO2). Secondly, manifestation of "incomplete" autoregulation on one of the channels of
recording may be accompanied by "ideal" autoregulation of the others. Thirdly, this
"incomplete" autoregulation is mediated in most of the cases by means of one or two
components of autoregulation. This "incompleteness" entails incorporation in the
autoregulatory process of the third component. At first glance, this idea might not appear to
be consistent with the autoregulatory principles we have described above, but one can resolve
the apparent dilema if one recalls that the biochemical homeostasis of the organism implies
Structural Organization in the Brain Blood Supply Autoregulation 61
maintenance of a number of definite environmental parameters. In speaking of the

autoregulation of CBF one implies not maintenance of CBF or local CBF on a strictly steady
level, but merely retention of their relative stability during SAP changes (Lassen, 1959;
Lassen, Christensen, 1976), they are maintained within a range. Thus, it becomes obvious
that the tasks of mechanisms subserving local CBF autoregulation are not absolute
compensation for disturbing effects and precise liquidation of local CBF deviations from the
original level, but their jobs are retention within a particular range that corresponds to
metabolic demands of brain tissue. Therefore, the inevitability of the incorporation and
degree of action of the neurogenic and metabolic components of autoregulation will be
defined not by the absolute amplitude of local CBF deviations, but by the extent to which its
value goes beyond the ranges which are required for maintaining homeostasis of the
environment. The myogenic component mediates regulation by an input influence. It is not
the maintenance of homeostasis of the environment, but decreasing the damaging action on
the vessels of SAP.
Each of the subsequent (by rapid action) components of autoregulation comes into play
only in the case when local CBF cannot be retained or returned to the boundary of
"homeostatic value ranges" by the means of the preceding components. Consequently,
nonincorporation of any component of autoregulation (if experimental conditions provide for
its normal functioning) despite the available deviation of local CBF from the original level,
addressees only the issue that the new level of local CBF appears to be within the given
range. Apparently the closer the original level of local CBF gets to the edge of the range
beyond which CBF is "driven" by SAP oscillation, the more accurate is autoregulatory return
back to the original level.
Bearing in mind that the width of homeostatic range may vary considerably depending
on the level of metabolism in the given tissue region it may be assumed that even in the case
when local CBF passively follows SAP changes which we thought were due to lack of
autoregulation, in spite of a normal development of reactions to preceding testing influence,
actually reflect only the fact that the observable deviation of local CBF takes place within the
homeostatic ranges.
SECTION 2:
REGULATION OF LOCAL CEREBRAL BLOOD
FLOW DURING OXYGEN INSUFFICIENCY
Chapter V
SOME THEORETICAL PREREQUISITES
Arterial hypoxia belongs to the class of one of the most essential external disturbing
influences on the system responsible for the regulation of the cerebral blood circulation.
Depending on its severity, there may arise changes in metabolism, blood circulation and
disturbances in brain functions. It is known, for example, that moderate hypoxia in man,
when oxygen tension in arterial blood (aPO2) falls to 50-40 mm Hg, results in disturbances in
short-term memory and recognition, whereas at aPO2 below 40 mm Hg there occurs drastic
impairment of all brain functions and at aPO2 equal to 30 mm Hg, as a rule, loss of
consciousness occurs (Siesjo et al., 1974). In animals with aPO2 equal to 20 mm Hg
consciousness is usually maintained but there appears changes in the electroencephalogram
(EEG), in particular, slow waves develop (Siesjo et al., 1975).
Measurements made both in man and animals (Kety, Shmidt, 1948; Cohen, 1967) have
demonstrated that at the levels of oxygen tension in arterial blood, when the brain functions
are being disturbed, one can usually observe a reduction in oxygen consumption by nerve
tissue, although the concentration of ATP, ADP and AMP in the tissue remain constant
(Schamhl et al., 1966; Siesjo, Nilsson, 1971; Duffy et al., 1972; MacMillan, Siesjo, 1972).
Disturbances in brain functions are supposed to occur long before the visualized signs of
reduction of the energetic processes (Siesjo et al., 1975)
At various stages in EEG studies, investigators focused much attention on trying to
determine of correlation between the level of oxygen content in inhaled gas mixture and the
EEG. Under conditions of hypoxia the EEG was shown to be characterized by a permanent
decrease of frequency (Lennox, Gibbs, 1932; Gibbs et al., 1935; Berger, 1938, Ozaki et al.,
1995; Papadelis, 2003; LaManna et al., 2004). Thus, when the oxygen saturation in the
arterial blood is 75-90% 8-14 Hz waves with 50 mcv amplitude is observable, while at 65-
75% saturation the frequency falls to 2-7 Hz (at the amplitude of 40-120 mcv). At the same
time it has been suggested that at the level of oxygen consumption 8-9 ml/100g/min the EEG
shows predominance of frequencies between 6 and 12 Hz, while at 5 ml/100g/min
frequencies of 0.5-4 Hz predominate.
It should be noted that measurements of PO2 on the surface of the cerebral cortex or in
brain tissue itself manifest, under normal conditions, a rather wide range of levels: from 6 to
60 mm Hg and more (Grote, 1967; Lubbers, 1968; Grunewald, 1969). According to the data
of Grunewald (1969) the level of tissue PO2 may reach 1-2 mm Hg without any signs of
hypoxia. Lubbers went still farther in his calculations, having determined that for the isolated
mitochondria the critical level of PO2 is below 0.05 mm Hg, he has come to the conclusion
that at tissue PO2 between 0 and 1 mm Hg anoxic conditions do not necessarily emerge
(Lubbers, 1974).
It is apparent that the value of PO2 obtained in this particular measurement (other
conditions being equal) depends solely on the type of the electrode used and the diameter of
its tip. Utilization of submacroelectrode levels make a significant difference because of the
varying distances from the blood vessel (Grechin, Borovikov, 1982). After several hundred of
randomized measurements of local tissue PO2 in the brain utilizing the platinum electrodes
histograms were obtained which showed the distribution of oxygen tension levels among
brain tissues (Figure 23, Lubbers, 1974). There is a distinctly large variability of "coexisting"
values of tissue PO2. What is then created is the possibility of obtaining different levels of
PO2 while measuring it in various brain structures while using various constructions of
measuring electrodes (Lukianova, 1964; Demchenko, Chuikin, 1975; Kovalenko et al., 1975;
Leniger-Follert et al., 1975; Smith et al., 1975; Crockard et al., 1976; Ivanov, Kislyakov,
1979).
Figure 23. Distribution of the oxygen tension levels in brain tissue (Lubbers, 1974).
As it becomes apparent, it is almost impossible to draw any conclusions about

sufficiency or insufficiency deficiency of oxygen supply to the brain tissue utilizing PO2 as
its measurement. Past experiments in which Davies and Bronk used covered electrodes,
significantly low levels of PO2 were obtained (from 4 to 10 mm Hg) in the cerebral cortex of
experimental animals and from this perspective views about functioning of the cerebral
cortex under conditions of physiological hypoxia were expounded (Davies, Bronk, 1942;
1957; Davies, 1962).
Analysis of a large body of data in the literature (Marshak et al., 1948; Abramson et al.,
1953; Sanotskaja, 1961; Kovalenko, 1962; Smith, Vane, 1966; Gurevich, Bernstein, 1967;
1978; Smirnov, Saveliev, 1968) indicates that during hypoxia the direction of the blood flow
changes and varies in different tissues. In adjacent microregions of brain tissue, diverse
changes in the microcirculation are described under conditions of moderate and acute
hypoxia (Leniger-Follert et al., 1976; Mitagvaria et al., 1976; 1978; Kozniewska et al., 1987).
This inherent local redistribution of blood flow during tissue hypoxia is due to different
levels of metabolism in the explored microregions. In sites of low metabolic activity, blood
flow may even decrease providing it increases in the sites where there is a high level of
metabolic demand. These observations have been confirmed at a microcirculatory level when
measurements of blood flow were made at the capillary level. Regarding regional blood flow,
unequivocal results exist in regards to the direction of changes of cerebral blood flow.
Under normal conditions, oxygen tension in the venous blood (in the segmental sinus)
amounts to 32 mm Hg. When it decreases to 28 mm Hg, blood flow starts increasing
(Lubbers, 1974). According to Opitz and Shneider (1980) at PO2 equal to 18-20 mm Hg
hypoxia develops in the brain tissue. Consequently, these levels may be considered as critical
for the brain as a whole. Under conditions of acidosis this critical level increases to 32 mm
Hg (Grote et al., 1973).
It has been firmly established that when aPO2 decreases below 50 mm Hg, local CBF
starts increasing (Kogure et al., 1969; 1970; MacDowall, 1969) and at aPO2 equal to 20-25
mm Hg it increases 4-5 times (Johansson, Siesjo, 1974; MacMillan et al., 1974). However,
data concerning the threshold level of oxygen in the inhaled air for the initiation of CBF
alteration are not uniform. In 1943 Noell and Shneider demonstrated that when the oxygen
content falls in the inhaled air below 11% there is a reduction of resistance of cerebral vessels
and increase in local CBF. It was found that with free moving cats, blood flow in the thalamic
and hypothalamic areas started to increase already when the oxygen content in the inhaled air
became 18% (Betz, 1972). Since we utilized anesthetized animals, the discrepancy in data
may be accounted for by a decrease of oxygen consumption in the brain of anesthetized
animals as compared to the waking ones (Sokoloff, 1959; MacDowall, 1969). Be it as it may,
a large group of investigators (Courtice, 1941; Opitz, Shneider, 1950; Schmidt, 1950; Lassen,
1959; Kety, 1961; Cohen, 1965; 1967) do consider that a system sensitive to oxygen tension
somehow sends messages to the cerebral vessels concerning the demand of brain cells for
oxygen, resulting in an increase in CBF. In the opinion of Siesjo et al. (1975) this increase is
a unique mechanism for the maintenance of energy homeostasis in the hypoxic brain. At the
present time, it is however still unknown which mechanism actually underlies the local CBF
elevation in hypoxia. In recent literature this increase was considered to reflect the action of a
Nitric Oxide (Faraci et al., 1994; Van Mill et al., 2002; Johannes et al., 2003; Joseph et al.,
2004) as well as common modulator (extracellular pH) which determined also the CBF
decrease in hypocapnia. At present it is known that maximal vasodilatation may also be
achieved without any considerable shifts in pH or in concentration of other possible "factors
of coupling" such as K+ or adenosine. Thus, in the studies of Dora et al., (1980) it was
demonstrated that during moderate hypoxia (15 min inhalation of 12-15% O2), in spite of the
absence of changes in K+ (as well as in the electrical activity of the brain) the tissue PO2
decrease was parallelled by dilatation of the cerebral vessels. No correlation was found
between either the dynamics of local CBF and the alteration of K+ concentration at fall of the
arterial PO2. Elevation in local CBF and a drop in the tissue PO2 appeared to precede the
tissue changes in pH (Shinozuka, Nemoto, 1981).
No significant findings were obtained when an attempt was made to link CBF increase
with the reactions of carotid and aortal chemoreceptors during hypoxia (Traystman,
Fitzgerald, 1981).
A study was made in which the power of smooth muscle contraction was to be dependent
directly upon the level of PO2. Detar and Bohr (1968) assumed that oxygen played an
important role in the metabolic process of the smooth muscle mitochondria cell, since it is the
final acceptor of electrons in the oxidation chain. In their opinion, this mechanism of
metabolic rate restriction, being rapidly reversible at the levels of PO2 from 5 to 100 mm Hg,
may serve as a regulator of high-energy "half-finished" products required for the contraction
of smooth muscles and may thus be the mechanism responsible for the regulation of local
CBF.
It is known that a reduction of extracellular PO2 below 50 mm Hg results in a gradual
suppression of the electromechanical activity of the vascular wall. Utilizing the portal vein of
a rat when a PO2 lower than 7 mm Hg occurred a total suppression of this activity occurred
(Hellstrand et al., 1977). Hypoxia appears to attenuate the spontaneous electrical discharges.
In their opinion, changes in PO2 within physiological ranges may affect the myogenic
activity of the vascular smooth muscles by acting at the membrane level. Such a mechanism
might participate in the regulation of blood flow. In studies of Carrier et al. (1964) similar
ideas are found in which regulation of myogenic tone of resistance and precapillary vessels
are accounted for by changes in local PO2. In contrast, in the investigations of Pittman and
Dulling (1978) it was concluded that at the level of small precapillary vessels any influence
of PO2 on contractability of smooth muscle fibers appear hardly probable.
In the study of Van Mill et al., (2002) the role of Nitric Oxide NO in hypoxia-induced
cerebral vasodilatation in young healthy volunteers has been investigated. The effect of the
NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on the cerebral blood flow
(CBF) was assessed during normoxia and during hypoxia. Subjects were positioned in a
magnetic resonance scanner, breathing normal air (normoxia) or a N2-O2 mixture (hypoxia).
The CBF was measured before and after administration of L-NMMA (3 mg/kg) by use of
phase-contrast magnetic resonance imaging techniques. Administration of L-NMMA during
normoxia did not affect CBF. Hypoxia increased CBF from 1,049 ± 113 to 1,209 ± 143
ml/min (P < 0.05). After L-NMMA administration, the augmented CBF returned to baseline
(1,050 ± 161 ml/min; P < 0.05). Similarly, cerebral vascular resistance declined during
hypoxia and returned to baseline after administration of L-NMMA (P < 0.05 for both). Use of
phase-contrast magnetic resonance imaging has shown that hypoxia-induced cerebral
vasodilatation in humans is mediated by NO.
To emphasize the discrepancy which exists from studies of hypoxia, we will present two
investigations. In 1968 Freemen demonstrated that not only in the process of hypoxia, but
also following it, autoregulation of cerebral blood flow remains disturbed, even after the
posthypoxic cerebral hyperemia is eliminated. Two years later Kogure et al. (1970) worked
with dogs with an inhalation of 6% O2 in the mixture with nitrogen described maintenance of
autoregulation during 4-6 min since arterial PO2 got below 25 mm Hg. In the author’s
opinion, autoregulation persists even in cases where hypoxia causes an increase in CBF.
These conclusions are in direct opposition to the findings of other authors.
Hence, one may consider as a firmly established fact that hypoxia:
1) disturbs the brain function,
2) causes an increase in CBF.
We observe the two aforementioned facts, but yet remain unaware of the intimate
mechanism underlying the CBF increase. Considering the opposing views in relation to the
persistence of CBF autoregulation under conditions of hypoxia, one must look deeper.
As has been already pointed out, the CBF increase is, as a matter of fact, considered to be
a unique mechanism which provides energy homeostasis in the hypoxic brain. However
Bicher and his associates (Bicher, 1973; 1974; Bicher et al., 1973; 1974; 1975) developed an
idea which somehow poses another question - the functioning of compensatory mechanisms
in the brain during hypoxia. While recording PO2 in separate microregions of nerve tissue by
means of microelectrodes the mentioned authors found that in the specific regions the level of
PO2 is characterized by a striking constancy and can only be altered by vigorous changes in
CBF or by change in content of the inhalable air. During short-term anoxia, tissue PO2 is first
attenuated, and then it remains at a relatively constant level. Upon increase in the arterial
PO2, tissue PO2 also increases, exceeding the initial level and then returning to the level
slowly. Simultaneous measurement (by means of one and same electrode) of PO2 and the
electrical activity in the nervous tissue has shown that at the decreased PO2 level there is a
considerable attenuation of the electrical activity too. Under conditions of hypoxia the CBF
increase sets in only when tissue PO2 starts to fall. During inhalation of pure nitrogen, a
decrease in the level of tissue PO2 in some cases appears to be 60 seconds later than that of
arterial PO2. Assuming that time constants of arterial and tissue electrodes are similar, the
author attributes this time delay to the work of a special mechanism, distinct from the
mechanism responsible for the CBF increase. By analyzing his collected data, Bicher draws
the following observations based on the sequence of cause-consequence events: a decrease of
arterial PO2 starts to show up when the level of tissue PO2 is lapsed due to a transport delay
(no less than 30 seconds). From this point on, tissue PO2 falls and then the CBF begins to
elevate (this is when the second protecting mechanism comes into action). In the case where
hypoxia continues and the CBF increase fails to compensate for it (arterial PO2 tends to zero),
a rapid disruption of the brain electrical activity occurs (this moment sets in when the tissue
PO2 falls approximately by 20%). On this basis the following conclusions can be drawn:
1. Neurons are very sensitive to their oxygen environment.
2. There exists a reflex suppression in the neuron activity, i.e. there are appropriate
oxygen receptors in the brain tissue.
3. Electrical silence appears to be a compensatory mechanism.
Opitz and Shneider (1950) have made a supposition that there exists oxygen receptor on
the venous end of capillaries. If this is actually the case, then they may have the properties to
both increase CBF and decrease it in a reflex way by the synaptic or neuronal potentials. As a
matter of fact while under conditions of hypoxia the homeostatic mechanisms establish a
novel regimen of operation for the brain to require a minimal expenditure of energy
resources. There is no doubt that this theory is not devoid of charm and considers "electrical
silence" under conditions of hypoxia from quite an unexpected point of view.
In contrast to the works considered above, which have been devoted largely to the
establishment of quantitative correlation of the level of arterial or tissue PO2 and CBF (or
EEG) under conditions of hypoxia, present studies have chosen a unique approach. An
attempt has been made, with the help of dynamic characteristics, to analyse the possible
reasons that underlie heterogenic reactions of local blood flow in adjacent microareas of brain
tissue in response to the influence of systemic type and mechanisms of the development of
posthypoxic hyperemia.
5.2. THE HOMEOSTATIC RANGE OF CBF AND ITS ROLE IN

HETEROGENITY OF CBF RESPONSES DURING HYPOXIA
In the previous section we have introduced the concept of the "Homeostatic Range" of
CBF, i.e. the range in which the limits of local CBF meets a metabolic demand of brain
tissue. It is evident that both the mean level and width of this range depends upon tissue
metabolic demand and gas content in the delivered blood. In particular, an essential role must
be played by the level of arterial oxygen tension (aPO2). It is therefore reasonable to suggest
that during decrease of the latter (or enhancement of tissue metabolic demand) the
homeostatic range should shift upward, and that the velocity of the shift and its amplitude
would be determined, under conditions of hypoxia, or anoxia, by the intensity of their
development. During transition to respiration with normal (or enriched with oxygen) air
homeostatic range of local CBF again shifts downwards and is dependent on the new
concrete conditions which coincide or does not coincide with the initial state.
It is also evident that depending on the direction of previous regulating influence the
initial level of local CBF at the given moment may be located both at the upper and lower
limits of homeostatic range. Let us consider theoretical diagrams presented in Figures 24-25.
Let us suppose that under conditions of developing hypoxia there is a stepwise (by
convention) shift upwards in the homeostatic range (HR),while during the transition to
normal respiration again it returns to the initial position. If this is the case then in two
microregions of brain tissue the initial levels (1 and 2) of local CBF are at the onset of
hypoxia at the opposite limits of the range. Therefore, their dynamics may vary in a sufficient
degree, despite the fact that the influence (hypoxia) has a global character and embraces not
only the brain but also the whole organism. In particular, local CBF, whose value under
conditions of low metabolic demand is at the upper limit of the homeostatic range (level 1,
Figure 24), will not react to hypoxia for a considerable length of time and will react only in
its last stage when the lower limit of homeostatic range will have exceeded level 1, which is
the regulating mechanism which increases local CBF in the given region. As soon as the
signal of discrepancy between metabolic demand and the level of local CBF disappears, the
regulatory mechanism ceases its operation and local CBF is stabilized on a novel level, which
is at the lower limit of the shifted homeostatic range. As the indicated range returns to the
initial position, the regulatory mechanism lowers the level of local CBF stabilization occurs
at the upper limit, since the entry of local CBF into the homeostatic range must eliminate the
signal of discomformity and the regulatory mechanism ceases its active functioning.
Figure 24. Theoretical diagrams of lCBF dynamics with two different initial levels (1 and 2) during
stepwise shift in the homeostatic range (HR) under condition of low metabolic demand. t - the latency
of lCBF response (initial level - 2), Max - maximal level of lCBF.
Figure 25. Same as in Fig.24, but under condition of high metabolic demand.
The local CBF with initial level 2 will behave in a similar way. However, elevation of
local CBF will start much earlier and the posthypoxic level will exceed the initial level,
virtually by the height of homeostatic range itself.
Thus, the first event is an increase of local CBF which starts with a long latency (t) and
then (in posthypoxic period) returns to the initial level. In the other case, the process of
regulation is characterized by a short latency and then there occurs the so-called posthypoxic
hyperemia.
We can also look at the dynamics of changes in local CBF in the course of hypoxia under
conditions of a high metabolic demand (Figure 25). In all cases one must determine the
location of the initial level of the local CBF homoeostatic range. In fact it is here that we
formulate a hypothesis which is able to partially explain the mechanisms underlying the
differences which are found in the local CBF patterns recorded in the adjacent regions of the
brain under conditions of hypoxia, and the subsequent development of posthypoxic
hyperemia. In the theoretical drawings 24-25 two conventional versions are presented: for the
lower level of metabolic demand (MD) (Figure 24), and a high level (Figure 25). At a similar
duration and intensity of hypoxia, the amplitude and curvature of displacement of the
homeostatic range (HR) would, apparently, be determined by MD in the given site of brain
tissue. In the case of the lower level of MD local CBF with the initial level 2 will elevate in
the course of hypoxia with certain latency and will remain at the elevated level provided
other conditions are unaltered. As compared to it, local CBF with initial level 1 will deviate
with a much longer latency (t) and will practically return to its initial level.
In the case of a high level of MD (Figure 25) while hypoxia is developing the
compensatory displacement of HR, leads to a maximum rise of local CBF, fails to satisfy the
existing MD, according to Bicher's theory described above (Bruley et al., 1971; Bicher, 1973;
Bicher et al., 1973; 1974;1975), there may "occur" a sharp decrease of functional activity in
the given tissue area usually leading to the reduction of MD and consequently to a reduction
of average level of homeostatic range. Thus the amplitude of the displacement would depend
on a set of variables (characteristics of new regimen of the work of neuro-glial populations,
residual saturation of the arterial blood with oxygen, hematocrit, etc.).
In the case of absence of such an active readjustment of functioning of hypoxic brain
area, there would apparently develop pathology and an attenuation of the functional activity
with all its resulting consequences.
Thus, the existence of a homeostatic range of CBF, as we propose, and its consequent
displacement under conditions of variable oxygen saturation of the arterial blood, offers some
explanation of:
a) The individual differences in time and amplitude of changes in CBF at various
microsites of brain tissue in response to overall hypoxia;
b) The mechanism which occurs in the development of posthypoxic hyperemia.
Assuming the first has no explanation at this point, we turn to the second idea.
Evaluation of the presence of the phenomenon of posthypoxic hyperemia in the brain was
attempted to be explained by disturbances of metabolic control (Lassen, 1969) assuming that
"following any kind of influences resulting in the development of tissue hypoxia - for
example, inhalation of pure nitrogen, a sharp drop of systemic arterial pressure, substantial
elevation of intracranial pressure, trauma or brain edema - there usually occur disturbances in
the metabolic control, during which CBF starts to exceed local metabolic demand" (Lassen,
1969, p.148). This deduction was made from data obtained in patients with acute occlusion of
the middle cerebral artery or who had tumors in the brain in which apart from the sites with
reduced CBF, there were sites with excess perfusion. This phenomenon, named by the author
"stealing phenomenon" or a "syndrome of Robin Hood" is detected under conditions of
formed pathology and, it, in our opinion, principally varies from the phenomenon of post-
hypoxic hyperemia which can be evoked locally following a short-term inhalation of pure
nitrogen (or an air with reduced oxygen content) or, for example, after short-lasting asphyxia.
If according to Lassen, such hyperemia may be due to acidosis (local accumulation of lactic
acid), then, in terms to our hypothesis, one ought to clearly delineate the mechanism of local
CBF increase during hypoxia and the mechanism of CBF maintenance at a particular level in
the post-hypoxic period. If the former is accomplished by the operation of some mechanism
of CBF regulation (in this case it does not matter whether it is metabolic, neural or humoral)
directed toward matching the level of local CBF to the homeostatic range, the latter must be
due to the "switching off" of the regulatory mechanism due to the disappearance of the signal
which exists to warn of the discrepancy between MD and the level of local CBF.
In our experiments we studied the local CBF dynamics under conditions of hypoxic
hypoxia (inhalation of air with a 10% content of oxygen), anoxia (inhalation of a 100% of
nitrogen) and asphyxia (switching off the artificial respiration). Our acquired data partly
confirms the hypothesis adopted by us, but the final verification is in need of quantitative
measurements of local CBF and a set of other electric and nonelectric parameters of the state
of explored areas of the brain - only in this way may one precisely establish the existence of a
homeostatic range of local CBF and determine its limits. However, at this time we lack such
data.
Chapter VI
DYNAMIC CHARACTERISTICS OF REGULATION

OF LOCAL BLOOD FLOW IN THE CEREBRAL
CORTEX UNDER CONDITIONS OF HYPOXIA,
ANOXIA AND ASPHYXIA
An essential portion of the results expounded below were obtained by one of the authors
at the Max Planck Institute of Physiological Systems (Dortmund, Germany).
Experiments were carried out on adult cats weighing 2-2.5 kg under Nembutal anesthesia
(25-30 mg/kg), immobilized by flaxedyl and maintained on artificial respiration. End-tidal
CO2 was controlled continuously and was maintained (before the onset of influence) within
normal limits. pH, hematocrit and RBC content in the arterial blood were measured at
definite intervals of time. Polygraphic recording of local blood flow in the cerebral cortex
was made by the method of electrochemical generation of hydrogen, described above
(Stosseck et al., 1974). Systemic arterial pressure was measured through a catheter inserted in
one of the femoral arteries.
Below in Figures 26-31 are presented the most typical results of these studies. While
making an analysis of records from the above-stated position one should by all means take
into account changes in systemic arterial pressure (SAP) which, as a rule, occur in hypoxia,
anoxia and asphyxia and which may, to a certain extent, determine the dynamics of local
CBF. In this way of utmost interest are the curves of local CBF changes whose shape differs
radically from the dynamics of SAP. Analysis of the dynamics of CBF under conditions of
asphyxia Johnson et al. (1979) have found no correlation between the CBF increase and
changes in arterial PO2, PCO2 and pH and therefore arrived at the conclusion that SAP is a
critical factor determining the level of CBF.
Dynamic characteristics obtained by us actually refute this conclusion and indicate a
sufficient independence of the local CBF dynamics of SAP changes. Patterns of local CBF
recorded concomitantly in adjacent microsites of the cerebral cortex may vary from each
other to a considerable degree and, actual elevation of the local CBF may start with latency
specific for each microsite of brain tissue. In the presence of clear-out posthypoxic (Figure
26, lCBF1), postasphyxic (Figure 27, lCBF1) or postanoxic (Figure 28, lCBF1) hyperemia
being on one channel, the other channels as a rule record virtually complete recovery of the
initial levels of local CBF. Differences in duration of post-hypoxic hyperemia in individual
microsites of the cerebral cortex are clearly seen in Figure 26. Almost similar, though
differing in latency changes in CBF may be observed both in anoxia (Figure 29) and asphyxia
(Figure 30). Under conditions of prolonged (100 seconds or longer) asphyxia (Figure 31),
despite a sufficient increase in SAP, in two microsites of the cortex in about a minute after
the onset of asphyxia there is an abrupt reduction of local CBF (recording channels 2 and 4),
while in the postasphyxic period local CBF gets stabilized in all microsites on the level below
the initial.
Figure 26. lCBF dynamics developed in three adjacent microregions of the brain cortex under
conditions of hypoxic hypoxia.
Figure 27. Local blood flow dynamics in 4 adjacent microregions of the brain cortex during asphyxia
(ASPHX) and hyperoxygenation (100% O2).
Dynamic Characteristics of Regulation of Local Blood Flow… 77
Figure 28. Same as in Figure 27, but during anoxia (N2-breathing).
Figure 29. Example of different latency of lCBF responses during anoxia in adjacent microregions of
the brain tissue.
All these peculiarities of local CBF variations appear to be entirely within the framework
of the hypothesis described above. In particular, behavior of lCBF1 in Figures 27 and 28,
corresponds, perhaps, to the variant presented in Figure 24, behaviour of lCBF2 and lCBF4
in Figure 31 (their attenuation during asphyxia and lower postasphyxic level compared to the
initial) corresponds to the variant given in Figure 25 which suggests a drastic fall of
metabolic demand and respective displacement of homeostatic range of local CBF
downwards. All other patterns of local CBF are more or less satisfactorily described in the
variant given in Figure 24.
Thus, proceeding from the figures herewith presented, a conclusion can be drawn which
states that in the majority of explored microsites of the cerebral cortex the medium level of
MD is in evidence and only in some cases are its lower or higher levels observed. Of course
we believe that such a gradation of MD levels is by convention, and that it corresponds

entirely to a normal law of distribution and is verified by our hypothesis.
Figure 30. Same as in Figure 29, but during asphyxia with nonsignificant elevation in SAP.
Figure 31. Same as in Figure 30, but with significant elevation in SAP.
Dynamic Characteristics of Regulation of Local Blood Flow… 79
Unfortunately, the data described does not allow one to estimate the intimate nature of
the mechanism of local CBF increase, but it does allow one to comprehend the basic
principles of adaptation to an impending oxygen deficit and describes accurately the ways in
which the system of blood supply regulation maintains its stable functioning of the brain
elements and virtually in all cases (except the one presented in Figure 31) demonstrate the
existence of a well pronounced autoregulation of CBF at the initial stages of development of
oxygen deficiency.
SECTION 3:
REGULATION OF LOCAL BLOOD FLOW IN THE
BRAIN DURING CHANGES IN ITS
FUNCTIONAL-METABOLIC ACTIVITY
Chapter VII
GENERAL PROBLEMS OF THE BRAIN

FUNCTIONAL ACTIVITY AND LOCAL BLOOD
FLOW COUPLING
7.1. BLOOD SUPPLY TO THE CORTEX OF "NONWORKING"

BRAIN
In the later part of the twentieth century intensive studies attempting correlate the
functional activity of individual cortical regions and hyperemia in these regions were
undertaken. Meynert was the first to claim the existence of this interrelationship. It is
interesting to note that this idea is still of interest today.
Even when the body is at rest there takes place a periodic alteration of the functional
activities in the various structures of the brain, which, in its turn, requires an adequate blood
supply.
The majority of the data at the mentioned period has been obtained under clinical
conditions (Ingvar, Gustafson, 1970; Sveinsdottir et al., 1970; Risberg, Ingvar, 1973; Ingvar,
Schwartz, 1974). It appears that in the quiet waking subjects, in a recumbent position with
closed eyes (i.e. complete rest) the level of blood flow is increased in the premotor and
frontal areas of the cerebral cortex (on an average, by 30% more than the mean level of blood
flow in the hemispheres). A relatively high level is observed also in the posterior Sylvian
area. The temporal lobe and parietal area of the cortex including a large part of Sulcus
Rolandi, are characterized by a low level of blood flow. Similar distribution of blood flow
was seen by Wilkinson et al.(1969).
As defined by Ingvar, this "hyperfrontal pattern" is sufficiently stable and does not
undergo change for years even in elderly people (in the absence of any psychic disorders and
signs of the brain damage (Ingvar, 1975). In the state of spontaneous sleep (Ingvar, 1975) or
under anesthesia (Herschat, Schmidt, 1973) this pattern of local blood flow disappears. In
patients suffering from traumatic or vascular affections, considerable deviations from this
pattern are observed (Obrist et al., 1979). These deviations are also observable in various
psychopathologic states (such as focal epilepsy, dementia, and chronic schizophrenia).
D.Ingvar considers these disorders to reflect the metabolic shifts. With the use of computer
tomography he has succeeded in demonstrating that in the focus of epilepsy, hyperemia was
accompanied by an increase in glucose uptake. In the state of depression the level of blood
flow decreases. A relationship between the depth of the depression state and the level of the
cerebral blood flow decrease is correlative (Mathew et al., 1980). In patients suffering from
chronic schizophrenia, a fall in the blood flow level to the frontal area is correlated with a
decrease in glucose uptake in the same area (Ingvar, 1981).
7.2. THE LOCAL BLOOD FLOW COUPLING WITH THE

CORTICAL ELECTRICAL ACTIVITY
It is well known that the cortical electrical activity is dependent upon the intensity of
afferent impulse volleys. Thus, the neurons from isolated strips of the cortex are
characterized either by lack of the electrical activity, or manifest unusual spontaneous activity
that is correlated with the metabolic demand and local blood flow (Creutzfeldt, Houchin,
1974).
Suppression of normal neuronal metabolism occurs during anoxia or acute hypoxia.
These states lead to a potent suppression of the neuronal activity in the cortex, which is in the
first stage a result of attenuation of excitatory influences of subcortical afferents on the
cortical neurons.
It is well known, that nerve cell density per unit of volume of the cerebral cortex
considerably varies within various areas. According to Shell (1953), the number of nerve
cells may be 2.106 per 1 cm2 in the human cerebral cortex and 6-15.106 per 1 cm2 in the feline
cortex. Taking into account: 1) density of neuronal distribution in an area, 2) mass of a single
nerve cell is 50.000 picogram, Hyden (1960) assume that each nerve cell generates 10 spikes
per second have obtained the following values of energy consumption: 1.4.10-4 cal/cm2 (given
the thickness of the human cerebral cortex is 2 mm) or 7.10-5 cal/g/sec. In the cat this
parameter appears to be within the range of 2-5.10-4 cal/g/sec during the spike activity.
Comparing these data with the results of calculations made by Kety and Schmidt (1948) on
the oxygen consumption, Creutzfeldt (1975) has come to the conclusion that only about 0.3-
3% or even less energy consumed by cortex can be attributed to the nerve cell spike activity.
Independent of external stimulation, the desynchronization of electrical activity which
developed in the cerebral cortex is, in the opinion of Demchenko (1983), the most reliable
sign of local blood flow increase. It is well known from the data available in the literature
that during the convulsive activity at the onset of an epileptic seizure blood flow to the brain
increases 2-3 fold (Brodersen et al., 1973; Howse et al., 1974, Chassagnon et al., 2007,
Jacobs et al., 2008 ), yet such a state of the brain is the least close to its normal activity. But
during experiments this may be the case since at this time there is a maximal activity of the
cortical neurons and perhaps one can more distinctly trace the interrelation between the
functional and hemodynamic shifts occurring in the brain.
Local changes in the activity of the individual structures may actually be induced by the
electrical stimulation of other brain structures having afferent connections with the area being
studied. With this in mind, Baldy-Moulinier (1975) chose to work with the septum while
General Problems of the Brain Functional Activity and local Blood Flow Coupling 85
stimulating the reticular formation followed by the hippocampus. Septal blood flow was
measured by the Xenon technique. Concomitantly with the appearance of the hippocampal
theta rhythm during the stimulation of the mesencephalic reticular formation the septal blood
flow started to increase. In the same experiments when the contralateral hippocampus was
electrically stimulated blood flow within the septum increased by 100% of the control.
The EEG pattern, characterized by the appearance of slow waves within the theta-delta
range, that is usually observable in the conditions of pathology and functional disorders, is
also of great interest. In the experiments of Demchenko (1983), such a state is attended by a
tangible decrease of local blood flow. A sharp decrease in blood flow and oxygen
consumption in the cortex was observed in clinics whose patients suffered from chronic
destructive affections of the brainstem (Ingvar, 1975; Gustafsson et al., 1982).
Baldy-Mouliner and Ingvar (1968) evaluated the correlation between blood flow and
EEG during photic stimulation. They found an intimate interrelation between these processes,
finding no dependence between the firing rate and blood flow (perhaps because of the
measurements being made not in the very visual area of the cortex but in the adjacent region);
on the other hand, a good correlation between local blood flow, electrical activity and the
firing rate was found while studying the lateral geniculate nuclei. Increases in cortical blood
flow was correlated with frequency of firing between 10 and 50 per second (Baldy-
Moulinier, 1975).
Compiling of data which has been reported in the literature allows certain inferences to
be made. That is that desynchronization of the cortical electrical activity is usually attended
by an increase in the local CBF, whereas the onset of the slow wave activity is followed by
its abrupt decrease.
There is no doubt that the process of energy loss and recovery must serve as the
associating link between the two events, although they are fairly diverse by their nature and
character.
Bearing in mind that nervous tissue does not have its own stores of energy and that the
latter must be steadily delivered by means of an adequate blood supply, the close correlation
described above between the most specific patterns of electrical activity in the cortex and the
dynamics of blood flow becomes understandable. As has been already indicated above, there
is no quantitative dependence between the degree of alteration of the functional state of the
brain and the change of its electrical parameters. Patterns of electrical parameters
characteristic of a variety of functional states have not been identified, while the "map" of
blood flow distribution, as seen above, has provided a vivid picture of transition from one
state to the other.
Further extension of studies on the dynamics of redistribution of blood flow in the brain
during the most different functional loads will, apparently, permit one to evaluate the
structural organization of the brains working much more efficiently than by only utilizing
electrical parameters.
7.3. BLOOD FLOW IN THE CORTEX DURING SENSORY

STIMULATION
Mean cerebral blood flow and metabolism under normal conditions can be altered but
insignificantly so (for instance, during voluntary activity, solution of a task, speech, reading,
etc.) reaches a high level of nociceptive stimulation. In this state of discomfort, a painful
sensation is rendered, by the pattern of lCBF, which appears to differ remarkably from all the
others. In the experiments of Ingvar (1975) electrical stimulation of the thumb of the
contralateral hand (with the intensity twice as much as threshold) resulted in a moderate
increase of local flow in sulcus Rolandi, being more pronounced in the premotor zone (as
compared to the postcentral one). If the increase in the stimulus elicited in the patient is a
feeling of discomfort or light pain, then the blood flow change has a more significant
character and embraces the entire sulcus Rolandi and frontal area, relatively low blood flow
in the temporal and parietal areas remaining unaltered. Similar data have been obtained in the
studies of Tsubokawa et al (1981).
Activation of the cortical terminals of the sensory analyzers in order to reveal the
correlation between the functional activity and blood circulation, a number of authors have
obtained intriguing results. Friberg et al. (1985) studied regional cerebral blood flow (rCBF)
in 10 patients suffering from various diseases that made intracranial surgical intervention
inevitable. rCBF measurements were made during calorimetric vestibular stimulation with
lukewarm water in 254 areas of the cerebral cortex. It was only in one site of the cortex
located in the upper temporal area, that rCBF was found to be increased, verifying that there
exists a considerable focal activation which occurs in the contralateral area of the stimulated
side of the hemisphere.
Kilibaeva (1985) stimulated the vibrissae in rabbits and obtained a clear-cut local focus
of increased blood flow within the area studied (as compared to the resting state).
Simultaneously with the blood flow increase, PO2 also increased which is a characteristic of
the reaction of functional hyperemia. In the adjacent regions, the dynamics of blood flow and
PO2 appeared unaltered. It should be noted that mean value of blood flow throughout the
studied area did not change at the stimulation of the vibrissae.
It is important to compare the dynamics of blood flow, PO2 and ECoG in the brain area
under study during sensory stimulation. Maximum of ECoG power increase and the reaction
of hyperemia were recorded 40-50 sec after the onset of sensory stimulation. Consequently,
the stimulation applied to the vibrissae resulted in the blood flow increase in a rather
localized region of the primary sensorimotor cortex in rabbits. No significant changes in
blood supply of the adjacent regions occurred, although there was a tendency for the blood
flow to change in them.
In evaluation of the spacial distribution of hemodynamics in response to photic
stimulation, Demchenko (1983) demonstrated that in the occipital cortex a mean increase in
local blood flow occurred by 25%, in the frontal area by 9%, and in the parietal areas there
were no significant changes, while in the temporal area a decrease was noted. In the same
experiment audiostimulation (with the frequency of 100Hz, intensity 100 Db) in cats resulted
in a rise of local blood flow in the temporal area. What is more, distinct from photic
stimulation, the increase in blood flow was more localized, and in particular, was mainly
found in the caudal part of the primary auditory field.
The most important results were obtained in the 1960s. Using the method of differential
thermometry, Marshak (1967) and Ryzhova (1968) showed local blood flow changes in the
cerebral cortex of cats and rabbits in response to photic stimulation. In particular, in the
examined animals in response to one and the same stimulation, for instance, photic, the blood
flow change occurred in the visual and auditory areas of the cortex, but the reactions always
had different directions, i.e. an increase in blood flow in the visual area was accompanied by
its attenuation in the auditory (Ryzhova, 1967).
A number of researchers (Antoshkina, Naumenko, 1960; Benua, Lesniak, 1967) found by
means of electroplethysmography qualitative changes occurring in the blood volume of the
visual area during illumination of the retina in cats.
7.4. BLOOD FLOW IN THE CORTEX DURING MOTOR

ACTIVITY
Gross et al. (1980) demonstrated that during treadmill exercises the total blood flow in
the canine brain undergoes no change, whereas the mean in local blood flow is increased by
40% in the structure responsible for the sensorimotor control. After injecting doxaprene, a
drug which elicits an elevation of the systemic arterial pressure while decreasing the PCO2 to
the level similar to that observed during treadmill exercises, the basal CBF fell and
spontaneous changes mentioned above were lacking. In spite of the presence of a
vasoconstrictor factor of hypocapnia, during motor activity, blood flow rises in the
sensorimotor area of the cortex, i.e. under certain conditions, enhancement of metabolism in
this structure dominates over the vasoconstrictor factors during regulation of the vascular
resistance.
Olesen (1971) demonstrated that working the hand and shoulder leads to a rise of local
blood flow in the contralateral area of sulcus Rolandi. A fairly faint increase was also
obtained during homolateral work. These findings have been confirmed by Ingvar (1975) as
well.
Studying of the distribution of blood flow during rhythmic hand clenching Olesen found
that the essential blood flow does change on the contralateral side. From the frontal area
which was the area of "highest blood flow" it shifted to the sulcus Rolandi. Later Halsey
(1979) and Lauritzen et al. (1981) obtained similar results, with increases reaching 50% and
more as compared to the resting value. Simultaneously, a decrease in blood flow was seen in
the frontal and temporal areas. Using the method of rheoencephalography Okhnianskaia and
Leninetskaia (1976) while working with the contralateral hand obtained an opposite effect,
they recorded blood flow increase by 60% in the temporal area. It is interesting to note that
blood flow increase during contralateral manual work (in Ingvar's experiments) was less
pronounced in preroland than postroland and adjacent parietal areas. This region has a
posterior position in relation to that which is activated by the sensory stimulation area. From
these findings, Ingvar made the following inference: Voluntary movements activate primarily
the sensory areas, since quantitatively; activation appears to be more pronounced in relation
to the precentral motor area. These findings were confirmed in animals too.
A tight coupling between the level of metabolism and local CBF has been shown in a
number of other works as well (Siesjo et al., 1980; Sokoloff, 1981; Katz-Brull et al., 2006). It
appears that sensory stimulation, be it motor or mental activity, regularly increase the
velocity of cerebral metabolism of oxygen and blood flow intensity while these parameters
remain unaltered in the entire brain as a whole. Sokoloff (1981), states that the level of local
blood flow is found to be distributed in the brain structures in exact proportion to its glucose
utilization rate. This rate alters when the local glucose uptake changes due to changes in its
functional activity. Therefore, it can be assumed that the level of functional activity in the
structural elements and functional components of the central nervous system (CNS) regulates
the local velocity of energetic metabolism while the local blood flow adjusts to the increased
metabolic demands. During acute hypoxia the coupling between the level of metabolism and
local blood flow may be disrupted.
7.5. BLOOD FLOW IN THE CORTEX DURING MENTAL

ACTIVITY
Matsuda et al. (1984) have studied rCBF in normal right-handers during movements of
the left hand and while reading aloud. A focal increase in rCBF was found to occur in the
prefrontal cortex, both of the secondary motor areas, the primary sensorimotor area of the
hand and the central gray matter on the right side.
While reading aloud the rCBF increase was noted in the primary visual cortex, the visual
cortex of the striated body, the prefrontal cortex, both accessory motor areas, the left
prefrontal area of the eye, as well as in the left angular sulcus.
Kurachi et al. (1985) using the method of inhalation of 133Xe determined the rCBF in 16
patients with schizophrenia and in 20 healthy volunteers. Mean values of the hemispheric
rCBF in schizophrenic patients were found to be lower than in healthy subjects. In
schizophrenic patients suffering from auditory hallucination a marked increase in rCBF was
seen in the left temporal area, while in patients without such signs, in the right one.
While studying the neurologically normal patients Ingvar and Schwartz (1974) found that
in a simple verbal testing (repetition of names, week days, etc.) the mean level of CBF
remains unaltered. However, a shift does occur in high levels of rCBF to the posterior
direction, involving the premotor area, sulcus Rolandi and Sylvian gyrus. In a small number
of cases speech was also shown to elicit various CBF changes in the non-dominant
hemisphere. In this hemisphere, blood flow tends to decrease, especially postcentrally, while
at the same time, an insignificant increase of local blood flow was found in sulcus Rolandi of
the non-dominant hemisphere.
While measuring local blood flow in a variety of cortical areas in man during mental
arithmetic, Oskalok (1979) found psychologic loading to cause statistically significant
changes in the majority of sites in both hemispheres, though the pattern and degree of CBF
changes varied during different kinds of counting. Almost under the same experimental
conditions, utilizing the hydrogen clearance method, Shakhnovich, Razumovski (1974)
obtained results which showed a local CBF increase by 33% over the initial level. In
addition, a 47% decrease of local blood flow in the right parietal area occurred during mental
arithmetic. As stated previously, attenuation of blood flow was rarely seen while utilizing the
various methods. Besides, "lack of blood flow changes in one point might be coupled with its
elevation or attenuation in the adjacent point". It has been demonstrated by Shakhnovich et
al., (1979) that with most patients with cerebrovascular disorders during a variety of
functional loadings the pattern of local blood flow changes and it is different in one and the
same regions of the brain. In their opinion, this is due to different functional significance and
differentiation of the studied structures.
In auditory tests Knopman et al. (1982) made measurements of rCBF (133Xe) in 11 areas
of either hemisphere in young healthy people. Perception appeared to result in a considerable
blood flow increase in the left posterior Sylvian area and changes were in line with the
character of the information heard.
In a series of experiments with psychological testing (memorization of digital material,
solution of tasks) the elevation of local blood flow was found in the premotor and frontal
areas (Risberg, Ingvar, 1973). At the same time, relatively low blood flow was in evidence
between the primary posterior zones of sulcus Rolandi where an increased level of blood
flow is usually observed.
7.6. BLOOD FLOW IN THE CORTEX DURING EMOTIONAL

