Understanding the Human Machine - A Primer for Bioengineering - Max E. Valentinuzzi

called Attention Deficit Hyperactivity Disorder (ADHD), frequently seen in school children and also in adults, might find its roots in this system.

2.7.4. The Autonomic System

It is absolutely involuntary. We cannot constrict our skin and muscle vessels to favor blood circulation in the guts or commit suicide by stopping respiration. These actions are carefully handled irrespective of our wishes by the autonomic system, which conveys sensory impulses from all of the organs in the chest, abdomen and pelvis through nerves to other parts of the brain (mainly the medulla, pons and hypothalamus). These action potentials often do not reach our consciousness, but elicit largely automatic or reflex responses through the efferent autonomic nerves, thereby eliciting appropriate reactions of the organs to variations in environmental temperature, posture, food intake, stressful experiences and other external changes.

There are two major divisions, the parasympathetic and the sympathetic sections. By and large, they have opposite effects. The afferent nerves subserving them convey impulses from the body organs to the controlling centers. From these centers, efferent signals are transmitted to all parts of the body by the parasympathetic and sympathetic nerves. The impulses of the parasympathetic system reach the organs of the body through the cranial nerves 3, 7, 9, and 10, and some sacral nerves, to the eyes, the gastrointestinal system, and other organs. The sympathetic nerves, in turn, reach their end organs through more complex pathways down the spinal cord to clusters of sympathetic bodies (ganglia) alongside the spine where the messages are relayed to other neural pathways that travel to all parts of the body.

Like other nerves, those of the autonomic nervous system send their messages to the end organs by releasing transmitter substances to which the receptors of the target cells are responsive. In the parasympathetic system, acetylcholine is responsible for most of these transmissions. In the sympathetic division, instead, information is transmitted by the release of norepinephrine (noradrenaline). There are, nonetheless, important exceptions to this general rules.

Let us illustrate briefly with some examples. When a stimulus arises in an organ, such as a bright light into the eyes, the message is conducted through sensory fibers to the midbrain to give rise to a stimulus that trav-

els through the parasympathetic fibers of the oculomotor nerves to the pupils, resulting in automatic contraction of the pupillary muscles to constrict the aperture and so reduce the amount of light reaching the retinae. Similarly, the stimuli associated with the entry of food into the stomach are conveyed by afferent fibers of the vagus nerve to the command station of the vagus in the brain, whence messages are automatically sent through efferent vagal fibers back to the stomach. These stimulate the secretion of gastric juices and peristaltic contractions to mix the food with the secreted digestive juices and gradually shift the gastric contents into the intestines where a similar process is initiated through essentially the same parasympathetic nerve pathways. Fortunately, emptying of the rectum and of the urinary bladder is not entirely automatic, but is subject to parasympathetic impulses that are voluntarily controlled.

The sympathetic nervous system is even more automatic and only exceptionally susceptible to any voluntary control. When the environmental temperature is raised on a hot summers day, the increased temperature initiates several responses. Thermal receptors send stimuli to control centers of the brain from which inhibitory messages travel along the sympathetic pathways to the blood vessels of the skin resulting in dilatation of blood vessels, thereby greatly increasing blood flow to the surface of the body from where heat is lost by radiation. Dilatation of the blood vessels in this way tends to lower the blood pressure and to promote oozing or transudation of fluid from the capillaries, which may result in swelling of the dependent limbs. Thus, fine adjustment in sympathetic control of vascular contraction and “tone” is required to prevent excessive vascular dilatation and undue reduction in blood pressure. Otherwise, this might result in severe gravitational pooling of blood in the lower limbs, thereby reducing blood flow to the brain and causing fainting spells. The sympathetic nervous system responds to environmental heat in another important way: The rise in body temperature is sensed by the hypothalamic center from which stimuli emanate via sympathetic nerves to the sweat glands, resulting in sweating. This serves to cool the body by the loss of heat resulting from evaporation of the sweat.

