Download Physiology of the Autonomic Nervous System

Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects During Cold Pressor
Test
Master in Biomedical Engineering, IST/FML
1st Year, 1st Semester
Lisbon, Portugal
Matos, Alexandre¹; Saraiva, Joana Catela²; Serafim, Joana³; Sousa, Joana⁴
¹[email protected], ²[email protected], ³[email protected], ⁴[email protected]
Group VI
Abstract
Autonomic nervous system (ANS) by regulating body homeostasis and homeodynamics
plays a important role in the maintenance of ocular function influencing intraocular pressure
(IOP) by regulating the outflow of the aqueous humor through the direct control of blood flow
in the ciliary body and aqueous-venous outflow. There are several eye disorders that are often
associated with changes in IOP which, when not treated or controlled, can damage the optic
nerve provoking loss of nerve cells and leading progressively to blindness. A category of eye
diseases that is often associated with changes in IOP is glaucoma which pathogenesis is not yet
well understood despite in terms of physiopathology ,the lower the IOP at which the damage
occurs or progresses, the higher the chance of finding additional risk factors. The autonomic
imbalance has been suggested as a risk factor, as systemic autonomic neuropathies were been
reported in patients with glaucoma. However, in order to evaluate ANS as a risk factor in
glaucoma patients, normal function tests need to be defined. With the present work, we
intended to evaluate with an autonomic provocative manouvre – the cold pressor test (CPT)the changes in IOP in correlation with modifications of arterial blood pressure (BP). Seven
healthy subjects (3M, 4F) with a mean age of 59±12 years were included in this study. IOP and
BP were continuously monitored and evaluated during basal and CPT periods. Medium (mPP),
diastolic (DPP) and systolic (SPP) perfusion pressures were also calculated for the same
periods. For statistical analysis, the t-Student test was used and differences considered
significant when p<0.05. Results showed a significant increase in BP, mPP, DPP and SPP
without any changes in IOP showing that ocular circulation was not affected by the increase of
sympathetic activity evoked by CPT despite the rise of systemic blood pressure.
Key Words – Autonomic Nervous System, Autonomic Disorders, Intraocular Pressure,
Cold Pressor Test
Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
1. Introduction
Autonomic Nervous System (ANS) is one of the two parts that constitute de nervous
system, taking a central role in the process of homeostasis. Using techniques of computing,
physiology and medicine knowledge, biostatistics and biomedical engineering, in particular
bioelectricity and biosignals, it is possible to comprehend the mechanism of the ANS, not
forgetting its straight connection to the Central Nervous System (CNS) and all the other body
systems. In particular, the study of ANS in the human being allows us to understand the
regulation of blood pressure, heart rate and its sympathetic “fight or flight” and
parasympathetic “rest and digest” reactions.
There is panoply of tests that let investigators know whether the ANS is working
properly. In this project, it was given special attention to the Cold Pressor Test in healthy
people, aiming to understand how the IOP varies in reaction to the stimulus provoked by this
manoeuvre. Another objective was to compare the variation of IOP with body blood pressure.
The analysis data was also used in another project to compare how differently works the
“healthy” ANS and the correspondent in people suffering of Glaucoma.
2. Autonomic Nervous System
The nervous system is divided into central and peripheral systems. Inside peripheral
nervous system (PNA), there is the somatic nervous system (SNS) and the autonomic nervous
system (ANS). The basic unit by which the nervous system exerts its activity is the reflex arc.
This arc consists of a sensory organ – the receptor – that conveys the sensory information
through an afferent neuron to a central integrating station or a sympathetic ganglion from
which new nervous information is generated and transported to the effector organs by an
efferent neuron.
The ANS controls most visceral functions of the body, helping in the control of arterial
pressure, heart rate, gastrointestinal motility and secreture, sweating and body temperature.
While some effector organs are totally controlled by the ANS, other are only partially.
However, the ANS is not strictly an efferent motor system because mixed with the motor fibres
there are sensory fibers. These fibers arise from visceral sensory neurons and transport the
information from receptors located in the end organs to central nervous system functioning as
a feedback system. This information is then integrated and processed in multineuronal
pathways in the brain and spinal cord and can modulate the autonomic outflow that controls
the end-organ.
Autonomic control centers are located, mainly, in the spinal cord, brain stem and
hypothalamus and they are organized for reflex adjustments directly in the end organ or to
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Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
connect different areas of the brain thus evoking a more complex response that includes also
endocrine and behavioral responses.