REACTIONS
Changes in local blood flow occur when there is an application of emotional stimuli.
Observations were made on humans with implanted electrodes. When the patients perceived
a nurse preparing a syringe with an injection, cerebral blood flow increased, while a state of
anxiety appeared and a psychomotor syndrome developed. In evaluating a vast body of data
obtained in patients Betz (1975) came to a conclusion that the local CBF responses to the
development of emotional tension vary in terms of the stimulus duration, and are as a rule
more pronounced at the application of the first stimulus than the subsequent ones. The
qualitative picture of the local CBF is determined both by the degree of body movement and
the extent of the patient's anxiety.
In experiments on cats Betz observed the following fact: if the sight of a stimulating
object (for instance, a mouse) causes local CBF to rise, then the attack results in a drastic fall
of blood flow below the initial level. A propos, a similar picture is in evidence when a cat
restrained to the operating table recovers from superficial anesthesia and attempts to get free
of the straps - local CBF sharply falls at this time below the initial level (Betz, 1975). During
artificially provoked emotions the most profound blood flow increase occurred in cats in the
pyriform gyrus (Sigurdsson et al., 1977; Delgado, Taigi, 1967)
While employing the method of thermal clearance on free moving cats Betz (1975)
demonstrated that occasional noise with the intensity of 50-100 db leads to blood flow
elevation in the thalamus and hippocampus. Increase in the intensity of noise augments also
the amplitude of blood flow increase until some maximum is reached. After repetitive noise
stimulations the local CBF responses begin, but after a certain period, it attenuates and finally
disappears provided the type of stimulus remains unaltered. Repetition of same stimulus in
the subsequent days again elicits blood flow increase. Using the same technique for
registering local CBF, Betz in his experiments on hungry cats observed blood flow increase
when the cat caught sight of a mouse. In satiated cats blood flow response was much weaker
or even absent altogether.
The experiments described above indicate the existence of a strict relationship between
the emotional state and the level of local CBF.
Chapter VIII
DYNAMIC CHARACTERISTICS OF LOCAL BLOOD

FLOW REGULATION IN DIFFERENT BRAIN
STRUCTURES DURING PERFORMANCE OF
BEHAVIORAL ACTS
8.1. CHOICE OF THE EXPERIMENTAL CONDITIONS
In studying the dynamics of cortical blood flow we used variations in functional and
metabolic activity in the different brain structures of albino rats in response to functional
load, which consisted of putting them in a complex maze.
Utilization of various maze techniques in studies of behavioral responses and memory in
animals was used at the beginning of the twentieth century and continues to be used to-date.
Figure 32. Construction of the maze.
The experiments used a variety of maze constructions; those which are the most
convenient and simple for rats proved to be the one consisting of platforms suspended on
supports as high as 30cm (Figure 32). This kind of construction allows it to be arbitrarily and
readily modified as to its configuration, creating a more complex or simple task, these
allowing observations on the animal’s behavior under various experimental conditions.
By the method of trial and error the rat learns to move along the optimal trajectory,
accomplishing this in several minutes to several seconds. Such a learning method was found
to be most acceptable and fitting to the task at hand - since the blood circulation is known to
be a relatively inert process it takes a definite lapse of time for its characteristic changes to be
detected. The "T" and "U"-shaped mazes, which are commonly used in behavioral studies of
electrophysiological correlates, were disregarded in our experiments. We used multi path
mazes. In order to evaluate the process and the level of learning the following parameters
were usually employed: number of errors made (i.e. number of deviation from the optimal
route) and time it takes to go through the maze.
Recording of the Studied Parameters
Using a simple electronic device, specially designed for this purpose, automatic
recordings were made of trajectory of the animals movement through the maze and of the
time of its stay on each of the platforms. The dynamics of lCBF (by means of electrochemical
generation of hydrogen) and ECoG were recorded using the combined implanted electrodes
(Figure 33). Coordinates in the atlas of Bures et al. (1967) were used for the implantation of
electrodes in the frontal, motor, visual and temporal areas, as well as the intermediate
between the areas of the cerebral hemispheres. Reference electrodes were fixed on the skull
in the frontal and occipital areas. In addition, an electrode was sutured in the pectoral area for
the purpose of recording the rate of heart beat.
Figure 33. Construction of the implanted electrode.
Experimental Technique
On the fourth day of the electrode implantation and after testing their workability
(according to a conventional CO2-test) animals were placed in the maze target-box.
Recording of the indicated parameters were done prior to, in the process and after passage of
the maze. In the first trial the animals were assisted in the search for an optimal runway from
the start-place to the target-box, and later on they were learned on their own by trial and
error. The experimental conditions remained constant. Three trials were run each day. Once
"automatism" in passing through the maze was reached, the mazes configuration was
Dynamic Characteristics of local Blood Flow Regulation… 93
modified and animals were allowed to relearn without any assistance on the part of the
experimenter. Experiments were run for five days, the animals were then sacrificed and the
localization of the electrodes verified.
The process of learning occurred without food reinforcement. Every subsequent
movement on the platform brings the animal to a novel situation and, is in its own right, a
stimulus for a new movement ahead. It is assumed that coming upon a deadlock and needing
to be returned to the beginning must be a very unpleasant event for the rat and it is perceived
as a punishment for an error. While reaching the target-box, therefore not going through the
nonethological conditions, is regarded as an essential reward - this serves as a motivation for
forward moving through the maze.
As shown in our results, such experimental conditions provide a sufficient level of
motivation for learning. After about 6-7 trials rats on an average, less commit more than one
error, i.e. they virtually attain the state of "automatism". Consequently, experimental
conditions of this kind simulate the process of learning and serve as an accurate basis for
studying the dynamics of lCBF in correlation with this process.
Using the method of trial and error, which somewhat extended the time of learning and
elaboration of "automatism", it also proved to be most adequate from the point of view of
specifically studying the parameter local cerebral blood flow. Local CBF changes are known
to be a relatively inertial process and a definite time interval is required for tracing them. Of
course, this does not apply to conditions when damaging influences occur and the system
responsible for lCBF regulation is able to react almost instantaneously, for example, to sharp
changes in SAP.
In a special series of experiments time-restricted model of blockade of cholinergic
structures was used. For this purpose, rats were preliminarily injected intraperitoneally with
anticholinergic drugs - amisyl (atropinelike) (15 mg/kg) or scopolamine (1 mg/kg).
Before their injection, one control trial through the maze for each rat was made in order
to obtain background records of the parameters under study. It is clear that with the
construction we used a single trial could not result in the rat learning the optimal runway to
the target-box.
An injection of scopolamine was given by way of halantamine (5 mg/kg) or eserine (1
mg/kg).
Choice of these drugs and their administration were used because it is well known that an
amnesic effect is observed when anticholinergic drugs are injected before learning and it is
absent when injected immediately after learning (Iljuchenok, 1972). It is also known that
disturbance of prominent blockade of cholinergic structures, even in the case of i.v. injection,
occurs in 1-2 minutes during which the process of memory trace consolidation is believed to
be terminated. 20 min after injection, all animals were tested.
8.2. REDISTRIBUTION OF LOCAL BLOOD FLOW IN

DIFFERENT CORTICAL AREAS DURING MAZE TASK SOLUTION
The process of maze learning itself was evaluated by variations in the number of errors
made from trial to trial in search of the optimal runway to the target-box.
Beginning with the third-fourth trial, in the process of learning an abrupt reduction of the
number of errors was noted, it did not exceed 2-3, while from the sixth-seventh trial almost
all the animals reached the state of "automatism" and, they passed the maze virtually without
errors, the run taking them less than 8 sec. When the maze configuration was modified, the
process of relearning was considerably faster (Figure 34) (presented in the figure are mean
statisticals of learning curves).
Figure 34. Mean statistical curves of learning and relearning.
Figure 35. Dynamics of local blood flow in the motor zone of the rat's brain in the process of learning.
II, VII and X - numbers of trials; arrows - the moment of the animal placing from the target-box to the
starting place.
Dynamics of local blood flow in the motor zone of the rat brain parietal cortex in the
process of learning is given in Figure 35. Upper tracing of the figure reflects in a variation of
lCBF, while the lower tracing reflects, as has been already pointed out, the trajectory of the
rat's movement through the maze. Arrows designate the moment of the animal's placing again
from the target-box to the starting place. The given figure shows the case in which the rat on
the tenth trial on (the second day of learning session) ran through the maze without a single
error. It becomes apparent that when the transfer of the animal from the target-box to the start
place occurs, the lCBF starts to rise sharply. During the run through the maze the dynamics of
lCBF appears to be strictly correlated with the animal's orientation reaction.
Figure 36. The results of multiple trials of rats at first through the maze of configuration M1 and then
through the maze of a modified configuration M2. The left axis - number of committed errors; II, VI, X
- numbers of trials during learning; I, IV - numbers of trials during relearning.
As soon as the rat ceases to continue to search for the runway and makes a stop on any
platform, lCBF starts to decrease (independently of the overall motor activity, for example,
during intensive "grooming"). Simultaneously when the rat begins again to search for the way
lCBF again starts to rise. Only when the animal arrives at the target-box does it slowly return
to its initial level. In the second, third and subsequent trials, not only is there a reduction in
the number of errors and a shortening of time it takes to run the maze, but there is a decrease
in the amplitude of lCBF increase and duration of its changes. During the "automatized"
maze passage, lCBF rise becomes stabilized on a steady level which is considerably lower
than the maximal deviation of lCBF from the initial level, which occurred in the first trials. If
under these conditions, i.e. during "automatized" behavior of rats, one alters the configuration
of the maze, thereby disturbing the elaborated stereotype, and in attempting to offer the
animal a new task, there occurs a sharp rise in lCBF and in the process of relearning the same
dynamics of alteration of lCBF pattern as was observed during the initial learning. Figure 36
represents the results of multiple trials of rats first through the maze of one configuration
(M1) and then through the maze of a modified configuration (M2). The left axis shows the
number of committed errors, while the right shows lCBF changes in conventional units.
Abscissa shows time. Thick lines on the axis reflect respectively change of the number of
errors from trial to trial (the tenth trial with no errors), deviation of lCBF and time of the run
through the entire maze. As in the previous figure, here too, in parallel with the process of
learning one can clearly see a reduction of the level of lCBF variation with the stabilization
of the level attained in the tenth trial. However, simultaneously with the modification of the
maze configuration, lCBF again sharply increases in strict correlation with the number of
errors.
Patterns of the ECoG spectrograms, obtained from the parietal area (from the site where
lCBF recording was made) of the cerebral cortex during quiet wakefulness of the animal in
the target-box and during resolution of the maze task are presented in Figure 37. As seen in
this figure, during the search for the runway through the maze the ECoG shows
synchronization in the theta-rhythm range (Figure 37B), although not infrequently its
complete desynchronization is also observed (Figure 37C).
Figure 37. Electrocorticogram (ECoG) spectrograms obtained from the parietal area of the cerebral
cortex during passive wakefulness of the animal in the target-box (A) and during resolution of the maze
(B,C).
Table 8. Statistical reliability of the observed dynamics of local Cerebral Blood Flow
Charcter of the lCBF changes P<

1 Increasing of lCBF during maze learning 0.05
2 Mitigation of the amplitude of lCBF increasing (from trial to trial) 0.05
3 Secondary increasing pf lCBF during relearning 0.05
Reproducibility of the results, described above, concerning the dynamics of lCBF in all
cases of localization of the electrodes in the motor zone of the cortex was 95%. Results of
nonparametric evaluation of statistical reliability of the dynamics of lCBF in the experiments

on 60 rats are given in Table 8.
In the very first stages of maze learning a similar dynamic of lCBF takes place in the
visual area of the cerebral cortex as well (Figure 38). However, it is distinct from the motor
area (Figure 39), when the state of automatism in maze run is reached (X trial in the given
figures) no increase in lCBF occurs.
Figure 38. lCBF dynamics in the visual area of the cerebral cortex. II-X - numbers of trials. White
triangles designate the moments of the animal placing to the start place, semyblack - the moments of
begining of movement in maze; black - end of maze task.
Figure 39. Same as in Figure 38, but for the motor area of the brain cortex.
Simultaneous recording of lCBF in the parietal and frontal areas (or visual and frontal)
has revealed that in the process of maze passage a rise in lCBF in the parietal and visual areas
is accompanied by its drop in the frontal area (Figure 40). At the same time, the prominence
of the decrease is mitigated from trial to trial. As to the temporal area and the sites between
the frontal and parietal areas, no changes in lCBF were found to occur there.
Figure 40. Simultaneous recording of lCBF in the parietal and frontal areas. (A) - 8% CO2-test; (B) -
resolution of the maze task. Designations are same as in Figure 38.
8.3. POSSIBLE MECHANISMS OF THE CORTICAL BLOOD

FLOW RESPONSES DURING FUNCTIONAL LOADS
It is evident that the physiological mechanism of acquiring maze habits may be

considered as a complex conditioned instrumental reflex, whose external manifestation is a
number of movements conditioned by the design of the maze.
In conventional maze experimentation, a hungry rat is placed at the entrance, it starts to
wander through different sections of the maze and comes upon deadlocks before it
eventually gets to the feeder. The animal's tendency is to make fewer and fewer errors
and spend less and less time from start to the target, by more often avoiding deadlocks and,
eventually, achieving the state of "automatism" and he can then run the entire route in a few
seconds.
There is a school of zoopsychologists who consider that a rat's behavior in the maze boils
down to the formation of simple connections between stimulus and responses. According to
this school, learning consists in consolidation of one connections and impairment of the
others. In terms of the "stimulus-response" scheme a rat in the process of learning in the maze
responds to a number of external stimuli, such as for example: light, sound, smell, etc.,
leaving a trace in its organs of sense. They are supplemented by a number of internal stimuli
arriving from the visceral system and from the skeletal musculature. These external and
internal stimuli determine the orientation reaction, walking, running, turning round, alertness,
etc.
Yet some schools exist which regard learning to consist not only in the formation of a
connection of the stimulus-response type, but in the formation in the nervous system of
"sets", which act like cognitive maps.
Such experiments usually fall into five basic types: 1) latent learning; 2) vicarial
(substituting) trial and error; 3) experiments for exploration of a stimulus; 4) experiments
with hypotheses; 5) experiments for spatial orientation (Tolman, 1980). Learning which was
not manifested until the presentation of food occurred referred to as "latent". A simple
illustration of learning of this type is shown in the following experiment. A Y-shaped maze
with two hole-boxes is used. At the right end a bowl containing water is placed, and at the
left, food. Prior to each experiment rats are given water and food. They pass through the
maze, and are returned to the cage with other animals. In a critical experiment rats are divided
into two groups: one is deprived of food, the other is deprived of water. It appeared from the
first trial the subgroup of hungry rats ran to the left end, while the thirsty subgroup ran to the
right end (Tolman, 1980). These results indicate that under conditions of preliminarily
nondifferentiated and very faintly reinforced experiments animals nevertheless learn the
location of water-bowl and food-bowl.
The term "vicarious trial and error", has been proposed by Muenzinger (1939) for the
definition of irresolute behavior: the animals time and again return to one or another section
as if being "keen on" choosing before they actually took one or another route.
We will not deal here with other kinds of experiments, since they in fact, have no relation
to the method employed by us in learning studies.
From the foregoing it is evident that no matter whether the animal receives a food reward
or not, it learns to find the shortest path leading to the target. The difference lies in the
duration of the course of learning process.
In the design of the maze employed there were several platforms erected over the
experimental ground (as high as 30 cm), and the process of learning with no food
reinforcement was evaluated. Every passage to the next cross-ways (when the animal has the
possibility of choosing which direction to go in) appears to be stimulus enough for continuing
on ahead. Reaching a deadlock necessitates being returned back, and must be perceived by
the animals as a punishment for an error, and it seems to elicit in them unpleasant sensations
which in turn make the rats avoid deadlocks and encourage exploring the way leading to the
target. Getting rid of nonethologic a condition (staying in the maze) serves as a motivation
for moving forward through the maze.
As it is evident from the results we have obtained that experimental conditions provide
the sufficient level of motivation for learning and, after about 6-7 trials rats commit on an
average less than one error, i.e. they actually achieve the state of "automatism".
Thus, in summing up it can be said that the experimental conditions which we employed
provided for the process of learning, which means that they were able to serve as a accurate
basis for studying the dynamics of local CBF in relation to the indicated process. Other than
the vicarial method of trial and error, though it somewhat increased the process of learning.
Acquisition of "automatism" proved to be the most acceptable for us in view of the specificity
of the basic parameter under study, i.e. local CBF.
In our experiments, even when the animal achieved the state of "automatism", the time
spent for the run through the maze (6-8 sec) appeared to be sufficient to reveal essential
changes in the dynamics of local blood flow in the cortical areas under study.
Our experiments yielded statistically significant results indicating that in the course of
solution of maze task in the cerebral cortex of albino rats the dynamics of local blood flow is
as follows: 1. Blood flow increases in the parietal area; 2. It decreases in the frontal area; 3. It
remains invariable in the intermediate areas, as well as in the temporal area; 4. As learning
proceeds, profound changes in local blood flow attenuate; 5. After the passage through the
maze local blood flow virtually returns to the initial level; 6. After full learning and the state
of "automatism" is achieved local CBF in the course of passage through the maze changes
only in the motor zone of the parietal cortex.
Despite the decrease in local blood flow, oxygen tension appears to be invariable in the
frontal area.
Let us attempt to make a comprehensive analysis of the effects. Both from the point of
view of cause consequence relationship and in investigating the mechanisms responsible for
the patterns of local blood flow as described above.
With Ingvar (1975) Gross et al., (1980), Olesen (1971) and some other authors, under
conditions of enhanced motor activity local blood flow undergoes substantial increase in the
structures responsible for the sensorimotor control.
However, as was demonstrated in our experiments the motor activity that is not related
with the orientation in the maze (for instance, during intensive grooming) local blood flow
even decreases in the parietal area, though this usually occurs in the face of already increased
level of blood flow. One does see changes in blood flow in the animals which are not
performing motor activity (for instance, while they make a stop at cross-way in the maze).
Thus, the patterns of local blood flow we have described above accompanying the process of
complex maze task solution can hardly be associated with the animal's locomotion. By the
way, this should be obvious also by the fact that a gradual attenuation of magnitude of its
changes from trial to trial, though the movement of the animal through the maze appears to
be less intensive in the first trials than in the subsequent ones.
A special analysis was made in order to establish the possible correlation between the
dynamics of lCBF and the heart rate. Superinposition of the corresponding cross-correlation
functions has yielded an unequivocal answer - there is virtually no presumed correlation
between the examined parameters.
In investigations devoted to the analysis of the dynamics of cerebral blood flow in man
and animals in response to emotional stimuli (Delgado, Taigi, 1967; Betz, 1975) an increase
of local blood flow was shown to occur in the thalamus, the hypothalamus and the pyriform
gyrus. Moreover, from stimulus to stimulus (as in our case from trial to trial in the maze)
pronounceness of blood flow responses is reduced and with invariable type of stimulus they
even disappear altogether.
Let us analyze the results of our own studies also from this angle, i.e. from the
motivational-emotional aspect of behavior.
I.P.Pavlov expressed a view that the process of formation and disturbance of dynamic
stereotype - of the stable system of animal's and humans' responses to environmental stimuli,
should be accompanied by generation of emotions.
Extending this view, Osipov (1924) introduced a concept on "emotional stage" of the
conditioned reflex as distinct from "cognitive intellectual stage" on the way to perfection of
the reflex at its second stage of formation. The first stage of the conditioned reflex formation
is characterized by generalized influences within vegetative sensory and motor spheres
(Simonov, 1975), i.e. emotions actually present the state of general mobilization of vegetative
and energy resources of the body. Vegetative shifts are more pronounced in the
cardiovascular system (Sokolov et al., 1980).
The first stage in the maze task learning as a behavioral act is seen in the scheme given
below:
MOTIVATION + EMOTION + ACTION
which during acquisition of automatism in movement renders as:
MOTIVATION + ACTION
At this time the emotional component is eliminated, though disturbance in the dynamic
stereotype of behavior instantly resumes the emotional component in the response to the
orientation reaction elicited by this disturbance.
After repeatedly trying to change the dynamic stereotype special systems of processes
thus create a definite alternation in the reaction which accounts in its turn for a rapid solution
of the task (Alexeev, 1977), for example, this occurs upon altering the configuration of the
maze.
Let us consider the redistribution of local CBF obtained in our maze learning studies on
rats. The dynamics of local blood flow will be considered as a vegetative component of
emotional tension arising during orientation reactions.
At the initial stage of learning with specific signs of generalized effects in the sensory,
motor and vegetative spheres there occurs a maximal enhancement in the level of local blood
flow in the parietal area and attenuation in the frontal area of the cerebral cortex. Beginning
with the 3rd-4th trials, as habits are being consolidated and a dynamic stereotype formed, the
amplitude of blood flow changes appear to decrease both in the parietal and frontal areas.
Changes in blood flow have a hypercompensatory character - recovery of the initial level
after the animal's return to the target-box lasts long (as compared to either its increase or
decrease). This once again tends to support the possibility that the local CBF changes are to
be considered as a vegetative component of emotional tension.
According to Simonov's scheme, in the automatized state the emotional component
disappears and therefore, one should expect a complete vanishing of the effects of either an
increase or a decrease in local CBF. The same as was the case in the visual area (Mitagvaria,
1983). However, in the parietal area, following the attainment of the automatism state there
was still evidence of a stable increase in blood flow. In these experiments local blood flow
measurements were made in the motor zone of the parietal cortex. Therefore the residual
increase in it was thought to be due to the motor activity of the animal and the resultant
enhancement of the level of functional activity in the area under study, i.e. due to the
coupling of "function+metabolism+blood flow". We therefore came to the conclusion that
the pattern of local blood flow which was recorded in the process of learning represents the
superposition of two effects - 1) the vegetative component of emotional tension and 2)
enhancement of metabolism as a result of general motor activity. It should be noted that the
first gradually disappears in the course of consolidation of habits, while the other persists.
Consequently, when functional changes are accompanied by emotional tension increase,
the patterns of local flow changes in the parietal and visual areas of the cerebral cortex and it
may have a two-component character which reflect: a) changes in the emotional sphere and
b) changes in the functional-metabolic activity. At the same time, the prominence of the first
component, particularly at the initial stages of learning (or during first functional trials), may
tangibly mask the manifestation of the latter component.
Evaluation of the data in the literature cited above indicates that blood flow changes in
individual brain structures occur in the face of virtually invariable global blood flow within
the brain. Consequently, these changes must be provided by local redistribution of blood
from the brain areas involved and is consequence of the law of blood flow continuity.
As suggested by our findings, an increase in local bloodflow in the parietal area is
parallelled by its decrease in the frontal area. Moreover, the dynamics of this decrease from
trial to trial in the maze makes a virtual mirror reflection of what is occurring in the parietal
area. As automatism is being acquired in behavior, local blood flow in the frontal area is not
in fact altered.
Proceeding from the known coupling of "function-metabolism-blood flow", decreases in
the level of the latter component should indicate the decrease of the level of activity of the
previous ones. On what neurophysiological premises can one claim that the functional
activity in the frontal area of the cerebral cortex under the experimental conditions decreases?
Analysis of the available literature concerning the functional activity of the brain during
performance of behavioral acts indicates that there is a sufficient body of evidence for the
existence of a correlation between the neuronal activity and the various aspects of behavior -
the environment, locomotion, target. In the majority of cases investigations of this kind were
undertaken within the framework of knowledge relating to the specific functions of
individual areas of the brain, therefore the neuronal population whose activity is related: a)
with performance of definite movements are usually studied in the "motor" structures (Evarts,
1973) b) with properties of the environment - in the respective projection areas (Supin, 1981),
c) with motivation or target behavior, in the so-called "motivational" structures (Mountcastle.
at al., 1975; Rolls et al ., 1976), etc. Thus, an understanding is reached about the specific
localization of neurons and their links with the various aspects in the relationship between the
organism and the environment.
In this context we are interested in the neuronal mechanisms of the involvement of the
frontal and motor areas of the cerebral cortex and its control of complex voluntary
movements.
These mechanisms have been studied in primates for a number of years. Thus, Kubota
and Niki (1971) while observing delayed reactions have demonstrated that efferent neurons
modify their activity at different stages of the behavioral act: 2/3 of neurons from the frontal
cortex become activated immediately after the termination of the delay period, whereas the
activity of 1/3 of the neurons are enhanced throughout the delay period.
Sakai (1978) has investigated the activity of cortical neurons in monkeys which lie
between the frontal and motor zones during the process of learning visual discrimination. The
animal was given the opportunity to press the lever, thereby increasing the strength applied.
When the needed strength was achieved, a red light corresponding to the increased strength (I
phase) was alternated by green light (II phase, corresponding to the needed strength)
Four types of neurons were found: Type "A" neurons were activated as compared to the
background in the first phase, while in the second phase (when intended strength was
achieved) the activity of type "A" neurons attenuated; the activity of type "B" neurons
enhanced in the second phase in the period corresponding to the required strength; type "C" -
in the second phase a reliable attenuation was observed in the neuronal activity and finally,
type "D", the activity was enhanced from the moment of delivery of a warning signal and
continued until the termination of the second phase. Such variability in neuronal activity is
attributed to the visual stimuli (illumination and change of the valve light), and not to the
motor activity, i.e. it is associated by him to the mental functions.
In 1979 Orlov and his associates conducted a study of neuronal responses from the
temporal cortex to signals of behavioral schedule with food as reinforcement. The animal
(monkey) was placed in a primate armchair. The experiment was comprised of two parts. The
first was instructive, during which a system of signals (instructions) were delivered to the
animal, and the other part was that of triggering, during which the animal had a possibility to
realize the given task, i.e. to perform a goal-directed movement and, receive a food
reinforcement equivalent to the success of the action performed.
The instructive part of the schedule fell into four stages: 1) a warning signal (fixation of
attention throughout the experiment); 2) a period of anticipation of a conditioned signal
(nonspecific anticipation); 3) presentation of a conditioned signal; 4) anticipation of a
triggering signal or delay (specific anticipation).
In the first stage, modulation of activity was noted in 64% of neurons, among them 27%
showed inhibition of the spontaneous activity, 23% - a complete suppression of the
spontaneous activity, in 8% there was augmentation of the activity and in 6% of the neuron
populations phasic excitatory reaction was noted.
The warning signal, in addition to fixing the attention, oriented the animal to begin to
count the time until the impending conditioned signal (irrespective of its peculiarities).
Therefore, tonic reorganization of the spontaneous activity of neurons in the frontal cortex
during a fixed period of nonspecific anticipation may be the reflection of mnemonic
processes during conditioned temporal reflex performance (Batuev, 1981).
In the second stage of instructive part of the schedule the activity of 32% of neurons did
not differ from the background activity, a decrease in discharge rate was seen in 57% of
neurons and 11% of cells generated one-two waves of enhanced of activity.
In comparison with the neurons of the frontal cortex, in the motor area the author failed
to reveal any reliable consistency in the character of reorganization of the activity, therefore,
the described reactions are of rather nonspecific nature.
In the third stage, the discharge rate increased in 17% of neurons, in 15% the response of
inhibitory type was observed, while in 10% a complete or partial suppression of activity was
in evidence. As a whole, in this stage the predominance of inhibitory reaction was noted in
about 34% of the neurons.
In the fourth stage there is a periodic short-lasting burst activity either in a different
neuron population at the onset of delay (in the middle or at its end), or in one and same
neurons. Only 5% of the cells appeared to be in the activated state throughout the entire
delay.
A triggering part of the schedule consisted of the switching on of the signal (removing of
the screen), performance of a goal-directed movement (pressing the key) and procuring of
food. In other words, removal of the screen offered the animal a possibility to realize the
preliminarily formulated on the basis of instructions of the behavioral schedule,
i.e.accomplish adequate choice of reinforcing key and pressing it.
In this part of the experiment modulation of activity in 64% of neurons is classified as the
following types: phasic augmentation of activity, tonic augmentation and tonic attenuation of
activity. The number of neurons from the frontal cortex with the attenuated activity (in
response to a triggering signal) appeared to be almost twice as many as those with augmented
activity (40% and 24%, respectively).
Thus in the course of almost the entire experiment (until the choice of keys) in the
overwhelming majority of cases the neuronal activity in the frontal area is attenuated as
compared to the background. In the final phase of the experiment when the animal chooses
the right key (it receives food as a reward) the neuronal activity becomes augmented, while in
the case of an incorrect choice (without food reinforcement) the activity remains at the
background level.
In a similar experiment the same authors (Orlov et. al., 1979) found no essential
modulation of neuronal activity in the temporal areas. In an insignificant number of neurons
from the temporal area they succeeded in finding the responses similar to those of frontal
neurons.
It may then be concluded that the level of functional activity in the frontal cortex both in
the instructive and triggering parts of the schedule appears to be attenuated as compared to
the background. It should be reemphasized that these results were obtained in primates.
While studying redistribution of blood flow in the brain in humans, Ingvar (1975) found
that the resting state is characterized by an increased level of blood flow in the frontal areas
of the cerebral cortex. He termed this phenomenon to be "hyperfrontal syndrome ". During
various functional loads the increased level of cerebral blood flow appeared to shift to the
other cortical areas.
Hence, the phenomenon of a decreased blood flow level in the frontal cortex during the
performance of a unitary behavioral act seen by us in albino rats, occurs in human brain too.
The above cited electrophysiological data, obtained in primates, confirm a decrease of the
functional activity level in the frontal cortex under the same conditions.
Comparison and analysis of data suggest that the coupling of "function-metabolism-
blood flow", established largely by clinical observations on humans, holds true for the animal
brain as well.
At the same time, we have already substantiated that at the initial stages of learning in
rats when there is high level of emotional tension (that is attended by signs of generalized
effects in the sensory, motor and vegetative spheres), blood flow response appears largely to
be the manifestation of a vegetative component of emotional tension. Now we can add that
these reactions do not contradict the functional-metabolic activity of other brain structures.
That is, redistribution of blood flow within the cerebral cortex is implemented by the
principle "function-metabolism-blood flow", but the effect is reinforced and supplemented by
the reaction which arises from the sphere of emotional tension.
Consistent with this concept is the data on the dynamics of oxygen tension in the frontal
cortex. As demonstrated above, despite decrease in the blood flow levels, PO2 remains
virtually at its original level, which, in our opinion, must indicate that in the given case there
is a decrease in the level of its consumption, i.e. decrease of the level of functional-metabolic
activity. Otherwise, decrease of the local blood flow level should have entailed attenuation of
the level of tissue oxygen tension as well.
While evaluating our findings there logically arose several questions. First, what is the
character of redistribution of local blood ? And, secondly, what is the nature of the
mechanism responsible for the redistribution?
It is apparent that the experimental conditions used by us (the maze, composed of
platforms) caused in animals a defense fear reaction. Let us turn again to the statement by
Simonov (1975): "When in the state of fear the animal gives a preventive response to a
number of stimuli, including those encountered in its life for the first time, the animal by no
means relies on the awareness of reliable signs of the threat and the means of its prevention.
Knowledge comes as a result of learning and choice, as a consequence of the process, in a
definite sense counteracting emotions and on a definite stage liquidating it. Designation of
fear (dominant) is to replace, compensate for the information deficit about the efficient means
of protection". Thus, the significance of emotions in goal-directed behavioral reactions "does
not boil down to more mobilization of the vegetative functions of the organism". Iljuchenok
and Eliseeva (1967) have demonstrated that suppression of the cholinoreactive system of the
brain by the central cholinolytics results in the blockage of the conditioned emotional defence
reaction of fear with persistence of the unconditioned. In particular, they have blocked the
muscarinic cholinoreactive structures by amisyl in the dose of 0.1-0.5 mg/kg and obtained
elimination of the state of fear in dogs, although the reaction of rage remained unaltered.
Amisyl is known to induce suppression of m-cholinoreceptors of the brain's reticular
formation, exerting on the EEG a synchronizing influence. It has also a peripheral m-cholino-
blocking action, though less prominent than that of the central m-cholino-receptors, and as a
result of this, mitigate spasms of the oculomuscles (Kharkievich, 1980).
In the present study we also made an attempt to employ a pharmacological method for
the abolishment of the emotional reaction of animals. But before looking at the results, let us
deal briefly with the basic principles of the pharmacological study of memory mechanisms.
8.4. DYNAMICS OF LCBF IN THE RAT'S CEREBRAL CORTEX

FOLLOWING INJECTION OF ANTICHOLINERGIC DRUGS
As been already stated, in our studies on the dynamic characteristics of the regulation of
lCBF in the rat cerebral cortex during solution of maze tasks we applied blockades of
cholinergic receptors by amisyl and scopolamine.
Injection of amisyl led to a definite ECoG response consisting in the synchronization of
slow waves (Figure 41). While at same time the process of learning appeared to be tangibly
retarded (Figure 42-A) and there was a sharp fall in the magnitude of lCBF increases in the
parietal cortex in the course of maze task solution (Figure 43-A). The pattern of lCBF, as a
matter of fact, under these conditions, became similar to that observed under conditions of
"automatic" behavior. Thus, the component of the lCBF pattern which, in our opinion,
reflects emotional tension is abolished and manifests itself only with the component which is
correlated with the motor activity.
It must be assumed that with the amisyl injection we succeeded in abolishing the
emotional defense reaction of fear (Iljuchenok, Eliseeva, 1967). As a result of this, an
important link of conditioned reflex activity was excluded and this considerably prolonged
the first stage of learning and concomitantly, the component of the lCBF pattern which under
normal conditions, the emotional tension was naturally removed.
Figure 41. ECoG spectrograms obtained prior (B) and after (A) amizyl injection.
Figure 42. A mean statistical curves of learning after the action of scopolamine (S) and amisyl (A).
Apart from amisyl, we have employed also another m-cholinoblocking agent

scopolamine which in contrast to amizil blocks preferentially the pheripheric m-
cholinoreceptors located on the membrane of effector cells at the terminals of postganglionic
cholinergic fibers (Kharkevich, 1980).
As has already been pointed out above, in disturbing the psychical activity scopolamine
is 10 times more active than atropine, while in respect to conditioned defense reactions, it is
more than 30 times (Iljuchenok, 1972). In reference to the background of the action of
atropine-like blockers there occurs a suppression of cholinergic influences on the heart and it
begins to dominate the tone of adrenergic (sympathetic) innervation (Kharkevich, 1980).
According to the data of Iljuchenok (1972), injection of scopolamine in our studies
completely disturbed the process of learning (Figure 42-S). Repeated trials led to no results -
in fact the rats found the runway to the target-box only with the help of an experimenter.
Simultaneously, as demonstrated in Figure 43-B, the effect of lCBF increase eliminated
altogether and, ECoG, as in the case of amisyl, showed synchronization of high-voltage slow
wave fluctuations (Figure 44).
Figure 43. Dynamics of lCBF in the cerebral cortex and trajectory of movement through the maze
(track) before and after amisyl (A) and scopolamine (B) injection. II, III, XIII - numbers of trials.
Figure 44. ECoG spectrograms obtained before (A) and after (B) scopolamine injection.
Why was there elimination of "residual" increase in lCBF when the animal's motor
activity in the face of severe amnesia persisted entirely? In a special series of acute
experiments on several groups of albino rats, which were under light hexanal anesthesia, a
serial photomicrography of the pial arteries was made. The results of the measurements alone
in two groups of arteries, those 20-50 mcm and 50-80 mcm in diameter are presented in Table
9.
Table 9. Cerebrovascular effects of the scopolamine and halantamine administration
Experimental conditions Diameters of the Pial Arteries (mcm)

Control 29.66±1.88 59.72±3.47
After injection of Scopolamine 16.91±1.50 37.50±2.94
After injection of Halantamine 26.66±2.05 54.16±3.14
As the statistical evaluation indicates, scopolamine leads to a reliable constriction of the

lumen of the pial arteries 20-25 min after the drug injection. After subsequent injections of an
anticholinergic drug antagonist (halantamine) the vascular lumen was virtually restored. In
repetitive experiments introduction of the indicated antagonist of the anticholinergic blocker,
as well as eserine, completely restored both the ECoG and the process of learning. At the
same time, the pattern of lCBF change is entirely restored.
The question of the role of cholinergic vasodilatation in the regulation of blood supply to
the brain was already discussed in Section 1 of this book. We shall only note here that
according to the described data the conclusions drawn are as follows: a) scopolamine, like
amisyl, abolishes the emotional reaction and as a result, the pattern of lCBF described for
normal conditions cannot occur; b) by blocking m-cholinoreceptors at the cholinergic fiber
terminals, it disturbs the functional mechanism of dilatation of the pial arteries and as a result,
during general motor activity no increase in local blood flow is observed in the motor zone of
the parietal cortex, and c) by disturbing the balance in favor of adrenergic innervation,
directed toward constriction, it brings the arterial system to a novel equilibrium with
enhanced hemodynamic resistence.
It is evident that the scopolamine-induced disturbance in the functional mechanism of the
pial artery's dilatation should aggravate the development of the process of amnesia because of
its psychotropic action. This fact once again confirms the significance of a neurogenic link in
the mechanism regulating cerebral blood circulation under conditions which alter the
emotional state of animals.
One should investigate the phenomenon of local blood flow decreasing in the frontal
lobe.
It might be assumed that active vasodilatation of the pial arteries in the parietal area and
the respective fall of hemodynamic resistance leads to a passive reflux of blood into the
frontal area. If this is the case, then the decrease of local blood flow must have been observed
in all zones embracing the parietal area. Actually, as the above data show, in all the zones,
directly adjacent to the parietal cortex including the temporal area too, local blood flow
remains unchanged both at the initial and final stages of learning. This vividly indicate that a
decrease in local blood flow in the frontal area is an active process (as is its increase in the
parietal area), i.e. decrease of local blood flow in the frontal area is likely to occur not only
during a decrease in hemodynamic resistance in the parietal area, but also by active
vasoconstriction in the frontal area. These contradictory processes seem to be developed
simultaneously.
Thus, the version of passive redistribution from the frontal to the parietal area is ruled out
in view of the fact of vasodilation of the latter, otherwise a decrease in local blood flow
should have occurred in all the zones surrounding the parietal area.
Now let us look at the mechanism of active vasoconstriction in the frontal area and as a
whole, the redistribution of blood flow in the cerebral cortex of albino rats while performing
a maze task solution.
Application of a potent antagonist of alpha-adrenoreceptors phenoxybenzamine in our
experiments led to an abolishment of the effect of local blood flow decrease in the frontal
area. In this case, the process is mediated by a mechanism of a neurogenic nature. Thus, it
may be concluded that during functional loadings the local redistribution of blood flow from
the brain areas less involved in the performance of that given behavioral act to those more
implicated in it is accomplished by the active vasoconstriction and vasodilatation reactions in
the relevant brain structures, developed concomitantly.
Pharmacological denervation removes the emotional component of the lCBF changes,
but leaves unaltered the functional-metabolic one. The former is accomplished through a
neurogenic link, while the latter occurs through a metabolic link of regulation of blood
supply to the brain. Moreover, the emotional component provides an excess of blood flow,
disturbing qualitatively the coupling "function-metabolism-blood flow".
Chapter IX
DYNAMICS OF LOCAL BLOOD FLOW AND

OXYGEN TENSION IN THE BRAIN IN DIFFERENT
PHASES OF THE SLEEP-WAKING CYCLE
Considerable changes have been observed in the emotional tension and the electrical
activity of various brain structures during the transition from one stage of the sleep-
wakefulness cycle to another. The circulatory changes that occur are no less significant.
One of the pioneering hypotheses on cerebral blood circulation during sleep was that of
cerebral ischemia. It was derived from a purely inductive assumption that during sleep the
cerebral activity decreases. Lack of adequate methods in verification of this hypothesis
prevented ongoing work. In 1881 an attempt was made in which Mosso (1881) using
plethysmography with great technical difficulties succeeded in recording, in three patients
with an exposed skull, a decrease in CBF during sleep and while noting its increase in the
extremities. The hypothesis on cerebral ischemia was confirmed. Tarkhanoff (1894) who
observed the dog's pial vessels during sleep came to the same conclusion.
Stewenson et al. (1929), while measuring intracranial pressure in patients during sleep,
found an independent increase in SAP (decrease of the latter in sleep has been shown earlier
(Brooks, Carrol, 1912; Landis, 1925). The increase in the intracranial pressure was attributed
to cerebral vasodilatation. This hypothesis was corroborated by studies of Bridges et al.
(1958) who registered the volume of cerebral vessels (together with other vascular beds)
during sleep. Such acquired data allowed assumptions concerning cerebral blood circulation
to be only indirect and offered no actual information about cerebral metabolism.
Gibbs et al. (1935) having developed a method of measurement of venous outflow
studied cerebral blood circulation in man during sleep. The studies failed to display any
marked changes in CBF as compared to the state of wakefulness. In 1952 Dust and Schneider
in healthy subjects measured the oxygen content of arterial blood in the state of wakefulness
and in deep sleep. The latter appeared to be attended by anoxemia. Thus, there again emerged
a problem of correlation of sleep and anoxia, however three years later Mangold et al., (1955)
refuted these data. In their work the authors studied total CBF in 50 young healthy persons
during sleep, not differentiating stages of paradoxical and slow wave sleep, yet the EEG data
showed that study was made mainly during the slow wave stage of sleep. It was found that
sleep leads to a marked rise of CBF (the method of Kety and Schmidt (1948) was employed).
At the same time, a decrease in SAP was also recorded. It should be emphasized that the
authors observed no changes in oxygen consumption (compared to wakefulness).
Intensive electrophysiological studies of the sleep-wakefulness cycle indicate that the
sleep stages are accompanied by redistribution of the neuronal activity in a variety of brain
structures (Huttenlocker, 1961; Findley, Hayward, 1969; Hobson, McCarley, 1971; Oniani,
1980, Orem, Trotter, 1992; Braun et al., 1992; Lin et al., 2006). As has already been pointed
out, shifts in the electrical activity of the brain should be attended by respective changes in
energy metabolism, and they, in turn, by lCBF changes. Proceeding from these premises,
Baust (1967) studied changes in local blood flow in rhombencephalic and mesencephalic
areas of the brain stem during sleep (measurement were made by means of thermistors).
During the paradoxical stage of sleep (PS) lCBF appeared to increase in the
rhombencephalon and decrease in the mesencephalon. In slow wave sleep (SWS) the changes
were not as significant, though still an increase in lCBF in the rhombencephalic reticular
formation and a decrease in the mesencephalic reticular formation were recorded (compared
to the levels of lCBF during wakefulness).
Reivich et al., (1968), obtained the most essential data on the redistribution of blood flow
in individual brain structures during the various phases of sleep. Using autoradiography for
qualitative measurement of local blood flow (Kety et al., 1955), they studied a variety of
brain structures in SWS and PS (with rapid eye movement - REM-sleep). Experiments were
carried out on cats with preliminary sleep deprivation (24-28 hours). The most tangible
changes in the lCBF level were detected in brain stem structures and less in the white matter,
sensory and motor areas of the brain. This work of Reivich et al. is classical and in most
reviews the results data analysis are as a rule compared with those of Reivich et al.
The data obtained by Seylaz et al. (1971) is also of interest. They demonstrated that in PS
there not only occurs an increase in lCBF (compared to SWS) but there is an abolishment of
the spontaneous oscillations in the lCBF level (2-4 per min), observable in wakefulness and
SWS.
In the article of Roysel et al. (1980) the results are being challenged of Reivich et al.
(1968). In particular, while using the thermoclearance technique it was demonstrated that
during SWS local blood flow in the cerebellum and hypothalamus of rats is maintained on a
high stable level and decrease occurs at the onset of each phase of arousal or PS, while during
the end of PS phase lCBF markedly increases again.
From the laboratory of Meyer a number of clinical observations are described (Meyer et
al., 1980; Sakai et al., 1979; 1980). Cerebral haemodynamics in healthy persons were studied
during sleep with those suffering from narcolepsia and insomnia. In these patients, the level
of CBF in the gray matter of cerebellum and brain stem appeared to be reduced as compared
to the control group. In narcoleptics, CBF was found to increase after having fallen asleep,
while in patients with insomnia a greater decrease in the gray matter was noted. In both cases
maximal changes are observed in the cerebellar and brain stem areas.
Dynamics of Local Blood Flow and Oxygen Tension in the Brain… 113
In evaluating the various phases of sleep and its effect on cerebral blood circulation, the
following observations were made: during sleep there is a considerable alteration in the level
of local blood flow to various brain structures. The most dramatic changes are observed in
PS. Many studies support the idea that to an augmentation in the neuronal activity in the PS
in the cortex (Evarts, 1964; Hobson, McCarley, 1971), in the thalamus (Bizzi, 1966), the
hippocampus (Noda et al., 1969; Oniani, 1980), the hypothalamus (Findley, Hayward, 1969)
and in the brain stem (Huttenloker, 1961), occur and that this activity is greater than what is
found in wakefulness. Knowing that the augmentation of the neuronal activity leads to the
enhancement of metabolism, it should be realized that during sleep considerable changes
must occur in the metabolic activity of individual structures and areas of the brain
(unfortunately, there is no direct data yet to be found that indicates accurately the level of the
brain's metabolic activity during sleep).
We again conclude that recording of lCBF may furnish us valuable information
concerning the level of the functional-metabolic activity of brain structures. This question
becomes extremely important when studying the sleep phenomenon. Since such an
experiment tangibly restricts the possibility of an experimenter. It should be also added that
the state of excitability in the brain structures may be accompanied not only by impulse
activity, but also by change of slow electrical potentials (Sergeev et al., 1968), that
significantly impede the identification of the functional state of this or another structure. For
example, it may said that a well-known phenomenon of hypersynchronization of theta-
rhythm in the dorsal hippocampus in the PS (Jouvet, 1967; Oniani et al., 1970) has been
diversely interpreted - there is no specific opinion as to whether it points to enhancement of
the hippocampal functional activity or it is just the contrary, it is indicative of its attenuation.
In our studies of cats the dynamics of local blood flow and oxygen tension was noted in the
dorsal hippocampus and sensorimotor area of the cortex (SMC) in different phases of the
sleep-wakefulness cycle. We, along with others, start from the fact, that the dynamics of
oxygen tension in nerve tissue is a parameter whose frequency of fluctuations reflects to a
considerable extent the intensity of the metabolic processes in neuro-glial populations and
should therefore be the carrier of important information about the functional state of nervous
structures (Snezhko, 1960; Berezovskii, 1978; Grechin, Kropotov, 1979).
9.2. LOCAL BLOOD FLOW AND PO2 CHANGES IN THE