Control of the rate and strength of cardiac contractions is also under the control of the autonomic nervous system. Thus, a fall in blood pressure resulting from traumatic injury causing blood loss is sensed by pressure-

sensitive parts of the arteries called baroreceptors. Evidence of reduced arterial distension is sensed by these baroreceptors and conveyed by the parasympathetic (mainly the glossopharyngeal) nerves to the cardiovascular control center in the medulla. From these nuclei, sympathetic stimuli transmitted by the cardiac nerves cause acceleration of the heart rate, complemented by simultaneous reduction in the parasympathetic stimuli via the vagus nerves which slow the heart rate. For example, a stimulus to contraction of the blood vessels is required in order to maintain the blood pressure when we arise from bed in the morning, so as to prevent fainting from excessive pooling of blood in the lower body. This stimulus is conveyed by norepinephrine release within the walls of the blood vessels from the nerve endings of the sympathetic nerves that innervate each blood vessel.

Dysautonomia indicates malfunction of the autonomic nervous system. It can be a serious and even terminal disease. Some of the specific disorders that fall within the group are Postural Orthostatic Tachycardia Syndrome (POTS), Neurocardiogenic Syncope, Mitral Valve Prolapse Dysautonomia, Pure Autonomic Failure, and Multiple System Atrophy (Shy–Drager Syndrome).

To get more details, visit the website by Dr. David H.P. Streeten, from SUNY Health Science Center, Syracuse, NY 13210, who graciously presents a very didactic section on this subject.

2.7.5. The Synapse

The word “synapse” refers to the site of functional apposition of two neurons. We already stated that the nervous system is formed by neurons that control all the conscious and unconscious activities of our life. The neurons have a central body or soma and short projections called dendrites. Besides, there is a long projection called axon. With these two projections, neurons make connections, or synapse, with other neurons.

The nervous impulses are generated in the neural soma and propagate along the axon at high speed (3 to 50 m/s). We have dealt with this conductive property above, in the Electrophysiology Section. When the axon synapses, that is, connects to another neuron, it makes possible the transmission of the message originated in the cellular body. Such transmission is unidirectional. Specific substances (chemical transmitters) are released at the pre-synaptic side, which, after traversing the space

between the two neurons, reach the post-synaptic side where there are receptors sensitive to the transmitter. Thus, a synapse means a discontinuity from an histological point of view. Typical chemical transmitters are acetylcholine, serotonin, noradrenaline (or norepinephrine) and dopamine. Acetylcholine was the first known transmitter and is one of the most important.

The process of transmission of the action potential through a synapse can be summarized in the following steps: The neurotransmitter is manufactured by the neuron and stored in vesicles at the axon terminal. When the action potential reaches the axon terminal, it causes the vesicles to release the neurotransmitter molecules into the synaptic cleft. The neurotransmitter diffuses across the cleft and binds to receptors on the postsynaptic cell. The activated receptors cause changes in the activity of the post-synaptic neuron. The neurotransmitter molecules are released from the receptors and diffuse back into the synaptic cleft. The neurotransmitter is reabsorbed by the postsynaptic neuron. This process is known as reuptake.

There are several websites where the interested student can find detailed information about synapses and the process of transmission across them. For the time being, the subject is beyond the scope of this book.

2.7.6. Cerebrospinal Fluid (CSF)

It is a liquid compartment that is small but significant part of the ECF, however, because of its importance in anesthesiology it is better to treat it as a subject of the CNS. The French physiologist Magendie rediscovered it in 1825 and one of the holes through which it flows carries his name, Magendie’s foramen. A young Italian physician, Domenico Cotugno, in Naples, made the first description in 1764 (Brazier, 1959).

The CSF is bounded by two membranes, the piamater, which covers all the brain and spinal cord structures, and the arachnoid, which is situated above the former covering the vascular network. Above the arachnoid there is the duramater. Thus, when the skull is penetrated by a surgical instrument (a trephanum) or when the spinal column is punctured, say, to practice peridural anesthesia, the duramater is the first membrane to encounter. Besides, the CSF occupies all spaces of the CNS, including the four cerebral ventricles.

