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Heart-brain communication
Veen, Frederik Martin van der
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1997
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Veen, F. M. V. D. (1997). Heart-brain communication Groningen: s.n.
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2
Neuroanatomical and Physiological
Background
The present chapter describes the neuroanatomical structures and physiological
mechanisms involved in the interaction between the brain and the cardiovascular
system. Central to this interaction is the regulation of cardiovascular functioning by
various structures in the brain. The ultimate goal of this regulation is maintaining an
optimal blood flow, and in this way an optimal supply of energy and oxygen to the
all parts of the body. The regulated variable in the cardiovascular system is blood
pressure (Guyton, 1980; Julius, 1988). Pressure is regulated by many subsystems (e.g.
kidneys, hormones), which are active in various time and pressure domains (for a
review see Guyton, 1980). For the purpose of the present thesis, in which only fast
responses in normal subjects are examined, only those systems are important that can
act very fast (i.e. within seconds) and act in normal pressure ranges (i.e. between 80
and 140 mmHg). The system that is dominant in this domain is the baroreflex, which
is schematically presented in Figure 2.1. In the baroreflex the blood pressure level is
adjusted when the actual pressure, as measured by the baroreceptors, differs from the
desired level. The baroreceptors are located in the aorta and the carotid sinuses, where
Venous Volume
Sympathetic
System
Systemic Resistance
Heart
&
Cardiovascular
Control
Center
Maximum Elastance
Parasympathetic
System
Circulation
Heart Rate
Baroreceptors
PA
Figure 2.1 Schematic presentation of the baroreflex. Arterial pressure (PA) is registered by the
baroreceptors and relayed to the cardiovascular control center. From there output of the autonomic
nervous system is adjusted, which controls the four effectors of the reflex. These effectors can adjust the
pressure to the desired level.
4
Neuroanatomical and Physiological Background
they register arterial blood pressure. The baroreceptors relay this pressure information
to a control center in the brain stem, which uses various effector mechanisms to adjust
the pressure; i.e. heart rate, maximum elastance, venous volume and systemic
resistance. These effectors can all adjust the pressure; i.e. heart rate determines the
frequency at which the heart contracts, the maximum elastance of the heart determines
the contraction force of the heart, venous volume is the amount of blood that flows
back to the heart, and systemic resistance is the resistance for the blood pumped out
of the heart. When the actual blood pressure is higher than the required pressure as
determined by the set-point in the control center, the baroreceptor output to the
control center will be enhanced. The control center will respond to this information
with a decrease in input to all effectors, which leads to a decrease in pressure. In this
way the pressure is adjusted until an acceptable level is reached.
In the following sections of this chapter, the role of various brain structures in
the regulation of blood pressure are discussed. Section 2.1 discusses the role of the
autonomic nervous system, which is for instance important in determining
relationships between various cardiovascular variables (i.e. heart rate, systolic blood
pressure). In section 2.2 the role of non-specific neurotransmitter systems will be
described. These systems play a major role in level-setting processes. In section 2.3 the
role of cortical structures will be described, which are especially important for the
relation with psychological processes.
2.1 Autonomic Control
The two branches of the autonomic nervous system play a crucial role in the
baroreflex. The parasympathetic (or vagal) system controls about 75% of the fastest
effector loop (i.e. HR) in the baroreflex. The sympathetic system controls the
remaining 25% of this effector, and further controls the maximum elastance of the
heart, the venous return to the heart, and total peripheral resistance in the circulation.
The most important anatomical structures and connections for autonomic control
within the baroreflex are schematically presented in Figure 2.2. As was stated in the
previous section, information about the present blood pressure in the system is
relayed to a control center in the brainstem. The brain structure that fulfills this role
is the Nucleus Tractus Solitarius (NTS), which lies in the dorsomedial part of the
brainstem. In this nucleus the pressure information is processed and translated into
a signal to the two branches of the autonomic nervous system.