DORSAL HIPPOCAMPUS AND SENSORIMOTOR CORTEX
DURING SLEEP-WAKEFULNESS CYCLE
Experiments were performed on adult cats of either sex with chronically implanted
electrodes in the dorsal hippocampus and the sensorimotor cortex. Apart from oxygen tension
and local blood flow, we have recorded the electrical activity of the indicated structures and
electrooculogram. Since spontaneous oscillations of PO2 in brain tissue are attributed to the
class of stochastic-statistical processes (Moskalenko et al., 1969), therefore for their
quantitative estimation we have used autocorrelation functions, calculated during sufficiently
prolonged (compared to the period of oscillations) intervals of time (Nikolaishvili et al.,
1983). In different phases of the sleep-wakefulness cycle in the symmetric sites of the dorsal
hippocampus and the sensorimotor cortex the spontaneous oscillations of PO2 and the
difference in their patterns were recorded, examples of which are given in Figure 45. It was
found that oscillations of PO2 have a complex - polymorphic character which differ in both
shape and its amplitude, in the ratio of duration of ascending and descending phases. It
appears that during transition from one phase of the cycle into another parameters of PO2
rhythmics undergo marked changes and that every level of wakefulness and sleep is
characterized by definite patterns of these oscillations. As a result of autocorrelation analysis
three groups of periodic and quasiperiodic constituents of PO2 rhythms with periods:
21.61±0.3; 60.7±0.7; and 123.4±1.1 s (Figure 46A, B and C) were obtained.
Figure 45. Oscillation of oxygen tension in the dorsal hippocampus and sensorimotor cortex in the state
of quiet wakefulness.1 - PO2 in the sensorimotor cortex; 2 and 3 - PO2 in the left and right dorsal
hippocampus.
Figure 46. Autocorrelation function of PO2 oscillations in the dorsal hippocampus and sensorimotor
cortex. On abscissa - time intervals, on ordinate - correlation coefficient.
Furthermore, we recorded PO2 oscillations whose autocorrelograms had no periodic

constituents (Figure 46D).
Analysis of the obtained autocorrelograms showed that during the transition from active
wakefulness to passive, and then to slow wave sleep there is a considerable slow-down of
PO2 oscillations in the dorsal hippocampus. While during the transition to PS, at the moment
of strong development of a hippocampal theta-rhythms, the frequency of PO2 oscillations
again increases and practically recovers to the initial frequency of PO2 oscillations occurring
during active wakefulness (Figure 47). As far as PO2 waves with a period 60.7+0.7 s are
concerned, irregardless of the phase of the sleep-wakefulness cycle, their occurrence in PO2
oscillations is very similar to the dorsal hippocampus (Figure 47). Statistical data
characterizing the emergence of PO2 waves of various duration in the dorsal hippocampus in
the sleep-wakefulness cycle are presented in Table 10.
Figure 47. Percent ratio of periodic constituents of PO2 oscillations in the dorsal hippocampus in active
wakefulness (AW), passive wakefulness (PW), slow wave phase of sleep (SWS) and the REM stage of
sleep. Mean periods of oscillations: I - 22 s, II - 61 s, III - 123 s.
Table 10. Frequency of manifestation of the different periodic and quaiperiodic

constituents of the PO2-iscillations during Sleep-Wakefulness cycle
Brain structures Periods of Frequency (%) during:

oscillation Wakefulness Sleep
(seconds) Passive Active REM SWS
Dorsal 21.6+/-2.7 29.4+/-2.7 39.4+/-4.4 42.4+/-1.3 19.8+/-2.1
Hippocampus 60.7+/-0.7 45.8+/-2.8 46.2+/-3.5 43.8+/-0.9 47.1+/-1.6
123.4+/-1.3 24.8+/-1.3 15.1+/-4.5 16.8+/-0.7 33.1+/-2.2
Sensorymotor 21.6+/-0.3 26.8+/-3.9 28.9+/-4.7 29.1+/-2.3 17.8+/-3.7
Cortex 60.7+/-0.7 46.4+/-2.1 47.3+/-2.3 50.4+/-1.0 41.1+/-3.1
123.4+/-1.3 26.8+/-4.4 23.3+/-3.4 20.5+/-1.7 41.1+/-3.1
Figure 48. Dynamics of recorded parameters in the hippocampus during SWS, PS and arousal (A).
Electrocorticogram (1), oculogram (2), electrical activity in the left and right dorsal hippocampus (3),
local blood flow in the hippocampus (4); thick line in blood flow lane - 20 seconds.
Figure 49. Dynamics of recorded parameters in the dorsal hippocampus during the transition from SWS
to PS. Designations the same as in the previous figure.
Under the same experimental conditions, we recorded the dynamics of local blood flow
in the dorsal hippocampus. Figure 48 represents such an example. In the curve of local blood
flow in the dorsal hippocampus (4) arrows indicate the regions to which the patterns of
electrical activity correspond to SMC (1), the left and right dorsal hippocampus (3) and
electrooculograms (2). The figure illustrates the transition from SWS to PS, then to SWS and
finally arousal (A) of the animal. As seen from the recordings, the hippocampal blood flow
increases dramatically during the transition from SWS to PS and its level approximate the
state of wakefulness. The REM (rapid eye movements) state in PS as a rule appears to
correspond to the plateaux of maximally increased blood flow, i.e. the process of a sharp
increase of lCBF itself precedes the development of REM. This is most vividly illustrated in
Figure 49.
Under the same experimental conditions in the dorsal hippocampus, the same parameters
were recorded in the sensorimotor area of the cortex. Changes in the frequency of these
oscillations in the sleep-wakefulness cycle appeared to be in general the same as in the
hippocampus. Some distinction is noted in the changes of rhythms with a period 60.7-0.7s -
in the sensorimotor cortex. In SWS its content in PO2 oscillations decrease, while in PS it
increases (Figure 50) Statistical data characterizing the emergence of PO2 waves of various
duration in the somatosensory cortex in the sleep-wakefulness cycle are presented in Table
10.
Figure 50. Percent ratio of periodic constituents of PO2 oscillations in the sensimotor cortex in different
phase of the sleep-wakefulness cycle. Designations the same as in Figure 47.
The general characteristic of changes in local blood flow in SMC appears to be similar to
that described above for the dorsal hippocampus. However, as distinct from the latter,
changes in lCBF are less pronounced in SMC (Figure 51). And in this case the state of REM
develops against the background of maximal increase of lCBF in PS which corresponds to
the level of lCBF in active wakefulness (AW) and exceeds that observable in passive
wakefulness (PW) (Figure 52).
In the last decade work appeared in which authors used indices which reflect, to some
extent, the intensity of metabolic activity, in order to estimate the functional states of various
brain structures. In particular, some investigators employed the dynamics of PO2 in the
cortex and subcortical structures as a correlative of the activity of nervous system in the
sleep-wakefulness cycle (Garsia-Aust et al., 1968; Velutti, Monti, 1976; Ricardo et al., 1977)
At the same time, many authors have shown the dependence of the character of PO2
oscillations on the level of functional activity of the examined brain structure. In particular, it
has been experimentally confirmed that elevation in the functional activity of the given brain
tissue region is accompanied by an increase in the frequency of PO2 oscillations in it and
vice versa (Meyer, Porthnoy, 1959; Grechin, 1974; Zaguskina, Zaguskin, 1974; Moskalenko
et al., 1975). This is also confirmed by our data on the dynamics of PO2 and lCBF in the
sensorimotor cortex. It is known that in AW and PS when ECoG shows desynchronization
the functional activity in the neocortex is enhanced, whereas in PW it is attenuated, reaching
the lowest level in SWS (Oniani, 1980). In the present experiments, both in AW and PS, i.e.
in the phases when the functional activity of the cortex is the highest, in PO2 oscillations
there is an increase in the waves with a mean period 21.6+0.3s, while in PS and especially in
SWS their content sharply decreases and oscillation with a mean period 123.4+1.1s start
dominating. Consequently, it may be concluded that such a change in PO2 oscillation
frequency is a reflection of shifts in the functional-metabolic activity of the cortex, the
direction of which indicates phases of the sleep-wakefulness cycle and is interpreted
unequivocally - that there is an increase in AW and PS and a decrease in PW and SWS.
Figure 51. Dynamics of local blood flow in the sensimotor cortex (4) and electrical indices during SWS,
PS and A. Designations the same as in Figure 48.
A similar conclusion is drawn also from our data on the dynamics of lCBF in SMC.
Thus, the results obtained in our studies of the somatosensory cortex, the area whose
functional state in our experimental conditions was a priori known, makes certain the
correctness of the criteria selected by us for estimating the functional state of the dorsal
hippocampus. Consequently, in AW and PS when one can observe a clear-cut
hypersynchronization of theta-rhythm, an increase in the PO2 oscillation frequency and a
sharp elevation of the level of local blood flow, the functional activity of the hippocampus is
enhanced. While in PW and SWS it is suppressed, since at these states PO2 oscillations
become infrequent and the level of lCBF, as compared to that in PS, falls.
Thus, our studies on the dynamics of lCBF and nerve tissue oxygen tension indicate that:
the functional-metabolic activity of the brain appears to be on the same maximal level in AW
and PS. Minimal level is reached in SWS and the transient phase - PW; during hyper-
synchronization in the dorsal hippocampus the functional-metabolic activity sharply
augments: a maximal level of lCBF is attained in the stage of "rapid eye movements" in PS.
Figure 52.The same as in Figure 51, but in the stage of PW and PS.
Reduction in the lCBF level during the transition from the state of wakefulness to SWS,
corroborates findings of Risberg, Ingvar (1973) and Townsend et al., (1973), but is found to
be diametrically opposed to the results obtained by Mangold et al.(1955); Seylas et al. (1975).
In attempting to explain, the difference one has, perhaps, to look at the methods used for
recording lCBF. The latter authors in their studies employed a thermometric technique with
the use of thermocouples. One of the essential drawbacks, which should be considered, is the
possibility of incorrect results of CBF measurements during changes in the metabolic activity
(which is known to lead to local changes of temperature in tissue). In addition, Seylaz himself
considers that "it would be surprising if the metabolism of the cortex in the waking state was
slower then during SWS..." (Seylaz et al., 1975, p. 242) and, failing to find any logical
explanation for his experimental results, he attributes it to the manifestation of neural
regulation. However, there emerges a question - why should neural regulation increase blood
flow in the brain during the transition from a high functions and metabolic activity to a lower
one? Similar objections concerning CBF decrease during the transition from the stage of
SWS to wakefulness occurs with Seylaz.
Therefore, it may be concluded that the reason for the discrepancy in the results may be
due to incorrect use of the thermometric method for lCBF measurement.
Table 11. Some parameters of arterial blood (Reivich et al., 1969)
PCO2 PO2 pH
Wakeful animals (control) 34+/-2.9 102+/-8.4 7.44+/-0.01
SWS 31+/-1.8 84+/-0.7 7.43+/-0.02
REM Sleep 32+/-1.2 85+/-1.3 7.44+/-0.02
Evaluation of the mechanisms, which provide the above-described changes in local blood
flow in the sensorimotor cortex and dorsal hyppocampus, our experimental findings, did not
permit us to arrive at any concrete conclusions. Therefore, we will resort to the data of other
authors. In particular, Reivich et al. (1969) in the experiments on cats measured PO2, PCO2
and pH in the arterial blood during wakefulness, SWS and in the stage of "REM" in PS (see
Table 11). As is seen from the table, changes in the mentioned parameters of the arterial
blood are not very essential during the transition from one stage of the sleep-wakefulness
cycle to the other and can hardly play any role in lCBF reduction in SWS and its increase in
PS. One ought also to rule out the effect of SAP, since in sleep stages (namely in SWS) the
most typical change in SAP, as mentioned above, is its reduction. Data on the dynamics of
cardiac expulsion in PS are not in correlation with lCBF either (Reivich et al., 1969).
Therefore, it in reasonable to resort to the known coupling "function - metabolism - blood
flow". That is, it must be thought that the changes in lCBF during the transition from one
phase of the sleep-wakefulness cycle to another are entirely and completely determined by
local functional metabolic shifts. However, how does closure of the feedback loop occur in
this case, is it via direct action of the products of metabolism on the cerebral vessels or is it
mediated through the neural mechanisms? This is an open question thus far.
SECTION 4:
CEREBRAL BLOOD FLOW, OXYGEN SUPPLY,
AND MORPHOLOGICAL CHANGES INDUCED BY
LOCAL HYPERTHERMIA
Chapter X
DYNAMICS OF LOCAL CEREBRAL BLOOD FLOW

DURING MICROWAVE RADIATION
From what was stated in Section I it is obvious that the neurogenic link plays a
paramount role in the regulation of blood supply to the brain. In the past several decades data
appeared permitting arguments concerning the existence of the centers (or a center)
subserving the regulation of cerebral blood circulation (Molnar, Seylaz, 1965; Moskalenko,
1967). In Moskalenko's monograph (1967) he considers that "... it is difficult to say anything
definitely about the principles of functioning and localization of the center or a system of
centers of regulation. It may be only affirmed here that this center (or centers) should receive
message about the state of inputs and outputs of the system" (p.197). Thirteen years later,
Moskalenko (1980) had again to substantiate that "... the accumulated material allows one to
make an inference that the central nervous formation does play a definite role in the
regulation of cerebral blood circulation. The most convincing data is that which indicates
modulation of the cerebral vascular responses to adequate stimuli upon the transection of or
damage to certain brain structures. However, the question of the existence of a structurally
determinated center for the regulation of cerebral blood circulation, is not to be answered at
this time" (pp.107-108).
What are the experimental prerequisites, which underlie these statements? In a number of
studies, it was demonstrated that electrical stimulation (Langfitt, Kassel, 1968; Meyer et al.,
1969), and occasionally lesion (Molnar, Seylaz, 1965) of rather extensive areas in the
reticular formation might modify cerebral blood flow. Reis et al. (1979, 1982) for years
studied the effect of stimulation of the cerebellar fastigial nuclei and the region of the dorsal
medullary reticular formation and found a prominent increase in CBF. This was conditioned
by two different mechanisms: in the first place, by direct vasodilatation and secondly, when it
was mediated through the enhancement of brain metabolism. Jadecola et al. (1982) obtained
similar results also.
Estimation of these numerous (but principally important) studies allow the following
conclusions to be drawn:
1. In rabbits and rats, electrical stimulation of two anatomically and functionally

varying intracerebral systems (the fastigial nuclei of the cerebellum and the dorsal
medullary reticular formation) may considerably increase local CBF.
2. Electrical stimulation of the fastigial nuclei of the cerebellum leads to a twofold
increase of global CBF, suppression of autoregulation and in some areas (the
hippocampus and the cerebral cortex) resulting in vasodilatation without metabolic
changes.
3. Electrical stimulation applied to the dorsal medullary reticular formation induces
CBF increase and suppresses autoregulation, but in all brain areas (particularly, in
the cortex) CBF increase appears to be strictly correlated with the enhancement of
metabolic activity.
4. The obtained CBF changes are mediated through the intrinsic neural systems of the
brain.
5. In the brain there are two systems of regulation of its blood supply: one is located in
the cerebellum and is capable of effecting vasodilatation and elevation of tissue
blood flow without enhancing the metabolic activity. The other is localized in the
dorsal medullary reticular formation and it may be considered as a secondary
vasodilatatory system, effecting control of the level of metabolism in the brain (Reis
et al., 1982).
All these inferences have an essential significance in formulating the theory of regulation
of blood supply to the brain. They were derived from the experiments where either
destruction of the indicated brain structures or their electrical stimulation were applied. It is
clear that it is difficult to predict the consequences of using destroyed structures. Because of
shifts that arise in the metabolism of the entire brain itself, application of electrical
stimulation of the reticular formation is also inadequate.
In the present study, we have attempted to revise the idea of existence of the intracerebral
center for CBF regulation with the help of the least invasive method, i.e. the use of local,
directed microwave radiation. The respective experiments on rabbits were performed at the
Department of Radiation Medicine of Roswell Park Memorial Institute in Buffalo, N.Y. and
in the Valley Cancer Institute - Los Angeles, California, USA.
10.1. EXPERIMENTAL AND CLINICAL STUDY OF MICROWAVE

RADIATION
At the end of XX century, due to increasing ecological significance of radiation of non-

ionizing nature, a large number of investigations emerged dealing with the assessment of
clinical and experimental data concerning the biological effects of electromagnetic waves, in
particular, those in the radiofrequency range (Presman, 1969, Guy et al., 1974; Michaelson,
1975; Baranski, Crzerski, 1976; Kholodov, Shishlo, 1979; Antipov et al., 1980).
The biologically most active is considered the microwave range of electromagnetic
radiation that takes a marginal state between radiowaves proper and the optic part of coherent
light waves (Antipov et al., 1980).
Dynamics of Local Cerebral Blood Flow during Microwave Radiation 125
The mechanism of the interactions of electromagnetic waves and biological objects is the
subject of special attention and we shall not deal with this topic now, but will point out only
that the most commonly accepted mechanism is considered oscillation of free ions and
rotation of dipole molecule with a frequency of the applied electromagnetic field.
In this section, we will briefly look at the effects of this interaction and their employment
in experimental and clinical studies.
The majority of studies on the evaluation of the effect of microwave radiation were done
on the central nervous and cardio-vascular systems. Severe changes in the vegetative nervous
system and pronounced modulation of electrical activity of the brain were displayed
(Bychkov, 1962; Ginzberg, Sadchikova, 1964; Tyagin, 1965). Many investigators believe
that alteration in function of the nervous system with predominance of viscero-vegetative
shifts and diencephalic syndromes testify both to direct and mediated influences of
microwaves on the CNS (Antipov it al., 1980).
In experiments on rats Lobanova (1964), has shown disturbance in the positive
conditioned reflexes induced by microwave radiation. In rats an increase (after the first
exposure of radiation) and then a decrease of excitability were noted (Minecki it al,. 1962).
In the monograph of Antipov et al., (1980), he represents generalized data concerning the
action of superhigh frequency (SHF) factor on the higher nervous activity, which vividly
indicates a rather wide variability and polymorphic character of functional changes..
In the electrical activity of the cerebral cortex, the following changes were noted: the
enhancement of synchronization; a long-term desynchronization; a short-term
desynchronization; generation of epileptic discharges (Kholodov, 1966; Gordon, 1966;
Presman, 1968; Baranki, Czerski, 1976).
However, some investigators cast doubts on the correctness of having used of the EEG
method while studying the biological effects of microwaves (Antipov et al,. 1980) in view of
the considerable distortion of the electromagnetic field and interference with an objective
evaluation of changes in the electrical activity of the cerebral cortex.
The influence of microwaves in the blood forming systems and blood has been subjected
to an intense study. Despite contradictions in data, one still may conclude that chronic
radiation affects the blood system in a definite way and primarily the manifesting effect is the
instability of its indices.
As is known, microwave radiation has been widely applied in clinics; in particular, its
thermal effect has been used to induce hyperthermia. Hyperthermia is successfully applied in
the treatment of malignant tumours of various genesis. Data of Cavaliere et al., (1967),
indicating selective thermosensitivity of tumour cells (compared to normal ones) within 42-
45oC temperature range, served as the point of departure for the commencement of intensive
studies in this direction.
Studying thermosensitivity of normal and tumor tissue, Giovanilla et al. (1973) have
demonstrated that 95% of tumor cells in culture perish after a 2-hr heating to 42.5oC. The
mere substantiation of the therapeutic effect of hyperthermia in oncological clinics, even with
no essential study of the mechanism of this effect, served as a powerful impetus for
development of methods and means for local induction of heat directly in tumor tissue. This
time the main problem was how to deliver, or to be more precise, focussing the warming-up
for required energy namely tumor tissue, especially if the latter was localized deep in the
patient's body.
In a critical survey of technical methods and means for the induction of local
hyperthermia, Storm and Morton (1983) consider the application of microwave technique as
the most efficient and perspective one. A large number of specially designed waveguides can
readily deliver microwave energy to the affected tumor region of the body.
Using a waveguide of the construction of Sandhu et al. (1978) for 2450 MHz frequency
microwaves, we did experimental and clinical studies looking at the dynamics of oxygenation
and microcirculation in tumor tissue under conditions of microwave hyperthermia (Bicher et
al., 1980a,b; 1983; Bicher, Mitagvaria, 1981). When the temperature reaches 43oC an abrupt
disturbance of microcirculation and impairment of oxygenation appeared to occur in tumor
tissue, this, in our opinion, must promotes death to the tumor cells.
In his earlier study Bicher (1978) demonstrated that microwave radiation (2450 MHz) of
the rabbit brain leads to disturbances of autoregulation of the oxygen supply to nerve tissue.
The disturbance occurs shortly after the development of local hyperthermia. The mechanism
of this phenomenon, in particular, as to whether it is hyperthermia-dependent or merely
develops in parallel with it, remains uncertain. However, the given study served as a basis for
us to study the effect of local microwave radiation of the brain on the regulation of its blood
supply.
10.2. DYNAMIC CHARACTERISTICS OF THE REGULATION OF

LCBF DURING LOCAL MICROWAVE RADIATION OF THE
BRAIN
Experiments were performed on rabbits using a generator of microwaves with 2450 MHz
frequency. Various regions of the cerebral cortex were subjected to radiation exposure with a
concomitant measurement of the intensity of local blood flow (or a conventional hydrogen
clearance and electrochemical generation of hydrogen), oxygen tension (microelectrodes of
the "gold in glass" type (Carter et al., 1959) and temperature (brass-tungstem thermocouples).
In addition, through one of the femoral arteries systemic arterial presuure (SAP) was
measured. All the parameters were registered on a poligraph of the firm "Grass" (USA).
An experiment on microwave radiation of the rabbit brain is schematized in Figure 53.
Control of the regimen of a microwave generator based on express-analysis of data was
implemented on a computer system of "Apple-II' type.
As a waveguide-applicator of microwaves we have used an applicator of the construction
of Sandhu et al. (1978), having in the transverse section sizes 5.5.cm and cylindrical antennas
(10 cm long and 3 mm in diameter).
Figure 53. A general view of experiment with microwave radiation of the rabbit brain.
Applicators were installed at the distance of 0.5-1 cm from the irradiated site, being
oriented in such a way that force lines of the field were strictly perpendicular to the
electrodes employed, otherwise there arose artefacts and registration of the parameters was
rendered impossible.
Animals were anesthetized by chloropromazine (50 mg/kg) in combination with
ketamine (40 mg/kg) immobilized by flaxedyl and maintained on artificial ventilation.
The first series of experiments was run by the scheme presented in Figure 54 that is the
electrodes for measuring PO2 and temperature were localized on the side of irradiated
hemisphere, while those for lCBF measurement, on the contralateral side.
Figure 54. A scheme of the location of a microwave applicator (MW) and electrodes during the
measurement of local blood flow in the contralateral hemisphere.
Typical dynamics of PO2 and lCBF obtained in the course of microwave radiation at this
disposition of electrodes and applicator is given in Figure 55. A time counter is set
simultaneously with the onset of radiation exposure and is set off with its termination (large
points are equal to 1 min).
In another series of experiments the electrodes were localized in the hemisphere to be

irradiated (Figure 56), but the electrode for lCBF measurement was installed at various
distances from the applicator. Figure 57 presents a scheme of disposition of the electrodes
and applicator of microwaves (the trepanation hole is drown by an oval. The mean distance
between the sites of lCBF measurement was 5-8 mm.
The results obtained with the use of the scheme given in Figure 57a are presented in
Figure 58. Sequence of reactions to irradiation in this case is such: rises temperature
(simultaneously with the switching on the generator), then with about 1 min latency increases
PO2 and with larger latency, starts a sharp increase lCBF.
Figure 55. Dynamics of the registered parameters during microwave radiation according to the scheme
presented in Figure 54.Scale of PO2 values in mm Hg; time counter indicates duration of microwave
(MW) radiation, large gradations correspond to one minute.
Figure 56. A scheme of the location of electrodes and microwave applicator for registration of
parameters in the hemisphere to be irradiated. Microwave applicator (1); reference electrodes (2,5,7);
the site of temperature measurement (3); the site of oxygen tension measurement (8); the site of lCBF
measurement (4,6,9).
When scheme "b" is employed (Figure 57b) there occurs a preliminary fall in lCBF
followed by its sharp elevation (Figure 59a,b). And finally at the point the most remote from
the applicator (Figure 57c) in the course of learning lCBF decreases and its recovery occurs
only after the withdrawal of the influence (Figure 60a,b,c).
Figure 57. Versions of the locations of electrodes and MW in the experiment according the scheme
presented in Figure 56. TO - trepanation opening.
Figure 58. Dynamics of recorded parameters during microwave exposure according to the scheme given
in Figure 57a. Designations the same as in the previous figures.
A repetitive irradiation (with 5-10 min intervals) develops stable hyperemia (Figure 61),
which cannot be removed by switching off the generator of microwaves.
In all cases, there is sharp enhancement of oxygenation of nerve tissue and rise in its
temperature variation depends on the density of the microwave power used.
In the third series of experiments a zone of the medulla oblongata is subjected to local
irradiation. As distinct from the previous series, in this case lCBF and PO2 appeared to be
increased in the frontal area of the cerebral cortex without any marked changes in the
temperature in these areas (Figure 62). Measurement of temperature in the site of exposure
usually shows its rise by 2-3 points above the initial value.
Figure 59. Dynamics of recorded parameters during microwave radiation according to the scheme given
in Figure 57b.
Figure 60. Dynamics of recorded parameters during microwave radiation according to the scheme
presented in Figure 57c.
Figure 61. Long-term increase of CBF level observed after repetitive microwave irradiation exposure.
Designations the same as in the previous figures.
Figure 62. Dynamics of recorded parameters during microwave radiation of a site in the medulla
oblongata and cerebellum.
Statistical evaluation of changes in the parameters registered in all series of experiments

has shown that they are highly reliable (P<0.01). Quantitative processing of data on the
measurement of local blood flow (done by the method of hydrogen clearance) and oxygen
tension has revealed that upon irradiation of a zone on the medulla oblongata lCBF enhances
in an average by 250%, while PO2 increase up to 130% of the initial level.
Analysis of the first two series of experiments with local irradiation of the cerebral cortex
when the measuring electrode of lCBF is localized on the ipsilateral cortex, indicate that the
reactions observed would be due only to the thermal effect of microwaves. This can be
verified by the pattern of lCBF changes as being dependent on the remoteness of the zone of
measurement from the applicator. As seen from the presented figures, as the applicator is
approached, the initial fall in lCBF (on the ipsilateral side) becomes less significant and in the
points of maximal approachment lCBF increases without any preliminary decrease. In view
of the fact that irradiation has a local character, thermal hyperemia in the site of tissue heating
may lead to a decrease of tissue blood flow in the surrounding area, and as heat is further
spread, the initial decrease is gradually replaced by an increase in lCBF, extending farther the
area of decreased blood flow.
Thus, it may be suggested that during irradiation of the cerebral cortex there occurs a
local redistribution of local blood flow, that is, the phenomenon similar to the well known
"Robin Hood's syndrome" (Lassen, 1968). As an additional support to what has been said
serves the lack of any changes in lCBF in the contralateral hemisphere.
The third series of experiments with irradiation of the site in the medulla oblongata has
clearly shown that microwaves may exert a powerful influence on the level of blood flow in
all areas of the cerebral cortex, without any temperature variation in them. Here it is
reasonable to suppose that blood flow reaches its maximal level, since anoxia induced under
these conditions by respiration of pure nitrogen (see Figure 63), despite an increase in SAP
and decrease in PO2, does not lead to any variation of the elevated lCBF. Bearing in mind
that the latency of the described total increase in lCBF does not exceed several seconds and
there is no increase in temperature in the site of lCBF measurement, perhaps there are no
grounds to think that the metabolic activity enhances. The totality of the vasodilatatory
responses must have a neurogenic character and should be due to the exposure of microwaves
namely in the area of the medulla oblongata (in as much similar exposure on the cortex led
only to local thermal hyperemia).
Figure 63. Effect of anoxia in the course of microwave radiation of the site in the medulla oblongata
and cerebellum.
Thus, in contrast to the investigations (Langfitt, Kassel, 1968; Molnar, Seylaz, 1965;
Meyer et al., 1969; Reis et al., 1982, where the authors employed electrical stimulation or
lesion of the cerebellar fastigial nuclei and the dorsal medullary reticular formation (what in
one case led to a sharp enhancement of the metabolic activity, and in the other to a significant
trauma), we have succeeded in obtaining, (perhaps in a "purer" form) the effect of
vasodilatation of cerebral vessels, described by the above authors. What is more, our
experiments enable to affirm with more certainty namely a neurogenic character of the vessel
vasodilatation (as maximally plausible). Although, we have to stimulate also, that site of
exposure in our case is less localized and it might embrace both the cerebellum and the
medulla oblongata (the depth of penetration of microwaves reaches 3 cm) and we therefore
are deprived of the possibility to differentiate the role of indicated structures in the observed
effect. However, as been already pointed out, the method used by us is minimally invasive
and permits to differentiate the secondary metabolic effect from the primary neurogenic.
The microwave induced thermal energy ought to be considered, in our case, as a factor
interfering with the functioning of the neurogenic center.
Besides mentioned hyperthermic exposure of the brain tissue might have direct thermal
effect on cerebral vessels and tissue and below we discuss some possible aspects of such an
effect.
Chapter XI
PHYSIOLOGICAL AND MORPHOLOGICAL

CHANGES IN CEREBRAL TISSUE, CAUSED BY
HYPERTHERMIA-INDUCED THROMBOSIS OF THE
CEREBRAL VESSELS
11.1. THE PHYSIOLOGICAL EFFECTS OF HYPERTHERMIA

TREATMENT
Method of hyperthermia is based on fact that with rise in temperature all vital functions
accelerate. This global rule was discovered in the end of XVIII by famous Dutch scientists
Svante Arrhenius and Jacobus Henricus Van’t Goff. Thanks to their research, already from
the school lessons we learn that rise in temperature per 10 degrees centigrade half fastens the
chemical reactions. As for the metabolic processes in living organism, their rate can be
increased ten times more.
Most important area of hyperthermia method application is the treatment of oncologic
diseases. The point is that heating of the organism to 43-43,50С has a direct cytocidal effect
on tumor cells; however, the mechanism of high temperature effect as such is not completely
figured out yet. It is supposed that simultaneously several factors are crucial for the final
impact: thermal damage of cells, delay of their division and triggering of the apoptosis. It
turned out that tumor cells are heating up much stronger than healthy cells; therefore they die
sooner.
The main goal of local hyperthermia treatment is affecting tumour tissue causing
apoptosis or necrosis depending on the level of temperature and duration of hyperthermic
exposure. It turned out that in tumour tissue most pronounced apoptosis is observed at
prolonged hyperthermia exposure (Toyota et al, 1998). But comparison of results of long-
lasting (6 hours) low temperature (400C) hyperthermia in combination with chemotherapy,
with short-term, high temperature hyperthermia, most pronounced apoptosis in tumour tissue
has been revealed using the high temperature short term heating (Toyota et al, 1998). At the
same time has been established, that an acidic environment (pH=6,6) enhanced the
hyperthermia-induced apoptosis in HL-60 human promyelocytic leukemia cells as judged by

the DNA fragmentation, flow cytometric analysis of DNA content, and cleavage of
poly(ADP-ribose) polymerase (Takasu et al., 1998). Hyperhermia exerted no effect on the
expression of Bcl-2 and Bax, regardless of the environmental acidity during heating. The
time of increase in apoptosis after heating coincided with the time of decrease in the G1-
phase cell population. The authors believe that the increase in heat-induced apoptosis in HL-
60 cells in an acidic environment was due to a direct increase in the proteolitic cleavage of
poly(ADP-ribose) polymerase by acidic caspases without the involvement of Bcl- and Bax,
and that heat-induced apoptosis occurred during G1 phase in HL-60 cells (Takasu et al.,
1998)
Recently the interest towards hyperthermia has been significantly increased thanks to the
thorough critical analysis of the results and several randomized studies that demonstrated the
considerable increase of treatment effectiveness after the incorporation of hyperthermia into
the medical schedule, provided that there was sufficient temperature-exposure of tumor
during the hyperthermia procedure (Van Der Zee, 2002). It is ascertained that hyperthermia
alone has the anti-cancer effect only in 12-13% of cases (Mardynski et al., 2001) while in
combination with radiotherapy and/or chemotherapy the effectiveness of treatment
substantially increases.
But potentialities of hyperthermia are even broader. It is proved that hyperthermia is fatal
not only towards the tumor cells, but also towards bacteria and viruses. In 1996 it was
announced that hyperthermia is effective towards HIV as well. Finally, there was information
about application of hyperthermia for elimination of physical drug addiction (Fradkin, 2003).
But let’s revert to the oncology problems. The principal reason for inclusion of artificial
hyperthermia into the multi-component treatment of oncologic patients is that it takes in
account those morphofunctional peculiarities of tumors that distinguish them from
homologous normal tissues by number of rather important and correlated parameters:
insufficiency of blood supply, especially on the level of microcirculation; degree of
oxygenation; capacity of glycolysis; levels of pH (Yarmonenko, 1987).
Through the application of strictly dosed regimen of hyperthermia and hyperglycemia, it
becomes possible to manage above mentioned morpho-functional parameters of tumorous
and normal tissues. This leads to the expansion of therapeutic range and, ultimately, to the
practical realization of the concept of selective enhancement of tumor sensitivity towards
radiation and medication. As a result of decreased volume blood flow (especially in hypoxic
areas), tumors may overheat at least 1-20С higher than surrounding normal tissues; at that,
their thermal damage and effect of consequent exposure to radiation are also amplified
Konopljannikov, (1991).
High effectiveness of hyperthermia, as adjuvant of radiotherapy, is caused by following
circumstances:
1. Hyperthermia has damaging action on cellular level, at that, this effect depends on
temperature value and duration of heating; from this it follows that exposure to
hyperthermia should be located in tumor area (as well as for the cases of application
of ionizing radiation);
Physiological and Morphological Changes in Cerebral Tissue… 137
2. In contrast to ionizing radiation, reduction of oxygen concentration in tissues during

exposure to hyperthermia does not lead to weakening of damaging action. Therefore,
hyperthermia allows overcoming radio resistance of hypoxic tumor cells.
3. During hyperthermia damaging action’s correlation with cell cycle stage is different
from what is typical for ionizing radiation. Thus, the highest resistance is typical for
S-period, while during the heating the most sensitive is the period of DNA synthesis.
That’s why the hyperthermia comes forward as the “ideal” adjuvant, which is
smoothening tumor cells’ survival rate fluctuations subject to the cell cycle stage, in
which exposure took place.
4. Usually, tumor cells’ thermo sensitivity is similar to that of cells in surrounding
normal tissues, but because of number of physiological peculiarities, such as low
blood flow, more acid medium as a whole, critically low pH in hypoxic areas and
insufficient maintenance, they are damaged much heavier than normal ones;
5. Together with damaging action, hyperthermia is characterized by significant radio-
sensitizing effect caused by the temporary disturbance of repair processes; this leads
to substantial increase of cellular radio sensitivity, which is also in correlation with
temperature, duration of heating and time interval between heating and radiation;
6. Apart from biological effects emerging on a cellular level, hyperthermia evokes
change of the blood flow in heated area; this effect has dynamic character and
correlates with heating in a complex way.
According to Kelleher D.K. and Vaupel P.W. (1995), exposure to hyperthermia evokes
complex pathophysiological processes in tumor tissues: changes in blood flow, oxygenation,
metabolic and energy status. At that, human tumors are characterized by the apparent
heterogeneity of blood flow, changes of which during heating are unpredictable and depend
on spatial arrangement and time. In some cases, increase of the blood flow may result it
increased heat diffusion, thus stipulating unattainability of therapeutic temperature values.
Thus, the rise in temperature of tissue during heating is largely dependent on the influx
of heat from the external heat source and also on the efflux of heat through dissipation by the
circulating blood (Guy, Chou, 1980; Song, 1982; 1984). Therefore, preferential heating and
damage of tumor can be expected only if heat is preferentially delivered to the tumor or if
heat dissipation by blood flow is slower in the tumors than in surrounding normal tissues.
Phenomenon of induced thermal tolerance is essential for application of hyperthermia in
thermo-radiation therapy. Thermotolerance is a nonheritable resistance to hyperthermia
induced by exposure to heat and other cytotoxic agents. It develops within 2-3 hours during
exposure to temperatures less than 430C (Engin, 1994). Cells exposed for a brief period to
temperatures higher than 430C are sensitized to exposure to temperatures below 430C, and it
was called “stepdown heating, SDH” (Engin, 1994). SDH results from the inhibition of
thermotolerance development by exposure to the high temperature. Cells are sensitized to
hyperthermia damage by acutely lowering pH, and thermotolerance development is reduced
at low pH. Reduced pH also enhances thermoradiosensitization. Since much of tumor
population is at low pH, and these tumor cells are very likely to be hypoxic and radio- and
chemoresistant, this offers one of the strongest reasons for combining hyperthermia with
radio- or chemotherapy in the treatment of human tumors (Bicher et al., 1980; 1983; 1986;
Engin, 1994; Van der Zee, 2002).
Thermotolerance was discovered during the study of thermal damages’ repair through
fractional exposure, similar to how the repair of sublethal ionizing radiation damage is
studied.
It was found that splitting of single hyperthermal exposure (of cells or tissues) into two
fractions is slackening their cumulative effect, while the extension of interval between
fractions results in increasingly more reparation of induced thermal damages. Half-period of
recovery from sublethal thermal damages for many cells of mammals in vitro and in vivo is
about three hours. After 12-24 hours after first heating, and following the full repair of
sublethal thermal damages, increased resistance to heat (so called induced thermal tolerance)
develops; when the thermal tolerance reaches its maximum value, sensitivity towards
hyperthermia decreases 2-4 times and more, which equals to 1-20С decrease of “effective”
heat doze.
As a matter of fact, thermotolerance is a biological response which enables organisms to
survive sub-lethal high temperatures prior to experiencing a non-lethal heat exposure (King et
al., 2002; Field, Bleehen, 1982). Many studies have demonstrated this phenomenon in
cultured cells and animals other than mammals (Mizzen, Welch, 1988; Kampinga, 1993;
Theodorakis et al., 1999). Limited studies in rodents have revealed that a marked whole-body
hyperthermia preconditioning (Kapp, Lord, 1983; Li., et al., 1983; Weshler et al., 1984). The
molecular mechanism of mammalian whole-body hyperthermia, however, has not been
investigated in detail (King et al., 2002).
Maximum induced tolerance after the first low-damage exposure to hyperthermia (430С,
30 minutes) is observed during 24-48 hours; its intensity and manifestation in time depends
on heat dose, which has caused the thermal tolerance.
It is illustrated that while transition from weaker to stronger “doses of heat” within the
non-damaging range, the value of maximum thermo-tolerance increases, but then, together
with further increase of heating dose and transition to the damaging doses, the value of
maximum thermo-tolerance starts to decrease. Thus, there exists certain optimal value of
“heat dose”, at which the maximum value of induced thermal tolerance develops.
In order to ignore in treatment regimen the additional effect of tumor thermo-tolerance
induced by the previous fraction, it is recommended to carry out the hyperthermia sessions no
more than 1-2 times per week; in this way there will be sufficient time interval between
hyperthermia fractions, during which above mentioned effect could be fully eliminated. From
the other hand, it is experimentally fixed that during the therapeutic heating, i.e. at the
temperature value more than 420С, thermotolerance in tissues, including tumor ones, does not
develop. This circumstance allows selecting any regimens of tumors’ thermoradiation
therapy, without fearing development of thermotolerance.
Besides, it is established, that an acidic and nutritionally deprived environment greatly
increases the thermosensitivity of tissue, inhibits the recovery of tissue from thermal damage,
and inhibits the development of thermotolerance (Gerweck, 1977; Goldin Leeper, 1981;
Overgaard, 1976; Overgaard, Nielsen, 1980).
In 1998 Jyh-Cherng Lin and Chang W. Song have studied the influence of vascular
thermotolerance on the heat-induced changes in blood flow, pO2, and cell survival in tumors.
Vascular thermotolerance in SCK tumors of A/J mice was studied by comparing the changes
in blood flow, as measured by the 86Rb uptake method, from a single heating with those from
two heatings. Authors considered that the heat-induced decline in 86Rb uptake on tumors
could be substantially inhibited when the tumors were preheated, indicating the development
of vascular thermotolerance. In SCK tumors, the vascular thermotolerance peaked 5 or 18 h
after the tumors were heated for 1h at 41,50C or 42,50C, respectively. Consequently, the
tumor blood flow decreased by 50% in 81 min when the tumors were heated at 43,50C
without preheating, whereas the tumor blood flow decreased by 50% in 195 min at 43,50C
when the tumors were preheated 18 h earlier at 42,50C for 1 h. The influence of vascular
thermotolerance on the heat-induced changes in intratumor pO2 was also investigated. The
average intratumor pO2 was 8,9 mm Hg before heating. Heating at 43,50C or 44,50C for 1 h
dramatically decreased the intratumor pO2 to 3,0 or 1,2 mm Hg respectively. However the
intratumor pO2 decreased to 6,6 or 3,8 mm Hg when the tumors were heated at 43,50C or
44,50C respectively, 18 h after preheating at 42,50C for 1 h. Heating the tumors vasculatures
were at peak thermotolerance relatively ineffective in suppressing tumor growth. These data
demonstrate that vascular thermotolerance in tumors may exert profound effects on tumor
response to multiple heating in clinical hyperthermia (Lin, Song, 1993).
Oxygenation of tumor shows tendency towards reflection of the changes in the blood
flow during the hyperthermia and may increase after the heating. This is equally peculiar both
for experimental and for human tumors, at least for mild hyperthermia. Substantial changes in
glucose concentration in tumors during the hyperthermia are noted; these changes are
apparently conditioned by changes in blood flow and development of interstitial edema.
During hyperthermia the amount of lactate increases as a result of glycolisis’ activation.
One of the most pronounced physiological change in tumors by heat is a prompt decrease
in intratumor pH with following recovery against the “thermal dose”. Decrease in intratumor
pH would accentuate the thermokilling of tumor cells and possibly inhibit repair of
thermodamage and development of thermotolerance in tumors (Emami, Song, 1984). Thus, it
is supposed that the differential effects of heat on vascular function and pH in tumors and
normal tissues may result in a greater damage in tumors than in surrounding normal tissues.
The mechanism of the decrease in blood flow and pH in the heated tumors completely is not
clear, but these two phenomena seem closely related (Song, 1982). At the same time, it is
known that bioenergy status of tumor worsens during hyperthermia, which is proved by
decreased concentration of ATP and phosphocreatinine and increased content of nonorganic
phosphate. Hydrolysis of ATP results in accumulation of purine catabolites of hypoxanthine,
xanthine and uric acid with formation of hydrogen ions that promote heating-produced
acidosis.
Local hyperthermia therapy for cancer can produce selective heating of solid tumors on
the basis of known physical laws. If energy is deposited in the general region of the tumor,
temperature tends to develop in the tumor higher than that in surrounding normal tissues
(Babbs, DeWitt, 1981).
The main goal of hyperthermia therapy is to achieve cytotoxic temperature elevations in
the tumor for an adequate period of time, without damaging nearby normal tissue. It is well
known fact that heat induces a prompt increase in blood flow accompanied by dilation of
vessels and increase in permeability of the vascular wall (Song, 1984; Song et al., 1980). The
mentioned authors have shown that the degree of pathophysiological changes in the vascular
system in normal tissue is, of course, dependent on temperature and duration of heating, and
an excess exposure of tissues to heat results in a breakdown of vasculature followed by
necrosis of the tissue.
Usually the blood flow in normal tissues increases remarkably when heated temperature
commonly used in hyperthermia is in range of 42-450C. The fact emerging from various
experimental data is that the heat-induced change in the blood flow in tumors is considerably
different from that in normal tissues. In accordance with data obtained by Song (1982) the
blood flow in tumor appears to increase slightly when heated at temperatures below 41-420C,
but drastically decreases at temperatures above 420C. It is necessary to underline, that
hyperthermia at therapeutic temperature (430-450C) causes a profound increase in blood flow
in normal tissues in experimental animal systems, while it induces, as has been mentioned,
only meager and temporal increases in blood flow in tumors. A severe vascular occlusion and
hemorrhage usually follows the increase in blood flow in the tumors at the above
temperatures (Emami, Song, 1984). Due to the vascular occlusion, the dissipation of heat in
the tumor becomes inefficient, and the temperatures in the tumor rise higher than those in
normal tissues during hyperthermia at temperature above 420C (Song, 1982).
While the majority of experimental study shows a decrease and even a lapse in blood
flow within microcirculation during or after hyperthermia, the data on human tumors are less
conclusive. Some of the investigators do not find a decrease in circulation, while others do
(Reinhold, Endrich, 1986). These authors consider that this is an important field of
investigation in the clinical application for hyperthermia because a shut down of the
circulation would not only facilitate tumor heating (by reducing venous outflow, and
reducing the heat clearance from the tumor), but would also facilitate tumor cell destruction.
More over, the same holds for alterations that occur subsequently to the circulatory changes,
like a heat-induced decrease of tissue pO2 and pH (Reinhold, Endrich, 1986). In
hyperthermic tumor therapy a number of complex processes and interactions take place
which deal with the heat-induced changes in the micro-physiology of tumors and normal
tissues which may not only enhance the exponential cell kill, but which may also culminate
in vascular collapse with ensuing necrosis of the tumor tissue in the areas affected (Reinhold,
Endrich, 1986). The speed and degree of vascular collapse is dependent on heating time,
temperature and tumor model used. Such vascular collapse generally occurs at temperatures
that cause a substantial blood flow increase in certain normal tissues, thus preferential anti-
tumor effects can be achieved (Horsman, 2006). The tumor vascular supply can also be
exploited to improve the response to heat. Decreasing blood flow, using transient
physiological modifiers or longer acting vascular disrupting agents prior to the initiation of
heating, can both increase the accumulation of physical heat in tumor, as well as increase heat
sensitivity by changing the tumor micro-environmental parameters, primarily an increase in
tumor acidity. Such changes are generally not seen in normal tissues, thus resulting in a
therapeutic benefit (Hosman, 2006).
Microcirculation is a very sensitive process. Under hyperthermia and artificial tissue
acidification, blood flow ceased regularly and reproducibly. This blood flow inhibition
imposes seemingly as a consequence of a progressing decrease of blood fluidity (von
Ardenne, Retnauer, 1985) or in other words, changes in blood rheological properties.
11.2. THE ROLE OF LOCAL BLOOD FLOW INTENSITY, BLOOD