The efferent signals of this system are transmitted by two major divisions: sympathetic
nervous system and parasympathetic nervous system. A third division the enteric nervous
system regulates the gastrointestinal and secretion and motility.
Anatomically, autonomic nerves differ from skeletal motor nerves (SNS) by having two neurons
instead of one: the preganglionic neuron and the postganglionic neuron, generally synapsing in
a ganglion. Besides these differences, all somatic motor nerves have excitatory effects and
secrete only acetylcholine (ACh), while ANS motor nerves have both exciting and inhibiting
effect and release ACh and norepinephrine (NE). Most organs have dual innervations from
ANS. [1,2]
Fig.1 Overview of the two major ANS divisions – the parasympathetic and sympathetic nervous
[2]
systems
2.1. Parasympathetic Nervous System
The parasympathetic system is also called the
craniosacral division. The cell bodies of preganglionic
neurons are located in the nuclei of four cranial nerves
(III,VII,IX,X) in the brain stem and in three sacral
segments of the spinal cord. Axons of the vagus nerve
(X) represent 80% of the parasympathetic outflow. Its
axons extend to ganglia in the heart, the airways of the
lungs, the liver, gallbladder, bile ducts, stomach,
pancreas, spleen, small intestine, transverse colon and
descending colon. Preganglionic axons of the
parasympathetic division synapse with postganglionical
3
Fig. 2 Parasympatehetic Nervous System
[2]
Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
neurons in terminal ganglia, close to or within the wall of the innervated organ. Thus,
parasympathetic preganglionic neurons are longer than sympathetic nerves and posganglionic
smaller. Besides, parasympathetic response is localized to a single effector because its neurons
connect only with only four or five other neurons that supply the same effector.
What concerns the neurotransmitters, both the parasympathetic and sympathetic
preganglionic neurons are cholinergic, secreting acetylcholine, but there are some differences:
•
•
All parasympathetic postganglionic neurons produce ACh – they are cholinergic.
Most sympathetic postganglionic neurons produce norepinephrine(NE) – they are
adrenergic -, except the nerves to the sweat glands and piloerector muscles of the
hairs. There is a specific situation where postganglionic neurons produce ACh: when
there is danger, there is vasodilatation of the peripheral parts of the human body
which facilitates defense reaction.
There is an enzyme, Acetylcholinesterase (AChE), that inactivates ACh, so parasympathetic
effects are short-lived and localized.
NE is inactivated much more slowly than acetylcholine, so the effects of sympathetic
activation are longer.[1,2,3]
2.2. Sympathetic Nervous System
In the sympathetic nervous system, once the
axon of a preganglionic neuron arrives the
sympathetic trunk ganglia, it may:
•
•
•
•
4
Synapse with postganglionic neurons in
the sympathetic trunk ganglion it first
reaches.
Ascend or descend to a higher or lower
sympathetic trunk ganglion, before
synapsing.
Continue without synapsing through the
trunk, arriving to the prevertebral ganglia.
[2]
Extend to the adrenal medulla.
Fig. 3 Pre and postganglionic neurons of ANS
Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
The cell body of each preganglionic neuron lies in the intermediolateral horn of the spinal
cord and its fiber passes through the anterior root of the cord into the corresponding spinal
nerve. Thus, the first cell extends from CNS via a cranial or a spinal nerve to an autonomic
ganglion. The latter lies entirely in the peripheral nervous system. Its cell body is in the
ganglion and its axon extends to the effector. ANS effectors are smooth muscle, cardiac muscle
and glands.
The sympathetic division is also called the
thoracolumbar division, because of the location of
its outflow of nerves impulses from thoracic and
lumbar segments of the spinal cord. The
preganglionic axons exit from the spinal cord
through the anterior root of a spinal nerve along
with axons of somatic motor neurons. After that,
they extend to a sympathetic ganglion. Because of
its proximity to the spinal cord, the preganglionic
axons are short. Sympathetic trunk ganglia lie in
two vertical rows around the spinal cord. Most
postganglionic axons emerging from the trunk
supply organs above the diaphragm. There are also
the prevertebral ganglia, whose postganglionic
axons
supply
organs
below
diaphragm.