Specialized capillaries, the choroidal plexuses, passively (as a ultrafiltrate) and actively (by secretion) extrude from blood through the capillary wall the CSF into the lateral cerebral ventricles, circulating via the interventricular foramens to the third ventricle and through the cerebral aqueduct into the fourth ventricle. From the latter, fluid passes via many apertures to the subarachnoid space to diffuse into all cerebral and spinal cord spaces. CSF is absorbed by the subarachnoid cilae, which project into the dural sinuses to return to the venous circulation. In the spinal cord the CSF returns to the general circulation via the spinal veins.

The volume is in the order 135 mL at a pressure of 10 mmHg. It flows at a very slow rate of 0.3 mL/min following the path described above. Cushing call it the “third circulation” (the lymphatic being the second and the blood circuit the first). Sodium, chloride, potassium and calcium plus glucose and some proteins are components of the fluid and it is isosmotic with plasma (i.e., 289 mOsm/L).

The main function of the CSF is purely mechanic: it acts as a buffer, some sort of pillow, to significantly decrease the traumatic effect of hits. The human adult brain weight is about 1,400 g, since it is floating in its own sea, the actual effective weight goes down to a bare 50 g.

Problem: What basic physical principle explains the brain weight reduction mentioned above? Search for the necessary numerical information to validate the numbers quoted above. Do not blindly accept them as an absolute truth.

It also plays a regulatory function that sows up in some pathologies of the CNS. For example, an increase in its hydraulic pressure leads to an increase in arterial blood pressure. The latter tends to stabilize at a value slightly higher than the pressure exerted against the medulla oblongata. This is known as Cushing’s law or reflex, described in 1901–2. This would be a protective mechanism to preserve blood flow to the central nervous structures in pathologies characterized by higher than normal intracranial pressure, such as hydrocephalia or brain tumors. The phenomenon can be beautifully demonstrated in the experimental animal (Evans and Geddes, 1969).

2.7.7. Closing Remarks of Section 7

Knowledge about the CNS is still incomplete. The process of quantification referred to in previous sections requires more evolution with a better

definition of the variables. Ablation and stimulation techniques and the appearance of pathologies and the results of accidents as well have permitted finding causal relationships among centers and anatomical areas.

Certain pathologies demonstrated the existence of feedback loops, as for example in the circuit cerebral cortex-basal ganglia-thalamus-cerebral cortex, which, when malfunctioning, is involved in diseases such as Parkinson’s, balism, chorea, and atetosis, all of them collectively named as dyskinesias (from Greek, dys, incorrect, and kinesis, movement). Another CNS feedback circuit is cerebral cortex-protuberance-cerebellum- thalamus-cerebral cortex, which would lead to ataxia or intention tremor. In the Middle Age, some of these diseases were indiscriminately called Saint Vitus’ Dance. History in this respect is quite attractive and sometimes sad.

Studies on the synapse are still going on since it appears as an extremely important and relevant subject to the Nervous System. The reader is encouraged to proceed further in it for its many connotations in the concepts of memory, adaptation, behavior, and also as inspiration in neural modeling. For the latter subject and for the Nervous System in general, we suggest the website http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookNERV.html,

where the Text ©1992, 1994, 1997, 1998, 2000, 2001, by M.J. Farabee (all rights reserved) is displayed. Its use for educational purposes is encouraged. Email: mj.farabee@emcmail.maricopa.edu

2.8. Muscular System

We look at it almost with worship, it is the driving engine to move us about and beyond, to fight and run; it gives us joy and pleasure, and yet, how far behind the mind it is!

2.8.1. Introduction

The skeleton and muscles function together as the musculoskeletal system. This system (often treated as two separate ones, muscular and skeletal) plays an important homeostatic role allowing the individual to move, for example, to more favorable external conditions. There are, however,

other not negligible functions, as the production of heat during muscle contraction (sometimes, in a cold day, we rub our hands together or jog swiftly on the same spot), and the dynamic and static support to the whole body supplied by the bony structure (otherwise, we would collapse as some sort of jelly).