RHEOLOGICAL PROPERTIES AND FREE RADICALS IN
DEVELOPMENT OF LOCAL HYPERTHERMIA-INDUCED
MORPHOLOGICAL CHANGES IN CEREBRAL TISSUE
The clinical use of hyperthermia for cancer treatment was increasingly accepted during
past decades and today there is well established fact that the hyperthermia pre-treatment at
temperatures between 40-440C enhances the therapeutic effect of radiotherapy or
chemotherapy (Van der Zee, 2002). In this temperature range due to the difference in
characteristics of normal and tumor tissue, tumor cell killing is achieved. Most biological
tissues, with the exception of the central nervous tissue, are tolerant to hyperthermia
treatment and can survive at a temperature of up to 440C (Fajardo, 1984). In regard to central
nervous tissue, there are some discrepancies in published data concerning irreversible
damages that were found after treatment: at 42-42.50C (Sminia et al, 1994), at 43.10C (el-
Sabban, Fahim, 1995) at 43.90C and greater (Fike et al., 1991). And, what is more, Matsumi
et al (1994) have showed no obvious irreversible changes in monkeys normal brain tissue at
440C and below in case of non-survival experiment, and just in survival experiment (animals
were sacrificed 7 days after the treatment) cerebral areas heated at 440C or above, coagulative
necrosis developed, the authors suggesting that the safety limit for brain hyperthermia is 430C
for 60 min.
Analysis of experimental data received on dogs (Harris et al., 1962; Lyons et al., 1984;
Sneed et al., 1986; Fike et al 1991; Eddy et al., 1992; Ikeda et al., 1994), cats (Samaras et al.,
1982; Britt et al., 1983; Lyons et al., 1986) and rabbits (Silberman et al., 1982) using
different techniques for brain local hyperthermia allowed P. Sminia and M. Hulshof (1998)
conclude that maximum tolerable heat dose is 42-42,50C for 40-60 min or 430C for 10-30
min. Effects of hyperthermia were expressed immediately or within a few days after
treatment. The most recent review on effect of local hyperthermia on the cerebral nervous
tissue was published by J. Haveman et al (2005).
It is accepted that hyperthermia-induced damages in central nervous tissue are mostly
conditioned by thrombosis and arteriolar constriction (el-Sabban, Fahim, 1995). The
microcirculation in its turn in many aspects is conditioned by rheological properties of blood.
One of the most significant rheological parameter of blood is its viscosity, which depends on
RBC aggregation and deformability, haematocrit, blood temperature and others. If by some
reason either haematocrit increased or fibrinogen and immunoglobulin rose, or there is a
hypothermic condition, or increased aggregation of erythrocytes or changes in their
deformability, or all named factors take place simultaneously, hyperviscosity of blood is
observed. Increased viscosity results in a slowing down of blood flow, stagnation of its
constituents and in ischemia (Larcan, Stoltz, 1983). Decrease in regional cerebral blood flow
(rCBF) and regional cerebral metabolic rate of oxygen were observed in the elderly (66.6+/-
4.6 years old) with increased blood viscosity as a result of various kind of polycythemia and
erythrocytosis (Shikatura, Kubota , Tamura, 1993). Plasma viscosity must also be taken into
consideration. Special investigation devoted to clarification of relationship between plasma
viscosity and cerebral blood flow (Tomiyama et al., 2000) has shown that rCBF more closely
follows changes in plasma viscosity rather than whole blood viscosity. Authors believe that
plasma viscosity may be the more important factor in controlling cerebral blood flow.
In accessible for us literature we did not find any data concerning changes in
hyperthermia-induced damages of cerebral tissue under different rheological properties of
blood.
Besides above-mentioned hyperthermia has a significant influence on cerebral
metabolism. The release of excitatory neurotransmitters and oxygen free radicals causes more
extensive blood-brain barrier breakdown (Arboix 2005). It has been hypothesized that
hyperthermia promotes oxygen-centered free radicals formation in cells. By means of
electron paramagnetic resonance spin trapping Flanagan et al. (1998) received direct
evidence for free radicals generation during hyperthermia in intact functioning cells. This
finding indicate that heat increases the flux of cellular free radicals and support the
hypothesis that increased generation of oxygen-centered free radicals and the resultant
oxidative stress may mediate in heat-induced cellular damage (Flanagan et al., 1998).
Taking into account above-mentioned, we tried to obtain more specific data, pertaining
to sensitivity of cerebral tissue to hyperthermia treatment and its immediate effect, manifested
by histological changes, and the role of local blood flow, blood rheological properties, and
the possible role of free radicals in development of mentioned changes.
Experimental Approach
Non-survival experiments were performed on pathology free adult mail Wistar rats
weghing 250-300g. Each rat was anesthetized by 0.15ml/100g bdy weight I/P injection of 4%
Chloral Hydrate solution. After catheterisation of right femoral vein, animals were mounted
in a stereotaxic apparatus. The skull was exposed and about 3 mm hole was drilled in the
parietal bone (right or left). The dura mater was carefully retracted, and a thermistor bead
probe for thermal clearance method (Xu et al., 1998; Zhu et al., 2005) was dipped into the
sensory motor area of the cerebral cortex at a depth of 0.5 mm. In parallel with the
temperature probe a silicon tube (0.5 mm internal diameter) connected to a peristaltic pump
was lowered to the cerebral surface (Figure 64).
After testing the thermistor probe it was connected to the thermistor data acquisition
block of polygraph “MX-01" (USSR). The silicon tube, lowered to the brain surface, was
connected to the outlet of one-channel peristaltic pump (MMC, Czechoslovakia). The pump’s
inlet, via polyethylene catheter, was connected to an ultra-thermostat’s reservoir, filled with
artificial cerebrospinal fluid heated up to the temperature necessary for achievement of stable
level of temperature on the brain surface (either 37, 41, 43 or 450C).
Rectal temperature was measured with a thermocouple probe, connected to the second
channel of temperature measuring block of polygraph, and was maintained on 370C by a
feedback-controlled infrared lamp.
Figure 64. Design of Experiment. Temperature of Artificial Cerebrospinal Fluid (ACSF) was
maintained by Ultra-thermostat (UT) on 370C (Control Group), 41, 43 and 450C (respectively in the
following three series of experiments). Core body temperature (measured rectally) was maintained on
370C by feedback controlled Infrared Lamp. ACSF heated up to desire temperature irrigates rats’ brain
surface during 60 minutes by means of peristaltic pump. The temperature on the cerebral surface and
thermal clearance was measured by means of thermistor bead probe.
After completion of the surgical procedure and placing the thermistor probe and silicon
tubing in the craniotomy location, controlled hyperthermic exposure was applied regionally
by irrigating the cerebral surface with cerebrospinal fluid heated in the thermostat reservoir
up to the desired temperature.
In the first series of experiments, the temperature of the artificial cerebrospinal fluid in
normothermic (control) Group 1 of animals (6 rats) was maintained on the level of 370C. In
the following three groups (6 animals in each) the temperature of the artificial cerebrospinal
fluid correspondingly was 41 (#2 Group), 43 (#3 Group), and 45 (#4 Group) degrees Celsius.
In the second series of experiments similar to the first series, 4 groups of animals (#5 –
normothermic, #6 – 41, #7 – 43 and #8 – 450C) 15 minutes prior to heating and 15 minutes
after its beginning 1ml of 10% high molecular weight Dextran T-500 (Pharmacia, Sweden)
was administered i/v. In order to maintain systemic arterial and venous pressure levels close
to the normal, the same amount of blood was withdrawn.
In the third series of experiments 4 groups of animals (#9 – normothermic, #10 – 41, #11
– 43 and #12 – 450C) 15 minutes prior to heating 0.3 ml/100g body weight 5% solution of
Dimethyl sulfoxide (DMSO) – well-known scavenger of free radicals was administered i/v.
The composition of the artificial cerebrospinal fluid (in mmolls/L) was the following:
NaC1 - 118.0; KCI - 4.7; NaHCO3 -14.9; KH2PO4 - 1.18; MgSO4.7H2O -1.17;
CaC12H2O - 2.5; Glucose - 11.0. Permissible changes in pH of this solution were in the
range of 7.35 - 7.45.
Duration of the brain local hyperthermic exposure in all experimental series was 60
minutes.
Before the temperature exposure in every animal the baseline local cerebral blood flow
(lCBF) was measured three times (with 5 minutes interval). For each temperature grade lCBF
was measured before (5-10 minutes after beginning of heating) and after (20-30 minutes after
beginning of heating) reaching the steady state level in brain tissue temperature. For
recording of “thermal clearance” curve in each measurement, 3 seconds duration heating
pulse was delivered to the cerebral cortex tissue and the temperature “clearance” was
recorded until to reaching the temperature level prior to heating pulse.
After completion of each experimental session, the animal was deeply anesthetized and
transcardially perfused with heparinized saline followed by 10% formalin solution. The brain
was removed and stored for subsequent histological processing.
Serial brain coronal sections 50 μm thick were prepared throughout the extent of
hyperthermic lesions, mounted on glass slides and later stained with Azure-Eosin. The area
(mm2) of injured tissue and character of histological changes on coronal sections’ was
determined under light microscope using an ocular micrometer and the volumes (mm3) were
calculated by summing of injured areas of all sections and multiplying by the interval
thickness between sections (Kim et al, 1996).
The Students’ t-test was used to examine the effect of different temperature exposure on
local cerebral blood flow and the geometric dimensions of damaged areas of brain tissue. A
value of P<0.05 was considered to be significant.
Normothermic Groups (#1, 5 and 9)
Data were analyzed from all series of experiments (18 rats). In each of them visual
(macroscopically) and histological examination confirmed the absence of changes to 370C
temperature exposure lasting 60 minutes (Figure 65). An average level of local blood flow in
cerebral cortex was 61.5±3.2 ml/100g/min.
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Figure 65. The absence of changes in sensory-motor cortex of rats’ brain to lasting 60 minutes 370C
temperature exposure. A – magnification: x15; B – framed area from the picture A, magnification: x40.
410C Hyperthermic Groups (#2, 6 and 10)
None of the visible alterations and differences from the control has been found during
visual examination of the cerebral surface of these groups of animals after completion of a
60-minute hyperthermic (410C) exposure.
In the animals from first series of experiments (#2 Group) changes on brain histological
slices (Figure 66) were well pronounced. The average area of the lesion was 1.2±0.15mm2
and the average volume of damaged tissue – 36.5 ±7.4 mm3. Individual thrombosed vessels
were found mainly in the 2nd and 3rd layers of cerebral cortex and very seldom in 5th and 6th
layers. The hyperthermia-induced lesion has semicircle form with clear delineated light
outlines in the 2nd and 4th layers. The layered structure of the cerebral cortex is poorly
disturbed and neuron disorientation is negligible, although the cell edges are significantly
modified.
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Figure 66. Sensory-motor cortex of the rats’ brain; 60 minutes hyperthermia (410C); Arrows show the
clear-cut edge of damaged tissue. A – magnification: x15; B – framed area from the picture A,
magnification: x40.
In this series of experiments hyperplasia and pycnosis of the cells occurred in the 3rd
layer of the rats’ cerebral cortex and most of them in pyramidal neurons.
In the animals from second series of experiments which before onset of hyperthermia
received Dextran T-500 pretreatment (#6 Group) the average area of the lesion were
3.3±0.4mm2 (Figure 67) and the average volume of damaged tissue – 100.3±12.6mm3.
Individual thrombosed vessels were found mainly in the II and III layers of cerebral cortex
and very seldom in V and VI layers. The layered structure of the cerebral cortex is disturbed
mildly and neuron disorientation is negligible, although the cell edges are significantly
modified.
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Figure 67. Sensory-motor cortex of the Dextran T500 pretreated rats’ brain; 60 minutes hyperthermia
(410C); Arrows show the clear-cut edge of damaged tissue. A – magnification: x15; B – framed area
from the picture A, magnification: x40.
In this series of experiments hyperplasia and pycnosis of the cells occurred in the III
layer of the rats’ cerebral cortex and most of them in pyramidal neurons.
In the animals from third series of experiments which before onset of hyperthermia
received Dimethyl sulfoxide (DMSO) pretreatment (#10 Group) the average area of the
lesion were 0.78±0.11mm2 (Figure 68) and the average volume of damaged tissue –
23.4±6.2mm3. The layered structure of the cortex practically is not impaired. The damaged
part of the tissue is not surrounded by a penumbra zone and disoriented neurons were not
observed. There are some partially pycnotic and hyperplasic neurons in the second and third
cortical layers and the density of their distribution is relatively high. The cell’s shape, as well
as nucleus and nucleolus are well recognizable.
The cerebral cortex surface in locations of 430C hyperthermic exposure similar to the
previous groups did not show the color changes or any other macroscopically visible
alterations.
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Figure 68. Sensory-motor cortex of the Dimethyl sulfoxide (DMSO) pretreated rats’ brain; 60 minutes
hyperthermia (410C); Arrows show the clear-cut edge of damaged tissue. A – magnification: x15; B –
framed area from the picture A, magnification: x40.
In #3 group of rats the hyperthermia-induced lesion’s average area in the central coronal
sections was 3.54 ± 0.8mm2 and the calculated average volume of the damaged tissue 106.2 ±
11.3mm3. The form of lesion on coronal sections of the brain was modified semicircle (Figure
69A). In the central part of the lesion thrombosed arterioles and capillaries were found and
usually located up to the 3rd layer of cerebral cortex. Perivascular accumulation of
erythrocytes was rare.
The layered structure of the cerebral cortex in the central parts of the hyperthermia –
induced lesions was impaired (Figure 69B). In the 3rd layer some pyknotic neurons with
difficult recognizable nucleus and nucleolus were observed. In this layer of the cortex
neurons were distributed with very high density and loss of neurons was not observed.
The 4th layer of the cerebral cortex in this group of animals was the most damaged. The
neurons in this layer were hyperplasic and the density of their distribution is very low. The
light border between the 4th and 5th layers of the cerebral cortex formed because of heavy
neuron loss was easily recognizable on the brain coronal slices. As a result of hyperthermic
exposure pyramidal neurons mainly survived in the 4th layer of cerebral cortex. Stellate cells
with identifiable soma with outgoing dendrites; nucleus and nucleolus were seldom found.
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Figure 69. Sensory-motor cortex of rats’ brain; 60 minutes hyperthermia (430C); Arrows show the
magnification: x40.
In the 5th layer of cerebral cortex neurons appeared disoriented around the area of lesion.
Pycnosis of the neurons in this layer is less pronounced in comparison with the neurons of the
3rd layer but the neurons of this layer are more disoriented. It is very difficult to determine
their type. The 6th layer of the cerebral cortex in this series of experiments was showed some
medium hyperplastic neurons.
In #7 group of Dextran T-500 pretreated animals (Figure 70) the average area of the
lesion was 5.9±0.7mm2 and the average volume of damaged tissue – 177.8±16.5mm3. The
layered structure of the cerebral cortex in the central parts of the hyperthermia–induced
lesions was impaired. In III layer some pycnotic neurons with difficult recognizable nucleus
and nucleolus were observed. In this layer of the cortex neurons were distributed with very
high density and loss of neurons was not observed. IV layer of the cerebral cortex was
significantly damaged. The neurons in this layer are hyperplasic and the density of their
distribution is very low. In V layer of cerebral cortex neurons appeared disoriented.
In #11 group of DMSO pretreated animals (Figure 71) the average area of the lesion was
1.2±0.13mm2 and the average volume of damaged tissue – 36.1±6.9mm3. In the first and
second layers of cerebral cortex some thrombosed arterioles and capillaries were found. The
cells in III-V layers are pycnotic (mostly in III layer). The 4-th layer is involved in penumbra
zone; here neurons are partially pycnotic and disoriented. As a whole, the layered structure of
the cortex is preserved.
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Figure 70. Sensory-motor cortex of the Dextran T500 pretreated rats’ brain; 60 minutes hyperthermia
After completion of local hyperthermic exposure lasting 60 minutes all animals brain
surface of #4 group on the exposed location had a rose color. The same changes in color at a
depth of about 2mm were observed on the hyperthermia-damaged brain 50 μm thick coronal
sections stained with Azure-Eosin. On the coronal section the hyperthermia-induced lesions
look like a modified semicircle with an average area in the central sections equal to 6, 13 ±
0,21mm2 (Figure 72A). The calculated volume of the hyperthermia-induced lesions in brain
tissue for this group of rats was 183.6 12.4mm2.
In the central part of the hyperthermia lesion numerous thrombosed arterioles and
capillaries were revealed, with perivascular accumulation of erythrocytes, mostly they were
found up to the 4th cortical layer. In the area of lesion the layered structure of the cortex was
significantly impaired and a loss of neurons (including the 4th layer) could be seen (Figure
72B).
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The damaged (practically burned-out) part of the tissue is surrounded by a well-

pronounced penumbra zone with disoriented neurons. The cell’s edges in both focus of lesion
and the penumbra area changed forms and identification of the type of cells was difficult.
Many of the neurons were swollen although the edge and nucleolus were still distinguishable.
Cell lesions in the perifocal, penumbra zone are less defined when compared with those
in the central part of the hyperthermic injury in all cortical layers.
In #8 group of Dextran T-500 pretreated animals (Figure 73) the average area of the
lesion was 10.21±1.3 mm2 and the average volume of damaged tissue – 315.7±26.3 mm3.
In the central part of the hyperthermia lesion numerous thrombosed arterioles and
capillaries were revealed, with perivascular accumulation of erythrocytes, mostly they were
found up to the VII cortical layers. In the area of lesion the layered structure of the cortex was
significantly impaired. The damaged part of the tissue is surrounded by a well-pronounced
penumbra zone with disoriented neurons. Many of the neurons were swollen although the
edge and nucleolus were still distinguishable.
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Figure 72. Sensory-motor cortex of rats’ brain; 60 minutes hyperthermia (450C); Arrows show the
magnification: x40;
In #12 group of DMSO pretreated animals (Figure 74) the average area of the lesion was
5.2±0.7 mm2 and the average volume of damaged tissue – 156.5±11.4 mm3. In the damaged
area of the cortex thrombosed arterioles and capillaries are sharply defined and they are
observed up to 6-th layer. The density of their distribution diminished in lower layers. Heavy
neuron loss was easily recognizable on sufficiently great areas of the brain coronal slices.
Some hyperplasic cells with changed shape have also been revealed.
Statistical data concerning immediate morphometrical changes in cerebral tissue, induced
by local hyperthermic exposure for all described experimental conditions are summarized in
Table 12 and graphically are presented in Figure 75.
Hyperthermia-induced alterations of local cerebral blood flow in normal rats as well as in
Dextran T-500 and Dimethyl sulfoxide pretreated rats are summarized in Table 13.
Percentages of these alterations in each series of experiments are presented on the figures 76-
78.
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Figure 73. Sensory-motor cortex of the Dextran T-500 pretreated rats’ brain; 60 minutes hyperthermia
The main goal of local hyperthermia treatment is affecting tumor tissue causing apoptosis
or necrosis depending on the level of temperature and duration of hyperthermic exposure. It
turned out, that in tumor tissue most pronounced apoptosis is observed at prolonged
hyperthermia exposure (Toyota et al, 1998). But comparison of results of long-lasting (6
hours) low temperature (400C) hyperthermia in combination with chemotherapy, during
procedure of short-term, high temperature hyperthermia most pronounced apoptosis in tumor
tissue has been revealed (Toyota et al, 1998).
In our early experimental studies of local hyperthermia effects on rabbit’s cerebral tissue,
microwave induced local hyperthermia caused remarkable changes in cerebral blood flow
manifested by increase of blood flow rates at the beginning of hyperthermia, and slump
decreasing of blood flow rates after raising the brain temperature upwards of 430C (Bicher,
Mitagvaria, 1980; Mitagvaria, Bicher, 1984).
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On the same animal species in conditions of whole body hyperthermia doubling of

cerebral blood flow intensity has been observed at the core body temperature 430C; 2.5 times
increasing of cerebral blood flow at 440C and 3.5 times increasing at 450C. At the same time
augmentation of tissue oxygen partial pressure and pH have been observed (Yamada, 1989).
In similar experiments carried out on canine brain (60 minutes duration 420C whole body
hyperthermia) microscopically investigation of the brain tissue did not reveal any damaged
brain area (Takahashi, et al, 1999). However, under slightly less temperature (41.80C)
increase in oxygen transport and consumption in tissue have been revealed (Kerner et al,
1999).
During whole body hyperthermia statistically significant increase of oxygen saturation in
arterial blood, arterial-venous difference in oxygen partial pressure and the level of venous
blood PCO2 were observed. At the same time, decrease of oxygen saturation and pH in
venous blood has also been observed (Hall et al, 1999). All these data testify that
hyperthermia caused cellular hypoxia in visceral tissue. Hypoxia and decrease of pH has been
credited by some authors as causing the anti-tumor effects of hyperthermia (Madden et al,
1990; Van der Zee et al, 1989).
Whatever the nature of hyperthermia’s positive effect on tumor tissue and increase of its
sensitivity to chemo-and radiotherapy, it is very important to ascertain normal tissue safety
and the absence of irreversible damage. From this point of view special attention has to be
paid to the central nervous tissue thermotolerance and sensitivity for hyperthermia (Sminia et
al., 1990; Haveman et al., 2005). As it already has been underlined above, there is a wide
discrepancy concerning the temperature sensitivity of brain tissue. Our experiments seem to
indicate irreversible damage to brain tissue at temperature close to those clinically used.
As we can see (Table 12) all three experimental levels of temperature (excepting the
control group) caused different pronounced histological changes in the brain tissue of rats.
Depending on temperature, hyperthermic lesions vary from group to group of animals. At
410C we can observe just superficial lesions of the cerebral cortex penetrating 2, and very
seldom 3 cerebral layers. Only a few cases of thrombosed cerebral microvessels have been
observed in this group of animals.
Table 12. Dimensions of 60 minutes hyperthermia-induced brain lesions in Normal,

Dextran T-500 and DMSO pretreated rats
Dimensions of hyperthermia-induced lesions in Sensory-motor cortex of rats’ brain
Intra peritoneal injection of 0.3

Intra venous injection of 1ml of
ml/100g body weight 5%
Normal rats 10% high molecular weight
solution of Dimethyl Sulfoxide
(M±S.E, n=18.) Dextran T-500
Temperature (DMSO)
(M±S.E., n=18)
(0C) (M±S.E., n=18)
Volume of lesion
Volume of lesion
Volume of lesion
Area of lesion
Area of lesion
Area of lesion
(mm2)
(mm3)
(mm2)
(mm3)
(mm2)
(mm3)
1.2 36.5 3.3 100.3 0.7 23.4
41 (1) (4) (7) (10) (13) (16)
±0.1 ±7.4 ±0.4 ±12.6 ±0.1 ±6.2
3.5 106.2 5.9 177.8 1.2 36.0
43 (2) (5) (8) (11) (14) (17)
±0.8 ±11.3 ±0.7 ±16.5 ±0.1 ±6..9
6.1 183.6 10.2 315.7 5.2 156.2
45 (3) (6) (9) (12) (15) (18)
±0.2 ±12.4 ±1.3 ±20.3 ±0.7 ±11.4
Statistical confidence of difference:
(1) vs (2) Signif. at P<0.05 (7) vs (8) Signif. at P<0.01 (13) vs (14) Signif. at P<0.01
(4) vs (5) Signif. at P<0.01 (10) vs (11) Signif. at P<0.05 (16) vs (17) Not Significant
(1) vs (7) Signif. at P<0.01 (4) vs (10) Signif. at P<0.01

(1) vs (13) Not Significant (4) vs (16) Not Significant
(2) vs (8) Not Significant (5) vs (11) Signif. at P<0.05
Table 13. 60 minutes hyperthermia-induced local blood flow changes (ml/100g/min) in

cerebral cortex of Normal, Dextran T-500 and Dimethyl Sulfoxide (DMSO) pretreated
rats
Second series Third Series Time of

First Series
Temperature (Dextran T-500 (Dimethyl Sulfoxide measurement
0 (normal animals)
C pretreated animals) pretreated animals) (after beginning of
M±S.E.
M±S.E. M±S.E. heating)
(1) 87.1±5.6 (n=6) (6) 76.2±6.6 (n=6) (10) 90.3±9.7 (n=6) 5-10 min
41
100.5±11.1
(2) 99.9±6.2 (n=6) (7) 91.7±8.5 (n=6) (11) 20-30 min
(n=6)
130.6±21.2 110.1±10.3 135.3±17.4
(3) (8) (12) 5-10 min
(n=6) (n=6) (n=6)
43
(4) 52.7±7.3 (n=6) (9) 21.2±5.5 (n=6) (13) 66.5±8.1 (n=6) 20-30 min
(5) 15.4±4.6 (n=6) Impossible to measure (14) 26.4±7.6 (n=6) 5-10 min
45
Impossible to measure Impossible to measure Impossible to measure 20-30 min
Statistical confidence of difference:

(1) vs (10) Not Significant (4) vs (9) Significant at P<0.05
(3) vs (8) Not Significant
400
Volume of lesion [mm 3]
350
300
250
200
150
100
50
0
41 43 45
0
Temperature [ C]
Normal Dextran T-500 pretreated DMSO pretreated
Figure 75. Temperature dependent changes in volume of hyperthermia-induced cerebral lesions in

Normal, Dextran T-500 and Dimethyl Sulfoxide (DMSO) pretreated rats.
The rise of temperature on 2 degrees of Celsius resulted in very severe lesions of cerebral
tissue. Morphological changes are well pronounced and numerous thrombosed vessels are
revealed.
The highest temperature (450C) caused most severe hyperthermic lesion of the cerebral
tissue – complete destruction of the layered structure of the cortex in the area of hyperthermic
exposure, numerous areas with lost neurons and thrombosed cerebral vessels with
perivascular accumulation of erythrocytes were revealed.
Hyperthermia-induced local blood flow changes in cerebral

cortex of normal rats
250
200
150
lCBF [%]
100
50
0
37 (control) 41 43 45
Temperature (0C)
5-10 min and 20-30 min after beginning of heating
Figure 76. Percentage of hyperthermia-induced local blood flow (lCBF) changes in cerebral cortex of
normal rats. lCBF was measured on 5-10 and 20-30 minutes after beginning of heating.

cortex of Dextran T-500 pretreated rats
200
150
lCBF [%] 100
50
0
37 (control) 41 43 45
Temperature (0C)
Dextran T-500 pretreated rats. lCBF was measured on 5-10 and 20-30 minutes after beginning of
heating.
In accordance with results of our experiments in the first stage of heating up to 430C
lCBF sharply increases but later (on 20-30 minutes of heating) it falls down. At the earliest
stage of 450C heating the level of lCBF is extremely low and then it stops. This kind of lCBF
dynamic is more pronounced in Dextran T-500 pretreated animals. In this case decrease of
lCBF on the second stage of 430C heating is sharply defined and in series of experiments
with 450C local blood flow in temperature exposed area of cortex is not measurable at all.
Injection of free radicals scavenger Dimethyl Sulfoxide gives an opposite to Dextran T-500
effect – late stage of 430C and first stage of 450C are slightly better, but in late stage of 450C
lCBF still is not measurable.

cortex of DMSO pretreated rats
250
200
150
lCBF [%]
100
50
0
37 (control) 41 43 45
Temperature (0C)
Dimethyl Sulfoxide (DMSO) pretreated rats. lCBF was measured on 5-10 and 20-30 minutes after
beginning of heating.
In normal conditions, the brain tissue temperature depends on local heat production, (a
corollary of metabolic activity), rate of cerebral blood flow and the temperature of the blood
(Rossi et al, 2001). The effect of local cerebral hyperthermia on responses of pial
microvessels of the mouse was investigated by F. El-Sabban and M. Fahim (1995). At the
end of 50 minutes hyperthermic exposure (43.10C), arterioles attained a constriction of 37%
and thrombus formation was massive enough to occlude fully the microvessels. The same
authors during hyperthermia have demonstrated numerous platelets in association with
scattered red blood cells and occasional white blood cells in a close proximity but not
adhered, to the endothelial wall of hyperthermic brain vessels. The site of platelet aggregation
in both venules and arterioles was accompanied by focal endothelial lucency land
denudation, vacuole formation, luminal membrane rupture and swelling of the nuclear
envelope (Fahim, el-Sabban, 1995).
It is known that there is no independent, direct effect of dextran on vascular tone, but
high molecular weight dextran can cause erythrocyte aggregation and affect blood flow
(Tomiyama, Brian, Todd, 2000). In experimental study Chen et al. (1989) have demonstrated
fourfold rising of plasma viscosity while apparent blood viscosity was increased about
twofold after administration of high molecular weight dextran (mol wt 500,000, 20% wt/vol).
Same authors suggest that dextran-induced hyperviscosity leads to a compensatory
vasodilatation in several vital organs (Chen et al., 1989).
Erythrocyte aggregation is modified in certain conditions; it tends to occur at the very
low shear rates encountered in the venous circulation, where most thrombi occur (Freyburger
et al., 1996). As already has been mentioned besides increased aggregability of red blood
cells number of other factors can contribute to rise of blood viscosity: increased haematocrit
(polycythaemia), increased serum proteins, drop in temperature, impaired erythrocyte
deformability due to various acquired or inherited disorders of red cell membrane or

cytoplasm (Larcan, Stoltz, Gaillard, 1981). Administration of Dextran T-500 (used in our
experiments) leads to increase of erythrocyte aggregability index about twofold (Mantskava
M., 2003). When erythrocyte aggregation develops, the normal blood flow structuring inside
of microvessels becomes inevitably disordered. This disturbs the blood rheological properties
and results in a local slow down to a full stop of flow, even though the microvessel lumina
and the pressure gradient along their course remain preserved (Mchedlishvili, Maeda, 2001).
Erythrocyte aggregation has been shown to affect venous vascular resistance and has
been suggested to play a role in determining microcirculatory hemodynamics (Baskurt,
Farley, Meiselman, 1997). This phenomenon was found to be associated with different
cardiovascular risk factors such as hypertension, hyperlipoproteinemia and smoking,
miocardial ischemia, thromboembolic states, retinal venous occlusion and others (Hadengue
et al., 1998).
As already has been mentioned, heat increases the flux of cellular free radicals (Flanagan
et al., 1998). It is well known that they are involved in the formation of thrombosis (Hillbom,
1999). Ischemic condition that, as we have seen, develops in the late stage of 430C
hyperthermia and in higher temperature also contributes in generation of free radicals and
thereby promotes to development of vascular thrombosis. Using of Dimethyl Sulfoxide
(DMSO) – an antioxidant, a scavenger of free radicals did not gave significant improvement
in case of 410C hyperthermia, but in experiments with 43 and 450C notable improvement was
observed in both: level of local cerebral blood flow (less pronounced hyperthermic ischemia)
and in smaller size of hyperthermia-induced cerebral lesion.
CONCLUSION
The scientific material presented on this book allows for some general and specific
conclusions as follows:
1. The autoregulation of cerebral blood supply during changes in systemic arterial

pressure is dependent on three interacting mechanisms defined as myogenic,
neurogenic and metabolic. We believe that these mechanisms are just the separate
links of one encompassing regulatory system.
It was already mentioned in this book that the discussion between the adherents of
different points of views concerning the role of each of these links has been going on
over several decades. Now it is going on qualitativly on another level then earlier,
and some priority is given to the neuregenic mechanism. This is seems to be due of
following: the loops of myogenic and metabolic regulation can be described
theoretically as a closed system of some links, while "to close" the loop of
neurogenic regulation is hardly possible, despite the availability of numerous
methodical procedures of experimental analysis (surgical and pharmacological
denervation, electrical stimulation of nerve tranks and brain structures and so on).
Logically there arises the question: how much correctly the task is posed and how far
correct are approaches used? In previous sections and chapters of this book we tried
to give answers on this question, but now let us consider two examples:
A). The cerebral vessels are supplied with abundant external and, perheps, internal
innervation, but even the most potent influences on this nervous apparatus, as it
was described above, do not produce any marked disturbances in the regulation
of blood supply to the brain. This became as a reason for some authors questions
the existence of a neurogenic link of autoregulation. The source of this incorrect
inference was a static character of the overwhelming majority of experimantal
data which were used for analytic evaluation. The conventional object of such
evaluation are the characteristics of the examined preparation in two stable
states: prior and after the impact, while the events occuring in the process of the
regulatory reactions proper remain beyond the field of vision of the investigator
and we hope that was clearly demonstrated in this book. Thus dynamic analysis
of autoregulatory responses indicates that blocade af adrenergic or cholinergic
innervation of cerebral vessels, as well as narcotization of the animal, having but

a little effect on the final result of the regulatory systems compensatory activity,
reliably alters the temporal characteristics of the responses (a fast component of
autoregulatory reaction is replaced by the slow one, see Figures 79 and 80).
Figure 79. Frequency of manifestation of functioning metabolic, neurogenic and myogenic lincs of
cerebral blood flow autoregulation during elevation in systemic arterial pressure under different
experimental conditions: WK - wakefullness, NMBTL - nembutal, PHNTL - phentolamine, PHNXB -
phenoxibenzamine, PRPRN - propranolol, SCPLM - scopolamine.
Figure 80. Same as on Fig.79, but during decrease in systemic arterial pressure.
Conclusion 163
This we can consider as a confirmation to the undoubtable involvement of the

neoregenic component - at least, of the external innervation of the cerebral
vessels - in regulationg the cerebral circulation under the influences of a
systemic character.
B). The action of sympathetic stimulation, under the normal conditions was shown
to be rapidly realized due to the so-called "escape mechanism", however in
hypertension this stimulation is rather effective (Marcus M. et al., 1982).
Apparantly, a principal mistake is made while analising this phenomenon:
electrical stimulation of sympathetic nerves - artificial impact aggrevationg
blood supply to the nervous elements of the brain tissue (that is observable at the
initial moment of stimulation), is indispensably perceived by a normal system of
regulation as irritation subject to compensation. Therefore, a sympathetic
vasoconstriction of larger arteries (with more density of innervation) is
accompanied by dilatation of the smaller arteries (Busija et a., 1982). That is the
electrical stimulation of the sympathetic system leads the CBF out of the
homeostatic range, while the system of regulation - exactly its metabolic link -
returns it to this range. Is not it known that a metabolic stimulus causes far
stronger vascular response then even the maximal stimulation of the efferent
nerves?
Thus, artificial sympathetic stimulation evokes activation of one links in the
regulation system "out of place", and this conditions just the natural activation of
another link, the initial status ie restored. While under the conditions of
hypertension stimulation of the sympathetic trunk evokes a clear-cut reduction
of CBF due to which to the neurogenic link has been attributed a role of the of
the link protecting the BBB from the disturbances at the ditension of vessels by
increased intravascular pressure (Marcus et al., 1982). It seems, however, right
to speak that in this case direction of the sympathetic activation coincides with
that of other links of the regulation system.
Thus, experiments with sympathetic stimulation also prove that the neurogenic
mechanism as a link of the system regulationg blood supply to the brain is
sufficiently powerful one.
2. In recent years there appeared works dealing with the effect of various intracerebral
structures of the CBF regulation: these are the mesencephalic reticular formation,
locus correleus, the parabracheal nuclei, the Raphe nuclei, the cerebral fastigial
nuclei, thalamus, hypothalamus (Reis et al., 1982). This opens a new chapter in
studying the nervous regulation of the CBF devoted to the search of intracerebral
innervations of vessels, i.e. internal pathways capable of "closing" the loop of
nervous regulation. However, even if such pathways will be found they can by no
means close the loop formed by the external innervations.
3. The principle of adecuacy of blood supply to the brain implies the realisation of the
coupling "function-metabolism-blood flow" i.e. the regulation of blood supply to
individual microregions of nerve tissue in strict quantitative consistence with their
metabolism and, consequently with the functional activity. How can external
innervation whose source appears to be outside the brain participate in the local self-
regulation of CBF in terms of the adecuacy principle? In terms of the ideas on the
closing the loops of regulation by the principle of feedback connection it should be
recognised that yet there is no answer to this question, since no nervous link of the
coupling of metabolism (input signal) with blood flow (output signal) is found.
However, there is no doubt that there exists also a inverse coupling "blood flow-
metabolism-function" and consequently, there is possibility of active regulation
under the noraml conditions of input signal, that automatically removes the question
of the link of feedback connection. And if the ideas of metabolic self-regulation of
local CBF by the principle of adecuacy do not leave the room for the neurogenic link
in this process, then it is only the nervous mechanism that is capable of realizing the
regulation by the chain "blood-flow-metabolism-function". What are the conditions
under which this coupling is to be realized?
The process of formation and disturbances of stereotyped reactions in animals and
man to environmental stimuli, as it was described above, should be accompanied by
the emergence of emotions. Consolidation and formation of a dynamic stereotype of
behavior resulted in a decrease of the amplitude of changes in lCBF (see Section 3).
The pattern of changes in lCBF recorded in the process of learning appear to be the
superposition of two effects: a vegetative components of emotional tension and
changes in the metabolic activity. the former in the course of consilidation is
dissepears, while latter persistsso that the pronaunceness of the emotional component
- especially at the initial stages of learning - may considerably mask the manifest of
the functional component.
Evaluation of the data reported in this book indicates that when different functional
tests are used, changes in the local blood flow in the brain individual structures occur
against the background of a virtually unaltered total CBF. Consequently, this
changes should be provided by local redistribution of blood flow from the brain
areas "less interested" in the performance of the given behavioral act to the "more
interested" ones. Moreover, it has been prooved that the redistribution of blood flow
occurs to the active vasodilation and vasoconstriction responses in the relevant brain
structures, developing concomitantly and in consensus. Pharmacological denervation
results in the elimination of the emotopnal component of the changes in local blood
flow, but leaves unaltered the functional-metabolic one. And an inference inevitably
comes to mind that the former occurs through the neurogenic link of regulation of
blood supply to the brain, while the latter through the metabolic one. The emotional
component providing an excess of blood flow disrupts the quantitative coupling of
the function-metabolism-blood flow.
The myogenic mechanism is manifest during fast systemic arterial pressure changes.
Its aim is compensation of pressure changes but not to maintain a constant blood
flow level in the brain during this pressure changes.
4. There is an homeostatic range of blood flow variations which can satisfy and interact
with metabolic demands. However, if the changes in lCBF exceed the limits of the
homeostatic range, the regulatory process is triggered. The random distribution of
blood flow within the homeostatic range in different brain structures and areas is the
cause for the heterogeneity of local responses to generalized vascular disturbance.
Conclusion 165
5. The generalized vasodilation that occurs within the brain upon microwave irradiation
of the cerebellum and medulla oblongata leads to the assumption that there is a
regulatory center for vascular responses, and gives an idea on its possible location.
6. In the dorsal hippocampus and sensorymotor cortex during different stages of the
sleep-wakefulness cycle the maximum blood flow increase takes place during
emotional wakefulness and REM sleep stages. The minimum level of CBF is
accomplished during slow wave sleep.
7. Our results confirmed very high sensitivity of cerebral tissue to hyperthermic
exposure even at a temperature of 410C and this finding suggests the need for very
quick preventive actions if core body temperature for some reason (during sickness
or changes of environmental temperature) is rising above 410C.
One of the most significant reasons for extensive damage of nervous tissue under
hyperthermic exposure is the formation of micro thrombi and occlusion of cerebral
vessels. Stoppage of cerebral blood flow in the zone of vascular occlusion decreases
of temperature clearance from the exposed area of the brain and that causes increase
in temperature and aggravates the destructive action of hyperthermia.
8. Increased (by any reason) viscosity of blood can slow down blood flow and create
favorable conditions for thrombosis especially in venous system but hyperthermic
exposure in such cases presumably must hinder thrombogenic activity with
simultaneous acceleration of fibrin formation (Pivalizza et al., 1999).
9. Our observations give a good reason to consider cerebrovascular thrombosis as one
of the most significant complication of brain hyperthermia. In case of deteriorated
blood rheological properties, hyperthermia-induced cerebral lesion is more
remarkable. Administration of antioxidants, scavengers of free radicals can partially
lessen hyperthermia induced cerebral lesion.
In this book, we try to summarize the current knowledge about the mechanisms of local
cerebral blood flow regulation and its interaction with cerebral functions, emotions and
cognitive activity as well as some critical points of thermotolerance of the brain tissue.
This is at the core of human behavior and our understanding of these interactions through
future research efforts can only help in our quest for knowledge and the conquest of CNS
disease.
REFERENCES
Abramson D.I., Landt H., Benjamin J.E. Peripheral vascular response to acute anoxia. Arch.
Intern. Med., 1953, 71,583-589.
Adamia T.E., Lataria K.D., Mitagvaria N.P. Issledovanie dinamiki mestnogo krovotoka v
temennoi kore mozga u krys pri reshenii labirintnoi zadachi. Izv. AN GSSR, Seriya Biol.,
1978, 4, 3, 206-213.
Adams R.N. Electrochemistry at solid electrodes. New York, Marcel Dekker Inc., 1969.
Adams T., Heisei S.R. Ventilation and sensitivity to induced hypercapnia related to
convective effects of ventriculacisternal perfusional and brain blood flow in the cat.
Brit.J.Physiol.,1986, 371, 107.
Agnoli A., Battistini N., Bozzao L., Fieschi C. Derangement de l'auto-regulation dans les
fouyers ischemiques cerebraux: possibilites therapeutiques au moyen de medicaments
hypertenseurs. In: Symposium international sur la circulation cerebrale. Paris, 15-16
octobbre 1965. Paris Editions Sandoz, 1966, pp.114-126.
Ahn Duck-Sun, Soo-Kyoung Choi, Young-Hwan Kim, Young-Eun Cho, Heung Mook Shin,
Kathleen G. Morgan, Young Enhanced Stretch-Induced Myogenic Tone in the Basilar
Artery of Spontaneously Hypertensive Rats. J Vasc Res 2007, 44, 182-191.
Akaevski I.A. Anatomiya domashnykh zhivotnykh. Kolos, Moskva, 1975.
Akça O., D. I. Sessler, D. Delong, R. Keijner, B. Ganzel, and A. G. Doufas Tissue
oxygenation response to mild hypercapnia during cardiopulmonary bypass with constant
pump output. Br. J. Anaesth., 2006, 96, 708 - 714.
Alberch E., Baguenna J. Modulation of symphathetic cerebral vasoconstriction by
acetylholine. Proc. XXVIII-th Congress Int. Union Physiol. Sci., Budapest, 1980, 294.
Alekseev M.A. Sistemnaya deyatelnost vysshikh otdelov golovnogo mozga i nekotorie
voprosy upravleniya dvizheniyami cheloveka. Zhurn. vyssh. nervn. deyat., 1967, 17, 5,
786-797.
Allen G.S., Geress C., French L.A., Chou S. Cerebral arterial spasm. Part 5: In vitro
contractile activity of vasoactive agents including human CSF on human basilar and
anterior cerebral arteries. J.Neurosurg., 1976, 44, 594-600.
Alm A., Bill A. The effect of stimulation of the cervical sympathetic chain on retinal oxygen
tension and on ureal, retinal and cerebral blood flow in cats. Acta physiol. Scand., 1973,
88, 84-94.
Anden N., Strombom U. Adrenergic receptor blocking agents: Effects on central

noradrenaline and dopamine receptors and on motor activity. Psychopharmacologia,
1974, 38, 91-103.
Anrep C. On local vascular reactions and their interpretation. J. Physiol., 1912, 45, 318-327.
Anrep G.V., Blalock A., Samaan A. Effect of muscular contraction upon blood flow in
sceletal muscle. Proc. Roy. Soc. London, B., 1934, 114, 223-245.
Anrep G.V., Saalfeld E. The blood flow through skeletal muscle in relation to its contraction.
J. Physiol., 1935, 85, 375-399.
Antipov V.V., Davydov B.I., Tikhonchuk V.S. Biologicheskoe deistvie elektromagnitnykh
izluchenii mikrovolnovogo diapazona. Nauka, Moskva, 1980, s.193.
Antoshkina E.D., Naumenko A.I. Izmeneniya krovosnabzheniya korkovykh kontsov
zritelnogo i slukhovogo analizatora pri razdrazhenii. Fiziol. zh. SSSR, 1960, 46, 1305-
1311.
Aoyagi M., Desmukh V.D., Meyer J.S., Kawamura Y., Tagashira Y. Effect of betaadrenergic
blockade with propanol on cerebral blood flow, autoregulation and CO2 responsiveness.
Stroke, 1976, 7, 291-295.
Arboix A. Invited Comment. Neurol. India, 2005, 53, 206-206.
Artru Alan A., Nichenfeldor John D. Effect of hypercarbia on canine cerebral metabolism
and blood flow with simultaneous direct and indirect measurement of blood flow.
Anesthesiology, 1980, 52, 6, 466-469.
Astrup J., Norbeg K. Potassium activity in cerebral cortex in rats during progressive severe
hypoglicemia. Brain Res., 1976, 193, 3, 413-423.
Aubineau P., Lusamvuku N.A.T., Sercombe R. Micro-electrode recording from rabbit
cerebral arteries in vitro. J.Physiol., 1978, 282, P31-P32.
Aubineau P., Sercombe R., Seylaz J. Parasympathomimetic influence of carbachol on local
cerebral blood flow in the rabbit by a direct vasodilator action and an inhibition of the
sympathetic-mediated vasoconstriction. Br. J.Pharmacol., 1980, 68, 3, 449-459.
Auer L., Kuschinsky W., Johansson B., Edvinsson L. Sympatho adrenergic influence on pial
veins and arteries in the cat. In: Cerebral bBlood Flow: Effects of nerves and
neurotransmitters (Eds.: D.Heistad, M.Marcus0. Amsterdam London-New York,
Elsevier North Holand Inc., 1982, pp.291-300.
Auer L.M., Trummer U.G., Johansson B. Alpha-adrenoreceptor antagonists and pial vessel
diameter during hypercapnia and hemorragic hypotension in the cat. Stroke, 1981, 12, 6,
847-851.
Aukland K. Hydrogen polarography in measurement of local blood flow; theoretical and
empirical basis. Acta neurol. Scand., 1965, 41, 14, Suppl., 42-45.
Aukland K. Measurement of local blood flow with hydrogen gas. In: blood flow through
organs and tissues. (Eds.: W.H.Bain, A.M.Harper and W.A.Mackey). Edinburgh-
London, E&S. Livingstone Ltd., 1968, pp.157-162.
Aukland K., Bower B.F., Berliner R.W. Measurement of local blood flow with hydrogen gas.
Circulat. Res., 1964, 14, 164 187.
Axelsson J., Wahletrom B., Johansson B., Jonsson O. Influence of the ionic environment on
spontaneous electrical and mechanical activity of the rat portal vein. Circulat. Res., 1967,
21, 609-618.
References 169
Azin A.L., Plekhanov I.P., Orlov R.S., Vishnevski G.A. Issledovanie mekhanizmov aktivatsii
sokratitelnikh kletok mozgovikh arterii i ven. Phiziol. jurn. SSSR, 1977, 63, 11, 1567-
1572.
Azin A.L., Plekhanov I.P. O roli kaltsievogo nasosa v sokratitelnoi deiatelnosti gladkoi
muskulaturi arterii golovnogo mozga. Phiziol. jurn. SSSR, 1980, 66, 10, 1488-1492.
Azin A.L. Rol pH v mekhanizme deistviia CO2 na gladkuiu muskulaturu arterii golovnogo
mozga // Bul. eksperim. biologii i meditsini, 1981, 91, 4, 388-389.
Babbs C.F., DeWitt D.P. Physical principles of local heat therapy for cancer. Med. Instr.,
1981, 15, 6, 367-373.
Bader H. The anatomy and physiology of the vascular wall. In: Handbook of Physiology:
Circulation. Vol.2. Edited by W.F.Hamilton. American Physiological Soc., Washington,
1963, p.878.
Baez S. Microcirculation. Ann. Rev. Physiol., 1977, 39, 2, 391-415.
Baldy-Moulinier M. Cerebral electrical activity and cerebral blood flow during brain
activation. In: Brain Work, (Eds. D.Ingvar, N.Lassen). Copenhagen, Munksgaard, 1975,
pp.353-361.
Baldy-Moulinier M., Ingvar D.H. EEG frequency content related to regional blood flow of
cerebral cortex in cat. Exp. Brain Res., 1968, 5, 55-60.
Balueva T.V., Semenyutin V.B., Teplov S.I. Bystri komponent autoregulyatsii mozgovykh
sosudov. Fiziol. Zh. SSSR, 1980, 66, 95, 1357-1362.
Baskurt O., Farley R., Meiselman H. Erythrocyte aggregation tendency and cellular
properties in horse, human and rat: a comparative study. Am. J. Physiol. 273 (Heart Circ.
Physiol. 42) 1997, H2604-H2612.
Batuev A. Visshie integrativnie sistemi mozga. Leningrad, Nauka, 1981, 225.
Baranski S., Czerski P. Biological effects of microwaves. Strousburg, Dowden Hutchinson
Ross, 1976, pp.232-233.
Baumbach G.L., Heistad D. Effects of sympathetic stimulation and changes in arterial
pressure on segmental resistance of cerebral vessels in rabbits and cats. Circulat. Res.,
1983, 52, 527-533.
Baust W. Local blood flow in different regions of the brainstem during natural sleep and
arousal. Electroencephalogr. Clin. Neurophysiol., 1967, 22, 365-372.
Bayliss V. On the local reactions of arterial wall to changes of internal pressure. J. Physiol.,
1902, 28, 220-237.
Bearini David J., Kassel Meal F., Sprowell Yames A., Olin Yulic. Intravertobral artery
adenosine failu tu artery after cerebral blood flow in the dog. Stroke, 1984, 15, 6, 1057-
1060.
Beck D., Vinters H., Pasquale A. Uptake of adenosine into cultured cerebral ondothelium.
Brain Res., 1983, 271, 1, 180-183.
Beck D., Vinters H., Moore S.,Hart M., Henn F., Pasquale A. Demonstration of adenosine
receptors on mouse cerebral smooth muscle membranes. Stroke, 1984, 15, 4, 725-727.
Begiashvili V.T. Nekotorie zakonomernosti razvitiya autoregulyatornykh sosudistykh
reaktsii. Avtoref. kand. diss. Tbilisi, 1981.
Begiashvili V.T., Meladze V.G., Mitagvaria N.P. Matematicheskoe opisanie vozmozhnogo

