Download Effect of Stimulation of Hypothalamus and Reticular Activating

Effect of Stimulation of Hypothalamus and
Reticular Activating System on Production
of Cardiac Arrhythmia
By Houshang J. Attar, M.D., Mario T. Gutierrez, M.D.,
Samuel Belief, M.D., and J. R. Ravens, M.D.
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• The role of: the central nervous system in
maintaining and modifying cardiac rhythmicity lias been extensively studied1"5 by many
investigators. Emphasis has been laid on the
diencephalic region as a pathway for important neurovcgetative fibers.
Pitts et al." showed that from both sides of
the hypothalamus, multiple pathways descend,
over which impulses converge on a single
preganglioiiic sympathetic neuron. Van Bogaert' postulated that the diencephalic region
serves as a passage of important neurovegetative fibers which connect with the medulla.
Previous studies on the medulla oblongata7's
have shown that centers that increase the
blood pressure in these regions comprise an
extensive zone within the lateral reticular formation, while the depressor center is located
in the medial reticular formation. Likewise,
stimulation of the reticular formation of the
mesencephalon produces both depressor and
pressor responses. The experiments of other
workers"" showed the importance of the reticular formation and corticospinal tracts for
the transmission of the sympathetic impulses
from the hypothalamus. "Weinberg and Foster' 4 postulated that the posteromedial hypothalamus exerts an effect chiefly upon the
sinus node, whereas the lateral hypothalamus
and subthalamus exert their influence principally upon the myocardium.
To clarify further the mode of action of
From tlie Division of Cardiology, Philadelphia
General Hospital, and the Department of Neuropathology, Graduate Hospital of the University of
Pennsylvania.
Dr. Attar and Dr. Gutierrez wore Besidents in
Cardiology at the Philadelphia General Hospital.
Dr. Ravens is a Neuropathologist, Graduate Hospital of the University of Pennsylvania.
Heceived for publication July 13, 1962.
14
the different areas of the hypothalamus and
especially their relationships to the reticular
activating system of the cerebral peduncle and
pons on cardiac rhythmicity, a series of experiments were performed in cats. An analysis of changes in the blood pressure, heart
rate, and electrocardiogram in relation to the
site and intensity of stimulation of certain
centers in the brain system was undertaken.
Methods
Twenty-three cuts weighing: between 2 6 and 3.2
Kg', were utilized in these experiments. Anesthesia was induced by injection of chloraloso, 70
mg-./Kg'. intraperitoneally. Tlie cat was tlion
placed in the supine position for isolation of the
femoral artery, and the blood pressure was recorded by the use of a. Statbam transducer, model
P-23 Gb. In addition, the electrocardiogram (lead
II), 25 mm./sec, was simultaneously recorded on
the Sanborn Twin-Viso. Two stainless steel electrodes (gauge 20) were coated with black Krylon
quick drying- enamel; the tips were then stripped
of enamel about 2 mm. from the tip. The remainder of the electrodes (10 cm.) was checked
for efficacy of insulation prior to each experiment
by the use of an ohmmeter. The electrodes wore
then placed in the stereotaxic apparatus and calibrated on the horizontal, vertical, and frontal
planes following- the atlas of the dienccphalon of
the cat by Jasper and Marsan.14 The zero line used
for the horizontal plane was situated 1 cm. above
the interaural line.
The stimulus employed consisted of a monophasic square wave current from a Grass Stimulator, 5 to 12 volts, with a 5-msec. pulse duration,
at a frequency of 80 to 100 cycles/sec. The
stimulation of each area was maintained for 30 to
120 seconds; each stimulus was applied three to
five times in each of the areas studied. A period
of recovery was permitted before a succeeding
stimulus was applied. During stimulation, no
struggling was noted in the cat, but occasionally
the pupils were dilated on the side stimulated. At
the end of the experiment, a D.C. current was
applied to the electrodes in order to mark the
Circulation Research, Volume X//, January 19GS
15
HYPOTHALAMUS AND CARDIAC ARRHYTHMIA
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FIGURE 1C
FIGURE IB
FIGURE 1
A. Effect of anterior hypothalannic stimulation. Note the increase in blood pressure
from 90/60 to 200/150 mm. Hg and electrocardiographic changes (increase of T-wave
inversion while normal rhythm is maintained). The electrocardiogram returns to the prestimulation pattern after two minutes. B. Coronal section of the brain of a cat through
the anterior commissure showing a lesion in the left anterior hypothalamus. C. Coronal
section of the brain of a cat through the anterior commissure to illustrate a lesion in
the anterior hijpothalamius of the left hemisphere. (Myclin sheath stain, Weil's method)
Circulation Research, Volume XII, January 1963
ATTAR, GUTIERREZ, BELLET, RAVENS
16
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areas of stimulation.14 The brain was then
fixed with 10 per cent formalin injected through
the carotids while it was still in the skull, and
after an hour, it was removed and placed in 4
per cent formalin for hardening and later morphological study.