Most of the tissues in the body is muscle. When the hand is set on the body surface, most probably it will seat on a muscle. The beef we eat is muscle. The handsome, powerful and frequently admired or sought after physique displayed by an athlete is essentially a well-organized and developed complex bundle of skeletal muscles.

In this section, we describe just a few selected topics of the Muscular System, specifically those which are perhaps more attractive to the future biomedical engineer or may be better amenable to the engineering methodology. The skeleton is left out, more properly treated in a course of anatomy or biomechanics.

Many websites are available for the curious mind, among them, we recommend http://www.umds.ac.uk/physiology/mcal/spinmain.html. For the intrinsic mechanism of muscular contraction, the classic article by H.E. Huxley (1969) is suggested, where the author describes a revealing model for cross-bridge action at variable muscular filament spacing. The paper by Uwe Proske (1997) is an excellent and well-referenced update about the muscle spindle. Keep also in mind that the muscular system is also intimately related to the nervous system, so much that you may also speak of the neuromusculoskeletal system.

2.8.2. Functional Unit: The Neuromuscular Junction

The spinal cord gives off efferent motor fibers that innervate specific skeletal muscles. One fiber controls several muscle fibers following orders emanated, say, voluntarily from the motor cortex, or reflexly from a spinal segment. In big strong muscles, as the biceps, or the triceps, or muscles of the leg, the ratio is very large, that is, a single nerve fiber may take care of 100 or 200 muscle fibers, while in fine movement muscles (as in the fingers or lips or the vibrissae of a rodent’s snout or cat whiskers), the ratio can be as small as 1 to 2 or 1 to 6. One nerve fiber and its set of innervated muscle fibers, be it large or small, is a functional motor unit. Stimulation of that nerve fiber produces contraction of all its associated muscle fibers. Removal of any of the component elements

(say, any of the fibers) destroys or damages the unit. For the understanding of the pathophysiology of muscle as well as for the development of adequate prostheses and motor assist devices, this concept is extremely important and must be clearly grasped.

A nerve is composed of many fibers and, thus, there is a multiplication effect as it enters the muscle because of the nerve fiber to muscle fiber ratio. However, even within the same muscle, not necessarily each fiber innervates exactly the same number of muscle fibers. There is some spread of values. Moreover, one nerve may innervate more than one muscle. For example, the musculocutaneous nerve, with its roots at cervical levels C5, C6 and C7, innervates three muscles: the biceps brachii, the brachialis and the coracobrachialis. One way of controlling the force of contraction is by recruiting more fibers in order, say, to lift a given weight.

The student is encouraged to search in the web for more information about this nerve and its three associated muscles. Find out what kind of movements they are responsible for. Besides, he/she should find examples of nerve fiber to muscle fiber ratios.

Nerve fibers connect to muscle fibers through a modified synapse, the socalled neuromuscular or myoneural junction, and, as in its nervous analogy, there is also a discontinuity: on one side, the nerve membrane can be seen under the electro microscope, on the other, the muscle membrane, and both are separated by extracellular fluid. Classic neuromuscular physiology describes three phenomena (one physiological, another biochemical and a third pathological) that clearly indicate the potential weakness of the junction, as if it were a “bottleneck” of the system:

1-If the nerve is stimulated repeatedly to obtain contraction of its muscle, soon the muscle will not respond appropriately. Contractions will become definitely weaker. However, the nerve will show a normal response to stimulation and the muscle will contract also normally when directly stimulated. This is a classical experiment in physiology. Obviously, there is some failure at the junction. It is now known that there is exhaustion of the acetylcholine (ACh) vesicles at the pre-junction site. This is called fatigue, and it is a physiological, that is, an expected normal phenomenon.