printsipa regulyatsii tonusa mozgovykh sosudov pri izmeneniyakh vnutrisosudistogo
davleniya. Izv. AN GSSR, Seriya biol., 1979, 5, 3, 266-276.
Begiashvili V.T., Meladze V.G., Mitagvaria N.P. Analogovaya model miogennoi
autoregulyatsii sosudistogo tonusa v golovnom mozgu. Izv. AN GSSR, Seriya biol., 1979,
5, 4, 375-384.
Begiashvili V.T., Meladze V.G., Mitagvaria N.P. Matematicheskaya model miogenno
aktivnogo krovenosnogo sosuda. Mekhanika kompozitnykh materialov, 1980, 2, 331-338.
Benua I.N., Lesnyak G.P. Regulyatsiya regionarnogo krovosnabzheniya golovnogo mozga v
usloviyakh adekvatnoi retseptornoi stimulyatsii. Fiziol. zh. SSSR, 1967a, 53, 930-936.
Benua I.N., Lesnyak G.P. Ob osobennostyakh regulyatsii mozgovogo krovoobrashcheniya
zritelnoi kory koshki v usloviyakh postepennogo uvelicheniya intensivnosti svetovogo
razdrazheniya glaza. Fiziol. zh. SSSR, 1967b, 53, 1034-1040.
Benua I.N., Lesnyak G.P. Osobennosti regulyatsii mozgovogo krovoobrashcheniya u kotyat.
Byull. eksper. biol. i med., 1968, 56, 18-21.
Berezovski V.A. Napryazhenie kisloroda v tkanyakh zhivotnikh i cheloveka. Naukova dumka,
Kiev, 1975.
Berezovski V.A. Kislorodni gomeostaz v norme i patologii. V kn.: Kislorodni gomeostazis i
kislorodnaya nedostatochnost. Naukova dumka, Kiev, 1978, 5-18.
Bergel D.H. The static elastic properties of the arterial wall. J.Physiol., 1961, 156, 445-457.
Berger H. Zur Lehre von der Blutzirkulation in der Schadelhohle des Menschen namentlich
unter dem Einflub von Medikamenten. Jena, Gustav Fischer, 1901.
Berger H. Untersuchungen uber die Temperatur des Gehirns. Jena, Gustav Fischer, 1910.
Berger H. Das Electroencephalogram des Menschen. Nova Acta Leopoldina, 1938, 6, 173-
309.
Berne R. The role of adenosine in the regulation of coronary blood flow. Circulat. Pes.,
1980, 47, 6, 807-813.
Berne R., Rubio R., Curnish H. Release of adenosine from ischemic brain effect on the
cerebral vascular resistance and incorporation into cerebral adenine nucleotides. Circulat.
Res.,1974, 35, 2, 262-271.
Berne R.M., Winn H.R., Rubio R. The local regulation of cerebral blood flow. Prog.
Cardiovasc. Dis., 1981, 24, 3, 243-260.
Betz E. Adaptation of regional cerebral blood flow in animals exposed to chronic alterations
of the pO2 and pCO2. In: Regional cerebral blood flow. Copenhagen, 1965, 121.
Betz E. Cerebral blood flow: its measurement and regulation. Physiol. Rev., 1972, 52, 595-
630.
Betz E. (Ed.). Vascular Smooth Muscle. Berlin, Springer Verlag, 1972.
Betz E. CBF during emotional stimuli. In: Brain Work (Eds. D.Ingvar, N.Lassen).
Copenhagen, Munksgaard, 1975, pp.366-370.
Betz E. Ionic interaction in Pial Vascular Smooth Muscles. Jon. Act. Vasc. Smooth Mus.
Spec. Regard. Brain Vessels. Berlin e.a., 1976, 75, 77. Discuss., 90-91.
Bets E. Ionic and metabolic control of local cerebral blood flow. Acta Clin. Belg., 1977, 32,
119-128.
References 171
Betz E., Enzenross H.G. Vlahov V. Interactions of the ionic mechanisms in the regulation of
the resistance of pial vessels. Cerebral Circ. and Metabolism.Berlin e.a., 1975, 49-51.
Betz E., Hensel H. Fortlaufende registrierung der lokalen durchblutung der inneren des
gehirns bei wachen, frei beweglichen tieren. Arch. Ges. Physiol., 1962, 274, 608-614.
Betz E., Kozak R. Der Rinflus der wasserst of ionen-concetration der Gehirurinde auf die
Regulation der corticaten Durchblutung. Pflugers Arch. Sen> 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, 275-
282.
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.
Bicher H.I., Vaupel P., O'Hara M., O'Brien T., Mitagvaria N.P. Tissue oxygenation and
normal and hyperthermic conditions. Adv. Physiol. Sci., Vol.25, Oxygen transport to
tissue. Budapest, Pergamon Press, Akademia Kiado, 1981, pp.215-224.
Bicher, H.I., Wolfstein, R.S., Lewinsky B.S., Frey H.S., Fingerhut A.G. Microwave
hyperthermia an adjunct to radiation therapy: Summary experience of 256 multifraction
treatment cases. Int J Rad Onc Biol Phys 1986; 12:1667-1671.
Bill A., Linder J. Sympathetic control of cerebral blood flow in acute arterial hypertension.
Acta physiol. Scand., 1976, 96, 114-121.
Bizzi E. Discharge patterns of single geniculate neurons during the rapid eye movements of
sleep. J. Neurophysiol., 1966, 29, 1087-1095.
Boisvert D., Jones J., Harper A.M. Cerebral blood flow autoregulation to acutely increasing
blood pressure during sympathetic stimulation. In: Cerebral Function, Metabolism and
Circulation (Eds. D.Ingvar, N.Lassen). Copenhagen, Munksgaard, 1977, pp.46-47.
Borodulya A.V., Plechkova E.K. Gistokhimicheskoe issledovanie sosudodvigatelnoi
innervatsii basseina vnutrennei sonnoi arterii. Fiziol. zh. SSSR, 1975, 61, 10, 1173-1177.
Boysen C., Ladengaard-Pedersen J.J., Henriksen H., Olesen J., Paulson O.B., Engell H.C.
The effect of PaCO2 on regional cerebral blood flow and internal carotid arterial pressure
during carotid clamping. Anesthesiology, 1971, 35, 286-300.
Brandt H., Enzenross H.G. Spontaneous actions of small pial vessels and the response to
transmural electrical stimulation. In: Ionic Action on Vascular Smooth Muscle with
Special Regard to Brain Vessels. Berlin e.a., Springer Verlag, 1976, pp.71-74.
Bremer F. Cerveau "isole" et physiologie de sommeil. C.R.Sci. Biol. (Paris), 1935, 118, 1235-
1241.
Britt R.H., Lyons B.E., Pounds D.W., Prionas S.D. Feasibility of ultrasound hyperthermia in
the treatment of malignant brain tumors. Med. Instrum., 1983, 17, 172-177.
Britton S.L., Lutherer L.O., Davies D.G. Effect of cerebral extracellular fluid acidity on total
and regional cerebral blood flow. J. Appl. Physiol., 1979, 47, 4, 818-826.
Bleyers RL, Cowen T. Innervation of cerebral blood vessels: morphology, plasticity, age-
related, and Alzheimer's disease-related neurodegeneration. Microscop Res Tech., 2001,
53, 2, 106-108.
Braun AR, TJ Balkin, NJ Wesenten, RE Carson, M Varga, P Baldwin, S Selbie, G Belenky,
and P Herscovitch. Regional cerebral blood flow throughout the sleep-wake cycle. An
H2(15)O PET study. Brain, 1997, 120, 1173 - 1197.
Brock M., Ingvar D.H., Sem-Jacobsen C.W. Regional blood flow in deep structures of the
brain measured in acute cat experiments by means of a new beta-sensitive semiconductor
needle detector. Exptl. Brain Res., 1967, 4, 126-137.
Brodersen P., Paulson O.B., Bolwing T.C., Rogon Z.E., Rafaelson O.J., Lassen N.A. Cerebral
hyperemia in electrically induced epileptic seizures. Arch. Neurol., 1973, 28, 334-338.
Brookes Zoë L. S. and Susan Kaufman. Myogenic responses and compliance of mesenteric
and splenic vasculature in the rat. Am J Physiol Regulatory Integrative Comp Physiol,
2003, 284, 1604.
Brooks H., Carroll J.H. A clinical study of the effects of sleep and rest on blood pressure.
Arch. Intern. Med., 1912, 10, 97-102.
References 173
Bruley D.F., Bicher H.I., Reneau D.D., Knisely M.H. Auto-regulatory phenomena related to
cerebral tissue oxigenation. Bio-med. Eng., Chemical Eng. Symposium Series, 1971, 67,
195-201.
Bulbring E., Kuriyama H. Effect of adrenaline on the smooth muscle of guinea-pig taenia coli
in relation to the degree of stretch. J.Physiol., 1963, 169, 198-212.
Bures J., Petran M., Zacher I. Electrophysiological Methods in Biological Research. Prague,
1967, 697.
Burgi S. Zur Physiologie und Pharmakologie der uberlebenden arterie. Helv. Physiol.
Pharmacol. Acta, 1944, 2, 345-356.
Burnstock G., Prosser C.L. Responses of smooth muscle to quick stretch: relation of stretch
to conduction. Amer. J. Physiol., 1960, 198, 921-925.
Burton A.C. On the physical equilibrium of small blood vessels. Amer. J. Physiol., 1951, 164,
219-229.
Busija D., Heistad D. Effects of cholinergic nerves on cerebral blood flow in cats. Circul.
Res., 1981, 48, 62-69.
Busija D.W., Heistad D.D. Atropine does not attenuate cerebral vasodilation during
hypercapnia. Amer. J. Physiol., 1982, 242, 4, H683-H687.
Busija D., Marcus M., Heistad D. Pial artery diameter and blood flow velocity during
sympathetic stimulation in cats. J.Cereb. Blood Flow Metabol., 1982, 2, 3, 363-367.
Busija D., Marcus M., Heistad D. Effects of sympathetic nerves on the cerebral circulation in
cats. In: Cerebral Blood Flow: Effects of Nerves and Neurotransmitters (Eds. D.Heistad,
M.Marcus). Amsterdam e.a., Elsevier North Holland Inc., 1982, pp.301-308.
Bychkov M.S. O mekhanizmakh deistviya sverkh vysokochastotnogo elektromagnitnogo
polya. V kn.: Voprosy biologicheskogo deistviya sverkhvysokochastotnogo (SVCh)
elektromagnitnogo polya. Izd. In-ta gigieny truda i prof. zabolevanii. Leningrad, 1962, 6-
8.
Cameron I.r., Caronna J. The effect of local changes in potassium and bicarbonate
concentration on hypothalamic blood flow in the rabbit. J.Physiol., 1976, 262, 415-430.
Carlsson A., Falek B., Hillarp N.A. Cellular localization of brain monoamines. Acta physiol.
Scand., 1962, 56, Suppl., 196, 1-28.
Carlyle A., Grayson G. Blood pressure and the regulation of brain blood flow. J. Physiol.,
1955, 162, 415-430.
Carpi A., Cartoni C., Giardini V. Segmental effects of histamine, acetilcholine and
bradykinine on cerebral vessels. Arch. Intern. Pharmacodyn., 1972, 196, 111-112.
Carrier O., Walker A.C., Guyton A.C. Role of oxygen in autoregulation of blood flow in
isolated vessels. Amer. J. Physiol., 1964, 206, 951-954.
Carter D.B., Silver I.A., Wilson G.M. Apparatus and technique for the quantitative
measurement of oxygen tension in living tissues. Proc. Roy. Soc. Lond. (Series B),
1959/1960, 151, 256-276.
Cavaliere R., Ciocatto E.C., Giovanella B.C. Selective heat sensitivity of career cells:
biochemical clinical studies. Cancer, 1967, 20, 1351-1381.
Cavazzuti M., Duffy T.E. Regulation of local cerebral blood flow in normal and hypoxic
newborn dogs. Ann. Neurol., 1982, 11, 3, 247-257.
Chang A.E., Detar R. Oxygen and vascular smooth muscle contraction revisited. Amer. J.
Physiol., 1980, 238, H716-H728.
Chassagnon S, Armspach JP, Namer IJ, Kehrli P, Hirsch E, Nehlig A. Epileptogenic and non-
epileptogenic zones: blood flow studies of temporo-limbic seizures. Rev Neurol. 2007,
163, 12, 1178-1190.
Chen R.Y., Carlin R.D., Simchon S., Jam K.M., Chien S. Effect of dextran-induced
hyperviscosity on regional blood flow and hemodynamics in dogs. Am. J.Physiol. Heart.
Circ. Physiol., 1989, 256, H898-H905.
Chen S., Gavish B., Zhang S., Mahler I., Yedgar S. Monitoring of erythrocyte aggregate
morphology under flow by computerized image analysis. Biorheology, 1995, 32, 487-
496.
Chernukh A.M., Aleksandrov P.N. Metody izucheniya mikrotsirkulyatsii. V kn.: Metody
issledovaniya krovoobrashcheniya. Nauka, Leningrad, 1976, 146-162.
Chertok V.M., Pigolkin Yu.I., Motavkin P.A. Kholinergicheskaya i adrenergicheskaya
innervatsiya vnutrimozgovykh arterii cheloveka v ontogeneze. Arkhiv anatomii,
gistologii i embriologii, 1983, 84, 2, 22-29.
Chorobski I., Penfield W. Cerebral vasomotor nerves and their pathway from the medulla
oblongata. Arch. Neurol. and Psychiatry, 1932, 28, 1257-1289.
Claassen Jurgen A. H. R. and René W. M. M. Jansen. Cholinergically Mediated
Augmentation of Cerebral Perfusion in Alzheimer's Disease and Related Cognitive
Disorders: The Cholinergic–Vascular Hypothesis. J. Gerontol. A Biol. Sci. Med. Sci.,
2006, 61, 267 - 271.
Clark L.C., Bargeron L.M. Detection and direct recording of right to left shunts with a
hydrogen catheter. Surgery, 1959, 46, 797-804.
Cloutier G., Shung K.K. Study of red cell aggregation in pulsative flow from ultrasonic
Doppler power measurements, Biorheology, 1993, 30, 443-461.
Cohen P.H. The effects of decreased oxygen tension on cerebral circulation, metabolism, and
function. In: Proc. Intern. Symp. Cerdiovascular and Respiratory Effects of hypoxia, 3-5
June 1965, Queens University Kingston (Ont.), Canada. New York, Karger, 1965, pp.81-
104.
Cohen P.H., Alexander S.C. Effects of hypoxia and normocarbia on cerebral blood flow and
metabolism in conscious man. J. Appl. Physiol., 1967, 23, 183-189.
Courtice F.C. The effect of oxygen lack on the cerebral circulation. J. Physiol., 1941, 100,
198-211.
Creutzfeldt O.D. Neurophysiological correlates of different functional states of the brain. In:
Brain Work (Eds. D.Ingvar, N.Lassen). Copenhagen, Munksgaard, 1975, 21-47.
Crockard H.A., Lindsay S., Branston N.M., Juhasz J., Wahid A. Measurements of oxygen
tension in the cerebral cortex of baboons. J. Neurol. Sci., 1976, 27, 1, 17-28.
Csornai M. The effect of serotonin and noradrenaline on the pial arteries. In: Ionic actions on
vascular smooth muscle (Ed. E.Betz). Berlin e.a., Springer Verlag, 1976, pp.83-86.
Czosnyka M, Smielewski P, Piechnik S, Steiner LA, Pickard JD. Cerebral autoregulation
following head injury. J Neurosurg 2001, 95, 756–763.
References 175
Dahlgren N., Ingvar D., Siesjo B.K. Effect of propranolol on local cerebral blood flow under
normocapnic and hypercapnic conditions. J. Cereb. Blood Flow Metab., 1981, 1, 4, 429-
436.
D'Alecy L.G. Sympathetic cerebral vasoconstriction blocked by adrenergic alpha receptor
antagonists. Stroke, 1973, 4, 30-37.
D'Alecy L.G., Feigl E.O. Sympathetic control of cerebral blood flow in dogs. Circul. Res.,
1972, 31, 267-283.
D'Alecy L., Rose C. Parasympathetic cholinergic control of cerebral blood flow in dogs.
Circul. Res., 1977, 41, 324-331.
Davenport V.B., Rut V.L. Vvedenie v teoriyu sluchainykh signalov i shumov. IL, Moskva,
1960.
Davies P.W. The oxygen cathode. In: Physical techniques in biological research. New York,
Raven Press, 1962, pp.137-179.
Davies P.W., Brink F. Microelectrodes for measuring local oxygen tension in animal tissue.
Rev. Sci. Instr., 1942, 13, 12, 524-533.
Davies P.W., Bronk D.W. Oxygen tension in mammalian brain. Fed. Proc., 1957, 16, 3, 689-
692.
Davignon J., Lorenz R.R., Shepherd S.T. Responses of human umbilical artery to changes in
transmural pressure. Amer. J. Physiol., 1965, 209, 51-59.
Dernbach PD, Little JR, Jones SC, Ebrahim ZY. Altered cerebral autoregulation and CO2
reactivity after aneurysmal subarachnoid hemorrhage. Neurosurgery 1988, 22,822–826.
Devadariani M., Meladze V., Mitagvaria N., Beradze G., Bekaia G. Effect of electrical
stimulation of cerebellar fastigial nuclei on local cerebral blood flow. Fisiol. J. SSSR,
1989, 75, 11, 1602-1607.
Dietzel F., Basic principles in hyperthermic tumor therapy. Recent Results Cancer Res., 1983,
86, 177-190.
Doba M., Reis D. Changes in regional blood flow and cardiodynamics evoced by electrical
stimulation of the fastigial nucleus in cat: similarity to orthostatic reflexes. J. Physiol.,
1972, 227, 729-748.
Dorochov J.H. Role of hydrogen peroxide and hydroxyl radicals formation in the killingof
Ehrlich tumor cells by anticancer quinines. Proc. Natl. Acad. Sci. USA, 1986, 83, 4514-
4518.
Dougherty H., Scott R.B., Jerry B., Dabney J., Haddy F.G. Local effect of O2 and CO2 on
limb, renal and coronary vascular resistance. Amer. J. Physiol., 1967, 213, 1102-1110.
Delgado J.M., Taigi H. Intracerebral temperatures in free-moving cats. Amer. J. Physiol.,
1967, 211, 755-769.
Demchenko I.T. Metody izucheniya mozgovogo krovoobrashcheniya. V kn.: Metody
issledovaniya krovoobrashcheniya. Nauka, Leningrad, 1976, 104-124.
Demchenko I.T. Krovosnabzhenie bodrstvuyushchego mozga. Nauka, Leningrad, 1983, 172.
Demchenko I.T., Chuikin A.E. Issledovanie mezhkapillyarnogo rasspredeleniya PO2 v
golovnom mozgu s pomoshchyu elektrodov. Fiziol. zh. SSSR, 1975, 61, 9, 1310-1316.
Demchenko I., Krivchenko A. O nervnom mechanizme regulirovaniya mozgovogo krovotoka
pri izmeneniyakh gazovogo sostava krovi. Regulyatsiya mozgovogo krovoobrashcheniya.
Tbilisi: Metsniereba, 1980, 65-69.
Denn H., Stone H. Autonomic innervation of dog coronary arteries. J. Appl. Physiol., 1976,
41, 1, 130-136.
Detar R. Mechanism of physiological-induced depression of vascular smooth muscle
contraction. Amer. J. Physiol., 1980, 238, H761-H769.
Detar R., Bohr D.F. Adaptation to hypoxia in vascular smooth muscle. Federation Proc.,
1968, 27, 1416-1419.
Diógenes Maria José, Catarina Cunha Fernandes, Ana Maria Sebastião, and Joaquim
Alexandre Ribeiro Activation of Adenosine A2A Receptor Facilitates Brain-Derived
Neurotrophic Factor Modulation of Synaptic Transmission in Hippocampal Slices. J.
Neurosci., 2004, 24, 2905 - 2913.
Dobrin P.B., Canfield T.R. Series elastic and contractile elements in vascular smooth muscle.
Circul. Res., 1973, 33, 454-464.
Donath T. Monoaminergic innervation of extra- and intracerebral vessels. Acta morph. Acad.
sci. Hung., 1968, 16, 3, 285-293.
Doppenberg EM, Zauner A, Bullock R, et al. Correlations between brain tissue oxygen
tension, carbon dioxide tension, pH, and cerebral blood flow—a better way of
monitoring the severely injured brain? Surg Neurol 1998, 49, 650–654
Dora E., Zeuthen T., Silver I.A., Change B., Kovach A.G.B. Effect of arterial hypoxia on the
cerebrocortical redox state, vascular volume, oxygen tension, electrical activity and
potassium ion concentration. Acta physiol. Acad. Sci. Hung., 1980, 54, 4, 319-331.
Doust L.J.W., Schneider R.A. Studies on the physiology of awareness: anoxia and the levels
of sleep. Brit. Med. J., 1952, 1, 449-455.
Duckles S.P. Acetylcholine and vasoactive intestinal polypeptide: cerebrovascular
neurotransmitters. In: Cerebral Blood Flow: Effects of Nerves and Neurotransmitters
(Eds. D.Heistad, M.Marcus). Amsterdam e.a., Elsevier North Holland Inc., 1982, pp.441-
446.
Duffy T.E., Nelson S.R., Lowry O.H. Cerebral carbohydrate metabolism during acute
hypoxia and recovery. J. Neurochem., 1972, 19, 959-977.
Dutta P., Jones A., Mustafa S. Uptake an afflux of calcium by canive coronary arteries and
the action of adenosine. Basic. Res. Cardiol., 1984, 79,5,519-330.
Eddy H.A., Salazar O.M., Amin P.P., Better W.E., Ro J. Acute histopathological changes in
brain following interstitial hyperthermia and irradiation. Endocurietherapy/Hyperthermia
Oncol., 1992, 8, 27-40.
Edvinsson L. Neurogenic mechanisms in the cerebrovascular bed. Acta physiol. Scand., 1975,
Suppl. 427, 1-35.
Edvinsson L., Jensen J. Adenosine: Receptors and Modul. Cell Funct. Proc. Int. Workshop
Adenosine and Xantine. Deriv Wiesbaden. Nov.19-20, 1984. Oxford, Washington, 1986,
409, 414. Discuss., 415-417.
Edvinsson L., MacKenzie E.T. Amine mechanisms in the cerebral circulation. Pharmacol.
Rev., 1977, 28, 275-348.
Edvinsson L., Nielsen K.C., Owman C. Cholinergic innervation of choroid plexus in rabbit
and cats. Brain Res., 1973, 63, 500-503.
Edvinsson L., Nielsen K.C., Owman C., Sporron C.E. Cholinergic mechanisms in pial
vessels. Z. Zellfosch., 1972, 134,311-325.
References 177
Ekstrom-Jodal B., Haggendal E., Nilsson N.J. On the relation between blood pressure and
blood flow in the cerebral cortex of dogs. Acta physiol. Scand., 1970, Suppl. 350, 29-42.
El-Sabban F., Fahim M.A. Local cerebral hyperthermia induces spontaneous thrombosis and
arteriolar constriction in the pia matter of the mouse. Int. J. Biometeorol, 1995 38, 2, 92-
97.
Emami B., Song C.W. Physiological mechanisms in hyperthermia: a review. Int. J. Radiat.
Oncol. Biol. Phys., 1984, 10, 2, 289-295.
Engelborghs K., Haseldonckx M., Van Reemps J., Van Rossem K., Wouters L., Borgers M.,
Verlooy J. Impaired autoregulation of cerebral blood flow in an experimental model of
traumatic brain injury. Journal of Neurotrauma, 2000, 17, 8, 667-677.
Engin K. Biological rationale for hyperthermia in cancer treatment. Neoplasma, 1994, 41, 5,
277-283.
Evans H.L., Patton R.A. Scopolamine effects on conditioned suppression. Influence of
diurnal cycle and transitions between normal and drugged states. Psychopharmacologia,
1970, 17, 1-13.
Evarts E.V. Temporal patterns of discharge of pyramidal tract neurons during sleep and
waking in the monkey. J. Neurophysiol., 1964, 27, 152-171.
Fahim M.A., El-Sabban F., Hyperthermia induces ultrastructural changes in mouse pial
microvessels. Anat. Rec., 1995, 242, 1, 77-82.
Fajardo L.F. Pathological effects of hyperthermia in normal tissues. Cancer Res., 1984, 44,
4826-4835
Falck B. Cellular localization of monoamines. In: Progress in Brain Research. Biogenic
Amines. Amsterdam e.a., Elsevier Scientific Publishing Company, 1964, p.28.
Faraci, FM, and Brian JEJ Nitric oxide and the cerebral circulation. Stroke 1994, 25, 692-
703.
Faucon G., Duchene-Marrilaz P., Lovarrene J., Collard M. La musculature vasculaine
repond'elle differemment slon son tonus? J. Physiol., 1965, 57, 609-620.
Fazio C. Autoregulation of the cerebral circulation. Triangle, 1970 9, 7, 244-249.
Feldbaum M.A. Teoriya avtomaticheskogo regulirovaniya i svyazi. Fizmatgiz, 1963.
Field S.B., Bleehen N.M. Hyperthermia in the treatment of cancer. Cancer Treat. Rev., 1979,
6, 63-94.
Fieschi C., Bozzao L., Agnoli A. Regional clearance of hydrogen as a measure of cerebral
blood flow. Acta neurol. Scand., 1965, 41, Suppl. 14, 46-52.
Fieschi C., Bozzao L., Agnoli A. The hydrogen gas to measure local blood flow in
subcortical structures of the brain with a comparative study with the 14C-antipyrine
method. Exp. Brain Res., 1969, 7, 111-119.
Fike J.R., Gobbel G.T., Satoh T., Stauffer P.R. Normal brain response after interstitial
microwave hyperthermia. J. Int. J. Hyperthermia, 1991, 7, 5, 795-808.
Findley A.L.R., Hayward J.N. Spontaneous activity of single neurons in the hypothalamus of
rabbits during sleep and waking. J. Physiol., 1969, 201, 237-258.
Finesinger I., Putnam C. Cerebral circulation induced variations in volume flow through the
brain perfused at constant pressure. Arch. Neurol. and Psychiatry, 1933, 30, 775-794.
Fitch W., McKenzie E.T., Harper A.M. Effects of decreasing arterial blood pressure on
cerebral blood flow in the baboon. Circul. Res., 1975, 37, 550-557.
Flanagan S.W., Moseley P.L., Buettner G.R. Increased flux of free radicals in cells subjected
to hyperthermia: detection by electron paramagnetic resonance spin trapping. FEBS Lett.,
1998, 17, 431, 2, 285-286.
Fog M. Om piaarteriernes vasomotoriske reaktioner. Kopenhagen, Munksgaard, 1934.
Fog M. Cerebral circulation. Reaction of the pial arteries to a fall in blood pressure. Arch.
Neurol. and Psychiatry, 1937, 37, 2, 351-364.
Fog M. Relationship between blood pressure and tonic regulation of pial arteries. J. Neurol.
Psychiatr., 1938, 1, 187-197.
Fog M. Cerebral circulation. II. Reaction of pial arteries to increase in blood pressure. Arch.
Neurol. Psychiatr., 1939, 41, 260-268.
Folkow B. Description of myogenic hypothesis. Circul. Res., 1964, 15, Suppl. 1, 279-286.
Forrester T., Harper A.M., McKenzie E., Thomson E.M. Vascular and metabolic effects of
systemic ATP on the cerebral circulation. In: Blood flow and metabolism in the brain
(Eds. A.M.Harper et al.). Edinburgh, Churchill Livingstone, 1975, pp.3.32-3.33.
Fox P., Raichle M. Focal physiological uncoupling of cerebral blood flow and oxidative
metabolism during somatosensory stimulation in human subjects (positron emission
tomography). Proc. Natl. Acad. Sci. USA, 1986, 83, 1140-1144.
Fradkin S.Z. Hyperthermic oncology: state of the art and future trends. Radiology in Medical
Diagnostics, Minsk, 2003, 63-71
Freeman J. Elimination of brain cortical blood flow autoregulation following hypoxia. Scand.
J. Lab. and Clin. Invest., 1968, Suppl. 102, V:E.
Freeman J., Ingvar D.H. Elimination by hypoxia of cerebral blood flow autoregulation and
EEG relationship. Exp. Brain Res., 1968, 5, 61-71.
Freyburger G., Dubreuil M., Boisseau M.R., Janvier G. Rheological properties of commonly
used plasma substitutes during preoperative normovolaemic acute haemodilution. Br. J.
Anaesth., 1996, 76, 519-525.
Friberg L., Olsen T., Kolend P. Focal increase of blood flow in the cerebral cortex of man
during vestibular stimulation. Brain, 1985, 108, 3, 609-623.
Fujishima M. The metabolic mechanism of cerebral blood flow autoregulation in dogs. Jap.
Heart J., 1971, 12, 4, 376-382.
Funaki S. Spontaneous spike discharges of vascular smooth muscle. Nature, 1961, 203, 192-
194.
Funaki S., Bohr D.F. Electrical and mechanical activity of isolated vascular smooth muscle of
the rat. Nature, 1964, 191, 1102-1103.
Fung Y.C. Elasticity of soft tissues in simple elongation. Amer. J. Physiol., 1967, 213, 1532-
1544.
Gaevii M. Pharmakologia mosgovogo krovoobrashchenia. M., Meditsina, 1980, 190.
Gannushkina I.V., Shafranova V.I., Ryasina T.V. Funktsionalnaya angioarkhitektonika
golovnogo mozga. Meditsina, Moskva, 1977.
Garcia-Austt F., Velutti R., Villar J.I. Changes of brain PO2 during paradoxical sleep in cats.
Physiol. a. Behav., 1968, 3, 3, 477-485.
Gerweck L.E. Modification of cell lethality at elevated temperature. The pH effect. Radiat.
Res., 1975, 10, 65-75.
References 179
Gibbs F.A. A thermoelectric blood flow recorder in the form of a needle. Proc. Soc. Exptl.
Biol. Med., 1933, 31, 141-146.
Gibbs F.A., Gibbs E.L., Lennox W.G. The cerebral blood flow during sleep in man. Brain,
1935, 58, 44-48.
Gibbs F.A., Gibbs E.L., Lennox W.G. Changes in human cerebral blood flow consequent on
alterations in blood gases. Amer. J. Physiol., 1935, 111, 557-563.
Gillian L.A. Potential collateral circulation to the human cerebral cortex. Neurology, 1974,
24, 941-948.
Ginzburg D.A., Sadchikova M.N. Izmeneniya elektroentsefalogrammi pri khronicheskom
vozdeistvii radiovoln. V kn.: O biologicheskom deistvii elektromagnitnikh polei
radiochastot. Izd. In-ta gigieny truda i prof. zabolevanii, Moskva, 1964, 126.
Giovanella B.C., Morgan A.C., Stehlin J.S. Selective lethal effect of supranormal
temperatures on mouse sarcoma cells. Cancer Res., 1973, 33, 2568-2578.
Gokina H., Gurkovskaia A. Vliianie ATF i adenozina na spontannuiu elektricheskuiu i
sokratitelnuiu aktivnost gladkomishechnikh kletok vorotnoi veni. Bull. ekcperim. biologii
i meditsini, 1981, 92, 9, 261-264.
Gokina N., Gurkovskaia A., Shuba M. Deistvie adenozina i ATF na elektrogenez i
sokrashchenie v gladkikh mishtsakh mozgovikh arterii. Phiziol. jurn. SSSR, 1983, 69, 6,
803-810.
Goldin E.M., Leeper D.B. The effect of law pH thermotolerance induction using fractionated
45 degrees C hyperthermia. Radiat. Res., 1981, 85, 472-478.
Gordon Z.V. Voprosy gigieny truda i biologicheskogo deistviya elektromagnitnykh polei
sverkhvysokikh chastot. Meditsina, Moskva, 1966, 162.
Gotoh F., Meyer J.S., Tomita M. Hydrogen method for determining cerebral blood flow in
man. Arch. Neurol., 1966, 15, 549-559.
Gotoh F., Tazaki Y., Meyer J.S. Transport of gases through brain and their extravascular
vasomotor action. Exp. Neurol., 1961, 4, 48-58.
Grande P.-O., Lundvall J., Mellander S. Evidence for a rate-sensitive regulatory mechanism
in myogenic microvascular control. Acta physiol. Scand., 1977, 99, 432-447.
Grande P.-O., Mellander S. Characteristics of static and dynamic regulatory mechanisms in
myogenic microvascular control. Acta physiol. Scand., 1978, 102, 231-245.
Grande P.-O., Mellander S. Beta-adrenergic inhibitory interference with myogenic vascular
reactivity during experimental intervention. Acta physiol. Scand., 1979, 106, 87-89.
Grechin V.B. K kharakteristike spontannykh i "vyzvannykh" kolebanii kisloroda v mozgu
cheloveka. V kn.: Polyarograficheskoe opredelenie kisloroda v biologicheskikh
obyektakh. Naukova dumka, Kiev, 1974, 153-166.
Grechin V.B., Kropotov Yu.D. Medlennie neelektricheskie ritmy golovnogo mozga
cheloveka. Nauka, Leningrad, 1979, 127.
Gregory P., Boisvert D., Harper M. Adenosine and pial arteriolar diameter - influence of
alterations in arteriel pCO2 and blood pressure. Acta neural scand., 1979, 60, 72, 582-
583.
Gregory P., Boisvert D., Harper M. Adenosine response on pial arteries influense of CO2 and
blood pressure. Phlugers Arch., 1980, 386, 2, 187-192.
Greisen G. Autoregulation of Cerebral Blood Flow. NeoReviews, 2007, 8, 1, e22.
Grodinz F. Teoriya regulirovaniya i biologicheskie sistemy. Nauka, Moskva, 1966.

Gross M., Meluin L., Marcus D., Heistad D. Regional distribution of cerebral blood flow
during exercise in dogs. J. Appl. Physiol., 1980, 48, 2, 213-217.
Grote G. Sauerstoffversorgung des Hundchirns, II. Mitteilung: Die Sauerstoffdruckverteilung
in der Gorobhirnrinde. Zool. Anz., 1967, 179, 330-340.
Grote J., Kreuscher H., Vaupel P., Gunther H. The effect of arterial hypoxia on cerebral
oxygen supply and cerebral metabolism during acidosis. In: Oxygen Supply. Theoretical
and practical aspects of oxygen supply and microcirculation of tissue (Eds. M.Kessler,
D.F.Bruley, L.C.Clark, D.W.Lubbers, I.A.Silver, J.Strauss). Munchen-Berlin-Wien,
Urban und Schwarzenberg, 1973, p.290.
Grote, D.Reneau, G.Thews, BerlMangold R., Sokoloff L., Conner E., Kleinerman J.,
Therman P.G., Kety S.S. The effect of sleep and lack of sleep on the cerebral circulation
and metabolism of normal young man. J. Clin. Invest., 1955, 34, 1-92-1100.
Grote J., Zimmer K., Schubert R. Effects of severe arterial hypocapnia on regional blood
flow regulation, tissue PO2 and metabolism in the brain cortex of cats. Pflugers Arch.,
1981, 391, 3, 195-199.
Grunewald W. Theoretical analysis of the oxygen supply in tissue. In: Oxygen transport in
blood and tissue (Eds. D.W.Lubbers, U.C.Luft, G.Thews, E.Witzle). Stuttgard, Thieme,
1969, pp.100-114.
Gupta AK, Hutchinson PJ, Fryer T, et al. Measurement of brain tissue oxygenation
performed using positron emission tomography scanning to validate a novel monitoring
method. J Neurosurg 2002, 96, 263–268
Gurevich M.I., Bernshtein S.A. O sootnosheniyakh izmenenii napryazheniya kisloroda i
regionarnogo krovotoka v tkanyakh pri ostroi gipoksii. Byull. eksp. biol. i med., 1967, 63,
3, 31-35.
Gurevich M.I., Bernshtein S.A. Mekhanizmy regionarnykh sosudistykh reaktsii pri
izmeneniyakh kislorodnogo balansa organizma. V kn.: Regionarnoe i sistemnoe
krovoobrashchenie. Nauka, Leningrad, 1978, 39-49.
Guy A.W., Chou C.K. Physical aspects of localized heating by radiowave and microwaves.
In: F.K. Storm (ed.), Hyperthermia in cancer therapy, 279-304, Boston: G.K. Hall
Medical Publishers, 1992.
Guyton A.C. Textbook of medical physiology. Phyladelphia, Saunders Company, 1976.
Haddy F.J., Scott J.E. Role of transmural pressure in local regulation of blood flow through
kidney. Amer. J. Physiol., 1965, 208, 825-831.
Hadengue A., Del-Pino M., Simon A., Levenson J. Erythrocyte disaggregation shear stress,
sialic acid and cell aging in humans. Hypertension, 1998, 32, 324-330.
Hall D.M., Baumgardner K.R., Oberley T.D., Gisolfi C.V. Splanchnic tissues undergo
hypoxic stress during whole body hyperthermia. Am. J. Physiol, 1999, 276, 5 Pt.I G1195-
G1203.
Halsey J.H., Blauenstein U.W., Wilson E.M., Wills E.H. Regional cerebral blood flow
comparison of right and left hand movement. Neurology (Minneap.), 1979, 29, 1, 21-28.
Hardebo J.E., Lindvall O., Nillson B. On the possible influence of adrenergic and cholinergic
mechanisms in normo- and hypercapnia. In: Cerebral Blood Flow: Effects of Nerves and
References 181
Neurotransmitters (Eds. D.Heistad, M.Marcus). Amsterdam e.a., Elsevier North Holland