Preganglionic axons have many branches, which
allow them to synapse with many postganglionic
neurons. [1,2,3]
Fig. 4 Sympathetic Nervous System
[2]
3. The Cardiovascular System and the Autonomic Nervous
System
Homeostasis is the property of the body that regulates its internal environment so as to
maintain stable, constant condition. [6]
Homeostasis the circulation of blood and heart rate. Blood flows normally flows from
regions of high pressure to regions of lower pressure. The greater the difference, the greater
the blood flow. It’s the contraction of ventricles that generates blood pressure (BP), which is
the pressure exerted by blood on the walls of vessels. Its highest value occurs in aorta, where
it reaches around 120 mmHg during systole and 80mmHg when diastole happens (in normal
people). Along its path, started in the left ventricle, the blood pressure decreases
progressively, reaching almost 0 mmHg, when entering the right aorta. BP depends in part of
the cardiac output (5 liters in average). When blood flows, there is an opposition too blood
flow due to its friction within vessel walls, the vascular resistance. When vascular resistance
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Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
grows, the same happens with BP. Vascular resistance depends essentially on the size of
lumen, blood viscosity and total vessel length.
Blood pressure (BP) can be calculated by the following formulas:
BP = CO*TPR
or
BP = SV*HR*TPR (CO = SV*HR)
Where SV is Systolic Volume, CO is Cardiac Output, HR is Heart Rate and TPR is Total
Peripheral Resistance.
Heart rate and stroke volume are regulated from the cardiovascular center (CV) –
constituted by the Nucleus Tratus Solitarius (NTS) and Nucleus Ambiguus (NA) - in the medulla
oblongata where there are received signals from higher brain centres, proprioceptors,
baroreceptors and chemoreceptors, sending them both to the sympathetic and
parasympathetic divisions of the autonomic nervous system. Proprioceptors provide input to
the CV, by sending signals from movements of joints and muscles. Baroreceptors have a critical
role in the control of blood pressure. In fact, they monitorize blood pressure. They are located
in “strategic” places, like the aorta, internal carotid arteries. When blood pressure falls, the
baroreceptors are less stimulated, sending signals at a slower rate to the CV through
glossopharyngeal nerves (IX). In response, the cardiovascular center decreases
parasympathetic stimulation of heart and increases sympathetic stimulation of this organ. As
result, the heart beats faster and stronger, increasing vascular resistance and, so, the blood
pressure, to a normal level. This is a result of the baroreceptor reflex. The signals arrive to the
heart via sympathetic cardiac accelerator nerves, that innerve atria and ventricles. At the same
time, the vagus nerves transport parasympathetic signals, releasing Ach, what decreases the
heart rate.[8,9]
Fig. 5 NTS reflex arc
6
[9]
Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
The chemoreceptors can be peripheral or central. The first are located in the two
carotid bodies and in the aortic body – sensitive to changes in O2, H+ and CO2
concentration - , the latter are in the medulla, monitoring blood levels of CO2 and H+.
Consequently, their primarily function is to regulate respiratory activity. Hypoxia or
hypercapnia, for example stimulate this receptors. Chemoreceptors affect also
cardiovascular activity - directly, when interacting with medullary vasomotor centers,
or indirectly, via altered pulmonary stretch receptor activity. The output from the CV
flows along sympathetic and parasympathetic fibers, acting in the vasomotor tone
(vasoconstriction). [7,9]
Related to blood pressure, there is the intra-ocular pressure (IOP), the fluid
pressure inside the eye, giving the relationship between aqueous humor, located
between the cornea and the lens, and its drainage to the Schlemm’s canal. Its normal
value in human is from 10 to 20 mmHg. [10]
Fig.6 The structure of the eye. [10]
Fig.2 - The eye
The arterial supply of the eye can be subdivided into two main groups: retinal
and choroidal. The former system of vessels supplies the optic nerve and the retina;
they are auto-regulated. The latter system provides nutrients to most of the eye,
including the optic nerve head, and is under control of the autonomic nervous system
and is not auto-regulated. When the sympathetic fibers are activated they cause
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Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
vasoconstriction. These fibers arise from the superior cervical ganglion and release
noradrenaline as a neurotransmitter. The parasympathetic fibers innervating the
choroidal vessels leave the brain stem in the facial nerve and synapse in the
pterygopalatine ganglion. Postganglionic neurons from this ganglion enervate the
choroidal blood vessels, but the neurotransmitter released is unknown. It is postulated
that vasoactive intestinal polypeptide may be the neurotransmitter used in this
system.