Samples of the brains of 15 cats were investigated following transverse coronal section from
the frontal to the occipital pole and horizontal
sections through the brain stem and cerebellum.
The areas of the lesions were selected for frozen
section,15 and these areas (sections) were imbedded
in paraffin and celloidin. The staining methods
used to localize the lesions consisted of: (1) for
myelin sheath (Weil's method) ; (2) for nerve cells
and fibers, Lngol-fast blue stain (Kluver-Barrera's
method); (3) for nerve cells, blood vessels, and
neuroglial components, cresyl-violet stain.
FIGURE 2A
FIGURE IB
FIGURE 2C
FIGURE 2
A. Effect of lateral hypothalamic. stimulation. Note
the arrhythmia observed immediately after stimu-
Results
Depending upon the localization of the
stimulus (of equal intensities ranging between
5 and 12 volts, 5 msec, SO to 100 cycles per
second), the following results were obtained:
Group 1 (31 cats) : TInilatei'al stimulation
of the hypothalamus, anterior, lateral, and
posterolateral regions (left or right side) revealed the following:
1. Stimulation of the anterior hypothalamus (four cats) on the right side or left side
produced an average rise in blood pressure
from 100/75 to 200/150 mm. Hg, which was
sustained for an average of 45 seconds during
the period of stimulation and returned to the
prestimulation level two minutes after cessation of the stimulus. The heart rate decreased
from a control average rate of 160 to 120
beats per minute. The electrocardiographic
changes consisted of slight ST segment elevations and marked deepening of the T-wave
inversions while sinus rhythm was mainlation, A-V dissociation, ventricular premature
systoles. The transitory zone between nodal
rhythms and sinus rhythms are well demonstrated
in 40 seconds after stimulation. "Return to prestimulation pattern is shown two minutes after
stimulation. B. Coronal section of the brain of a
cat through the posterior portion of the optic, chiasma demonstrating a lesion of the lateral hypothalamus. C. Coronal section of the brain of a cat
through the posterior portion of the mammillary
bodies demonstrating a lesion in the lateral hypothalamus of the right hemisphere (x). (Myelin
sheath stain, Weil's method)
Circulation Research, Volume Xll, January 196S
HYPOTHALAMUS AND CARDIAC ARRHYTHMIA
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tained. All of these changes returned to prestimulation pattern after a period of about
two minutes (fig. 1A). The morphological
examination of two brains in this group
showed punctures on the vertex of the left
hemisphere, at the junction of the anterior
and middle third of the lateral gyrus. On
corona] section, the lesion was found in the
left anterior hypothalamus. The puncture
goes through the anterior portion of the fornix
(fig. IB). The anatomical characteristic of
the lesion at this level is shown in the photomicrograph (fig. 1C).
2. Stimulation of the lateral hypothalamus
(three cats) on the right and left sides resulted in a rise of blood pressure from an
average of 125/95 to 170/110 mm. Hg. This
increase was maintained for almost 50 seconds
after cessation of stimulation. The electrocard iographic changes consisted of transitory
periods of auriculoventricular (A-V) dissociation with frequent premature ventricular
systoles in spite of a relatively slight rise in
blood pressure (fig. 2A). Coronal section
through the posterior portion of the optic
chiasma (fig. 2B) showed the puncture
clearly demarcated and the lesion situated at
the level of the lateral hypothalamus (two
brains). The miscroscopic section shown in
figure 2C confirms the site of the stimulated
area.
3. Stimulation of the posterolateral hypothalamus (four cats) showed a rise in blood
pressures from an average of 110/75 to 200/
140 mm. Hg during the period of stimulation ;
this rise was maintained for an average period
of 60 seconds after the stimulus was removed.