Inc., 1982, pp. 377-383.
Harder D., Medden J. Cellular mechanism of foree development in cat middle cerebral artery
by reduced pCO2. Pflugers Arch., 1985, 403, 4, 402-404.
Harper A.M. Autoregulation of cerebral blood flow: influence of the arterial blood pressure
on the blood flow through the cerebral cortex. J. Neurol. Neurosurg. Psychiat., 1966, 29,
398-403.
Harper A.M., Desmukh V.D., Rowan J.O., Jennett W.B. The influence of sympathetic
nervous activity on cerebral blood flow. Arch. Neurol., 1972, 27, 1-6.
Harris A.B., Erickson L., Kendig J.H., Mingrino S., Goldring S. Observations oselective
brain heating in dogs. J. Neurosurg., 1962, 19, 514-521.
Hartman A., Kushinsky W, eds, Cerebral Ischemia and Hemorheology. Springer, Berlin,
1987.
Hasegawa T., Ravens I.K., Toole I.P. Precapillary arteriovenous anastomoses. "throughfare
channels" in the brain. Arch. Neurol., 1976, 16, 217-224.
Haggendal E. Elimination of autoregulation during arterial and cerebral hypoxia. Scand. J.
Lab. Clin. Invest., 1968, Suppl. 102, A:E.
Haggendal E., Johansson B. Effects of arterial carbon dioxide tension and oxygen saturation
on cerebral blood flow autoregulation in dogs. Acta physiol. Scand., 1968, 66, Suppl.
258, 27-53.
Havveman J., Sminia P., Wondergem J., Van der Zee J., Hulshof M. Effects of hyperthermia
on the central nervous system: What was learn from animal studies? Int. J.
Hyperthermia, 2005, 21, 5, 473-487.
Hedquist P., Predholm B. Effects of adenosine on adrenergic mencotransmission
prejunctional inhibition and postjunctionalenhancement. Nannyn-Schmiedeberg's Arch.
Pharmacol., 1976, 93, 3, 217-223.
Heiss W.D. Cerebral blood flow: physiology, pathophysiology and pharmacological effects.
Adv. Oto-Rhino-Laringol., 1981, 27, 26-39.
Heiss W.D., Turnheim M., Vollmer R., Rappelsberger P. Coupling between neuronal activity
and local blood flow in experimental seizures. Electroencephalogr. Clin. Neurophysiol.,
1979, 47, 4, 396-403.
Heistad D., Marcus M. (Eds.). Cerebral blood flow: effects of nerves and neurotransmitters.
Amsterdam e.a., Elsevier North Holland Inc., 1982.
Heistad D., Marcus M., Gross P. Effects of sympathetic nerves on cerebral vessels in dog, cat
and monkey. Amer. J. Physiol., 1978, 235, H544-H552.
Held K., Niedermayer W., Gottstein W., Schaefer J. Reactive changes of cerebral vascular
resistance at different transmural pressure. In: Vascular Smooth Muscle (Ed. E.Betz),
Berlin e.a., Springer Verlag, 1972, pp.95-97.
Hellstrand P., Johansson B., Norberg K. Mechanical, electrical and biochemical effects of
hypoxia and substrate removal on spontaneously active vascular smooth muscle. Acta
physiol. Scand., 1977, 100, 69-83.
Hermsmeyer K. Multiple pacemaker sites in spontaneously active vascular muscle.
Circul.Res., 1973, 33, 244-251.
Hernandez-Perez M.J., Raichle M.E., Stone H.L. The role of the peripheral sympathetic
nervous system in cerebral blood flow autoregulation. Stroke, 1975, 6, 284-292.
Hernandez-Perez M., Stone H. Sympathetic innervation of the Circle of Willis in the
macaque monkey. Brain Res., 1974, 80, 3, 507-512.
Herrschaft H., Schmidt B. Das verhalten der globalen und regionalen hirndurchblutung unter
dem Einfluss von Propanid, Ketamine und Thipental-natrium. Anaesthes., 1973, 22, 486-
495.
Hillbom M. Oxidants, antioxidants, alcohol and stroke. Frontiers in Bioscience, 1999, 4, 67-
71.
Hill L. The physiology and pathology of the cerebral circulation. London, J. & A. Churchill,
1896.
Hirsch H., Korner K. Uber die Druck-Durchblutungs-Relation der Gehirngefasse. Pflugers
Arch., 1964, 280, 316-325.
Hlatky R, Furuya Y, Valadka AB, et al. Dynamic autoregulatory response after severe head
injury. J Neurosurg 2002, 97,1054–1061.
Hobson J.A., McCarbey R.W., Wyzinski P.W. Sleep cycle oscillation: reciprocal discharge
by two brain stem neuronal groups. Science, 1975, 189, 55-58.
Hoffman B.F., Bassett A.L., Bartelstone H.J. Some mechanical properties of muscle. Circul.
Res., 1968, 23, 291-312.
Holman M.E., Kasby C.B., Suthers M.B., Wilson J.A. Some properties of the smooth muscle
of rabbit portal vien. J.Physiol., 1968, 196, 111-132.
Hong Ki Whan,, Hwa Kyoung Shin, Chi Dae Kim, Won Suk Lee, and Byung Yong Rhim .
Restoration of vasodilation and CBF autoregulation by genistein in rat pial artery after
brain injury Am J Physiol Heart Circ Physiol 2001, 281: H308-H315.
Horsman M.R. Tissue physiology and response to heat. Int. J. Hyperthermia, 2006, 22, 3,
197-203.
Howse D., Carona J.J., Duffi T. Cerebral energy metabolism, pH and blood flow during
seizures in the cat. Amer. J. Physiol., 1974, 227, 1444-1451.
Huttenlocker P.R. Evoked and spontaneous activity in single units of medial brain stem
during natural sleep and waking. J.Neurophysiol., 1961, 24,451-468.
Hyman C., Paldino E., Zimmerman E. Local regulation of effective blod flow in muscle.
Circul. Res., 1963, 12, 76-81.
Hysell J.W., Bohr D.F. Renal vascular response to plasma and to known vasoactive
substances. Proc. Soc. Exp. Biol. Med., 1970, 135, 930-933.
Ichinose Masashi, Shunsaku Koga, Naoto Fujii, Narihiko Kondo, and Takeshi Nishiyasu
Modulation of the spontaneous beat-to-beat fluctuations in peripheral vascular resistance
during activation of muscle metaboreflex. Am J Physiol Heart Circ Physiol, 2007, 293,
H416 - H424.
Ikeda N., Hayashida O., Kameda H., Ito H., Matsuda T. Experimental study on thermal
damage to dog normal brain. Int. J. Hyperthermia, 1994, 10, 553-561.
Ilyuchyonok R.Yu. Farmakologiya povedeniya i pamyati. Nauka, Novosibirsk, 1972.
Ilyuchyonok R.Yu., Eliseeva A.G. Kholinergicheski mekhanizm emotsionalnoi reaktsii
strakha. Zhurn. vyssh. nervn. deyat., 1967, 17, 2, 330-337.
References 183
Ingvar D.H. Quantitative measurement of regional metabolism, pO2, PCO2 in the cerebral
cortex. Neurology, 1961, 11, 4, 68-71.
Ingvar D.H. Correlation between cerebral function and cerebral blood flow and its
disappearance following anoxia. In: Pharmacologie der lokalen Gehirndurchblutung.
Munich, Springer Verlag, 1969, pp.66-69.
Ingvar D. Patterns of brain avtivity revealed by measurements of regional cerebral blood
flow. In: Brain Work (Eds. D.Ingvar, N.Lassen). Copenhagen, Munksgaard, 1975, 307-
413.
Ingvar D. Brain work in presenile dementia and in chronic schizophrenia. In: Brain Work
(Eds. D.Ingvar, N.Lassen). Copenhagen, Munksgaard, 1975, 286-302.
Ingvar D. Measurements of regional blood flow and metabolism in psychopathological states.
Eur. Neurol., 1981, 20, 3, 294-296.
Ingvar D.H., Gustafsson L. Regional cerebral blood flow in organic dementia with early
onset. Acta neurol. Scand., 1970, 46, Suppl. 43, 42-73.
Ingvar D., Lubbers D., Siessjo B. Normal and epileptic EEG patterns related to cortical
oxygen tension in cat. Acta Physiol. Scand., 1962, 55, 2-3, 210-224.
Ingvar D.H., Schwartz M.S. Blood flow patterns induced in the dominant hemisphere by
speech and reading. Brain, 1974, 96, 274-288.
Ivanov K.I., Kislyakov Yu.Ya. Energeticheskie potrebnosti i kislorodnoe obespechenie
golovnogo mozga. Nauka, Leningrad, 1979, 215 s.
Jacobs J, Hawco C, Kobayashi E, Boor R, Levan P, Stephani U, Siniatchkin M, Gotman J.
Variability of the hemodynamic response as a function of age and frequency of epileptic
discharge in children with epilepsy. Neuroimage. 2008, 40, 2, 601-614.
Jackson I.L., Batinic-Haberle I., Sonveaux P., Dewhirst M.W., Vujaskovic Z. ROS
production and angiogenic regulation by macrophages in response to heat therapy. Int. J.
Hyperthermia, 2006, 22, 4, 263-273.
Jadecola L., Arbit E., Nakai M. et al. Increased regional cerebral blood flow and metabolism
elicited by stimulation of the dorsal medullary reticular formation in the rat: evidence for
an intrinsicneural system in brain regulationg cerebral metabolism. Cerebral blood flow:
effects of nerves and neurotransmitters (D.Heistad and M.Marcus eds.), Amsterdam,
Flrevier/North-Holland Inc., 1982, 485-492.
Jadecola C., Arneric S., Tucker L.W., Reis D.J. Cerebral cortical neurons are required for the
corticalcerebrovasodilatation elicited by electrical stimulation of the fastigial nucleons in
rat. Brain-85, Lund, 1985, 238.
James I., Miller R., Purves M. Observations on the extrinsic neural control of cerebral blood
flow in the baboon. Circul. Res., 1969, 25, 77-93.
Jasper H.H., Ajmone-Marsan C. A stereotaxic atlas of diencephalon of the cat. The National
Research Council of Ottawa, Canada, 1954.
Johannes J. Van Lieshout, Wouter Wieling, John M. Karemaker, and Niels H. Secher.
Syncope, cerebral perfusion, and oxygenation. J Appl Physiol, Mar 2003; 94: 833.
Johnson P.C. (Ed.). Autoregulation of blood flow. Circul. Res., 1964, 14-15, suppl.1.
Johansson B., Bohr D.F. Rhythmic activity in smooth muscle from small subcutaneous
arteries. Amer. J. Physiol., 1966, 210, 801-806.
Johansson B., Mellander S. Static and dynamic components in the vascular myogenic
response to passive changes in length as revealed by electrical and mechanical recordings
from the rat portal vein. Circul. Res., 1975, 36, 76-83.
Johansson H., Siesjo B.K. Blood flow and oxygen consumption of the rat brain in profound
hypoxia. Acta physiol. Scand., 1974, 90, 281-282.
Johnson G.N., Palahniuk R.J., Tweed W.A., Jones M.V., Wade J.G. Regional cerebral blood
flow changes during severe fetal asphyxia produced by slow partial umbilical cord
compression. Amer. J. Obstet. Gynecol., 1979, 135, 1, 48-52.
Jones R.D., Berne R.M. Local regulation of blood flow in skeletal muscle. Circul. Res., 1964,
14-15, Suppl. !, 30-38.
Johnston AJ, Steiner LA, Gupta AK, Menon DK. Cerebral oxygen vasoreactivity and
cerebral tissue oxygen reactivity. Br J Anaesth., 2003, 90, 6, 774-86.
Joseph C. LaManna, Juan Carlos Chavez, and Paola Pichiule. Structural and functional
adaptation to hypoxia in the rat brain. J. Exp. Biol., Aug 2004; 207: 3163 - 3169.
Jovet M. The neurophysiology of the states of sleep. Physiol. Rev., 1967, 47, 117-125.
Joyce G.C., Rack P.M.H., Westbury D.R. The mechanical properties of cat soleus muscle
during controlled lengthening and shortening movements. J.Physiol., 1969, 204, 461-
474.
Just Armin. Mechanisms of renal blood flow autoregulation: dynamics and contributions. Am
J Physiol Regulatory Integrative Comp Physiol, 2007, 292, R1 - R17.
Kajikawa H. Mode of the sympathetic innervation of the cerebral vessels, demonstrated by
the fluorescent histochemical technique in rats and cats. Arch. Jap. Chir., 1969, 38, 2,
227-235.
Kalaria R., Harik S. Adenosine and the blood-brain-barrier (BBB) receptors transporter and
enzymes of metabolism. Neurosci.Lett., 1985, 22, 559.
Kaley Gabor. Role of 20-HETE in the Modulation of Myogenic Reactivity. Circulation
Research. 2000, 87, 4-5.
Kampinga H.H. Cell biological effects of hyperthermia alone or combined with radiation or
drugs: a short introduction to newcomers in the field. Int. J. Hyperthermia, 2006, 22, 3,
191-196.
Kampinga H.H. Thermotolerance in mammalian cell. Protein denaturation and aggregation,
and stress proteins. J. Cell. Sci., 1993, 104, 11-17.
Kapp D.S., Lord P.F. Thermal tolerance to whole body hyperthermia. Int. J. Radiat. Oncol.
Biol. Phys., 1983, 9, 917-921.
Karino T., Koga S., Maeta M. Experimental studies of the effects of local hyperthermia on
blood flow, oxygen pressure and pH in tumors. Jpn. J. Surg., 1988, 18, 3, 276-283.
Katz-Brull R, Alsop DC, Marquis RP, Lenkinski RE. Limits on activation-induced
temperature and metabolic changes in the human primary visual cortex. Magn Reson
Med. 2006, 56, 2, 348-355.
Kawamura Y., Meyer J.S., Hiromoto H., Aoyagi M., Hashi K. Neurogenic control of cerebral
blood flow in the baboon. Effects of alpha-adrenergic blockade with phenoxybenzamine
on cerebral autoregulation and vasomotor reactivity to changes in PaCO2. Stroke, 1974,
5, 747-758.
References 185
Kawamura Y., Meyer J.S., Hiromoto H., Aoyagi M., Tagashira Y., Ott E.O. Neurogenic
control of cerebral blood flow in the baboon. Effects of the cholinergic inhibitory agents,
atropine, on cerebral autoregulation and vasomotor reactivity to changes in PaCO2.
J.Neurosurg., 1975, 43, 676-688.
Kelleher D.K., Engel T., Vaupel P.W. Changes in microregional perfusion, oxygenation,
ATP and lactate distribution in subcutaneous rat tumours upon water-filtered IR-A
hyperthermia. Int. J. Hyperthermia. 1995, 11, 2, 241-55.
Kerner T., Deja M., Ahlers O., Loffel J., Hildebrandt B., Wust P., Gerlah H., Riess H. Whole
body hyperthermia: a secure procedure for patients with various malignancies? Intensive
Care Med., 1999, 25, 9, 959-965.
Kennedy J.C., Taplin G. Shunting in cerebral microcirculation. Amer. Surgeon, 1967, 33,
763-771.
Kety S.S. Cerebral circulation. In: Handbook of Physiology, Sect. 1, Vol.III. Washington,
D.C. Amer. Physiol. Soc., 1961, p.1751.
Kety S.S., Landau W.M., Freygang W.H., Rowland L.P., Sokoloff L. Estimation of regional
circulation in the brain by uptake of inert gas. Fed. Proc. Fed. Amer. Soc. Exp. Biol.,
1955, 14, 85.
Kety S.S., Schmidt C.F. The nitrous oxide method for the quantitative determination of
cerebral blood flow in man: theory, procedure and normal values. J. Clin. Invest., 1948,
27, 476-483.
Khalfen E., Denisova S. Vliyanie nekotorikh preparatov, ispolzuemikh pri lechenii
khronicheskoi koronarnoi nedostatochnosti, na metabolizm adenozina. Kardiologia,
1975, 7, 51-56.
Kharkevich D.A. Farmakologiya. Meditsina, Moskva, 1980.
Khenan E. Analiz vremennykh ryadov. Nauka, Moskva, 1964.
Kholodov Yu.A. Vliyaniye elektromagnitnykh i magnitnykh polei na tsentralnuyu nervnuyu
sistemu. Meditsina, Moskva, 1966, s.59.
Kholodov Yu.A., Shishko M.A. Elektromagnitniye polya v neirofiziologii. Nauka, Moskva,
1979, 168 s.
Kilibaeva G. Raspredelenie krovotoka v somatosensornoi oblasti kori mozga krolikov pri
razdrajenii vibriss. Phisiol. J.SSSR, 1985, 71, 9, 1166-1170.
King Y.T., Lin C.S., Lin J.H., Lee W.C. Whole-body hyperthermia-induced thermotolerance
is associated with the induction of Heat Shock Protein 70 in mice. J. Exp. Biol., 2002,
205: 273
Kingwell B.A. Nitric oxide-mediated metabolic regulation during exercise: effects of training
in health and cardiovascular disease. The FASEB Journal, 2000, 14, 1685-1696.
Kinney J., Lister J., Moore F. Relationship of energy expenditure to total exchangeable
potassium. Ann. N. J. Acad. Sci., 1983, 110, 711-722.
Kiss F., Tarjan S. Hirnkreislauf und Schwanger-schaftstovikose. Leipzig, 1959.
Klosovski B.N. Tsirkulyatsiya krovi v mozgu. Medgiz, Moskva, 1951.
Klosovski B.N., Kosmarskaya E.N. Kolichestvennaya i kachestvennaya korrelyatsiya mezhdu
krovosnabzheniem i funktsiyei mozgovogo veshchestva. V kn.: Korrelyatsiya
krovosnabzheniya s metabolizmom i funktsiyei. Metsniereba, Tbilisi, 1969, 15-25.
Klugman K.P., Mitchell S., Rosendorff C. Cholinergic regulation of intracerebral

noradrenergic pathway - induced hypothalamic vasodilatation. Stroke, 1980, 11, 5, 522-
527.
Knabe U., Betz E. The effect of varying extracellular K+, Mg+ and Ca++ on the diameter of
pial arterioles. In: Vascular Smooth Muscle (Ed. E.Betz). Berlin e.a., Springer Verlag,
1972, pp.83-85.
Knopman D.S., Rubens A.B., Klassen A.C., Meyer M.W. Regional cerebral blood flow
correlation of auditory processing. Arch. Neurol., 1982, 39, 8, 487-493.
Kobari M., Gotoh F.,Fuknuchi Y., Tanaka K., Suzuki N., Ulmatsu F. Quantitative
measurement of blood flow velocity in feline pial arteries during hemmoragic
hypotension and hypercapnia. Stroke (MF), 1987, 18, 2, 457-463.
Kobayashi S., Waltz A.G., Rhoton A.L. Effects of stimulation of servical sympathetic nerves
on cortical blood flow and vascular reactivity. Neurology, 1971, 21, 297-302.
Kogure K., Scheinberg P., Kishikawa H., Utsunomiya Y., Busto R. Adrenergic control of
cerebral blood flow and energy metabolism in the rat. Stroke, 1979, 10, 2, 179-184.
Kogure K., Scheinberg P., Reinmuth O., Fujishima M., Busto R. Mechanisms of cerebral
vasodilatation in hypoxia. Trans. Amer. Neurol. Assoc., 1969, 94, 292-294.
Kogure K., Scheinberg P., Reinmuth O., Fujishima M., Busto R. Regional cerebral blood
flow in dogs. Local and remote effect of carbon dioxide. Arch. Neurol., 1970, 22, 528-
540.
Kokura S., Yoshikawa T., Kiahi A., Tomii T., Tujigiwa M., Yasuda M., Ichikawa H., Takano
H., Takahashi S., Naito Y., Ueda S., Oyamada H., Tainaka K., Kondo M. Role of oxygen
derived free radicals for antitumor effects of intra-arterial injection withAdriamycin. Jpn.
J. Cancer Chemother., 1990, 17, 1711-1714.
Konopliyannikov A.G. Electromagnetik hyperthermia in treatment of neoplastic and
nonneoplastic illnesses. Phys. Med.,, 1991, 1, 1-11
Konradi G.P. Regulyatsiya sosudistogo tonusa. Nauka, Leningrad,1973.
Konradi G., Levtov V. Zavisimost reaktivnoi giperemii v ckeletnikh mishtsakh ot dlitelnosti
prekrashchenia krovotoka. Phisiol.J. SSSR, 1970, 56, 366-374.
Kontos H.A., Wei E.P., Navari R.M., Levasseur J.E., Rosenblum W., Patterson J.L.
Responses of cerebral arteries and arterioles to acute hypotension. Amer. J. Physiol.,
1978, 234, 4, H371-H383.
Koshu K., Kamiyama K., Oka N., Endo S., Takaku A., Saito T. Measurement of regional
blood flow using hydrogen gas generated by electrolysis. Stroke, 1982, 13, 4, 483-487.
Kovach A., Dora E. Contribution of adenosine to the regulation of cerebral blood flow: the
role of calcium ions in the adenosine-induced cerebrocortical vasodilatation. Oxygen
Transp. Tissue B.:Proc.Mech. Dortmund 15-17 Sept., 1982. New-York, London, 984,
315-325.
Kovalenko E.A. O vliyanii vysokikh stepenei razrezheniya atmosfery na napryazhenie
kisloroda v tkanyakh mozga. Fiziol. zh. SSSR, 1962, 28, 2, 150-156.
Kovalenko E.A., Berezovski V.A., Epshtein I.Ya. Polyarograficheskoe opredelenie kisloroda
v organizme. Nauka, Moskva, 1975, 231 s.
References 187
Krylov S.S. Kharakteristiki deistviya na tsentralnuyu nervnuyu sistemu kholinoliticheskikh

veshchestv, blokiruyushchikh M i N-kholinoreaktivnie sistemy. Fiziol. zh. SSSR, 1955,
41, 4, 375-381.
Kurachi Masayoshi, Kobayashi Katsuji, Marsubara Rokuro. Regional cerebral blood flow in
schizophrenic disorders. Europ. Neurol., 1985, 24, 3, 176-181.
Kuschinsky W., Wahl M. Alpha-receptor stimulation by endogenous and exogenous
norepinephrine and blockade by phentolamine in pial arteries of cats. Circul. Res., 1975,
37, 168-174.
Kuschinsky W., Wahl M. Interaction of norepinephrine with H+ and K+ at pial arteries of
cats. In: Ionic actions on vascular smooth muscle with special regard to brain vessels.
Berlin e.a., Springer Verlag, 1976, pp.87-89.
Kuschinsky W., Wahl M. Local chemical and neurogenic regulation of cerebral vascular
resistance. Physiol. Rev., 1978, 58, 656-689.
Lam Eugene, Peter Skarsgard and Ismail Laher. Inhibition of myogenic tone by mibefradil in
rat cerebral arteries. European Journal of Pharmacology, 1998, 358, 2, 165-168
LaManna Joseph C., Juan Carlos Chavez, and Paola Pichiule. Structural and functional
adaptation to hypoxia in the rat brain. J. Exp. Biol., 2004, 207, 3163 - 3169.
Landis C. Changes in blood pressure during sleep as determined by the Erlanger method.
Amer. J. Physiol., 1925, 73, 551-555.
Langer S.Z. Presynaptic regulation of the release of catecholamines. Pharmacol. Rev., 1981,
32, 4, 337-362.
Langfitt I.W., Kassel N.F. Cerebral vasodilatation produced by brainstem stimulation.
Neurogenic control vs autoregulation. Amer. J. Physiol., 1968, 215, 1, 90-97.
Laptook A. The effects of sodium bicarbonate on brain blood flow and O2 delivery during
hypoxemia and acidemia in the pigiet. Pediat. Res., 1985, 19, 315-319.
Larcan A, Stoltz J., Blood hyperviscosity syndromes. Classification and physiopathological
understanding. Therapeutic deductions. Ann Med Interne (Paris), 1983, 134(5): 395-410.
Larcan A., Stoltz J., Gaillard S. Blood vicosity. Measurement and applications (hyper-and
Hypoviscosity syndromes). Nouv Presse Med., 1981, 10 (17), 1411-5.
Lassen N.A. Cerebral blood flow and oxygen consumption in man. Physiol. Rev., 1959, 39,
183-238.
Lassen N.A. Prisposoblenie regionarnogo krovoobrashcheniya k mestnoi metabolicheskoi
potrebnosti v mozgu i narushenie etoi regulyatsii vsledstvie gipoksii. V kn.:
Korrelyatsiya krovosnabzheniya s metabolizmom i funktsiyei. Metsniereba, Tbilisi, 1969,
147-153.
Lassen N.A., Christensen M.S. Physiology of cerebral blood flow. Brit. J. Anaesth., 1976, 48,
719-734.
Lassen N.A., Ingvar D.H. Blood flow of the cerebral cortex determined by radioactive
Kripton 85. Exrerientia, 1961, 17, 42-45.
Lassen N.A., Ingvar D.H. Radioisotopic assessment of regional blood flow. Prog. Nucl.
Med., Vol.1, 1972, pp.376-409.
Lassen N.A., Skinhoj E. Regional cerebral circulation in man and its regulation. Modern
Trends in Neurology, 1975, 6, 59-81.
Laszt L. Neue Grrundlagen zur erkenntnis der regulation des hautkreislaufes und des
peripheren kreislaufes im Allgemeinen. Ann. Ital. dermatol. clin. sperim., 1969, 23, 236-
245.
Lauritzen M., Henriksen L., Lassen N.A. Regional cerebral blood flow during rest and skilled
band movements by Xenon-133 inhalation and emission computerized tomography. J.
Cerebral Blood Flow Metab., 1981, 1, 4, 385-387.
Law M.P., Ahier R.G., Field S.B. The response of the mouse ear to heat applied alone of
combined with x-ray. Br. J. Radiol., 1978, 51, 132-138.
Lazarthes G. Etude critique des nerfs vasodilatateurs. Acta neuroveg., 1956, 14, 1-4, 74-86.
Lee T.J.-F. Morphopharmacological study of cerebral vasodilator and constrictor nerves. In:
Cerebral Blood Flow: Effects of Nerves and Neurotransmitters (Eds. D.Heistad,
M.Marcus). Amsterdam e.a., Elsevier North Holland Inc., 1982, pp.431-440.
Leniger-Follert E., Lubbers D.W. Behavior ofmicroflow and local pO2 of the brain cortex
during and after direct electrical stimulation. Pflugers Arch., 1976, 356, 1, 39-44.
Leniger-Follert E., Lubbers D.W., Wrubetz W. Regulyatsiya mestnogo tkanevogo PO2 v
kore mozga koshki. Fiziol. zh. SSSR, 1975, 61, 10, 1513-1517.
Leniger-Follert E., Wrubetz W., Lubbers D.W. Local tissue PO2 and microflow of the brain
cortex under varying arterial oxygen pressure. In: Oxygen Transport to Tissue - II (Eds.
J.Grote, D.Reneau, G.Thews). Berlin e.a., Springer Verlag, 1976, pp.361-367.
Lennox W.G., Gibbs E.L. The blood flow in the brain and the leg of man and the changes
induced by alterations of blood gases. J. Clin. Invest., 1932, 11, 1155-1177.
Lenzi G.L. Brain work: function, metabolism and blood flow. Arch. Ital. Biol., 1982, 120, 1-
3, 189-200.
Levtov V.A. Khimicheskaya regulyatsiya mestnogo krovoobrashcheniya. Nauka, Leningrad,
1967.
Levtov V.A., Parolla D.I. Reaktivnost sosudov k tsirkuliruyushchim katekholaminam i
iskhodni sosudisti tonus. V kn.: Voprosy regulyatsii regionarnogo krovoobrashcheniya.
Nauka, Leningrad, 1969, 96-105.
Leyko W., Bartosz G. Membrane effects of ionizing radiation and hyperthermia. Int. J.
Radiat. Biol., 1986, 49, 743-770.
Li G.C., Meyer J.I., Hahn G.M. Heat induced protection of mice against thermal death.
Cancer Res., 1983, 43, 5758-5760.
Lin J.C, Song C.W. Influence of vascular thermotolerance on the heat-induced changes in
blood flow, pO2, and cell survival in tumors. Cancer Research, 1993, 53, 2076-2080.
Lin Shih-Chieh, Damien Gervasoni, and Miguel A. L. Nicolelis Fast Modulation of
Prefrontal Cortex Activity by Basal Forebrain Noncholinergic Neuronal Ensembles. J
Neurophysiol, Dec 2006; 96: 3209 - 3219.
Linder J. Effects of facial nerve section and stimulation on cerebral and ocular blood flow in
hemorragic hypotension. Acta physiol. Scand., 1981, 112, 185-193.
Lip G.Y.H., Beevers D.G. Abnormalities of rheology and coagulation in hypertension. J.
Hum. Hypertens., 1994, 8, 693-702.
Lluch S., Reimann G., Glick G. Evidence for the direct effect of adrenergic drugs on the
cerebral vascular bed of the unanaesthetized goat. Stroke, 1973, 4, 50-56.
References 189
Lobanova E.A. Izmeneniya uslovnoreflektornoi deyatelnosti zhivotnykh pri vozdeistvii

mikrovoln razlichnykh chastotnykh diapazonov. V kn.: O biologicheskom deistvii
elektromagnitnykh polei radiochastot. Izd. In-ta gigieny truda i prof. zabolevanii.
Moskva, 1964, vyp.2, 13-19.
Loizou L. Uptake of monoamines into central neurons and the blood brain barrier in the
infant rat. Br. J. Pharmacol., 1970, 40, 800-813.
Lombard J.H., Duling B.R. Relative contributions of passive and myogenic factors to
diameter changes during single arteriole occlusion in the hamster cheek pouch. Circul.
Res., 1977, 41, 365-373.
Lombard J.H., Duling B.R. Multiple mechanism (metabolic, myogenic, and passive)
contribute to reactive hyperemia. Am J Physiol Heart Circ Physiol, 1981, 241, H748-
H755.
Lott Mary E. J., Michael D. Herr, and Lawrence I. Sinoway. Effects of transmural pressure
on brachial artery mean blood velocity dynamics in humans. J Appl Physiol, Dec 2002;
93: 2137.
Lowe R.F., Gilboe D.D. Demonstration of alpha and beta adrenergic receptors in canine
cerebral vasculature. Stroke, 1971, 2, 193-200.
Lu K., J. W. Clark, Jr., F. H. Ghorbel, C. S. Robertson, D. L. Ware, J. B. Zwischenberger,
and A. Bidani. Cerebral autoregulation and gas exchange studied using a human
cardiopulmonary model. Am J Physiol Heart Circ Physiol, 2004; 286: H584 - H601.
Lubbers D.W. Regional cerebral blood flow and microcirculation. In: Blood Flow through
Organs and Tissues (Eds. W.H.Bain, A.M.Harper). Edinburgh, Livingstone, 1968,
pp.162-166.
Lubbers D.W. Microcirculation and oxygen supply of the brain. Acta Cardiologica, 1974,
Suppl. 19, 209-219.
Lukyanova L.D. Izuchenie napryazheniya kisloroda v mozgovoi tkani s pomoshchyu metoda
"kislorodnogo katoda". V kn.: Mater. k nauchn. konf. po opredeleniyu napryazheniya
kisloroda v zhivykh tkanyakh polyarograficheskim metodom v eksperimente i klinike.
Gorki, 1964, 50-52.
Lyons B.E., Britt R,H, Strohbehn J.W. Localized hyperthermia in the treatment of malignant
brain tumours using an interstitial microwave antenna array. IEEE Trans. Biomed. Eng.,
1984, 31, 53-62.
Lyons B.E., Obana W.G., Borchich J.K., Kleinman R., Singh D., Britt R.H. Chronic
histological effects of ultrasonic hyperthermia on normal feline brain tissue. Radiat. Res.,
1986, 106, 234-251.
MacMillan V., Salford L.G., Siesjo B.K. Metabolic state and blood flow in rat cerebral
cortex, cerebellum and brainstem in hypoxic hypoxia. Acta physiol. Scand., 1974, 92,
105-113.
MacMillan V., Siesjo B.K. Brain energy metabolism in hypoxemia. Scand. J. Clin. Lab.
Invest., 1972, 30, 127-136.
Marcus M., Gross P., Heistad D. Temporal and regional characteristics of cerebral vascular
responses to sympathetic nerve stimulation. Circulation, 1978, 68, Suppl. 2, 58.
Marcus M.L., Heistad D.D., Erhardt J.C., Abbound F.M. Total and regional cerebral blood
flow measurements with 7-10 m, 15 m, 25 m, 50 m diameter microspheres. J. Appl.
Physiol., 1976, 40, 501-607.
Madden A., Glaholm J., Leach M.O. An assessment of the sensitivity of in vivo 31 P nuclear
magnetic resonance spectroscopy as a means of detecting pH heterogeneity in tumors a
simulation studies. Br. J. Radiol., 1990, 63, 746, 120-124.
Mantskava M., Momtselidze N., Mchedlishvili G., Pargalava N. Comparative significance of
the principal factors responsible for microcirculatory disorders in type II diabetes
mellitus. Proc. Georgian Acad. Sci., Biol. Ser. A, 2003, 28, 5-6, 483-487.
Mardynski Yu.S., Kurpeshev O.K., Tkachev S.I. Hyperthermia as a universal radiosensitizer.
V Russian Oncological Conference, Moscow, 2001.
Matsumi N., Matsumoto K., Mishima N., Moriyama E., Furuta T., Nishimoto A., Taguchi K.
Thermal damage threshold of brain tissue- histological study of heated normal monkey
brains, J. Neurol. Med. Chir, 1994, 34, 4 209-215.
Mascia L, Andrews PJ, McKeating EG, Souter MJ, Merrick MV, Piper IR. Cerebral blood
flow and metabolism in severe brain injury: the role of pressure autoregulation during
cerebral perfusion pressure management. Intensive Care Med 2000, 26, 202–205.
Marshak M.E. O regulyatsii zonalnogo krovoobrashcheniya v kore golovnogo mozga. Vest.
AMN SSSR, 1967, 6, 29-34.
Marshak M.E. O mekhanizmakh samoregulyatsii regionarnogo i zonalnogo
krovoobrashcheniya. Vest. AMN SSSR, 1968, 2, 17-23.
Marshak M.E., Ardashnikova L.I., Aronova G.N., Blinova A.M., Boll M.M. Vliyanie
uglekisloty pri gipoksemii na krovoobrashchenie i potreblenie kisloroda v razlichnykh
organakh. V kn.: K regulyatsii dykhaniya, krovoobrashcheniya i gazoobmena. Moskva,
1948, 65-68.
Mathew R.J., Meyer J.S., Semchuk K.M., Francis D., Mortel K., Claghorn J.L. Regional
cerebral blood flow in depression: a preliminary report. J. Clin. Psychiatry, 1980, 41, 12,
71-72.
Matsuda M., Meyer J.S., Desmukh V., Tagashira Y. Effect of acetylcholine on cerebral
circulation. J. Neurosurg., 1976, 45, 423-431.
Mchedlishvili G.I. Fiziologicheskie mekhanizmy mozgovogo krovoobrashcheniya pri
terminalnych sostoyaniyakh. Fiziol. zh. SSSR, 1960, 46, 1210-1217.
Mchedlishvili G.I. Funktsiya sosudistykh mekhanizmov golovnogo mozga. Nauka, Leningrad,
1968.
Mchedlishvili G.I. (Red.). Regulyatsiya mozgovogo krovoobrashcheniya. Metsniereba,
Tbilisi, 1980.
Mchedlishvili G.I., Nikolaishvili L.S. Evidence of a cholinergic nervous mechanism
mediating the autoregulatory dilatation of the cerebral blood vessels. Pflugers Arch.,
1970, 315, 27-37.
Mchedlishvili G., Nikolaishvili L., Antia R. Are the pial arterial responses dependent on the
direct effect of intravascular PO2, PCO2 and pH. Micrivasc. Res., 1975, 10, 3, 298-311.
Mchedlishvili G.I., Baramidze D.G., Nikolaishvili L.S., Ormotsadze L.G. Funktsiya
sosudistykh mekhanizmov mozga, obespechivayushchikh ego adekvatnoe
References 191
krovosnabzheniye. V kn.: Korrelyatsiya krovosnabzheniya s metabolizmom i funktsiei.