Intraocular pressure is controlled by two factors: the rate of production and the
rate of outflow of aqueous humor. The autonomic nervous system does not directly
influence the rate of production of aqueous humor, but it does control the arterial
blood flow in the ciliary body and the aqueous-venous outflow. The latter may be
modulated by the sympathetic control of the system of veins that connect the canal of
Schlemm to the episcleral venous plexus. Stimulation of the parasympathetic nervous
system causes an increase in intraocular pressure. Stimulation of the cervical
sympathetic nerve causes a decrease in intraocular pressure. This may be mediated
primarily by the episcleral venous system.[4,5,10]
4. Autonomic Disorders
When the nervous system does not work properly, homeostasis is affected and, in
extreme cases, it can actually put life in risk. This result from an imbalance between
the sympathetic and the parasympathetic nervous system, which corresponds to an
autonomic disorder. Autonomic disorders are generally due to the aging of the
nervous system, absence of receptors, effectors or lesions. They can be classified as
primary or secondary. The first are congenital. On the other hand, secondary disorders
are acquired during the life of the individual.
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Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
Table I Examples of autonomic disorders.
[3]
There are many procedures or tests which evaluate the function of the
autonomic nervous system. These tests consist of the provocation of this system
generally in a non-invasive way.
Their major aims are:
•
•
•
•
To determinate whether autonomic function is normal or abnormal
To assess the degree of dysfunction
To set the kind of dysfunction (primary, secondary)
Therapeutic
There are many kinds of tests, as the cardiovascular, gastrointestinal and sexual, among
others. The cardiovascular evaluation can be physiological or pharmacological. Some of the
physiological tests are:
•
•
•
•
9
Deep breathing
Head-up tilt
Valsalva maneuver
Cold pressor test
Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
The deep breathing test attempts to standardize respiratory changes and their relation to
heart rate, hence to vagal activity. In this test, the individual is supposed to breathe about six
times per minute instead of the normal twelve to sixteen inspirations per minute. This test
purpose is to analyze the variations in the cardiovascular system.
In the head-up tilt test the individual starts in a horizontal position, and then the bed
changes its position till 45 or 60 grades, depending on the laboratory. The duration varies with
the aim of the study (in order to obtain hypotension, 10 minutes; to obtain syncope, 40
minutes).
Valsalva test evaluates the reaction of the nervous system when the individual exhales
against a closed airway, Variations of the maneuver can be used either in medicine, as a test of
cardiac function and autonomic nervous control of the heart or to ‘clear’ the ears and sinuses
(equalize pressure) when ambient pressure changes, as in diving or aviation.
Cold pressor test is performed by immersing the hand into a melting ice container (4°C)
usually for about three minutes, and measuring changes in blood pressure and heart rate.
Sensory afferents trigger a systemic sympathetic activation, leading to marked
vasoconstriction that elevates blood pressure. [3,7]
5. Purpose
There is panoply of tests that let investigators know whether the ANS is working
properly. In this project, it was given special attention to the Cold Pressor Test in healthy
people, aiming to understand how the IOP varies in reaction to the stimulus provoked by this
manoeuvre. Another objective was to compare the variation of IOP with body blood pressure.
The analysis data was also used in another project to compare how differently works the
“healthy” ANS and the correspondent in people suffering of Glaucoma.
6. Methods and Materials
Our project was based in the analysis of the autonomic nervous system with focus in
the Cold Pressor Test.
The population was constituted by 7 healthy volunteers (3 females and 4 males) with a
mean age of 59 ± 12. None of these subjects had clinical signs of cardiovascular,
neurological or metabolic disorders and none was under medication. Tests were
performed in a dedicated autonomic laboratory, in a quiet environment with
controlled temperature and humidity, during the morning, after a light breakfast
without ingestion of caffeine or other xanthines. Alcohol and tobacco were not
allowed in the previous day and on the day of the test. Studies were approved by the
Ethics Committee of the Faculty of Medicine of Lisbon and performed under informed
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Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
consent according to the Declaration of Helsinki. (According to J. L. Ducla-Soares and
others)
5.1
Experimental protocol
The individual being on a standing
position, a tonometer was placed into the
corneal surface of the eye and a blood
pressure and a rest period of 15 min was
allowed to guarantee a stable condition, after
which the subject’s right hand was immersed
in ice-cold water (4°C) for 1 minute. Subjects
were instructed to breath normally and to
avoid sustained inspiration that would mimic
a Valsalva manoeuvre. Blood pressure, heart
rate and intraocular pressure were
continuously monitored.