The parasympathetic branch of the autonomic nervous system projects to the
heart through the vagal nerve. The synapses of the vagal nerve are located near the
heart and influence the frequency of contraction of the heart by the excretion of the
neurotransmitter acetylcholine. The acetylcholine transmits its message by binding to
5
Chapter 2
Venous Volume
RVLM IML
NTS
(Sympathetic)
Systemic Resistance
Heart
&
Maximum Elastance
Circulation
(Control Center)
NA
(Parasympathetic)
Heart Rate
Baroreceptors
PA
Figure 2.2 Schematic representation of the role of the autonomic nervous system in the baroreflex and the
structures and connections that are involved. NTS= Nucleus Tractus Solitarius, RVLM= Rostral
Ventrolateral Medulla, IML= intermediolateral cell column, PA= Arterial Pressure and NA= Nucleus
Ambiguus.
muscarinic receptors located on the cardiac smooth muscle, in which more excretion
of acetylcholine leads to deceleration of the heart. An increase in vagal outflow to the
heart causes a deceleration of HR. The parasympathetic system acts fast and powerful,
and can change HR within one heart beat.
The largest part of the vagal projections to the heart originate in the nucleus
ambiguus (NA), while a minority originates in the dorsal motor nucleus of the vagus
(DMV) (Loewy & Spyer, 1990; Hopkins, Bieger, De Vente & Steinbusch, 1996). For
reasons of simplicity only the apparently more important NA is presented in Figure
2.2. The NA is located in the medullary part of the reticular formation beginning
posterior to the facial nucleus and extending caudally to the first cervical level (C1)
of the spinal cord. The DMV lies in the dorsomedial portion of the caudal medulla
oblongata close to the floor of the fourth ventricle and it also extends caudally to C1
in the spinal cord. The NA receives afferents from several distinct areas in the
brainstem and from parts of the limbic system (e.g. hypothalamus, amygdala). From
the perspective of the baroreflex the afferents from the NTS, which functions as a
control center, are the most important. The crucial efferent projections of the NA,
besides the projection to the vagus that was mentioned earlier, are back to the NTS
and to the rostral ventrolateral medulla (RVLM).
The sympathetic division of the autonomic nervous system acts slower. The
sympathetic system projects to the sino-atrial node, the cardiac muscle, the arterial
smooth muscles, and the venous smooth muscles. By targeting receptors on these
places, the sympathetic system can change the previously mentioned effector systems
6
Neuroanatomical and Physiological Background
(i.e. HR, contractility, venous volume, and peripheral resistance). These four different
systems have different time constants and delays in their action. The HR effector loop
is fastest, and can induce a change within 2.5 to 3 seconds, while the peripheral
resistance system is slowest. The synapses of sympathetic nerves influence their target
organs by the excretion of epinephrine (=adrenaline) and norepinephrine
(=noradrenaline). Both neurotransmitters, which also play a role in the hormonal
regulation of blood pressure, transmit their message by binding differentially to the
four types of adrenergic receptors ("1, "2, $1 and $2).
Sympathetic projections to the heart and circulation originate in sympathetic
motoneurons which are located in the intermediolateral cell column (IML) of different
levels of the spine. The IML receives afferent information from different sites in the
medulla (A1 cell group, Raphé Obscurus, Raphé Pallidus and ventral parts), the pons
(A5 cell group and Kölliker Fuse nucleus) and hypothalamus (paraventricular
nucleus). From the perspective of the baroreflex one of the ventral medullary parts,
the earlier mentioned RVLM, is most important. The many afferents coming from the
NTS makes this center the most important sympathetic part in the baroreflex.