Metsniereba, Tbilisi, 1969, 85-100.
Mchedlishvili G.I., Mitagvaria N.P., Ormotsadze L.G. Opredelenie soprotivleniya v
krupnykh i melkikh arteriyakh golovnogo mozga s pomoshchyu adekvatnoi
matematicheskoi modeli. Fiziol. zh. SSSR, 1971, 57, 4, 575-583.
Mchedlishvili G.I., Mitagvaria N.P., Ormotsadze L.G. Fiziologicheskie mekhanizmy
"autoregulyatsii" krovosnabzheniya mozga. Fiziol. zh. SSSR, 1972, 58, 2, 224-229.
Mchedlishvili G., Maeda N. Blood flow structure related to red cell flow: a determinant of
blood fluidity in narrow microvessels. Japanese Journal of Physiology, 2001, 51, 1, 19-
30.
Mc Dowall D.G. Pharmacology of the cerebral circulation. Intern. Anaesthesiol. Clin., 1969,
7, 557-578.
Meladze V.G., Begiashvili V.T., Gobechia L.Sh., Tsereteli K.V., Mitagvaria N.P. Nekotorie
dinamicheskie kharakteristiki sistemy regulyatsii mestnogo krovotoka v kore golovnogo
mozga koshki. Soobshch. AN GSSR, 1977, 87, 169-172.
Mellander S. Rate-sensitivity in myogenic autoregulation. In: Proc. Int. Union Physiol. Sci.
27th Int. Congr., Paris, 1977, Vol.12, Paris, 1977, p.301.
Mellander S., Arvidsson S. Possible "dynamic" component in the myogenic vascular
response related to pulse pressure distension. Acta physiol. Scand., 1974, 90, 283-285.
Mellander S., Lundvall J., Grande P.O. Evidence for a dynamic component in the myogenic
control of blood vessels tone in vivo. Acta physiol. Scand., 1976, 96, 40A-41A. (Meyer
J.S., Gotoh F.)
Meyer J.S., Gotoh F. Metabolic and electroencephalographic effects of hyperventillation.
Arch. Neurol. Psychiat., 1980, 3, 539.
Meyer J.S., Gotoh F. Interaction of cerebral hemodynamics and metabolism. Neurology,
1961, 11, 4, 46-65.
Meyer J.S., Nomura F., Sakamoto K., Kondo A. Effect of stimulation of the brainstem
reticular formation on cerebral blood flow and oxygen consumption. Electroencephalogr.
Clin. Neurophysiol., 1969, 26, 125-132.
Meyer J.S., Porthnoy H.D. Post-epileptic paralysis. A clinical and experimental study. Brain,
1959, 82, 162-185.
Meyer J.S., Sakai F., Karacan I., Derman S., Yamamoto M. Sleep apnea, narcolepsy and
dreaming: regional cerebral hemodynamics. Ann. Neurol., 1980, 7, 5, 479-485.
Meyers H., Honig C. Influence of initial resistance on magnitude of response to vasomotor
stimuli. Amer. J. Physiol.,1969, 216, 1429-1436.
Meynert Th. Der Bau der Grosshirnrinde und seine ortlichen Ve rschiedenheiten, nebst einem
pathologisch-anatomischem Corollarium. Teil I und Teil II. Vierteljahrsschrift f.
Psychiatr. 1 und 2, 1867/1868, pp.87-113.
Michaelson S.M. Sensation and perception of microwave energy. In: Fundamental and
Applied Aspects of Nonionizing Radiation. New York-London, Raven Press, 1975,
pp.213.
Milsum J. Analiz biologicheskikh sistem upravleniya. Mir, Moskva, 1968.
Minacki L., Olubek K., Romaniuk A. Lmiany czynnosci odruchowowarunkowej szczurow
pod wplywem dziabania mikrofal (Pasmos), Med. pracy, 1962, 73, 255.
Mitagvaria N.P. Control of brain blood supply. In: Regulation and Control in physiological
Systems (Eds. A.S.Iberall, A.C.Guyton). Pittsburgh, Instrument Society of America.
1973, pp.391-393.
Mitagvaria N.P. Regulation of local cerebral blood flow. In: Oxygen Transport to Tissue-VI
(Eds.: D.Bruley, H.Bicher, D.Reneau). Plenum Press. N.Y. and London, 1984, 861-879.
Mitagvaria N.P. Ustoichivost tsirkulyatornogo obespecheniya funktsii golovnogo mozga.
Metsniereba, Tbilisi, 1983, 177 s.
Mitagvaria N.P. Obshchie printsipy regulyatsii organnogo krovoobrashcheniya. V kn.:
Krovoobrashchenie i okruzhayushchaya sreda. Simferopol, 1983, 126-133.
Mitagvaria N.P., Adamia T.E., Lataria K.D. Izmenenie dinamiki mozgovogo krovotoka pri
amizilovoi i skopolaminovoi amneziyakh. Soobshch. AN GSSR, 1978, 91, 3, 693-696.
Mitagvaria N.P., Begiashvili V.T., Meladze V.G. Regulyatsii mestnogo mozgovogo
krovotoka: ponyatie "gomeostaticheskogo diapazona". Fiziol. zh. SSSR, 1983, 69, 12,
1595-1601.
Mitagvaria N., Bicher J. Effect of microwave irradiation on local blood flow and oxygenation
in cerebral tissue. Bulletin of Experimental Biology and Medicine, 1984, 7, 37-39.
Mitagvaria N.P., Meladze V.G., Begiashvili V.T. Strukturnaya organizatsiya protsessa
autoregulyatsii krovosnabzheniya golovnogo mozga. Fiziol. zh. SSSR, 1984, 70, 6, 822-
828.
Mitagvaria N.P., Meladze V.G., Begiashvili V.T., Zakariadze N.G. Mekhanizmy regulyatsii
mozgovogo krovoobrashcheniya pri izmenenii sistemnogo arterialnogo davleniya. Izv.
AN GSSR, Seriya biol., 1981, 7, 3, 204-207.
Mitagvaria N.P., Meladze V.G., Lataria N.D., Begiashvili V.T. Nekotorie aspekty
samoregulyatsii lokalnogo mikropotoka krovi v kore golovnogo mozga koshki.
Soobshch. AN GSSR, 83, 717-720.
Mitagvaria N.P., Meladze V.G., Ognev I.A., Begiashvili V.T. K voprosu o
raznonapravlennom kharaktere reaktsii mestnogo krovotoka v smezhnykh
mikrouchastkakh kory bolshikh polusharii golovnogo mozga. Soobshch. AN GSSR, 1978,
92, 1, 169-172.
Mizzen L., Welch W.J. Characterization of the thermotolerant cell. Effects on protein
synthesis activity and the regulation of heat-shock protein 70 expression. J. Cell. Biol.,
1988, 196, 1105-1116.
Molnar R., Seylaz J. Mise en evidence et interpretation des effects de la decerebration et des
sinus carotidiens sur la circulation cerebrale. CR Acad. Sci. (Paris), 1965, 260, 3164-
3167.
Morgalyov Yu.N., Demchenko I.T. Prostranstvennoe raspredelenie krovotoka i pO2 v kore
golovnogo mozga. Fiziol. zh. SSSR, 1979, 65, 985-990.
Moskalenko Yu.E. Zakonomernosti regulyatsii krovosnabzheniya golovnogo mozga. Vestnik
AN SSSR, 1974, 11, 41-50.
Moskalenko Yu. Phunktsionalnaia ustoichivost sistemi mosgovogo krovoobrashchenia.
Phisiol. J. SSSR, 1978, 64, 589-597.
Moskalenko Yu.E. Fiziologicheskie i biofizicheskie aspekty regulyatsii vnutricherepnogo
krovoobrashcheniya. V kn.: Aktualnie voprosy fiziologii krovoobrashcheniya.
Simferopol, 1980, 104-109.
References 193
Moskalenko Yu.E., Khilko V.A. Principy issledovania sosudistoi sistemy golovnogo mozga
cheloveka. Leningrad, Nauka, 1984.
Moskalenko Yu.E., Vainshtein G.B., Demchenko I.T., Kislyakov Yu.Ya., Krivchenko A.I.
Vnutricherepnaya gemodinamika: biofizicheskie aspekti. Nauka, Leningrad, 1975.
Moskalenko Yu.E., Zelikson B.B. Sootnoshenie sdvigov tsentralnoi gemodinamiki i
mozgovogo krovotoka. V kn.: Tsentralnaya regulyatsiya gemodinamika. Kiev, 1973, 62-
66.
Mosso A. Uber den Kreislauf des Blutes in mensehlichen Gehirn. Leipzig, Viet, 1881.
Motavkin P., Vlasov G. Gistiphisiologicheskaia kharakteristika efferentnoi innervatsii arterii
osnovaniia golovnogo mosga v ontogeneze u kris. Arkh. anat., 1976, 71, 7, 41-46.
Motavkin P., Markina-Palashchenko L., Bojko G. Sravnitelnaia morphologia sosudistikh
mekhanizmov mozgovogo kroovoobrashcheniia u pozvonochnikh. M., Nauka, 1981, 205.
Mountcastle W., Lynch J., Geogropoulos A. Posterior parietal association cortex of the
monkey: command junction for operations within extrapersonal space. J.Neurol., 1975,
38, 4, 871-908.
Mozgov I.E. Farmakologiya, Kolos, Moskva, 1979.
Mrwa U.I., Achtig I., Ruegg J.C. Influence of calcium concentration and pH on the tension
development and ATPase activity of the arterial actomyosin contractile system. Blood
Vessels, 1974, 11, 277-286.
Muenzinger K. Vicarious trial and error at a point of choice. J. genet. Psychol., 1939, 53, 75-
86.
Muralidhazan E., Tateishi N., Maeda N. A new laser photometric technique for the
measurement of erythrocyte aggregation and sedimentation kinetics. Biorheology, 1994,
31, 277-285.
Muravchik S., Bergofsky E. Adrenergic receptors and vascular resistance in cerebral
circulation of the cat. J. Appl. Physiol., 1976, 38, 32-39.
Nakajima A., Horn L. Electrical activity of single vascular smooth muscle fibers. Amer. J.
Physiol., 1967, 213, 25-30.
Nielsen K., Edvinsson L., Owman C. Cholinergic innervation and vasomotor response of
brain vessels. In: Cerebral Circulation and Metabolism. Berlin, Springer Verlag, 1975,
pp.474-475.
Nielsen K., Owman C. Adrenergic innervation of pial arteries related to the Circle of Willis
in the cat. Brain Res., 1967, 6, 4, 773-776.
Nikitina E.I., Shuba F.M. Mechanizmy deistvia adenozina na gladkomyshechnye kletki
koronarnykh arterii. Fiziol. J. SSSR, 1983, 3, 332-339.
Nikolaishvili L.S., Gobechia L.Sh., Mitagvaria N.P. Issledovanie dinamiki napryazheniya
kisloroda v gippokampe i sensomotornoi kore vo vremya tsikla bodrstvovaniye-son.
Fiziol. zh. SSSR, 1983, 69, 12, 1543-1548.
Noda H., Manchar S., Adey W.R. Spontaneous activity of cat hippocampal neurones in sleep
and wakefulness. Exp. Neurol., 1969, 24, 217-231.
Noell W., Schneider M. Uber die Durchblutung und die Sauerstoffrersorgung des Gehirns im
akuten Sauerstoffmangel. I Mitteilung: Die Gehirndurchblutung. Pflugers Arch., Ges.
Physiol., 1943, 246, 181-200.
Obrist W.D., Gennareli T.A., Segawa H., Dolinskas C.A., Langfitt T.W. Relation of cerebral
blood flow to neurological status and outcome in head-injured patients. J.Neurosurg.,
1979, 51, 3, 292-300.
Ogata J., Feigin I. Arteriovenous communications in the human brain. J. Neuropath. Exp.
Neurol., 1972, 31, 519-525.
Okhnyanskaya A.G., Lipenetskaya T.D., Garicheva E.B., Nikiforova N.A. Otsenki
mozgovogo regionarnogo krovotoka cheloveka metodom vneokklyuzionnoi
reopletizmografii. Byull. eksp. biol. i med., 1976, 82, 11, 1402-1404.
Olesen J. Contralateral focal increase of cerebral blood flow in man during arm work. Brain,
1971, 13, 635-646.
Olesen J. The effect of intracarotid epinephrine, norepinephrine and angiotensin on the
regional cerebral blood flow in man. Neurology, 1972, 22, 978-987.
Olesen J. Effect of intracarotid isoprenaline, propranolol and prostaglandin E1 on regional
cerebral blood flow in man. In: Blood Flow and Metabolism in Brain (eds. A.M.Harper
et al). Edinburgh, Churchill Livingstone, 1975, pp.4.10-4.11.
Oniani T.N. Integrativnaya funktsiya limbicheskoi sistemy. Metsniereba, Tbilisi, 1980.
Oniani T.N., Molnar P.P., Naneishvili T.L. O prirode paradoksalnoi fazy sna. Fiziol. zh.
SSSR, 1970, 56, 689-693.
Opitz E., Schneider M. Uber die Sauerstoffversorgung des Gehirns und den Mechanismus
von Mangelwirkungen. Ergeb. Physiol. Biol. Chem. Exptl. Pharmakol., 1950, 46, 126-
260.
Orem J., and R. H. Trotter Postinspiratory neuronal activities during behavioral control,
sleep, and wakefulness. J Appl Physiol, 1992, 72, 23-69.
Orlov A., Pirogov A., Shefer V. Sravnitelnaia kharakteristika aktivnosti neironov lobnoi i
motornoi kori pri osushchestvlenii tselenapravlennogo dvijeniia. Phisiol. J. SSSR, 1979,
55, 1727-1733.
Orlov R.S. Neposredstvennie reaktsii gladkikh myshts arterii golovnogo mozga na
rastyazheniye. V kn.: Regulyatsiya mozgovogo krovoobrashcheniya. Metsniereba,
Tbilisi, 1980, 21-24, 31-47 (disk.).
Orlov R.S., Plechanov N.I., Azin A.L. K izucheniyu cokratitelnykh reakcii kletok gladkoi
muskulatury mozgovykh sosudov. Fiziol. J. SSSR, 1972, 58, 1, 79-82.
Osipov V.N. V sbornike, posvyashchyonnom 75-letiyu akad. I.P.Pavlova. Leningrad, 1924,
s.109.
Oskalok L.N. Izmeneniye lokalnogo mozgovogo krovotoka u cheloveka pri schetnykh
operatsiyakh. Nauchn. dokl. vyssh. shkoly biol. nauk, 1979, 2, 39-44.
Overgaard J. Influence of extracellular pH on the viability and morphology of tumor cells
exposed to hyperthermia. J. Natl. Cancer Inst., 1976, 56, 1243-1250.
Overgaard J., Nielsen O.S. The role of tissue environmental factors on the kinetics and
morphology of tumor cells exposed to hyperthermia. Ann. NY Acad. Sci., 1980, 335, 254-
280.
Owman C., Aubineau P., Edvinsson L., sercombe R. Cholinergic inhibition of sympathetic
vasoconstrictor tone in the cerebrovascular bed mediated by nicotine-type receptors. Acta
physiol. Scand., 1980, Suppl. 479, 39-42.
References 195
Owman C., Edvinsson L. (Eds.). Neurogenic control of the brain circulation. Oxford e.a.,
Pergamon Press, 1977.
Owman C., Edvinsson L., Nielsen K.C. Autonomic neuroreceptor mechanisms in brain
vessels. Blood Vessels, 1974, 11, 2-31.
Owman C., Hardebo J. Functional aspects of the blood brain barrier, with particular regard to
effects of circulating vasoactive neurotransmitters. In: Cerebral Blood Flow: Effects of
Nerves and Neurotransmitters (Eds. D.Heistad, M.Marcus). Amsterdam e.a., Elsevier
North Holland Inc., 1982, pp.119-128.
Ozaki H. Watanabe S. Suzuki H. Topographic EEG changes due to hypobaric hypoxia at
simulated high altitude. Electroencephalography and Clinical Neurophysiology, 1995,
94, 5, 349-356
Papadelis C., C. Kourtidou-Papadeli, P. Bamidis, N. Maglaveras, K. Pappas. The effect of
hypobaric hypoxia on multichannel EEG signal complexity. Clinical Neurophysiology,
2003, 118, 1, 31-52.
Parolla D.I., Beer G. Autoregulatory responses of cerebral blood vessels in hypercapnia.
Israel J. Med. sci., 1975, 11, 5, 469-475.
Parolla D.I., Mikhailova G.I. Zavisimost konstriktornykh i dilyatatornykh reaktsii sosudov
mozga ot ikh iskhodnogo tonusa. Fiziol. zh. SSSR, 1967, 53, 400-408.
Patterson I.L., Heyman A., Battley L.L., Fercuson R.W. Treshold of response of the cerebral
vessels of man to increase in blood carbone dioxide. J.Clin.Invest., 1955, 34, 12, 1857-
1864.
Picard I.D., Simone F., Sourway N.C., Vinnal F., Langfitt T. Mechanisms of the pH effect on
tone of bovine middle cerebral arterial strips in vivo. In: Blood flow and metabolism in
the brain (Eds. Harper et al., Edinburgh, Churchill, Livingstone, 1976, 17-19.
Pivalizza E.G., Koch S.M., Mehlhorn U., Berry J.M., Bull. The effects of intentional
hyperthermia on the thrombelastograph and Sonocolt analyser. Int. J. Hyperthermia,
1999, 15 (3), 217-23.
Plum F., Duffy Th. The couple between cerebral metabolism and blood flowduring seazures.
In: Brain work (Eds. D.Ingvar, N.Lassen,Copenhagen, Munksgaard, 1975, 197-214.
Pavlov I.P. Polnoe sobraniye sochinenii, 3, kn.2, Moskva-Leningrad, 1951, 230 s.
Pedata F., C. Corsi, Melani A., Bordony F., and Latini S. Adenosine Extracellular Brain
Concentrations and Role of A2A Receptors in Ischemia. Ann. N.Y. Acad. Sci., 2001; 939:
74
Pedersen M., Brandt C.T., Knudsen G.M., Ostergaard C., Skinhoj P., Frimodt-Moller N.,
Moller K. Cerebral blood flow autoregulation in early experimental S. pneumoniae
meningitis. Appl. Physiol., 2007, 102, 72-78.
Peerless S.J., Yasagril M.G. Adrenergic innervation of the cerebral blood vessels in the
rabbit. J. Neurosurg., 1971, 35, 148-154.
Pinard E., Purves M.J., Seylaz J., Vasquez J.V. The cholinergic pathway to cerebral blood
vessels. Physiological studies. Pflugers Arch., 1979, 379, 165-172.
Pittman R.N., Duling B.R. Oxygen sensitivity of vascular smooth muscle. I. In vitro studies.
Microvasc. Res., 1973, 6, 202-211.
Ponte J., Purves M.J. The role of the carotid body chemoreceptors and carotid sinus
baroreceptors in the control of cerebral blood vessels. J. Physiol., 1974, 237, 315-340.
Poole E.W. reactions of the cat pial circulation to hypotensive states induced by
hexamethonium bromide. Arch. Neurol. Psychiatr., 1954, 71, 640-647.
Preisman S., R. Marks, O. Nahtomi-Shick, and A. Sidi Preservation of static and dynamic
cerebral autoregulation after mild hypothermic cardiopulmonary bypass. Br. J. Anaesth.,
2005, 95, 207 - 211.
Pressman A.S. Elektromagnitniye polya i zhivaya priroda. Nauka, Moskva, 1968, 288 s.
Prosenz P. Investigations on the filter capacity of the dog's brain. A contribution to the
question of cerebral arteriovenous shunts. Arch. Neurol., 1972, 26, 479-488.
Pugachyov V.S. Vvedeniye v teoriyu veroyatnostyei. Nauka, Moskva, 1968.
Purves M.J. Do vasomotor nerves significantly regulate cerebral blood flow? Circul. Res.,
1978, 43, 485-493.
Rapela C.E., Green H.D. Autoregulation of cerebral blood flow. Circul. Res., 1964, 14-15,
Suppl. 1, 205-211.
Rappaport H., Bruce D., Langfitt T.W. The effect of lowered cardiac output on cerebral
blood flow. In: Cerebral Circulation and Metabolism (Eds. Langfitt T.W., McHenry
L.C., Reivich M., Wollman H.). New York e.a., Springer Verlag, 1975, pp.14-17.
Rashner R. Dynamika serdechno-cocudistoi sistemy. Medicina, Moskva, 1981.
Reinhold H.S., Berg-Blok A.V.D. Features and limitations of the “in vivo” evaluation of
tumor response by optical means. Brit. J. Cancer, suppl., 1980, 4, 64-68.
Reinhold H.S., Endrich B. Tumour microcirculation as a target for hyperthermia. Int. J.
Hyperthermia, 1986, 2, 2, 111-137.
Reis D.J., Jadecola C., McKenzie E. et al. Primary and metabolically coupled
cerebrovascular dilation elicited by stimulation of two intrinsic systems of brain.
Cerebral blood flow: effects of nerves and neurotransmitters. Eds.: D.Heistad,
M.Marcus. Amsterdam, Flrevier/North-Holland Inc., 1982, 475-484.
Reivich M. Arterial PCO2 and cerebral hemodynamics. Amer. J. Physiol, 1964, 206, 1, 25-
35.
Reivich M., Isaacs G., Evarts E., Kety S.S. The effect of slow wave sleep and REM sleep on
regional cerebral blood flow in cats. J. Neurochem., 1968, 15, 301-306.
Reivich M., Isaacs G., Evarts E., Kety S.S. Mestni krovotok v mozgu vo vremya sna. V kn.:
Korrelyatsiya krovosnabzheniya s metabolizmom i funktsiyei. Metsniereba, Tbilisi, 1969,
36-47.
Reivich M., Marshall W.J.S., Kassel N. Loss of autoregulation produced by cerebral trauma.
In: Cerebral Blood Flow (Eds. Brock M., Pieschi C., Ingvar D.H., Lassen N.A.,
Schurmann K.). Berlin e.a., Springer Verlag, 1969, pp.205-208.
Reynier-Rebuffel A.M., Lacombe P., Aubineau P., Sercombe R., Seylaz J. Multiregional
cerebral blood flow changes induced by a cholinomimetic drug. Eur. J. Pharmacol.,
1979, 60, 2-3, 237-240.
Ricardo V., Julio V., Garsia-Hustt-Elio C. Cerebellum PO2 and the sleep-waking cycle in
cats. Physiol. a. Behav., 1977, 18, 1, 19-23.
Richard L. Hughson, Michael R. Edwards, Deborah D. O’Leary, and J. Kevin Shoemaker.
Critical Analysis of Cerebrovascular Autoregulation During Repeated Head-Up Tilt.
Stroke, 2001, 32, 2403 - 2408.
References 197
Risberg J., Ingvar D.H. Increase of gray matter blood flow in "association areas" during
memorization and abstract thinking. Panminerva Med., 1971, 13, 5, 177.
Risberg J., Ingvar D.H. Pattern of activation in the gray matter of the dominant hemisphere
during memorization and reasoning. Brain, 1973, 96, 737-756.
Rolls F., Burton M., Moro F. Hypothalamic neuronal responses assosiated with the right of
food. Brain Res., 1976, 111, 53-66.
Romanenko A.V. Zakhvat adenozina nervnymi okonchaniami i ego regulacia. Neirochimia,
1985, 4, 3, 327-336.
Rossi S., Zanier E.R., Mauri I., Columbo A., Stacchetti N. Brain temperature, body core
temperature, and intracranial pressure in acute cerebral damage. J. Neurol. Neurosurg.
Psychiatry, 2001, 71, 448-454.
Ross J., Kaiser G., Klocke F.J. Observations on the role of diminished oxygen tension in the
functional hyperemia of skeletal muscle. Circul. Res., 1964, 14-15, Suppl. 1, 473-484.
Roussel B., Dittmar A., Ghouvet G. Internal temperature variations during the sleep-wake
cycle in the rat. Waking Sleeping, 1980, 4, 1, 63-75.
Rowbotham C.F., Little E. A new concept of the circulation and the circulation of the brain.
Brit. J. Surg., 1965, 52, 539-542.
Roy G.S., Sherrington C.S. On the regulation of the blood supply of the brain. J. Physiol.,
1890, 11, 85-108.
Rozenfeld D., Wolfson L.I. The effects of activation procedures on regional cerebral blood
flow in humans. Semin. Nucl. Med., 1981, 11, 3, 172-185.
Rozet Irene, Monica S. Vavilala, Andrew M. Lindley, Elizabeth Visco, Miriam Treggiari,
and Arthur M. Lam. Cerebral Autoregulation and CO2 Reactivity in Anterior and
Posterior Cerebral Circulation During Sevoflurane Anesthesia. Anesth. Analg., 2006,
102, 560 - 564.
Ryzhova N.M. Zonalniye izmeneniya krovosnabzheniya v kore golovnogo mozga pri
adekvatnykh razdrazheniyakh v usloviyakh khronicheskogo eksperimenta. Byull. eksp.
biol. i med., 1968, 54, 8-10.
Sadoshima S., Thames M., Heistad D. Cerebral blood flow during elevation of intracranial
pressure: role of sympathetic nerves. Amer. J. Physiol., 1981, 241, H78-H84.
Sakai M. Single unit activity in a border area between the dorsal prefrontal and premotor
regions in the visually conditioned motor tark of monkeys. Brain Res., 1978, 147, 377-
383.
Sakai F., Meyer J.S., Karacan I., Dennan S., Yamamoto M. Normal human sleep: regional
cerebral hemodynamics. Ann. Neurol., 1980, 7, 5, 471-478.
Sakai F., Meyer J.S., Karacan I., Yamaguchi F., Yamamoto M. Narcolepsy: regional cerebral
blood flow during sleep and wakefulness. Neurology (Minneap.), 1979, 29, 1, 61-67.
Sakuma H. Experimental studies on the neurogenic factors in autoregulation of regional
circulation in dog's brain. Brain, and Nerve, 1977, 29, 779-786.
Samaras G.M., Salcman M., Cheung A.Y., Abdo H.S., Schepp R.S. Microwave-induced
hyperthermia: An Experimental adjunct for brain tumour therapy. Natl. Cancer Inst.
Monogr., 1982, 61, 477-482.
Sanotskaya N.V. Izmeneniya napryazheniya kisloroda v tkanyakh pri gipo- i giperoksii.
Byull. eksp. biol. i med., 1961, 51, 6, 33-36.
Sapareto S.A., Raaphorst P.G., Dewey W.C. Cell killing and the sequencing of hyperthermia
and radiation. Int. J. Oncol. Biol. Ohys., 1979, 5, 343-347.
Scarrer E. Arteries and viens in mammalian brain. Anat. Res., 1940, 78, 173-196.
Scarrer E. the blood vessels of the nervous tissue. Quart. Rev. Biol., 1944, 19, 308-319.
Schamhl F.W., Betz E., Dettinger E., Hohorst H.J. Energistoffwechsel der Grosshirnrinde
und Elektroencephalogram bei Sauerstoffmangel. Pflugers Arch., 1966, 292, 46-59.
Schmidt C.F. The cerebral circulation in health and disease. Springfield, Thomas, 1950, p.78.
Schmidt C.F., Creutzfeldt O.D. Verauderungen von spontanaktivitat und reizanwort retinale
ler und genicularer neurone der Katze bei franktionierter injektion von pentobarbital -Na
(nembutal). Pflugers Arch., 1968, 300a, 129-147.
Schneider M. Durchblutung und Sauerstoffversorgung des Gehirns. Verhandl. Deut. Ges.
Kreislauf. forsch., 1953, 19, 3-25.
Sercombe R., Aubineau P., Edvinsson L., Mamo H., Owman Ch., Pinard E., Saylaz J.
Neurogenic influence on local cerebral blood flow. Effect of catecholamines or
sympathetic innervation. Neurology, 1975, 25, 10, 954-963.
Sercombe R., Aubineau P., Edvinsson L., Mamo H., Owman Ch., Saylaz J. Pharmacological
evidence in vitro and in vivo for functional beta receptors in the cerebral circulation.
Pflugers Arch., 1977, 368, 3, 241-244.
Sercombe R., Lacombe P., Aubineau P., Mamo H., Pinard E., Reynier-Rebuffel A., Seylaz J.
Is there an active mechanism limiting the influence of the sympathetic system on the
cerebral vascular bed? Evidence for vasomotor escape from sympathetic stimulation in
the rabbit. Brain Res., 1979, 164, 81-102.
Sercombe R., Wahl M. Microapplication of the carbochol during pial artery constriction
induced by sympathetic stimulation. Cerebral blood flow: Effects of nerves and
neurotransmitters. Holland, 1982, 385-392.
Sergeev G.A., Pavlova P.P., Romanenko N.F. Statisticheskiye metody issledovaniya
elektroentsefalogrammy cheloveka. Nauka, Leningrad, 1968.
Seylaz J., Mamo H., Goas J.Y., MacLeod P., Caron J.P., Houdart R. Local cortical blood
flow during paradoxical sleep in man. Arch. Hal. Biol., 1971, 109, 1-14.
Seylaz J., Sercombe R., Lacombe P., Pinard K. Study of the effects of sympathetic
stimulation on cerebral blood flow by means of free complementary techniques. In:
Neurogenic control of the brain circulation (Eds.: Ch.Owman, L.Edvinsson. Oxford,
Pergamon Press, 1977, 301-315.
Shakhnovich A.R., Razumovski A.E. Funktsionalnaya mozaika mozgovogo krovotoka i yiyo
zavisimost ot psikhicheskoi deyatelnosti. V kn.: Neirokhirurgiya i patologiya sosudov
golovnogo mozga. Nauka, Moskva, 1974, 24-30.
Shakhnovich A.R., Serbinenko F.A., Razumovski A.E. Funktsionalnaya mozaika mozgovogo
krovotoka pri psikhologicheskikh testakh u bolnykh s tserebrovaskulyarnymi
narusheniyami. Fiziol. cheloveka, 1979, 5, 1, 25-34.
Shatz N.A., Vunnam C.R., Sellinger O. S-adenosyl-L-homocysteine hydrolase from rat barin.
In: Transmethylation, Amsterdam, Elsevier., Holland, 1978, 143-153
Shenderov S.M. Miogenni tonus i mekhanika krovenosnykh sosudov. V kn.: Itogi nauki i
tekhniki VINITI. Fiziologiya cheloveka i zhivotnykh, 1979, t.23, 3-45.
References 199
Shepelev A.P. Effect of acute physical overheating of animals on the peroxidation of lipids.
Vopr. Med. Khim., 1976, 22, 47-51.
Shikatura T., Kubota K., Tamura K. Blood viscosity and cerebral blood flow in aged. Nippon
Ronen Igakkai Zasshi, 1993, 30(3): 174-81.
Shinozuka T., Nemoto E.M. Dynamics of cerebrovascular responses to oxygen.
Anesthesiology, 1981, 55, 3A, 235.
Siesjo B.K., Berman L., Nilsson B. Regulation of microcirculation in the brain. Microvasc.
Res., 1980, 19, 158-170.
Siesjo B.K., Johansson H., Ljunggren B., Norberg K. Brain dysfunction in hypoxia and
ischemia. In: Brain Dysfunction in Metabolic Disorders (Ed. F.Plum), Vol.53. New
York, Raven Press, 1974, pp.75-112.
Siesjo B.K., Johansson H., Norberg K., Salford L. Brain function, metabolism and blood flow
in moderate and severe arterial hypoxia. In: Brain Work (Eds. D.Ingvar, N.Lassen).
Copenhagen, Munksgaard, 1975, pp.101-125.
Siesjo B.K., Nilsson L. The influence of arterial hypoxemia upon labile phosphates and upon
extracellular and intracellular lactate and pyruvate concentration in the rat brain. Scand.
J. Clin. Lab. Invest., 1971, 27, 83-96.
Sigurdsson S.B., Johansson B., Mellander S. Rate-dependent myogenic response of vascular
smooth muscle during imposed changes in length and force. Acta physiol. Scand., 1977,
99, 183-189.
Silberman A.W., Morgan D.F., Storm F.K., Rand R.W., Bubbers J.E., Brown W.J., Morton
D.L. Localized magnetic-loop indication hyperthermia of the rabbit brain. J. Surg.
Oncol., 1982, 20, 174-178.
Simonov P.V. Vysshaya nervnaya deyatelnost u cheloveka. V kn.: Motivatsionno-
emotsionalniye aspekty. Nauka, Moskva, 1975.
Smiesko V., Kriska M., Kovalcik V. Bayliss myogenic response in the isolated ductus
arteriosus of guinea-pig and rabbit fetuses. Experientia, 1978, 34, 745-746.
Sminia P., Haveman J., Troost D. Thermotolerance of the spinal cord after fractionated
hyperthermia applied to the rat in the cervical region. International Journal of
hyperthermia, 1990, 6, 269-278.
Sminia P., Hulshof M. Hyperthermia and the central nervous system. Progress in Brain
Research (H.S.Sharma and J. Westman (Eds)), 1998, 115, 337-350.
Sminia P., Van der Zee J., Wondergem J. Effect of hyperthermia on the central nervous
system: a review. Int. Hyperthermia, 1994, 10, 1-130.
Smirnov Yu.M., Savelyev N.I. Regulyatsiya krovoobrashcheniya v konechnosti u sobak pri
dykhanii vozdukhom s povyshennym soderzhaniyem kisloroda. Fiziol. zh. SSSR, 1968,
54, 6, 712-716.
Smith R.H., Guilbveau E.J., Reneau D.D. An experimental investigation within descrete
volume of cerebral cortex. In: Proc. 28th Ann. Conf. Eng. Med. Biol., New Orleans, 1975,
p.331.
Smith A.L., Neigh J.L., Hoffman J.C., Wollman M. Effects of general anesthesia on
autoregulation of cerebral blood flow in man. J. Appl. Physiol., 1970, 29, 665-669.
Smith F.J., Vane J.R. Effects of oxygen tension on vascular and other smooth muscles. J.
Physiol., 1966, 186, 284-294.
Sneed P.K., Matsumoto K., Stauffer P.R., Fike J.R., Smith V., Guitin P.H. Interstitial
microwave hyperthermia in canine brain model. Int. J. Radiat. Oncol. Biol. Phys., 1986,
12, 1887-1897.
Snezhko A.D. Ritmicheskiye izmeneniya kisloroda v zhivykh tkanyakh. Dokl. AN SSSR,
1960, 133, 4, 984-987.
Soehle M, Czosnyka M, Pickard JD, Kirkpatrick PJ. Continuous assessment of cerebral
autoregulation in subarachnoid hemorrhage. Anesth Analg 2004, 98,1133–1139.
Sokolov E.I., Podachin V.N., Belova E.V. Emotsionalnoye napryazheniye reaktsii serdechno-
sosudistoi sistemy. Nauka, Moskva, 1980.
Sokoloff L. The action of drugs on the cerebral circulation. Pharmacol. Rev., 1959, 11, 1-85.
Sokoloff L. Relationship among local functional activity, energy metabolism and blood flow
in the central nervous system. Fed. Proc., 1981, 40, 8, 2311-2316.
Sokoloff L., Mangold R., Weschler R.L., Kety S.S. The effect of mental arithmetic on
cerebral circulation and metabolism. J. Clin. Invest., 1955, 34, 1101-1108.
Song C.W. Effect of hyperthermia on vascular functions of normal tissues and experimental
tumors. Brief communication. J. Nat. Cancer Inst., 1978, 60, 711-713.
Song C.W. Effect of local hyperthermia on blood flow and microenvironment: a review.
Cancer Research (Suppl.), 1984, 44, 4721s-4730s.
Song C.W. Physiological factors in hyperthermia. Natl. Cancer Inst. Monogr., 1982, 61, 169-
176.
Song C.W., Kang M.S., Rhee J.G., Levitt S.H. Effect of hyperthermia on vascular function,
pH and cell survival. Radiology, 1980, 137, 795-803.
Sparks H.V. Effect of quick stretch on isolated vascular smooth muscle. Circul. Res., 1964,
14-15, Suppl. 1, 254-260.
Sparks H.V., Bohr D.F. Effect of stretch on passive tension and contractility of isolated
vascular smooth muscle. Amer. J. Physiol., 1962, 202, 835-840.
Steiner LA, Coles JP, Johnston AJ, et al. Assessment of cerebrovascular autoregulation in
head-injured patients: a validation study. Stroke 2003, 34, 2404–2409.
Steiner LA, Coles JP, Johnston AJ, et al. Responses of posttraumatic pericontusional cerebral
blood flow and blood volume to an increase in cerebral perfusion pressure. J Cereb
Blood Flow Metab 2003, 23, 1371–1377.
Stephanovich V. Uptake of adenosine by isolated bovine cortexmicrovessels. Neurochem.
Res., 1983, 8, 11, 1459-1469.
Stewenson L., Christensen B.E., Wortis S.B. Some experiments in intracranial pressure in
man during sleep and under certain other conditions. Amer. J. Med. Sci., 1929, 178, 663-
677.
Stjernschantz J., Bill A. Parasympathetic stimulation and cerebral blood flow. Acta Neurol.
Scand., 1979, 60, Suppl. 72.
Stonestreet B.S., Laptook A., Schanler R., Oh W. Hemodynamic responses to asphyxia in
spontaneously breathing newborn term and premature lamb. Early Hum. Dev., 1982, 7, 1,
81-97.
Storm E.K., Norton D. Localized hyperthermia in the treatment of cancer. CA-A Cancer
Journal for Clinicians. 1983, 33, 1, 44-56.
References 201
Stosseck K. Bestimmung der Mikrodurchblutung im Gehirn durch lokale Gabe von

gasformigem Wasserstoff. Pflugers Arch., 1970, 316, R20.
Stosseck K. Hydrogen exchange through the pial vessel wall and its meaning for the
determination of local blood flow. Pflugers Arch., 1970a, 320, 111-119.
Stosseck K., Lubbers D.W. Determination of microflow of the cerebral cortex by means of
electrochemically generated hydrogen. In: Brain and Blood Flow (Ed. R.W.Russel).
London, 1970, pp.80-84.
Stosseck K., Lubbers D.W., Cottin N. Determination of local blood flow (microflow) by
electrochemically generated hydrogen. Construction and application of the measuring
probe. Pflugers Arch., 1974, 348, 225-238.
Stromberg D.D., Fox J.R. Pressure in the pial arterial microcirculation of the cat during
changes in systemic arterial blood pressure. Circul. Res., 1972, 31, 229-239.
Sundgreen Claus, Fin Stolze Larsen, Tina Maria Herzog, Gitte Moos Knudsen, Soren
Autoregulation of Cerebral Blood Flow in Patients Resuscitated From Cardiac Arrest
Boesgaard, and Jan Aldershvile Stroke, 2001, 32, 128 - 132.
Sveinsdotter E., Torlop P., Risberg J., Ingvar D.H., Lassen N.A. Calculation of regional
cerebral blood flow (rCBF): initial-slope-index compared to height-overtotal-area values.
In: Brain and Blood Flow (Ed. R.W.Russel). London, 1970, pp.85-93.
Sveinsdotter E., Torlop P., Risberg J., Ingvar D.H., Lassen N.A. Calculation of regional
cerebral blood flow (rCBF): initial-slope-index compared to height-overtotal-area values.
In: Brain and Blood Flow (Ed. R.W.Russel). London, 1970, pp.85-93.
Symon L. A comparative study of middle cerebral pressure in dogs and macaques. J.
Physiol., 1967, 191, 449-465.
Symon L., Held K., Dorsch N.W. On the myogenic nature of the autoregulatory mechanism
in the cerebral circulation. Europ. Neurol., 1972, 6, 11-18.
Symon L., Held K., Dorsch N.W. A study of regional autoregulation in the cerebral
circulation to increased perfusion pressure in normocapnia and hypercapnia. Stroke,
1973, 4, 139-147.
Tada K. A study on cerebral blood flow autoregulation. Med. J. Osaka Univ., 1978, 28, 321-
337.
Tagashira Y., Matsuda M., Welch K.M.A., Chabi E., Meyer J.S. Effect of cyclic AMP and
dibutyryl cyclic AMP on cerebral hemodynamics and metabolism in the baboon. J.
Neurosurg., 1977, 46, 484-493.
Takahashi S., Tanaka R., Watanabe M., Takahashi H., Kakinuma K., Suda T., Yamada M.,
Takahashi H. Effects of whole-body hyperthermia on the canine central nervous system.
Int. J. Hyperthermia, 1999, 15, 3, 203-216.
Takasu T., Lyons J.C., Park H.J., Song C.W. Apoptosis and Perturbation of cell cycle
progression in an acidic environment after hyperthermia. Cancer Research, 1998, 58,
2504-2508.
Tanahashi N., Tomita M., Kobari M., Takeda H., Yokoyama M., Takao M., Fukuuchi I.
Platelet activation and erythrocyte aggregation rate in patients with cerebral infarction.
Clin. Hemorheol., 1996, 16, 497-505.
Tarchanoff I. Quelques observations sur le sommeil normal. Arch. Ital. Biol., 1894, 21, 318-
320.
Teplov S.I. Neirogennaya regulyatsiya krovosnabzheniya serdtsa i golovnogo mozga. Nauka,

Leningrad, 1980.
Teplov S.I. Obshchiye i regionarniye zakonomernosti regulyatsii krovoobrashcheniya v
organakh i tkanyakh. V kn.: Aktualniye voprosy fiziologii krovoobrashcheniya.
Simferopol, 1980, 139-142.
Teplov S.I., Balueva T.V. O razlichnoi prirode regionarnoi Vazodilyatatsii pri reflektornom
tormozhenii simpaticheskogo tonusa. Fiziol. zh. SSSR, 1974, 60, 3, 409-414.
Teplov S.I., Borisova E.N., Mikhailova G.P. Neirogormonalniye mekhanizmy
gipotalamicheskikh vliyanii na tonus mozgovikh sosudov. Fiziol. zh. SSSR, 1980, 64, 4,
467-473.
Teplov S.I., Mikhailova G.P., Borisova E.N. Materialy k neirogormonalnoi regulyatsii
mozgovogo krovoobrashcheniya. V kn.: Regionarnoye i sistemnoye krovoobrashcheniye.
Nauka, Leningrad, 1978, 85-92.
Theodorakis N.G., Drujan D., deMaio A. Thermotolerant cells show an attenuated expression
of Hsp70 after heat schok. J. Biol. Chem., 1999, 274, 12081-12086.
Tibble RK, Girling KJ, Mahajan RP. A comparison of the transient hyperemic response test
and the static autoregulation test to assess graded impairment in cerebral autoregulation
during propofol, desflurane, and nitrous oxide anesthesia. Anesth Analg 2001, 93, 171–
176.
Tolmen E. Kognitivniye karty u krys i u cheloveka. V kn.: Khrestomatiya po istorii
psikhologii. Izd. MGU, 1980, 63-82.
Tomiyama Y., Brian J.E., Todd M.M. Plasma viscosity and cerebral blood flow. Am J.
Physiol Heart Circ Physiol., 2000, 279, H1949-H1954.
Toth A., Pal M., Intaglietta M., Johnson P. Contribution of anaerobic metabolism to reactive
hyperemia in skeletal muscle. Am J Physiol Heart Circ Physiol., 2007, 292, H2643-
H2653.
Toyoda K., K. Fujii, S. Ibayashi, S. Sadoshima and M. Fujishima. Changes in arterioles,
arteries, and local perfusion of the brain stem during hemorrhagic hypertension. AJP -
Heart and Circulatory Physiology, 1996, 270, 4, H1350-H1354
Toyota N., Strebel F. R., Stephens L. C., Rowe W., Matsuda H., Oshiro T., Jenkins G.N.,
Bull J.M. Effect of altered duration of 41.5 degrees C whole body hyperthermia in
combination with cis-diammineddichloroplatinum (II) on tumor and normal tissue
apoptosis and tumor response in rats. Oncol. Rep., 1998, 5, 5, 1231-1236.
Traystman R.J., Fitzgerald R.S. Cerebrovascular response to hypoxia in baroreceptor and
hemoreceptor-denervated dogs. Amer. J. Physiol., 1981, 241, 5, H724-H731.
Traystman R.J., Rapela C.E. Effect of sympathetic nerve stimulation on cerebral and cephalic
blood flow in dogs. Circul. Res., 1975, 36, 620-630.
Tsinamdzgvrishvili B., Beritashvili N., Mchedlishvili G. Further insight into blood
rheological disturbances in essential hypertension. Clinical Hemorheology, 1995, 15, 5,
697-705.
Tsubokawa T., Katayama Y., Kondo T., Ueno Y., Hayashi N., Moriyasu N. Changes in local
cerebral blood flow and neuronal activity during sensory stimulation in normal and
sympathectomized cats. Brain Res., 1980, 190, 1, 51-64.
References 203
Tsubokawa T., Katayama Y., Ueno Y., Moriyasu N. Evidence for involvement of the frontal
cortex in pain-related cerebral events in cats: increase in local cerebral blood flow by
noxious stimuli. Brain Res., 1981, 217, 1, 179-185.
Tyaggin N.V. Posledstviya vozdeistviya sverkhvysokochastotnogo elektromagnitnogo polya
na cheloveka. Voyenno-med. zhurn., 1965, 2, 36-40.
Uchida E., Bohr D.F., Hoobler S.W. A method for studying isolated resistance vessels from
rabbit mesentary and brain and their responses to drug. Circul. Res., 1967, 21, 525-538.
Uchida E., Bohr D.F. Myogenic tone in isolated perfused resistance vessels from rats. Amer.
J. Physiol., 1969, 216, 1343-1350.
Vainstein G.B., Parfenov V.E., Gaidar B.V. Dinamica mozgovogo krovotoka i reaktivnosti
cerebralnykh sosudov posle dvukhstoronnei okklusii sonnykh arterii. Fiziol. J. SSSR.,
1988, 74, 6, 820-826.
Van Aken J. Influence of anesthesia on autoregulation of the cerebral blood flow. Acta
Anaesth. Belgica, 1976, 1, 11-19.
Van Ardenne M., Reitnauer P.G. Some experimental and methodological experiences on the
selective inhibition of blood micrcirculation in tumor tissues as the central mechanism of
the cancer multistep therapy (CMT). Arch. Geschwulstforsch, 1985, 55, 3, 177-186.
Van der Zee J., Broelmeyer-Reurink M. P. Van Den Berg A.P. van Geel B.N., Jansen R.F.,
Kroon B.B., van Wijk J., Hagenbeek A. Temperature distribution and pH changes during
hyperthermic regional isolation perfusion. Eur. J. Cancer. Clin. Oncol., 1989, 25, 8,
1157-1163.
Van der Zee. Heating the patient: a promising approach? Annals of Oncology, 2002, 13,
1173-1184.
Van Mil A.H.M., Aart Spilt, Mark A. Van Buchem, Edward L. E. M. Bollen, Luc Teppema,
Rudi G. J. Westendorp, and Gerard J. Blauw. Nitric oxide mediates hypoxia-induced
cerebral vasodilation in humans. J Appl Physiol, 2002, 92, 962-966.
Vanhoutte P.M. Control of vascular function. Role of the nonmuscle components. Mayo Clin.
Proc., 1982, Suppl. 57, 20-27.
Vasques I., Purves M. Studies on the dilator pathway to cerebral blood vessels. Neurogenic
control of the brain circulation (Eds. Owman Edvinsson), Oxford Plenum Press, 1977,
59-73.
Velutti R., Monti J.M. PO2 recording in the amygdaloid complex during the sleep-waking
cycle of the cat. Exper. Neurol., 1976, 50, 798-805.
Voitinski E.Ya., Livshits M.E., Romm B.I., Ryzhikov V.S. Analyz biopotentsialov na
tsifrovoi adaptivnoi sisteme. Nauka, Moskva, 1972.
Wachholder K. Haben die rhytmischen spontankontraktionen der gefasse einen
nachweisbaren einfluss aut den blutstrom? Pflugers Arch., 1921, 190, 223-229.
Wade O.L., Bishop J.M. Cardiac output and regional blood flow. Oxford-Blackwell, 1962.
Wahl M., Kuschinsky W. The dilatatory action of adenosine on pial arteries of cats and its
inhibition by theophylline. Pflugers Arch., 1976, 362, 55-59.
Wahl M., Kuschinsky W. Influence of H+ and K+ on adenosine-induced dilatation at pial
arteries of cats. Blood Vessels, 1977, 14, 285-293.
Walker Matthew, III, Lisa M. Harrison-Bernard, Anthony K. Cook, and L. Gabriel Navar
Dynamic interaction between myogenic and TGF mechanisms in afferent arteriolar blood
flow autoregulation. Am J Physiol Renal Physiol, 2000, 279, 858.
Warocquier R., Scherrer K. RNA metabolism in mammalian cells at elevated temperature.
Eur. J. Biochem, 1969, 10, 362-370.
Wei E.P., Kontos H.A. Responses of cerebral arterioles to increased venous pressure. Amer.
J. Physiol., 1982, 243, H442-H447.
Wei E.P., Raper A., Kontos H., Patterson J. Determinations of response of pial arteries to
norepinephrine and sympathetic nerve stimulation. Stroke, 1975, 6, 654-658.
Weshler Z., Kapp D.S., Lord P.F., Hayes T. Development abd decay of systemic
thermotolerance in lizard. Proc. Natl. Acad. Sci. USA, 1992, 98, 1666-1670.
Willis T. Cerebri anatome.London, Martin & Allestry, 1864.
Winn H. Welsh I., Rubio R., Berne R. Brain adenosine production in rat during sustained
alteration in systemic blood pressure. Amer. J. Physiol., 1980, 239, 5, 636-641.
Winn H., Morri S., Berne R. The role of adenosine in autoregulation of cerebral blood flow.
Ann. Biomed. Eng., 1985, 13, 3,4, 321-328.
Wodick R. Moglichkeiten und grenzen der bestimmung der blutversorgung mit hilfe der
lokalen wasserstoffclearance. Habilitationsschrift zur erlangung der venia legendi fur
das fach physiologie. Hamburg, 1973.
Wodick R., Lubbers D.W., Grunewald W. Auswertverfahren zur Bestimmung der
Organdurchblutung nach Atmung von Wasserstoffgemischen. Pflugers Arch., 1969, 307,
R51.
Xu L., Zhu L., Holmes K. Blood perfusion in the canine prostate during transurethral
hyperthermia. Ann. N.Y. Acad. Sci., 1998, 858, 21-29.
Yakovleva E.S. Razvitiye vnutrennei sonnoi arterii i chudesnoi seti osnovaniya cherepa
nekotorykh mlekopitayushchikh. Avtoref. dokt. diss., Moskva, 1948.
Yamada N. The effects of hyperthermia on cerebral blood flow, metabolism and
electroencepohalogram. No to Shinkei, 1989, 41, 2, 205-212.
Yarmonenko S.P. Thermoradiotherapy of cancer: state of the art, future trends. Medical
Radiology, 1987, 1, 10-18.
Yoshida K., Meyer J.S., Saramoto K., Handa J. Autoregulation of cerebral blood flow.
Electromagnetic flow measurements during acute hypertension in the monkey. Circul.
Res., 1966, 19, 4, 726-738.
Yoshikawa T., Kokura S., Tainaka K., Itani K., Oyamada H., Kaneko T., Naito Y., Kondo M.
The role of active oxygen species and lipid peroxidation in the antitumor effect of
hyperthermia. Cancer Research, 1993, 53, 2326-2329.
Yumatov E.A. O prilozhenii teorii avtomatocheskogo regulirovaniya k probleme regulyatsii
dykhatelnykh pokazatelei organizma. V kn.: Aktualniye voprosy sovremennoi fiziologii.
Nauka, Moskva, 1976.
Zaguskina L.D., Zaguskin S.L. Zavisimost kolebanii napryazheniya kisloroda nad
poverkhnostyu nervnoi kletki ot yiyo funktsii. V kn.: Polyarograficheskoe opredelenie
kisloroda v biologicheskikh obyektakh. Naukova dumka, Kiev, 1974, 225-229.
Zeidan Asad, Ina Nordström, Sebastian Albinsson, Ulf Malmqvist, Karl Swärd, and Per
Hellstrand. Stretch-induced contractile differentiation of vascular smooth muscle:
References 205
sensitivity to actin polymerization inhibitors. Am J Physiol Cell Physiol, 2003, 284,

C1387 - C1396.
Zelikson B.B. Osobennosti autoregulyatsii mozgovogo krovotoka pri izmeneniyakh
arterialnogo davleniya. Fiziol. zh. SSSR, 1973, 59, 613-620.
Zhang Rong, Julie H. Zuckerman, Kenichi Iwasaki, Thad E. Wilson, Craig G. Crandall, and
Benjamin D. Levine. Autonomic Neural Control of Dynamic Cerebral Autoregulation in
Humans. Circulation, 2002, 106, 1814 - 1820.
Zhu L., Pang L., Xu L. Simultaneous measurements of local tissue temperature and blood
perfusion rate in the canine prostate during radio frequency thermal therapy.
Biomechanics and Modelling in Mechanobiology, 2005, 4, 1, 1-9.
Zvetnow N. CBF autoregulation to blood pressure and intracranial pressure variations. Scand.
J. Lab. Clin. Invest., 1968, Suppl. 102, V:A.
Zvetnow N., Kjallquist A., Siesjo B.K. Elimination of autoregulation following a period of
pronounced intracranial hypertension: is hypoxia involved? Scand. J. Lab. Clin. Invest.,
1968, Suppl. 102, V:F.
INDEX
albino, 91, 100, 104, 108, 109

A
alcohol, 182
alertness, 99
abdominal, 9, 11, 14, 35
alkalosis, 171
acceptor, 68
alpha, 2, 30, 32, 49, 55, 109, 175, 184, 189
acetylcholine, 23, 29, 33, 190
alters, 88, 95, 162
achievement, 142
Alzheimer, 172, 174
acid, 26, 137, 171
amnesia, 108, 109
acidic, 24, 135, 138, 201
amplitude, 38, 43, 61, 65, 70, 72, 89, 95, 96, 101,
acidification, 140
114, 164
acidity, 136, 140, 172
anaerobic, 22, 202
acidosis, 13, 25, 67, 72, 139, 180
anaesthesia, 11
actin, 205
analog, 3
action potential, 22
anastomoses, 3, 181
activation, 5, 24, 26, 27, 86, 88, 139, 163, 169, 182,
anatomy, 2, 169
184, 197, 201
angiogenic, 183
active oxygen, 204
angiotensin, 14, 28, 194
activity level, 104
animal studies, 181
acute, 15, 32, 60, 67, 72, 84, 88, 108, 167, 172, 176,
animals, 2, 25, 31, 32, 36, 39, 48, 58, 59, 60, 65, 66,
178, 186, 197, 199, 204
67, 87, 88, 91, 92, 93, 94, 99, 100, 105, 109, 119,
adaptation, 79, 184, 187
138, 141, 142, 143, 145, 146, 147, 148, 149, 150,
adenine, 24, 170
151, 152, 155, 156, 157, 164, 170, 199
adenosine, 24, 25, 26, 27, 67, 169, 170, 176, 181,
anoxia, v, 69, 70, 73, 75, 76, 77, 84, 111, 132, 167,
186, 200, 203, 204
176, 183
administration, 25, 27, 31, 34, 42, 51, 55, 68, 93,
anoxic, 66
108, 158
antagonist, 49, 50, 108, 109
ADP, 24, 65, 136
antagonists, 34, 168, 175
adrenaline, 173
antenna, 189
adrenergic neurons, 51
anticancer, 175
adult, 75, 113, 142
anti-cancer, 136
age, 172, 183
anticholinergic, 93, 105, 108
agent, 10, 28, 51, 53, 55, 107
antioxidant, 159
agents, 31, 42, 44, 49, 51, 140, 167, 168, 185
antioxidants, 165, 182
aggregation, 141, 158, 159, 169, 174, 184, 193, 201
antitumor, 186, 204
aging, 180
anti-tumor, 140, 154
air, 67, 68, 69, 70, 72, 73
anxiety, 89
208 Index
aorta, 9, 14, 35 binding, 3

apnea, 191 biochemical, 60, 173, 181
apoptosis, 135, 153, 202 biological, 124, 125, 137, 138, 141, 175, 184
application, 1, 2, 4, 17, 24, 27, 48, 55, 58, 59, 89, biologically
124, 126, 135, 136, 137, 140, 201 blocks, 107
arginine, 68 blood plasma, 28
argument, 5, 22 blood pressure, 9, 11, 21, 24, 39, 172, 177, 178, 179,
arithmetic, 89 181, 187, 201, 204, 205
arousal, 112, 116, 117, 169 Blood pressure, 173
arterial hypertension, 172 blood stream, 10
arteries, 2, 3, 11, 12, 14, 17, 22, 24, 25, 26, 27, 28, blood supply, iv, 1, 2, 3, 5, 6, 12, 14, 23, 29, 30, 32,
29, 30, 31, 32, 33, 34, 43, 75, 108, 109, 126, 163, 34, 44, 50, 51, 57, 79, 83, 85, 86, 108, 109, 123,
168, 171, 174, 178, 179, 183, 186, 187, 193, 202, 124, 126, 136, 161, 163, 164, 192, 197
203, 204 blood vessels, 16, 18, 23, 28, 38, 39, 40, 41, 51, 172,
arterioles, 29, 30, 148, 149, 150, 151, 152, 158, 186, 173, 190, 191, 195, 198, 203
202, 204 blood-brain barrier, 25, 31, 32, 49, 142
arteriovenous shunt, 196 body temperature, 143, 154, 165
artery, 3, 10, 25, 27, 28, 30, 50, 72, 109, 169, 171, body weight, 143, 155
173, 181, 182, 189, 198 Bohr, 22, 23, 28, 29, 39, 40, 43, 68, 176, 178, 182,
artificial, 27, 28, 73, 75, 127, 136, 140, 142, 143, 183, 200, 203
163 boils, 98
asphyxia, v, 9, 72, 73, 75, 76, 77, 78, 184, 200 bone, 142
assessment, 18, 124, 187, 190, 200 bovine, 28, 195, 200
assumptions, 111 bradycardia, 14
ATF, 179 bradykinin, 23
ATP, 23, 24, 65, 139, 178, 185 brain damage, 83
ATPase, 25, 193 brain functions, 1, 65
atropine, 27, 34, 107, 185 brain injury, 11, 182, 190
attention, 2, 5, 65, 103, 125, 155 brain stem, 112, 113, 182, 202
autocorrelation, 113, 114 brain structure, v, 3, 5, 66, 84, 88, 91, 102, 104, 109,
automation, 22 111, 112, 113, 118, 123, 124, 161, 164
autonomic, 2, 31 brain tumor, 172
autoradiography, 112 brainstem, 85, 169, 187, 189, 191
autoregulate, 16 branching, 3
availability, 161, 171 brass, 126
averaging, 15 breakdown, 24, 25, 140, 142
awareness, 105, 176 breathing, 68, 77, 200
by-products, 24
B
C
bacteria, 136
baroreceptor, 29, 202 Ca++, 27, 186
barrier, 25, 31, 184, 189, 195 calcium, 26, 27, 176, 186, 193
basilar artery, 3 caliber, 38
BBB, 163, 184 cancer, 6, 124, 139, 141, 169, 173, 177, 179, 180,
Bcl-2, 136 186, 188, 194, 196, 197, 200, 201, 203, 204
behavior, 2, 77, 91, 95, 98, 99, 100, 101, 102, 106, cancer treatment, 141, 177
164 capacity, 9, 15, 16, 38, 40, 42, 58, 60, 136, 196
beta, 2, 30, 32, 51, 53, 172, 189, 198 capillary, 3, 12, 67
bicarbonate, 173, 187 carbohydrate, 176
bifurcation, 31 carbohydrate metabolism, 176
Index 209
carbon, 176, 181, 186 chemical composition, 43

carbon dioxide, 176, 181, 186 chemical reactions, 135
cardiac output, 196 chemoreceptors, 30, 68, 195
cardiopulmonary, 167, 189, 196 chemoresistant, 137
cardiopulmonary bypass, 167, 196 chemotherapy, 135, 136, 138, 141, 153
cardiovascular, 101, 159, 185 chiasma, 3
cardiovascular disease, 185 children, 183
cardiovascular risk, 159 cholinergic, 5, 29, 30, 31, 33, 34, 44, 49, 53, 54, 55,
cardiovascular system, 101 93, 105, 107, 108, 161, 173, 175, 180, 185, 190,
carotid arteries, 3, 11, 27 195
carotid sinus, 31, 195 cholinergic block, 44, 49, 53, 55
carrier, 113 choroid, 176
caspases, 136 chronic, 15, 83, 85, 125, 170, 183
catecholamines, 187, 198 circulation, iv, 1, 2, 3, 4, 5, 6, 10, 11, 21, 29, 30, 32,
catheter, 75, 142, 174 33, 38, 43, 51, 59, 65, 86, 92, 109, 111, 113, 123,
cathode, 18, 175 140, 158, 163, 167, 173, 174, 176, 177, 178, 179,
cats, 24, 25, 26, 27, 32, 35, 44, 52, 55, 67, 75, 86, 87, 180, 182, 185, 187, 190, 191, 192, 193, 195, 196,
89, 112, 113, 120, 141, 167, 169, 173, 175, 176, 197, 198, 200, 201, 203
178, 180, 184, 187, 196, 202, 203 classical, 4, 112
cell, 26, 27, 28, 68, 84, 136, 137, 138, 140, 141, 145, classification, 38
146, 147, 151, 159, 174, 178, 180, 188, 191, 192, classified, 104
200, 201 cleavage, 136
cell cycle, 137, 201 clinical, 2, 11, 14, 83, 104, 112, 124, 125, 126, 139,
cell killing, 141 140, 141, 171, 172, 173, 191
centigrade, 135 clinical trial, 171
central nervous system, 88, 181, 199, 200, 201 clinics, 6, 85, 125
cerebellum, 30, 112, 124, 131, 132, 133, 165, 189 closure, 120
cerebral arteries, 3, 25, 26, 27, 28, 30, 167, 168, 186, CNS, 88, 125, 165
187 CO2, 12, 23, 26, 27, 35, 60, 75, 92, 98, 168, 169,
cerebral cortex, 1, 2, 16, 26, 35, 38, 43, 50, 52, 54, 175, 179, 197
55, 56, 66, 75, 77, 83, 84, 86, 87, 96, 97, 100, coagulation, 188
101, 102, 104, 105, 107, 109, 124, 125, 126, 130, cognitive, 99, 101, 165
131, 132, 142, 144, 145, 146, 147, 148, 149, 155, cognitive activity, 165
156, 157, 158, 168, 169, 171, 174, 177, 178, 181, cognitive map, 99
183, 187, 189,Ű199, 201 collateral, 3, 14, 179
cerebral damage, 197 communication, 3, 200
cerebral function, 165, 183 compatibility, 23
cerebral hemisphere, 30, 92 compensation, 57, 58, 60, 163, 164
cerebral hypoxia, 181 complementary, 198
cerebral ischemia, 24, 111 complexity, 2, 195
cerebral metabolism, 88, 111, 142, 168, 180, 183, compliance, 172
195 components, 22, 40, 44, 46, 47, 48, 55, 56, 57, 58,
cerebrospinal fluid, 25, 142, 143 59, 60, 61, 88, 164, 184, 203
cerebrovascular, 5, 89, 165, 176, 194, 196, 199, 200 composite, 58
certainty, 60, 132 composition, 143
cervical, 30, 32, 167, 199 compression, 13, 184
channels, 13, 50, 60, 76, 181 computer, 42, 84, 126
charm, 69 concentration, 12, 24, 25, 26, 27, 28, 29, 65, 67, 137,
chemical, 29, 31, 43, 135, 187 139, 173, 176, 193, 199
chemical agents, 31 concrete, 13, 39, 40, 70, 120
210 Index
conduction, 173 decerebration, 192