2-There are substances, as for example curare (an extract obtained from various species of Strychnos, which are plants found in Southamerica),

that have a reversible blocking action on the myoneural junction leading to paralysis of the skeletal muscles. The Indians poisoned their arrows to hunt animals or against the Spanish conquistadores. Death from curare is caused by asphyxia, because the skeletal muscles become relaxed and then paralyzed. However, the poison only works in the blood; poisoned animals have no harmful effects on humans if ingested (orally). Its vapors are not poisonous. During curare poisoning the heart continues to beat, even after breathing stops, which means that heart function is not stopped by curare. The horror of curare poisoning is that the victim is very much awake and aware of what is happening until the loss of consciousness. Consequently, the victim can feel the progressive paralysis but cannot do anything to call out or gesture. If artificial respiration is performed throughout the ordeal, the victim will recover and have no ill effects.

3-There is a disease, myasthenia gravis, precisely located at these junctions. The action potentials are not efficiently transmitted through the gap (also called cleft) and the net result is a weak muscular contraction (thus, the etymology of the term is well explained, from Greek, myo, muscle, asthenia, weakness, gravis, serious). The usual cause is an acquired immunological abnormality, but some cases result from genetic abnormalities. The prevalence of myasthenia gravis in the United States is estimated at 14/100,000 population. Patients with myasthenia gravis come to the physician complaining of muscle weakness. The course of disease is variable but usually progressive. After 15 to 20 years, weakness often becomes fixed and the most severely involved muscles are frequently atrophied. The normal neuromuscular junction releases acetylcholine (ACh) from the motor nerve terminal in discrete packages. ACh diffuses across the synaptic cleft and binds to receptors on the muscle end-plate membrane. Stimulation of the motor nerve releases ACh that depolarizes the muscle end-plate region and, thereafter, the muscle membrane causing muscle contraction. In myasthenia, the concentration of ACh receptors on the muscle end-plate membrane is reduced because antibodies are attached to the membrane competing with acetylholine. ACh is released normally, but its effect on the post-synaptic membrane is reduced. The post-junctional membrane is less sensitive to applied ACh, and the prob-

ability that any nerve impulse will cause a muscle action potential is reduced.

A little police story to check your Sherlock Holmes aptitudes: Two persons have dinner together and eat exactly the same food poisoned with curare. One of them dies soon thereafter while the other one survives with no after-effect of any kind. There was suspicion of murder. What disease had the victim? Who was probably the murderer and what knowledge did he/she have?

To think over: Curare is used in anesthesiology, but very well controlled. What for?

The motor unit (neuron and its associated muscles fibers) constitutes and essential component of the muscular system. In fact, it can be considered as its building block. The myoneural junction, in turn, appears as a unique sensitive site where complex electro-biochemical phenomena take place. Similar to its relative, the nerve synapse (connecting nerve to nerve fibers), it is also unidirectional, that is, conduction of the action potential only occurs in this case from nerve to muscle.

2.8.3. Muscle Spindle and Golgi Organ: Posture

Muscles, small or large, are composed of bundle of fibers. Usually, they are strongly attached to bones by tendons, which are strong ligaments to keep muscles in place and where stretch sensing cells conforming the organ of Golgi are located. The bibliography is full of excellent histological and anatomical details. A particular differentiated portion of the muscle is the muscle spindle, which is found within the belly of the muscle and runs in parallel with the main muscle fibers. The spindle is a biological transducer, for it senses muscle length and changes in length, in fact, it is sensitive to stretch. It has sensory nerve terminals whose discharge rate increases as the sensory endings are stretched. This nerve terminal is known as the annulospiral ending, so named because it is composed of a set of rings in a spiral configuration. These terminals are wrapped around specialized muscle fibers that belong to the muscle spindle (intrafusal fibres) and are quite separate from the fibers that make up the bulk of the muscle (extrafusal fibres). The muscle spindle itself contracts very little as compared to the highly contractile muscle fibers.

Let us explain in a very simplified manner the stretch reflex, the inverse stretch reflex and the biasing action of the gamma efferent fibers (Figure 2.73). When the muscle is stretched as a whole (as for example during an