(According to J. L. Ducla-Soares and others)
Fig 7 Intraocular pressure measuring
[11]
5.2. Data Analysis
The analysis of the cardiovascular variables (blood pressure, heart rate and
intraocular pressure) was done during two periods: 30 seconds before the stimulus
[basal] and 30 seconds after the maximal value achieved during the test [CPT]. The
mean value of the cardiovascular variables is calculated in this period.
For CPT (Cold Pressor Test), a analysis of the differences of the higher value between
the mean of control values and the values of each individual period of analysis was
made using Student’s unpaired t test and differences were considered significant
where P < 0.05. (GraphPAD Instruments). All data were expressed as means ± SD.
(According to J. L. Ducla-Soares and others)
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Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
7. Results
Our results show an overall significant increase (p<0.05) in all variables except for IOP as is
shown in table II.
Variables considered:
•
•
•
•
•
Mean Blood Pressure
Intraocular Pressure (IOP)
Systolic Perfusion Pressure (SPP)
Diastolic Perfusion Pressure (DPP)
Mean Perfusion Pressure (MPP)
Table II – Changes in the analyzed variables during basal conditions and during CPT (n=7; data
expressed as mean ± SD)
Variables
Mean Blood Pressure
(mmHg)
IOP
(cmH2O)
Systolic Perfusion Pressure
(mmHg)
Diastolic Perfusion Pressure
(mmHg)
Mean Perfusion Pressure
(mmHg)
12
Basal
Cold Pressor
Test
Significant (S) /
Not Significant
(NS)
90.8 ± 11.1
110.0 ± 10.9
S
18.2 ± 3.4
23.0 ± 7.8
NS
104.5 ± 14.8
120.0 ± 15.5
S
62.1 ± 10.8
75.2 ± 12.6
S
72.6 ± 10.5
87.0 ± 12.9
S
Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
Graphic I - Representation of the significant variation of Mean Blood Pressure between Basal and CPT.
Graphic II – Representation of the non significant variation of IOP (Intraocular Pressure) between Basal
and CPT.
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Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
Graphics III, IV, V – representation of the significant variation of the SPP, DPP and MPP (Mean Perfusion
Pressure), respectively, between Basal and CPT.
Graphic III
Graphic IV
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Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
Graphic V
8. Discussion/Conclusion
Our results shown an increase in all analyzed variables except in IOP showing that ocular
circulation was not affected by the increase of sympathetic activity evoked by CPT despite the
rise of systemic blood pressure. In fact, Cold Pressor Test is classically defined as an adrenergic
autonomic provocative manouvre as it causes an increase of sympathetic activity which evokes
an increase of systemic blood pressure. Despite the small number of subjects included in our
study this finding is somewhat contradictory with the literature that states that ANS influences
IOP through the ocular circulation and allows speculating about balance between the ANS and
auto-regulatory processes at the ocular circulation, at least in the presence of a thermic insult.
9. References
[1] Tortora, Gerard J.;Grabowski, Sandra Reynolds . Introduction to the Human Body, Wiley,
2004
[2] Textbook of Medical Physiology. Guyton and Hall, 20th edition, 2000 Saunders
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Physiology of the Autonomic Nervous System
Intraocular Pressure Variation Evaluation in Healthy Subjects in Cold Pressor Test
Biomedical Engineering
[3] Mathias, Christopher J.; Bannister, Roger. Investigation of Autonomic Disorders, in
Autonomic Failure, Ed. Mathias and Bennister, 4th edition, 1999
[4] Autonomic Control of the Eye. A. D. Loewy in Central Regulation of Autonomic Functions,
Ed. Loewy and Spyer, Oxford University Press, 1990
[5] Neves, Carlos Marques . Influências Autonómicas na Circulação Ocular in Tese de
Doutoramento orientada pelo Prof. Doutor Luís Silva Carvalho, 2004
[6] hppt://en.wikipedia.org/wiki/homeostasis
[7] http://cvpharmacology.com/vasodilator/Ganglion.htm
[8] Stewart, J. M. . Autonomic Testing, Heart Rate Variability, Blood Pressure Variability, and
the Baroreflex. ANS Human Evolution. July, 2008.
[9] Richter, D. W.; Spyre, K. M. . Controlling cardiorespiratory function: the baroreceptor and
the chemoreceptor reflexes and the hypothalamic defense area, ANS experimental evolution,
July 2007
[10] http://en.wikipedia.org/wiki/Intraocular_pressure
[11] http://www.zyoptix.com.br/site/images/preopslitlamp.jpg
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