confidence, 155, 156 deduction, 41, 72
configuration, 91, 92, 94, 95, 101 defense, 105, 106, 107
consciousness, 65 deficiency, 66, 79
consensus, 164 deficit, 28, 79, 105
consolidation, 93, 98, 102 definition, 99
construction, 18, 19, 35, 91, 93, 126 deformability, 141, 159
consumption, 1, 105, 154 deformation, 5, 22
continuing, 99 degree, 2, 3, 14, 15, 23, 25, 38, 43, 61, 70, 75, 85,
continuity, 102 88, 89, 136, 140, 173
contralateral hemisphere, 127, 132 delivery, 103, 187
control, 4, 13, 24, 29, 51, 52, 72, 85, 87, 93, 100, delta, 85
102, 112, 119, 124, 143, 145, 155, 170, 172, 175, demand, 67, 70, 71, 72, 77, 84
179, 183, 184, 185, 186, 187, 191, 194, 195, 198, dementia, 83, 183
203 denaturation, 184
control group, 112, 155 dendrites, 148
controlled, 14, 39, 75, 142, 143, 184 denervation, 32, 34, 109, 161, 164
convective, 167 density, 3, 84, 129, 147, 148, 149, 152, 163
conversion, 23 depolarization, 27, 28
coronary arteries, 176 depression, 84, 176, 190
correlation, 3, 25, 28, 38, 46, 65, 67, 70, 75, 85, 86, desire, 143
93, 96, 100, 102, 111, 114, 120, 137, 186 destruction, 124, 140, 157
correlation coefficient, 114 desynchronization, 2, 84, 85, 96, 118, 125
correlation function, 100 detection, 178
cortex, 1, 26, 49, 50, 52, 53, 54, 55, 66, 76, 83, 84, deviation, 19, 45, 57, 61, 92, 95
85, 86, 87, 88, 89, 96, 97, 103, 104, 113, 114, differentiation, 1, 44, 89, 204
117, 118, 119, 124, 131, 132, 145, 146, 147, 148, diffusion, 15, 17, 27, 137
149, 150, 151, 152, 153, 154, 155, 157, 165, 180, dilation, 9, 24, 29, 30, 33, 42, 43, 51, 52, 139, 196
188, 193 dipole, 125
cortical, 24, 26, 27, 43, 83, 84, 85, 86, 88, 91, 93, 98, direct action, 25, 26, 31, 120
100, 103, 104, 147, 150, 151, 178, 183, 186, 198 direct measure, 2, 11, 15
cortical neurons, 24, 26, 84, 103, 183 discharges, 68, 125, 178
coupling, v, 5, 16, 22, 67, 83, 84, 88, 101, 102, 104, discomfort, 86
109, 120, 163, 164 discrimination, 103
cranial nerve, 33 diseases, 86
craniotomy, 143 displacement, 72, 77
critical analysis, 136 disposition, 127, 128
critical points, 165 distribution, 25, 29, 42, 66, 78, 83, 84, 85, 86, 87,
CSF, 25, 33, 167 147, 148, 149, 152, 164, 180, 185, 203
culture, 125 diurnal, 177
cyclic AMP, 201 division, 135
cytoplasm, 159 DNA, 136, 137
cytotoxic, 137, 139 dogs, 25, 28, 32, 68, 105, 141, 173, 174, 175, 177,
cytotoxic agents, 137 178, 180, 181, 186, 201, 202
dopamine, 168
D
Doppler, 15, 174
dreaming, 191
data analysis, 112
drug addict, 136
data processing, 35
drug addiction, 136
death, 126, 188
drug-induced, 171
decay, 204
Index 211
drugs, 93, 105, 184, 188, 200 environment, 43, 61, 69, 102, 135, 138, 168, 201
ductus arteriosus, 199 environmental, 57, 61, 100, 136, 140, 164, 165, 194
dura mater, 25, 31, 142 environmental factors, 194
duration, 13, 14, 17, 38, 47, 72, 76, 89, 95, 99, 114, environmental stimuli, 100, 164
115, 117, 128, 135, 136, 137, 140, 144, 153, 154, enzymatic, 24
202 enzymes, 184
epilepsy, 83, 183
E
epileptic seizures, 172
epinephrine, 194
ecological, 124
equilibrium, 109, 173
edema, 72, 139
erythrocyte, 158, 174, 193, 201
EEG, 2, 65, 70, 85, 105, 112, 125, 169, 178, 183,
erythrocytes, 141, 148, 150, 151, 157
195
erythrocytosis, 141
EEG patterns, 183
estimating, 118
efferent nerve, 163
evidence, 1, 2, 4, 10, 16, 21, 23, 26, 27, 29, 43, 59,
ego, 190, 197
77, 89, 101, 102, 103, 142, 171, 183, 192, 198
elaboration, 93
excitability, 113, 125
elasticity, 40, 41
excitation, 59
elderly, 83, 141
exclusion, 55, 60
electric current, 17
exercise, 180, 185
electrical, 1, 2, 22, 24, 26, 30, 32, 33, 34, 67, 68, 69,
exogenous, 31, 187
84, 85, 86, 111, 112, 113, 116, 117, 118, 123,
experimental condition, 16, 39, 43, 56, 61, 88, 91,
124, 125, 132, 161, 163, 168, 169, 172, 175, 176,
92, 93, 99, 102, 105, 117, 118, 152, 162
181, 183, 184, 188
expert, 4
electrochemical, 17, 75, 92, 126
experts, 6
electrodes, 17, 35, 36, 66, 69, 89, 92, 93, 96, 113,
exponential, 140
127, 128, 129, 167
exposure, 4, 45, 125, 126, 127, 129, 130, 131, 132,
electroencephalogram, 65
133, 135, 136, 137, 138, 140, 143, 144, 145, 147,
electrolysis, 186
148, 150, 152, 153, 157, 158, 165
electromagnetic, 124, 125
expulsion, 120
electromagnetic waves, 124, 125
extracellular, 24, 26, 27, 67, 68, 172, 186, 194, 199
electron, 33, 142, 178
extrinsic, 183
electron paramagnetic resonance, 142, 178
eye, 83, 88, 112, 117, 119, 172
electrons, 68
eye movement, 112, 117, 119, 172
electrophysiological, 92, 104, 112
elongation, 178 F
emission, 15, 188
emotional, 89, 90, 100, 101, 102, 104, 105, 106, 108, facial nerve, 30, 33, 188
109, 111, 164, 165, 170 fear, 105, 106
emotional reactions, 89 feedback, 13, 26, 120, 142, 143, 164
emotional state, 90, 109 fetal, 184
emotional stimuli, 89, 100, 170 fetuses, 199
emotions, 89, 100, 101, 105, 164, 165 fiber, 30, 108
employment, 125 fibers, 22, 30, 33, 68, 107, 193
endogenous, 187 fibrin, 165
endothelial cell, 25 fibrinogen, 141
endothelial cells, 25 fixation, 15, 103
endothelium, 25, 31 flow, 9, 10, 15, 16, 17, 23, 26, 28, 32, 33, 34, 43, 67,
energy, 1, 67, 68, 69, 84, 85, 101, 112, 126, 137, 83, 84, 85, 86, 87, 88, 89, 100, 101, 102, 104,
139, 182, 185, 186, 189, 191, 200 105, 109, 112, 116, 117, 120, 132, 136, 137, 139,
energy consumption, 1, 84
212 Index
140, 141, 153, 159, 164, 168, 174, 177, 178, 182, heating, 125, 132, 135, 136, 137, 138, 139, 140, 143,
183, 184, 187, 191, 195, 204 144, 156, 157, 158, 180, 181
flow rate, 153 height, 71, 201
flow value, 9, 10, 18, 43 hematocrit, 72, 75
fluctuations, 107, 113, 137, 182 hemisphere, 26, 86, 88, 89, 127, 128, 183, 197
fluid, 12, 24, 25, 27, 143, 172 hemodynamic, 3, 29, 84, 109, 183
food, 93, 99, 103, 104, 197 hemodynamics, 23, 86, 159, 174, 191, 196, 197, 201
fragmentation, 136 hemorrhage, 140
free radicals, 141, 142, 143, 158, 159, 165, 178, 186 heterogeneity, 16, 137, 164, 190
frontal cortex, 102, 103, 104, 105, 203 high pressure, 11
frontal lobe, 109 high temperature, 135, 137, 138, 153
functional approach, 4, 31 high-speed, 38
functional changes, 102, 125 hippocampal, 85, 113, 115, 117, 193
hippocampus, 85, 89, 113, 114, 115, 116, 117, 118,
G
119, 124, 165
Hippocampus, 115
ganglia, 3, 30
histamine, 23, 31, 173
ganglion, 30, 32
histochemical, 33, 184
gas, 35, 65, 70, 185, 189
histogram, 66
gas exchange, 189
histological, 15, 29, 142, 144, 145, 155, 189, 190
gases, 32, 34, 179, 188
HIV, 136
general anesthesia, 199
homeostasis, 57, 60, 67, 69
generation, 1, 15, 17, 18, 19, 22, 35, 75, 92, 100,
homocysteine, 198
125, 126, 142, 159
homogeneous, 13
genistein, 182
hormone, 29
glass, 17, 19, 126, 144
hormones, 21, 23
glial, 72, 113
horse, 169
glucose, 84, 88, 139
Hsp70, 202
glycolysis, 136
human, 1, 2, 25, 84, 104, 136, 137, 138, 139, 140,
goal-directed, 2, 103, 104, 105
165, 167, 169, 175, 178, 179, 184, 189, 194, 197
goal-directed behavior, 2, 105
human behavior, 165
gold, 126
human brain, 1, 104, 194
government, iv
human cerebral cortex, 84, 179
gray matter, 32, 88, 112, 197
human subjects, 178
groups, 24, 99, 108, 114, 143, 145, 147, 182
humans, 1, 2, 29, 68, 89, 100, 104, 180, 189, 197,
gyrus, 88, 89, 100
203
H Hydrate, 142
hydrogen, 15, 17, 18, 19, 35, 75, 88, 92, 126, 131,
H2, 172 139, 168, 174, 175, 177, 186, 201
haematocrit, 141, 158 hydrogen gas, 168, 177, 186
harm, 60 hydrogen peroxide, 175
harmony, 60 hydroxyl, 175
head, 174, 182, 194, 200 hypercapnia, 11, 24, 26, 27, 51, 167, 168, 173, 180,
head injury, 174, 182 186, 195, 201
health, 185, 198 hypercarbia, 168
heart, 14, 25, 92, 100, 107, 169, 174, 178, 182, 189, hyperemia, 1, 21, 23, 24, 25, 29, 68, 70, 71, 72, 75,
202 83, 84, 86, 129, 132, 172, 189, 197, 202
heart rate, 100 hyperglycemia, 136
heat, 1, 15, 125, 132, 136, 137, 138, 139, 140, 141, hyperlipoproteinemia, 159
142, 158, 159, 169, 173, 182, 183, 188, 192, 202 hyperplasia, 146, 147
Index 213
hypertension, 14, 32, 33, 35, 159, 163, 180, 188, inhibition, 103, 137, 140, 168, 181, 194, 203
202, 204, 205 inhibitor, 68
hyperthermia, v, vi, 6, 121, 125, 126, 135, 136, 137, inhibitors, 205
138, 139, 140, 141, 142, 145, 146, 147, 148, 149, inhibitory, 33, 103, 179, 185
150, 151, 152, 153, 154, 155, 156, 157, 158, 159, initial state, 70
165, 171, 172, 176, 177, 178, 179, 180, 181, 184, initiation, 67, 140
185, 186, 188, 189, 194, 195, 196, 197, 198, 199, injection, 13, 14, 17, 33, 49, 50, 51, 52, 53, 54, 55,
200, 201, 202, 204 56, 89, 93, 105, 106, 107, 108, 142, 155, 186
hypocapnia, 24, 27, 67, 87, 180 injections, 33, 49, 108
hypotension, 13, 14, 24, 35, 168, 186, 188 injury, 60, 151
hypotensive, 196 innervation, 5, 29, 30, 31, 33, 51, 107, 108, 161, 163,
hypothalamic, 67, 173, 186 171, 176, 182, 184, 193, 195, 198
hypothalamus, 30, 100, 112, 113, 163, 177 inorganic, 25, 27
hypothesis, 1, 13, 22, 23, 26, 30, 33, 71, 72, 73, 77, insight, 202
78, 111, 142, 178 insomnia, 112
hypoxemia, 187, 189, 199 instability, 125
hypoxia, 11, 24, 29, 65, 66, 67, 68, 69, 70, 71, 72, integration, 41
73, 75, 76, 84, 88, 154, 174, 176, 178, 180, 181, intensity, 1, 17, 26, 29, 33, 70, 72, 84, 86, 88, 89,
184, 186, 187, 189, 195, 199, 202, 203, 205 113, 117, 126, 138, 141, 154
hypoxic, 67, 69, 72, 73, 76, 136, 137, 173, 180, 189 interaction, 16, 23, 30, 33, 59, 125, 165, 170, 187,
hypoxic stress, 180 191, 204
interactions, 125, 140, 165
I
interference, 125, 179
international, 167
identification, 113, 151
interpretation, 9, 21, 26, 168, 192
illumination, 87, 103
interstitial, 24, 139, 176, 177, 189
image analysis, 174
interval, 4, 93, 137, 138, 144
imaging, 68
intervention, 179
immunoglobulin, 141
intracerebral, 3, 30, 43, 124, 163, 176, 186
impotency, 60
intracranial, 33, 72, 86, 111, 197, 200, 205
in vitro, 44, 138, 168, 198
intracranial pressure, 33, 72, 111, 197, 200, 205
in vivo, 15, 22, 33, 138, 190, 191, 195, 196, 198
intravascular, 9, 10, 11, 16, 21, 22, 23, 26, 28, 38,
inactivation, 2, 31
57, 163, 190
inclusion, 136
intravenous, 49, 51
independence, 75
intravenously, 49
indication, 1, 30, 199
intrinsic, 2, 124, 196
indicators, 15
invasive, 124, 133
indices, 117, 118, 125
investigations, 42, 196
indirect measure, 168
ionic, 168, 171
individual differences, 11, 72
ionizing radiation, 136, 137, 138, 171, 188
induction, 13, 17, 125, 126, 179, 185
ions, 18, 23, 25, 26, 27, 125, 139, 186
inert, 32, 34, 92, 185
ipsilateral, 131
inertia, 15
irradiation, 128, 129, 130, 131, 132, 165, 176, 192
infarction, 201
irritation, 163
inferences, 43, 85, 124
ischemia, 11, 21, 28, 111, 141, 159, 199
inferior vena cava, 14, 35
ischemic, 21, 170
infinite, 4
isolation, 1, 203
infrared, 142
inhalation, 17, 26, 67, 68, 69, 72, 73, 88, 188 K
inherited, 159
inherited disorder, 159 K+, 27, 28, 67, 186, 187, 203
214 Index
ketamine, 127 maintenance, 1, 6, 24, 61, 67, 68, 72, 137

kidney, 10, 11, 25, 180 malignant, 125, 171, 172, 189
killing, 198 malignant tumors, 171
kinetics, 193, 194 mammalian brain, 175, 198
mammalian cell, 184, 204
L
mammalian cells, 204
mammals, 138
lactic acid, 25, 72
mask, 31, 102, 164
land, 158
mathematical, 39, 40
laser, 193
maze learning, 93, 96, 97, 101
latency, 53, 71, 72, 75, 77, 128, 132
maze tasks, 105
latent learning, 99
measurement, 2, 9, 15, 16, 17, 32, 34, 35, 66, 69,
law, 17, 78, 102, 179
111, 112, 119, 126, 127, 128, 131, 132, 144, 156,
laws, 139
168, 170, 173, 183, 186, 193
lead, 5, 21, 22, 27, 28, 32, 33, 43, 51, 55, 57, 58, 60,
measures, 18
84, 119, 132, 137
mechanical, iv, 12, 15, 43, 168, 178, 182, 184
learning, 92, 93, 94, 95, 98, 99, 100, 101, 102, 103,
mechanical properties, 182, 184
104, 105, 106, 107, 108, 109, 129, 164
mediation, 27
learning process, 99
medication, 136
lesions, 11, 144, 148, 149, 150, 151, 155, 156
medulla, 3, 130, 131, 132, 133, 165, 174
leukemia, 136
medulla oblongata, 3, 130, 131, 132, 133, 165, 174
leukemia cells, 136
membranes, 25, 51, 169
limitation, 28, 34, 42
memory, 91, 93, 105
limitations, 4, 196
meningitis, 12, 195
linear, 4, 15, 26, 33
mental activity, 1, 2, 88
linear systems, 4
mental arithmetic, 88, 200
links, 3, 13, 56, 58, 102, 161, 163
mesencephalon, 112
lipid, 25, 204
messages, 67
lipid peroxidation, 204
metabolic, v, 1, 2, 5, 6, 12, 21, 23, 28, 29, 43, 51, 56,
lipids, 199
57, 58, 59, 60, 61, 67, 68, 70, 71, 72, 77, 81, 84,
liquidation, 61
88, 91, 102, 104, 105, 109, 113, 117, 119, 120,
liquor, 24
124, 132, 135, 137, 141, 158, 161, 162, 163, 164,
literature, 6, 10, 11, 13, 26, 39, 40, 41, 43, 56, 67,
170, 178, 184, 185, 189
84, 85, 102, 142
metabolic changes, 124, 184
local anesthesia, 45
metabolic rate, 68, 141
localization, 13, 15, 93, 96, 102, 123, 173, 177
metabolic shift, 84, 120
location, 71, 99, 127, 128, 143, 150, 165
metabolism, 3, 12, 21, 23, 24, 25, 28, 29, 31, 51, 61,
locomotion, 100, 102
65, 67, 84, 86, 87, 88, 101, 102, 104, 105, 109,
locus, 30, 163
112, 113, 119, 120, 123, 124, 163, 164, 174, 178,
long-term, 125
180, 182, 183, 184, 186, 188, 189, 190, 191, 195,
loss of consciousness, 65
199, 200, 201, 202, 204
lumen, 4, 16, 29, 34, 108
metabolites, 21, 22, 23, 29
luminal, 158
MgSO4, 143
lying, 17, 22
mice, 139, 185, 188
M microcirculation, 17, 67, 126, 136, 140, 141, 171,
180, 185, 189, 196, 199, 201
macrophages, 183 microcirculatory, 67, 159, 190
magnetic, 29, 68, 199 microelectrodes, 69, 126
magnetic resonance, 29, 68 microenvironment, 200
magnetic resonance imaging, 29, 68 micrometer, 144
Index 215
microscope, 144 neurogenic, 5, 12, 23, 26, 27, 29, 30, 31, 32, 33, 34,
microspheres, 33, 34, 190 44, 49, 50, 52, 55, 56, 57, 58, 59, 60, 61, 109,
microvascular, 179 123, 132, 133, 161, 162, 163, 164, 176, 184, 185,
microwave, 6, 123, 124, 125, 126, 127, 128, 129, 187, 195, 197, 198, 203
130, 131, 132, 133, 153, 165, 171, 177, 189, 191, neurons, 26, 27, 84, 102, 103, 104, 146, 147, 148,
192, 200 149, 150, 151, 157, 172, 177, 189
microwave radiation, v, 6, 123, 124, 125, 126, 127, neurophysiology, 184
128, 130, 131, 132 neurotransmitter, 31
microwaves, 125, 126, 128, 129, 131, 132, 133, 169, neurotransmitters, 31, 142, 168, 176, 181, 183, 195,
180 196, 198
mirror, 102 nicotine, 33, 194
mitochondria, 66, 68 Nielsen, 5, 30, 33, 138, 176, 193, 194, 195
mnemonic processes, 103 nitrogen, 68, 69, 72, 73, 132
modeling, 42 nitrous oxide, 185, 202
modulation, 103, 104, 123, 125 NO, 29, 68
modulus, 40 NO synthase, 68
molecular weight, 143, 155, 158 nociceptive, 86
monkeys, 32, 103, 141, 197 noise, 89
monograph, 123, 125 nonparametric, 97
morphological, v, vi, 1, 121, 135, 141 noradrenaline, 14, 25, 33, 168, 174
morphology, 172, 174, 194 norepinephrine, 187, 194, 204
motivation, 93, 99, 102 normal, 9, 22, 27, 32, 57, 58, 59, 61, 66, 67, 68, 70,
motor activity, 87, 95, 100, 101, 103, 106, 108, 168 75, 78, 84, 86, 88, 106, 108, 125, 136, 137, 139,
motor area, 88, 97, 102, 103, 112, 142 140, 141, 143, 152, 155, 156, 157, 158, 159, 163,
mouse, 89, 90, 158, 169, 177, 179, 188 171, 172, 173, 177, 180, 182, 185, 189, 190, 200,
movement, 89, 92, 93, 95, 97, 100, 101, 103, 104, 201, 202
107, 180 normal conditions, 32, 57, 58, 59, 66, 67, 86, 106,
MRI, 15 108, 158, 163
muscle, 5, 22, 25, 26, 27, 28, 68, 168, 181, 182, 184 normal development, 61
muscles, 21, 22, 25, 27, 28, 68 normocapnia, 201
nuclear, 158, 190
N
nuclear magnetic resonance, 190
nuclei, 27, 85, 123, 124, 132, 163, 175
narcolepsy, 191
nucleolus, 147, 148, 149, 151
National Research Council, 183
nucleons, 183
natural, 21, 163, 169, 182
nucleotides, 24, 27, 170
necrosis, 135, 140, 141, 153
nucleus, 30, 147, 148, 149, 175
Nembutal, 45, 58, 75
nurse, 89
neocortex, 118
neoplastic, 186 O
nerve, 5, 9, 24, 25, 26, 29, 30, 33, 58, 65, 69, 84,
113, 119, 126, 129, 161, 163, 171, 189, 202, 204 observations, 22, 28, 48, 55, 58, 67, 69, 91, 104, 112,
nerve cells, 84 113, 165, 201
nerve fibers, 5, 24 occipital cortex, 86
nerves, 9, 25, 30, 31, 32, 34, 163, 168, 173, 181, occlusion, 9, 11, 14, 22, 72, 140, 159, 165, 189
183, 186, 188, 196, 197, 198 oncological, 6, 125
nervous system, 99, 118, 125 oncology, 136, 178, 203
network, 3, 22 operator, 15
neural mechanisms, 120 opposition, 69
neural systems, 124 optical, 196
neurodegeneration, 172 organ, 9, 10, 13, 22, 23, 28
216 Index
organic, 183 permit, 85, 120

organism, 1, 60, 70, 102, 105, 135 peroxidation, 199
organization, 2, 4, 6, 10, 31, 59, 60, 85 PET, 172
orientation, 2, 95, 99, 100, 101 pH, 25, 27, 67, 75, 119, 120, 135, 136, 137, 139,
oscillation, 60, 61, 115, 118, 125, 182 140, 143, 154, 169, 176, 178, 179, 182, 184, 190,
oscillations, 3, 112, 113, 114, 115, 117, 118 193, 194, 195, 200, 203
oxidation, 68 pharmacological, 5, 30, 31, 34, 42, 105, 161, 181
oxidative, 142, 178 phosphate, 139
oxidative stress, 142 phosphates, 51, 199
oxide, 177, 185, 203 phosphocreatine, 24
oxygen, v, 1, 6, 12, 28, 63, 65, 66, 67, 68, 69, 70, 72, photon, 15
73, 79, 84, 85, 88, 100, 105, 111, 113, 114, 119, physiological, 4, 6, 9, 10, 27, 31, 41, 66, 68, 98, 135,
121, 126, 128, 131, 137, 141, 142, 154, 167, 171, 137, 139, 140, 171, 176, 178, 192
173, 174, 175, 176, 180, 181, 183, 184, 186, 187, physiologists, 4, 9
188, 189, 191, 195, 197, 199 physiology, iv, 5, 10, 29, 140, 169, 176, 180, 181,
oxygen consumption, 1, 65, 67, 84, 85, 112, 184, 182
187, 191 physiopathology, iv
oxygen saturation, 65, 72, 154, 181 pig, 173, 199
oxygenation, 126, 129, 136, 137, 167, 171, 172, 180, pigs, 25
183, 185, 192 plasma, 141, 158, 178, 182
plasticity, 172
P
platelet, 158, 201
platelet aggregation, 158
pacemaker, 181
platelets, 158
PaCO2, 172, 184, 185
platforms, 91, 92, 99, 105
pain, 86, 203
platinum, 17, 19, 66
paradoxical, 1, 112, 178, 198
play, 3, 26, 51, 53, 57, 61, 120, 123, 159
paradoxical sleep, 178, 198
plethysmography, 111
paralysis, 191
plexus, 176
parameter, 3, 4, 14, 16, 84, 93, 99, 113, 141
poly(ADP-ribose) polymerase, 136
parasympathetic, 30, 31, 33, 34
polycythemia, 141
parenchyma, 31
polyethylene, 142
parietal cortex, 95, 100, 101, 106, 108, 109
polygraph, 142
Paris, 167, 172, 187, 191, 192
polymerase, 136
passive, 2, 22, 32, 38, 40, 96, 109, 115, 117, 184,
polymerization, 205
189, 200
population, 102, 104, 136, 137
pathology, 3, 72, 85, 142, 182
portal vein, 68, 168, 171, 184
pathophysiological, 137, 140
positron, 178, 180
pathophysiology, 181
positron emission tomography, 178, 180
pathways, 14, 24, 30, 59, 163
postsynaptic, 26
patients, 72, 83, 85, 86, 88, 89, 111, 112, 136, 185,
potassium, 23, 25, 27, 173, 176, 185
194, 200, 201
power, 21, 68, 86, 129, 174
penumbra, 147, 149, 151
preconditioning, 138
perception, 191
preference, 43
performance, v, 25, 91, 102, 103, 104, 109, 164
prefrontal cortex, 88
perfusion, 11, 12, 14, 23, 29, 51, 72, 183, 185, 190,
preoperative, 178
200, 201, 202, 203, 204, 205
preparation, iv, 161
periodic, 83, 104, 114, 115, 117
pressure, 2, 5, 6, 7, 9, 10, 12, 13, 14, 15, 16, 18, 21,
peripheral, 167
22, 23, 24, 26, 28, 29, 32, 35, 36, 37, 38, 39, 41,
peritoneal, 155
43, 44, 45, 46, 50, 51, 57, 72, 75, 87, 111, 154,
permeability, 27, 139
Index 217
159, 161, 162, 163, 164, 169, 172, 175, 177, 180, rats, 24, 27, 28, 51, 91, 93, 95, 97, 99, 100, 101, 104,
181, 184, 188, 189, 190, 191, 200, 201 107, 108, 109, 112, 124, 125, 143, 144, 145, 146,
preventive, 105, 165 147, 148, 149, 150, 151, 152, 153, 154, 155, 156,
primary visual cortex, 88, 184 157, 158, 168, 184, 202, 203
primate, 103 reactivity, 27, 35, 175, 179, 184, 185, 186
primates, 32, 102, 104 reading, 86, 88, 183
probability, 17, 38, 39, 46, 48 reality, 42
probe, 15, 142, 143, 201 reasoning, 197
procedures, 14, 161, 197 receptors, 5, 25, 30, 31, 34, 49, 51, 52, 54, 69, 105,
production, 1, 15, 33, 158, 183, 204 168, 169, 184, 189, 193, 194, 198
progressive, 168 recognition, 31, 65
promote, 139 recovery, 76, 85, 101, 129, 138, 139, 176
promyelocytic, 136 red blood cell, 158
propagation, 171 red blood cells, 158
property, 10, 40, 41 red light, 103
propofol, 202 redistribution, 67, 85, 101, 102, 104, 105, 109, 112,
proportionality, 38, 40 132, 164
propranolol, 49, 51, 52, 53, 55, 162, 175, 194 redox, 176
prostaglandin, 194 reduction, 3, 11, 12, 13, 17, 42, 43, 53, 54, 59, 65,
prostate, 204, 205 67, 68, 72, 76, 94, 95, 120, 137, 163
protection, 105, 188 reflection, 102, 103, 118, 139
protein, 192 reflexes, 59, 125, 175
protein synthesis, 192 regional, 10, 12, 27, 67, 86, 141, 169, 170, 172, 174,
proteins, 158, 184 175, 180, 183, 185, 186, 187, 189, 190, 191, 194,
psychological, 89 196, 197, 201, 203
pulse, 3, 18, 144, 191 regular, 2, 23
punishment, 93, 99 regulation, 1, 2, 3, 4, 5, 6, 9, 10, 13, 16, 23, 24, 25,
pycnosis, 146, 147 27, 29, 30, 31, 32, 33, 34, 35, 41, 45, 48, 51, 52,
pyramidal, 146, 147, 148, 177 59, 60, 61, 65, 68, 71, 73, 75, 79, 87, 91, 93, 105,
pyruvate, 199 108, 109, 119, 123, 124, 126, 161, 163, 164, 165,
167, 170, 171, 173, 178, 180, 182, 183, 184, 185,
Q
186, 187, 188, 192, 197
Reimann, 188
quantitative estimation, 113
reinforcement, 93, 99, 103, 104
relationship, 25, 84, 90, 100, 102, 141, 178
R relaxation, 28
relevance, 171
radiation, 124, 125, 126, 127, 128, 136, 137, 171, reliability, 1, 44, 47, 96, 97
172, 184, 191, 198 REM, 112, 115, 117, 119, 120, 165, 196
radiation therapy, 137, 172 renal, 175, 184
radio, 137, 205 repair, 137, 138, 139
radiofrequency, 124 reparation, 138
radiotherapy, 136, 141, 155 research, 135, 165, 175
radius, 40 researchers, 2, 87
random, 164 reservoir, 3, 15, 30, 142, 143
range, 11, 19, 61, 66, 70, 71, 72, 73, 77, 84, 85, 96, resistance, 10, 12, 24, 33, 51, 67, 68, 87, 109, 137,
124, 125, 136, 138, 140, 141, 143, 163, 164 138, 159, 169, 170, 171, 175, 181, 182, 187, 191,
rat, 12, 24, 51, 68, 92, 93, 94, 95, 98, 105, 142, 168, 193, 203
169, 171, 172, 178, 182, 183, 184, 185, 186, 187, resistence, 109
189, 197, 198, 199, 204 resolution, 15, 16, 96, 98
218 Index
resources, 69, 101 series, 44, 46, 47, 89, 93, 108, 127, 128, 130, 131,
respiration, 70, 73, 75, 132 132, 143, 144, 145, 146, 147, 149, 152, 156, 157
responsiveness, 14, 168 serotonin, 23, 30, 174
resting potential, 27 serum, 158
restoration, 53 severity, 65
retardation, 48 sex, 35, 113
retention, 61 shape, 75, 114, 147, 152
retina, 87 shear, 29, 158, 180
returns, 32, 70, 71, 100, 163 shear rates, 158
rheological properties, 140, 141, 142, 159, 165 shock, 192
rheology, 188 short-term, 65, 69, 72, 125, 135, 153
rhythm, 14, 22, 85, 96, 113, 118 short-term memory, 65
rhythms, 114, 115, 117 shoulder, 87
ribose, 136 shunts, 174
right-handers, 88 sialic acid, 180
RNA, 204 sign, 84
rodents, 138 signals, 29, 30, 103
ROS, 183 signs, 65, 66, 83, 88, 101, 104, 105
silicon, 142, 143
S
similarity, 175
simulation, 190
safeguard, 32, 58
sinus, 3, 67, 192
safety, 141, 155
sinuses, 3
saline, 144
sites, 31, 67, 72, 88, 98, 114, 128, 181
SAP, 2, 5, 6, 11, 13, 14, 18, 33, 35, 36, 37, 38, 39,
skeletal muscle, 11, 168, 184, 197, 202
44, 45, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57,
skin, 9
58, 60, 61, 75, 78, 93, 111, 112, 120, 126, 132
sleep, 83, 111, 112, 113, 114, 115, 117, 118, 120,
saturation, 18, 19, 65, 72, 154
165, 169, 172, 176, 177, 179, 180, 182, 184, 187,
scavenger, 143, 158, 159
193, 194, 196, 197, 200, 203
schizophrenia, 83, 88, 183
sleep deprivation, 112
schizophrenic patients, 88
sleep stage, 112, 120, 165
school, 98, 99, 135
sleep-wake cycle, 172, 197
scientific, 161
smoking, 159
scientists, 135
smooth muscle, 5, 10, 12, 21, 22, 23, 24, 25, 26, 27,
SDH, 137
28, 29, 31, 34, 39, 40, 41, 68, 169, 173, 174, 176,
search, 1, 92, 93, 95, 96, 163
178, 181, 182, 183, 187, 193, 195, 199, 200, 204
sedimentation, 193
smooth muscle cells, 24, 28, 31, 40, 41
seizure, 26, 84
sodium, 187
seizures, 174, 181, 182
soleus, 184
selecting, 138
solid tumors, 139
self-regulation, 164
solutions, 41, 42
semicircle, 145, 148, 150
somatosensory, 117, 118, 178
semiconductor, 172
spatial, 42, 99, 137
sensation, 86
species, 2, 25, 32, 154, 204
sensations, 99
specificity, 1, 99
sensitivity, 26, 136, 137, 138, 140, 142, 155, 165,
spectroscopy, 190
167, 173, 190, 191, 195, 205
spectrum, 14
sensorimotor cortex, 86, 113, 114, 117, 118, 120
speech, 86, 88, 183
separation, 1
speed, 14, 140
septum, 84
spheres, 101, 104
sequencing, 198
Index 219
spin, 142, 178

T
spinal cord, 199
stability, 57, 61
tangible, 85, 112
stabilization, 44, 70, 96
target behavior, 102
stable states, 161
temperature, 9, 119, 125, 126, 127, 128, 129, 130,
stages, 65, 79, 97, 102, 103, 104, 109, 112, 164, 165
132, 135, 136, 137, 138, 139, 140, 141, 142, 143,
statistical analysis, 17, 42
144, 145, 153, 154, 155, 156, 157, 158, 159, 165,
steady state, 4, 144
178, 184, 197, 204, 205
stellate cells, 148
temporal, 32, 46, 47, 48, 51, 52, 56, 59, 83, 86, 87,
stereotype, 95, 100, 101, 164
88, 92, 98, 100, 103, 104, 109, 140, 162
stimulus, 29, 86, 89, 90, 93, 98, 99, 100, 163
temporal lobe, 83
stochastic, 113
tension, v, 9, 12, 17, 18, 19, 26, 29, 40, 41, 42, 44,
strength, 103
65, 66, 67, 70, 89, 100, 101, 102, 104, 105, 106,
stress, 2, 29, 180, 184
111, 113, 114, 119, 126, 128, 131, 164, 167, 173,
stretching, 9, 21
174, 175, 176, 181, 183, 193, 197, 199, 200
stroke, 182
terminals, 26, 29, 30, 33, 86, 107, 108
structuring, 159
TGF, 204
subarachnoid hemorrhage, 175, 200
thalamus, 89, 100, 113, 163
subcortical structures, 26, 118, 177
theoretical, 23, 70, 72, 168
substances, 23, 27, 28, 182
theory, 2, 4, 5, 9, 12, 13, 21, 22, 23, 28, 29, 30, 33,
substitutes, 14, 178
69, 72, 124, 185
suffering, 83, 86, 88, 112
therapeutic, 125, 136, 137, 138, 140, 141
superposition, 102, 164
therapy, 138, 139, 140, 169, 175, 180, 183, 197, 203,
supply, 2, 5, 14, 32, 66, 83, 121, 126, 140, 163, 171,
205
180, 189
thermal, 3, 89, 125, 131, 132, 133, 135, 136, 137,
suppression, 25, 26, 40, 59, 68, 69, 84, 103, 105,
138, 139, 142, 143, 144, 182, 188, 205
107, 124, 177
thermal energy, 133
surgery, 174
theta, 85, 96, 113, 115, 118
surgical, 14, 86, 143, 161
threat, 105
surgical intervention, 14, 86
threshold, 11, 40, 67, 86, 190
surplus, 16
threshold level, 67
survival, 137, 138, 141, 142, 188, 200
thromboembolic, 159
survival rate, 137
thrombosis, vi, 135, 141, 159, 165, 177
susceptibility, 42
thrombus, 158
swelling, 158
time, 1, 2, 3, 4, 9, 10, 13, 15, 22, 24, 25, 27, 30, 33,
switching, 73, 104, 128, 129
38, 40, 41, 42, 44, 46, 47, 48, 53, 54, 55, 57, 65,
sympathectomy, 32, 42
67, 69, 70, 72, 73, 75, 84, 88, 89, 92, 93, 95, 98,
sympathetic, 25, 30, 31, 32, 33, 34, 107, 163, 167,
99, 100, 101, 102, 103, 104, 105, 108, 112, 113,
168, 169, 172, 173, 181, 182, 184, 186, 189, 194,
114, 118, 123, 125, 127, 128, 135, 137, 138, 139,
197, 198, 202, 204
140, 154
sympathetic fibers, 30, 33
time periods, 15
sympathetic nervous system, 182
tissue, vi, 1, 3, 6, 12, 15, 16, 17, 18, 19, 21, 23, 24,
synapses, 59
25, 26, 28, 29, 31, 41, 51, 58, 61, 65, 66, 67, 69,
synaptic clefts, 24
70, 72, 75, 77, 85, 105, 113, 118, 119, 124, 125,
synaptic transmission, 59
126, 129, 132, 133, 135, 137, 138, 139, 140, 141,
synchronization, 2, 96, 105, 107, 119, 125
142, 144, 145, 146, 147, 148, 149, 150, 151, 152,
syndrome, 72, 89, 104, 132
153, 154, 155, 156, 157, 158, 163, 165, 171, 172,
synthesis, 35, 137
173, 175, 176, 180, 184, 188, 189, 190, 192, 194,
systems, 26, 33, 34, 101, 124, 125, 140, 162, 196
198, 202, 205
tolerance, 137, 138, 184
220 Index
tonic, 21, 29, 103, 104, 178 variables, 72

training, 185 variation, 5, 6, 9, 10, 14, 18, 21, 22, 23, 36, 39, 40,
trajectory, 92, 95, 107 41, 42, 44, 46, 95, 96, 129, 132
transection, 123 vascular, 1, 2, 3, 4, 5, 9, 10, 12, 15, 16, 17, 21, 22,
transfer, 95 23, 24, 25, 26, 28, 29, 30, 31, 32, 35, 36, 38, 39,
transformation, 53, 55 40, 41, 42, 43, 48, 51, 52, 53, 57, 58, 60, 68, 83,
transition, 70, 85, 111, 114, 115, 116, 117, 119, 120, 87, 108, 111, 123, 125, 138, 139, 140, 158, 159,
138 163, 164, 165, 167, 168, 169, 170, 174, 175, 176,
transitions, 177 178, 179, 181, 182, 184, 186, 187, 188, 189, 191,
translation, 6 193, 195, 198, 199, 200, 203, 204
transmembrane, 26 vascular occlusion, 140, 165
transmission, 49, 59 vascular reactions, 9, 28, 31, 39, 42, 168
transparent, 15 vascular system, 1, 2, 4, 53, 125, 140
transport, 25, 26, 69, 154, 171, 172, 180 vascular wall, 9, 28, 29, 39, 40, 41, 42, 43, 68, 139,
transverse section, 126 169
trauma, 72, 132, 196 vasculature, 140, 172, 189
traumatic brain injury, 177 vasoactive intestinal polypeptide, 176
trend, 2 vasoconstriction, 12, 29, 33, 50, 53, 54, 55, 109, 163,
trepanation, 128, 129 164, 167, 168, 175
trial, 32, 92, 93, 94, 95, 96, 97, 98, 99, 100, 102, 193 vasoconstrictor, 25, 87, 194
trial and error, 92, 93, 99, 193 vasodilatation, 29, 67, 68, 108, 109, 111, 123, 124,
tumor, 125, 126, 135, 136, 137, 138, 139, 140, 141, 132, 158, 186, 187
153, 155, 171, 175, 194, 196, 202, 203 vasodilation, 25, 27, 29, 50, 53, 54, 55, 109, 164,
tumor cells, 125, 126, 135, 136, 137, 139, 175, 194 165, 173, 182, 203
tumor growth, 139 vasodilator, 22, 168, 171, 188
tumors, 72, 136, 137, 138, 139, 140, 184, 188, 190, vasomotor, 25, 27, 39, 50, 174, 179, 184, 185, 191,
200 193, 196, 198
tumour, 125, 135, 197 vasomotor nerves, 174, 196
tumours, 125, 185, 189 vein, 3, 11, 31, 142
type II diabetes, 190 velocity, 13, 14, 15, 16, 17, 27, 32, 33, 34, 40, 41,
42, 44, 70, 88, 173, 186, 189
U
venous pressure, 143, 204
ventilation, 127
ultrasound, 172
ventricles, 24
umbilical artery, 175
venules, 158
umbilical cord, 184
vertebral artery, 25
unconditioned, 105
vessels, vi, 2, 3, 5, 9, 10, 11, 12, 14, 15, 16, 21, 22,
uniform, 67
23, 24, 25, 26, 28, 29, 30, 31, 32, 33, 38, 39, 41,
urea, 24
42, 43, 44, 50, 51, 52, 57, 61, 67, 68, 111, 120,
uric acid, 139
132, 133, 135, 139, 145, 146, 156, 157, 158, 161,
V 163, 165, 169, 171, 172, 173, 176, 181, 184, 187,
193, 195, 203
vacuole, 158 viruses, 136
vagus, 14, 30, 51 viscosity, 40, 41, 141, 158, 165, 199, 202
vagus nerve, 14, 30 visible, 145, 147
validation, 200 vision, 161
values, 10, 18, 25, 26, 34, 39, 42, 43, 46, 66, 84, 88, visual, 3, 26, 85, 87, 88, 92, 97, 98, 101, 102, 103,
128, 137, 185, 201 144, 145
variability, 18, 24, 66, 103, 125 visual area, 85, 87, 97, 98, 101, 102
variable, 16, 72 visual stimuli, 103
Index 221
visualization, 15
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-ray, 188
yield, 13

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INTRODUCTION

(regular 10/sec alpha-waves) and mental activity (predominant beta-activity) (Berger,

1. Cerebrovascular smooth muscles have characteristics which differ from those of

SOME THEORETICAL PREREQUISITES

1.1. HISTORICAL BACKGROUND

autoregulation has also been demonstrated in a rat model of Streptococcus pneumoniae

1.2. POSSIBLE REASONS FOR CONTROVERSIAL

Input Disturbing Factor

a). a). Elevation of SAP is accomplished by means of infusion of blood or blood

Methods Advantages Disadvantages

Choice of the Parameter to be Regulated

Measurement of Local CBF by means of Electrochemical Generation of

The technique, as a matter of fact, is a modification of commonly known method of

Figure 2A represents a principal scheme of local generation of hydrogen and

MAIN THEORIES OF AUTOREGULATION OF CBF

2.1. MYOGENIC THEORY

2.2. METABOLIC THEORY

terminals and the enhancement of the postsynaptic reaction to noradrenaline (Hedqvist,

2.3. NEUROGENIC THEORY OF AUTOREGULATION

As proposed by neurogenic theory, disturbances in cerebral blood circulation are

In contrast to Linder's data, in the experiments of Mchedlishvili and Nikolaishvili (1970) a

ANALYSIS OF DYNAMIC CHARACTERISTICS OF

3.1. ANALYSIS OF THE DYNAMIC CHARACTERISTICS OF

Technique Utilized in Local CBF Autoregulation Studies

The following regularities appeared to be characteristic of local CBF autoregulation:

Table 2. Distribution of the individual types of autoregulatory responses

Type of vascular responses Probability of its observation (P<0.01)

Description of a Mathematical Model of a Blood Vessel

A comprehensive analysis of all cumulative characteristics of local CBF autoregulation,

Pv(t) = Pe(t) + Pa(t) = kR(t) + Pa(t) (2)

|dP(ti)/dt| >= V (3)

dPa(t)/dt = bdP(t)/dt (4)

where b is a coefficient of proportionality, determined apparently by the current state of

|dPa(t)/dt| <= B (5)

0 <= Pa(t) <= P* (6)

6. A vessel behaves as a visco-elastic body with fixed parameters - elasticity coefficient k

c . ρ . dR(t)/dt + k*R(t) + Pa(t) = P(t) (7)

where c is a coefficient determined apparently by the vessel geometry.

c . ρ . dR(t)/dt + kR(t) + Pa(t) = P(t)

Pa(t) = Pa(t1, t2,..., ti,...tn-1) + b*$tn dP(tn)/dt dt

0 <= Pa(t) <= P*

dP(ti) >= V, i = 1, 2,..., n

dPa(t) <= B (8)

3.2. DYNAMIC CHARACTERISTICS OF AUTOREGULATION OF

In order to evaluate the function of the autoregulatory neurogenic mechanism of cerebral

Table 4. Parameters of prolonged changes of the Mean Systemic Arterial Pressure

Parameters of mean systemic The state of the animal

In the first series of experiments (with no anesthesia) two components of autoregulation

Table 5. Mean temporal characteristics of components of the local CBF autoregulation

Conditions of the Component 1 Component 2 Component 3

Table 6. Frequency of manifestatition of the autoregulatory components in anethetised

Mode of influence Frequency of Manifestation (%)

Following the application of anesthesia, frequency of manifestation of the second

Figure 11. Manifestation of the all three components of lCBF autoregulation.

In investigating the concept of a possible neurogenic nature of the described second

The Role of Adrenergic System

Phentolamine is the most commonly used antagonist of alpha-adrenoreceptors. It acts

The Role of the Cholinergic System

Presented in Figure 19 are the results of experiments which allowed us to make a

Thus, by administration of a muscarinic cholinergic blocking agent, scopolamine, the

Table 7. The frequency of manifestation of different components of lCBF autoregulation

Experimental Components of Frequency of manifestation (%) of the autoregulatory components after

Figure 20. Transformation of the dynamic characteristics of vasodilatory autoregulation of lCBF in

Hence, from the dynamic characteristics of the three components of autoregulation we