2.2 Neurotransmitter Systems and Cardiovascular Functioning
Blood pressure regulation by the baroreflex can be influenced by many cortical and
subcortical structures. These structures can be subdivided in areas which have direct
specific influences and are related to specific behavior, and areas that have a more
general effect and are not related to specific behavior. This distinction is also made in
the description of the emotional motor system (EMS) (e.g. Holstege, Bandler & Saper,
1996). The EMS can be seen as a separate motor system which acts independently
from the primary somatic motor system. The EMS influences generally the same
motoneurons as the somatic system, but is controlled by limbic structures. In this way
the autonomic nervous system which is often seen as a part of the motor system, can
also be influenced by the EMS. The EMS consists of a medial and a lateral part. The
lateral part contains structures which are involved in specific emotional reactions such
as the fight/flight response, whereas the structures in the medial part are involved in
non-specific reactions such as level setting. Most structures in the medial part project
divergently to many output systems, and in this way they cannot be involved in
behavior specific reactions. In the medial part the neurotransmitter provider systems
play an important role. The most well-known are the norepinephrine system mainly
originating from the locus coeruleus (LC), the serotonin system mainly originating
from the raphe nuclei, the acetylcholine system mainly originating from the nucleus
basalis of Meynert, and the dopamine system mainly originating from the substantia
nigra. These systems have in common that they are thought to influence general level
7
Chapter 2
of activity (e.g. level setting, signal to noise ratio) of the brain areas to which they
project. The first two systems (norepinephrine and serotonin) are thought to be more
active in the sensory domain, whereas the second two systems (acetylcholine and
dopamine) are thought to be more active in the motor domain.
The most specific hypotheses about the role of these systems in cardiovascular
functioning are made about the norepinephrine system. The LC projects divergently
to areas throughout the entire central nervous system (Jones and Yang, 1985) and the
activation of the LC covaries with the state of arousal in the mechanism. In this way
the LC can influence the base level of activity of areas which are thought to be
involved in cardiovascular regulation. The LC projects for instance heavily to the
anterior cingulate cortex, which is assumed to play an important role in regulating the
cardiovascular responses during associative learning (see next section). More direct
evidence for the role of the norepinephrine system in cardiovascular regulation comes
from stimulation studies, which showed that activation of the LC leads to a decrease
in SBP and HR (Sved & Felsten, 1987). How this effect is caused is not exactly known,
because the LC does not project directly to autonomic preganglionic nuclei. It is
speculated, however, that projections to the bed nucleus of the stria terminalis and the
lateral hypothalamic area are probably involved (Jones and Yang, 1985). Both these
areas project to the nucleus ambiguus and in this way they can influence
cardiovascular functioning.
2.3 Cortical Control of Cardiovascular Functioning
A number of cortical areas appear to be involved in both the perception and the motor
control of cardiovascular functioning. These areas are mostly located in the frontal
cortex and include parts of the cingulate cortex, the insular cortex and the
orbitofrontal cortex (Mesulam & Mufson, 1982; Neafsey, 1990; Cechetto & Saper,
1990). Especially the first two areas are recognized by many reseachers as important
cortical sites involved in cardiovascular functioning.
The connections of the anterior cingulate cortex (ACC) with important
cardiovascular centers in the brain, as well as the cardiovascular response pattern that
is found when this area is stimulated, show that the ACC is involved in regulating
cardiovascular functioning. In Figure 2.3 a schematic presentation is given of the most
important afferent connections of the ACC to centers that are directly involved in
cardiovascular control by the baroreflex. Various tracer studies showed that the ACC
has efferent connections to the NTS, the lateral hypothalamic area, parabrachial
nucleus, the nucleus ambiguus and the dorsal vagal motor nucleus (Neafsey, 1990;
Cechetto & Saper, 1990; Powell, Buchanan and Gibbs, 1990). Stimulation studies
showed that when the ACC is stimulated, generally a HR deceleration and a blood
8
Neuroanatomical and Physiological Background
LATERAL
HYPOTHALAMIC
AREA
ANTERIOR
CINGULATE
CORTEX
Venous Volume
RVLM IML
NTS
(Sympathetic)
Systemic Resistance
Heart
&
Maximum Elastance
Circulation
(Control Center)
NA
Heart Rate
(Parasympathetic)
Baroreceptors
PA
Figure 2.3 Schematic presentation of the direct (dotted) and indirect (dashed) afferent connections of the
anterior cingulate cortex to the important structures in the baroreflex.