The arrhythmias in this group consisted of
the appearance of A-V nodal rhythms with
aberrant ventricular conduction, frequent
premature ventricular beats from different
foci, and, in a few instances, fusion beats (fig.
3A). Two brains in this group illustrate, on
coronal section through the middle portion of
the thai am us and the anterior portion of the
pineal gland, the lesion located in the posterior hypothalamus (fig. 3B, x).
Group II (12 cats) : Stimuli applied on
the reticular activating system (mesencephaCirculation Research, Volume XII, January 196S
17
lie region) produced the following results:
1. The blood pressure rose from an average
of 100/70 to 200/120 mm. Hg, remained
elevated for almost 90 seconds after the period
of stimulation, and gradually returned to the
prestimulation levels in about three minutes.
2. The electrocardiogram taken immediately
after the stimulation showed an average increase in the heart rate from a control of 150
to 170 beats.
The most conspicuous finding was a shift
of the pacemaker from the sinus to the A-V
node with the control of the ventricular
rhythm by a lower, subsidiary pacemaker.
Transitory A-V dissociation with multiple
auricular premature beats and A-V nodal
escapes were a common finding. Betopii'
beats of ventricular origin from different
foci, interrupted by A-V nodal rhythm, and
fusion beats were also present. In some portions of the tracing, widening of the QRS
complexes due to aberrant ventricular conduction was observed. Deep and symmetrically inverted T waves were also noted. These
disturbances in rhythm and abnormalities in
the QKST complex returned to the normal
control pattern within about two to three
minutes after cessation of stimulation (fig.
4A). Morphological study (two brains) revealed a puncture in the vertex of the right
hemisphere at the level of the posterior third
of the right lateral gyms. These punctures
were close to the lateral sulci, as illustrated in
figure 4B. The terminal point of the puncture
was located in the reticular formation between
the nucleus ruber and substantia nigra. In
the first of the two brains of this group, the
terminal point of the puncture was located
in the right inferior colliculus and reticular
formation of the pons (fig. 4C, x. x ) .
Discussion
These findings demonstrate that stimulation
of the anterior hypothalamus produced a
bradycardia rather than a tachycardia, most
likely because the parasympathetic tone is
most predominant in this region."'1 '" A rise
in blood pressure in this group was never accompanied by arrhythmias although the slight
ATTAR, GUTIERREZ, BELLET, RAVENS
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FIGURE 3A
ST segment deviation and deepening of the
inverted T waves were often observed.
Following posterior hypothalamic stimulation, the various types of arrhythmias were
obtained in spite of a smaller rise in blood
pressure as compared to that of anterior hypothalamic stimulation. Similarly, "Weinberg
and Foster3'4 observed that stimulation of the
lateral and posterior hypothalamus produced
T-wave changes, bigeminy, trigeminy, A-V
FIGURE 3B
FIGURE 3
A. Effect of stimulation of posterolateral hypothalamns. Note the rise of blood pressure from
IOO/7:~> to 200/150. Note nodal rhythm, aberrant
ventricular conduction, premature auricular systoles, and occasional fusion beats and return to
prestimulation pattern two minutes after stimulation. B. Coronal section of the brain of a cat
through the middle of the thalamus to show a lesion of the lateral posterior hypothalamus in the
right hemisphere (x). (Myelin sheath stain, Weil's
•method)
Circulation Research, Volume XII. January 196S
HYPOTHALAMUS AND CARDIAC ARRHYTHMIA
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FIGURE 4A
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FIGURE 4B
FIGURE 4C
FIGURE 4
A. Effect of stimuki'tion of the reticular formation (mesencephalic region). Note rise
of blood pressure to 175/125 mm. Hg 90 seconds after stimulation. Note nodal, ventricular rhythms, premature auricular and ventricular beats. Electrocardiogram and blood
pressure return to prestimulalion pattern three minutes after. B. Coronal section of
the brain of a cat through the cerebral peduncle to shou; a lesion of the retivtihtr formation. C. Photomicrograph of the right parasagittal section through the inferior eolliculns.
pom, medulla oblongata, and the right cerebellar hemisphere to illustrate a lesion in the
inferior colliculus (x) which passes through the reticular formation in the pons (.<:').