pressure decrease are found (Neafsey, 1990; Cechetto & Saper, 1990; Powell et al.,
1990). The most interesting evidence for a role of the ACC in cardiovascular control
comes from a series of studies with rabbits. In these studies it is found that the ACC
plays an important role in mediating cardiovascular changes during associative
learning tasks (for an overview see Powell et al., 1990). From classical conditioning
studies it is known that HR decelerates in many species in the interval between the
conditioned stimulus and the reinforcing stimulus, while a strong accelerative
response can be found directly following the reinforcing stimulus. The learning of
both responses in rabbits appears to be dependent on whether a specific network in
the brain, which includes the ACC and the mediodorsal thalamus, is intact. According
to Powell et al. both areas, which are strongly interconnected, act in an opposite but
complementary fashion during classical conditioning. The ACC plays a role during
the decelerative phase of the response, which is attenuated when this site is lesioned.
The mediodorsal thalamus seems to be especially active during the accelerative
response to the reinforcing stimulus, which is attenuated when this part of the
thalamus is lesioned. Powell et al. proposed a simple three stage model for associative
learning, consisting of a first stage in which the conditioned stimulus is perceived, a
second stage involved in determining the relevance of the stimulus, and a last stage
involved in the selection of appropriate behavioral adjustments. According to Powell
et al. the ACC is mainly involved in the second stage of associative learning.
The precise role of the insular cortex in cardiovascular functioning is less clear.
The insular cortex appears to be involved in both monitoring of autonomic
functioning and making cardiovascular adjustments. These roles are confirmed by
both the cardiovascular reactions that can be obtained by stimulating this area and the
afferent and efferent connections with important structures involved in cardiovascular
control. The efferent connections to the control structures in the baroreflex are
schematically presented in Figure 2.4. Both pressor and depressor blood pressure
responses and both decelerative and accelerative heart rate responses can be obtained
by stimulating different parts of the insular cortex of rats (Butcher & Cechetto, 1995),
9
Chapter 2
LATERAL
HYPOTHALAMIC
AREA
Venous Volume
RVLM IML
NTS
INSULAR
CORTEX
(Sympathetic)
Systemic Resistance
Heart
&
Maximum Elastance
Circulation
(Control Center)
NA
Heart Rate
(Parasympathetic)
CENTRAL
NUCLEUS
AMYGDALA
Baroreceptors
PA
Figure 2.4 Schematic presentation of the direct and indirect afferent connections of the insular cortex to
the important structures in the baroreflex
rabbits (Powell, Hernandez & Buchanan, 1985) and humans (Oppenheimer, Gelb,
Girvin & Hachinski, 1992). The obtained responses seem to be moderate when
compared to responses obtained from the cingulate gyrus. The pattern of
cardiovascular responses which is generated by stimulating the insular cortex is best
known from the studies with rats mentioned earlier (Butcher & Cechetto, 1995). From
these studies it was concluded that the insular cortex tonically inhibits sympathetic
activity, while phasic activation leads to enhancement of sympathetic activity. This is
caused by projections to both sympathoexcitatory and sympathoinhibitory neurons,
of which the first are only activated when the insular cortex is stimulated directly. The
connections of the insular cortex appear to suggest a more important role for the
insular cortex in monitoring of autonomic functioning (Cechetto & Saper, 1990). In rats
it is found that the insular cortex has both afferent and efferent connections with the
NTS, the parabrachial nucleus, the central and basolateral amygdaloid nuclei, the
lateral hypothalamic area, the infralimbic and the ventroposterior parvocellular
thalamic nucleus (Cechetto & Saper, 1990). From studies with monkeys it is known
that the posterior insular cortex is reciprocally connected to many other cortical areas
including auditory, somestetic and paramotor areas, while the anterior insular cortex
has stronger connections with areas involved in gustatory, olfactory and autonomic
functions (Mesulam & Mufson, 1982). In monkeys the posterior and anterior part are
also strongly interconnected and connected to limbic structures. According to
Mesulam and Mufson especially these last two properties could make the insular
cortex an important area for adding motivational value to ongoing events on the one
hand, and the selection of appropriate emotional responses on the other.
10