(Lugol-fast blue stain, Kluver-Barrera's
method)
dissociation, ventricular tachycardia, and even
complexes resembling those of the Wolff-Parkinson-White syndrome. These results indicate the diversity of effect of stimulation of
different areas of the hypothalamus. It is a
well-established fact that the property of
Circulation Research. Volume XII. January 196S
rhythmieity of the heart resides in the sinus
node; however, this may be influenced by extracardiac factors. A transitory depression of
the sinus node due to stimulation of the cardiac-neurovegetative nerves in the hypothalamus is the important factor in establishing a
20
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subsidiary pacemaker and ectopic foci of
auricular and ventricular origin. The P wave
changes in the electrocardiogram frequently
encountered in this group of experiments are
evidences of such transitory sinus node depression. The explanation why the anterior
hypothalamus causes only myocardial abnormality rather than arrhythmias cannot be
elucidated by the above statements.
The similarity of the arrhythmias observed
following stimulation of the reticular formation of the cerebral peduncle- and pons with
those observed following stimulation of the
posterolateral hypothalamus suggest the presence of similar functional activity of these two
ai%eas. The efferent pathways emanating
from the reticular formation to the upper
cerebral neurons have been extensively investigated.- ' " • 18 The afferent pathways of
the retk'iilar formations are described as multiple relay systems between the hypothalamus,
medulla, and spinal c o r d ' ; however, their
interrelationships have not been well established. Harris describes the reticular formation as multiple neuron relays from the tegmentum of the medulla and midbrain up to
the cerebral cortex via the hypothalamus and
thalamus.
Previous experience has shown the importance of the reticular formation and the corticospinal tract for the transmission of sympathetic impulses from the hypothalamus.7' s It
seems that in regard to arrhythmias observed,
the function of the reticular formation is intimately related to the function of the hypothalamus, especially the posterolateral area.
Marked disturbances following stimulation of
the mesencephalic reticular formation as observed in these experiments and the similarity
of responses with those of stimulation of the
posterolateral hypothalamus confirm the above
hypothesis. The presence of multisynaptic
transmissions occurring in the ascending and
descending pathways of the reticular formation indicate the integrating role of the latter.
Consequently we are inclined to believe that
the hypothalamus serves as a pathway for
the impulses reaching the medulla and cardiac
neurovegetative systems and that the reticular
ATTAR, GUTIERREZ, BELLET, RAVENS
formation of the pons is also intimately related to it in affecting cardiac rhythmicity.
Summary and Conclusions
Changes in blood pressure and the electrocardiogram were studied before and after the
stimulation of the hypothalamus (anterior,
lateral, and posterior) and the reticular formation of the pons in anesthetized cats.
The stimulation of the anterior hypothalamus produced a rise of blood pressure and
usually bradycardia; tachycardia was rarely
observed. Arrhythmias were not observed,
and the electroeardiographic changes consisted only of slight ST elevation and deepening of the T waves. Stimulation of the
lateral hypothalamus produced a rise in blood
pressure of a lesser magnitude than that of
the anterior hypothalamus but was associated
with a transitory phase of A-V dissociation
and frequent premature systoles. Stimulation
of the posterolateral hypothalamus resulted
in the same rise in blood pressure as that of
stimulation of the lateral hypothalamus and
was accompanied by nodal rhythms, aberrant
ventricular conduction, and fusion beats.
Stimulation of the reticular formation produced a rise in blood pressure similar to stimulation of the lateral and posterolateral
hypothalamus and was associated with slight
tachycardia, widening of the QRS complexes,
transitory A-V dissociation with nodal escapes
and ectopic beats of ventricular origin, and
fusion beats.
These findings suggest that: (1) the
hypothalamus serves as a pathway for cardiac
neurovegetative stimuli, probably via the
reticular formation, producing predominantly
sinus node depression; (2) the posterolateral
hypothalamus and reticular formation have
similar functions in the production of cardiac
arrhythmia.
References
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Circulation Research, Volume XII, January 19GS
HYPOTHALAMUS AND CARDIAC ARRHYTHMIA
3. FOSTER, J. il., AND WEINBERG, J.:
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Effect of Stimulation of Hypothalamus and Reticular Activating System on Production of
Cardiac Arrhythmia
HOUSHANG J. ATTAR, MARIO T. GUTIERREZ, SAMUEL BELLET and J. R. RAVENS
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Circ Res. 1963;12:14-21
doi: 10.1161/01.RES.12.1.14
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