1.1 THE CONCEPT OF BIOELECTROMAGNETISM

Bioelectromagnetism is a discipline that examines the electric, electromagnetic, and magnetic phenomena which arise in biological tissues. These phenomena include:

The behavior of excitable tissue (the sources)

The electric currents and potentials in the volume conductor

The magnetic field at and beyond the body

The response of excitable cells to electric and magnetic field stimulation

The intrinsic electric and magnetic properties of the tissue

It is important to separate the concept of bioelectromagnetism from the concept of medical electronics; the former involves bioelectric, bioelectromagnetic, and biomagnetic phenomena and measurement and stimulation methodology, whereas the latter refers to the actual devices used for these purposes.

By definition, bioelectromagnetism is interdisciplinary since it involves the association of the life sciences with the physical and engineering sciences. Consequently, we have a special interest in those disciplines that combine engineering and physics with biology and medicine. These disciplines are briefly defined as follows:

Biophysics: The science that is concerned with the solution of biological problems in terms of the concepts of physics.

Bioengineering: The application of engineering to the development of health care devices, analysis of biological systems, and manufacturing of products based on advances in this technology. This term is also frequently used to encompass both biomedical engineering and biochemical engineering (biotechnology).

Biotechnology: The study of microbiological process technology. The main fields of application of biotechnology are agriculture, and food and drug production.

Medical electronics: A division of biomedical engineering concerned with electronic devices and methods in medicine.

Medical physics: A science based upon physical problems in clinical medicine.

Biomedical engineering: An engineering discipline concerned with the application of science and technology (devices and methods) to biology and medicine.

Fig. 1.1. Currently recognized interdisciplinary fields that associate physics and engineering with medicine and biology:

BEN = bioengineering,

BPH = biophysics,

BEM = bioelectromagnetism,

MPH = medical physics,

MEN = medical engineering,

MEL = medical electronics.

Figure 1.1 illustrates the relationships between these disciplines. The coordinate origin represents the more theoretical sciences, such as biology and physics. As one moves away from the origin, the sciences become increasingly applied. Combining a pair of sciences from medical and technical fields yields interdisciplinary sciences such as medical engineering. It must be understood that the disciplines are actually multidimensional, and thus their two-dimensional description is only suggestive.

1.2 SUBDIVISIONS OF BIOELECTROMAGNETISM

1.2.1 Division on a Theoretical Basis

The discipline of bioelectromagnetism may be subdivided in many different ways. One such classification divides the field on theoretical grounds according to two universal principles: Maxwell's equations (the electromagnetic connection) and the principle of reciprocity. This philosophy is illustrated in Figure 1.2 and is discussed in greater detail below.

Maxwell's Equations

Maxwell's equations, i.e. the electromagnetic connection, connect time-varying electric and magnetic fields so that when there are bioelectric fields there always are also biomagnetic fields, and vice versa (Maxwell, 1865). Depending on whether we discuss electric, electromagnetic, or magnetic phenomena, bioelectromagnetism may be divided along one conceptual dimension (horizontally in Figure 1.2) into three subdivisions, namely

(A) Bioelectricity,

(B) Bioelectromagnetism (biomagnetism), and

Subdivision B has historically been called "biomagnetism" which unfortunately can be confused with our Subdivision C. Therefore, in this book, for Subdivision B we also use the conventional name "biomagnetism" but, where appropriate, we emphasize that the more precise term is "bioelectromagnetism." (The reader experienced in electromagnetic theory will note the omission of a logical fourth subdivision: measurement of the electric field induced by variation in the magnetic field arising from magnetic material in tissue. However, because this field is not easily detected and does not have any known value, we have omitted it from our discussion).

Reciprocity

Owing to the principle of reciprocity, the sensitivity distribution in the detection of bioelectric signals, the energy distribution in electric stimulation, and the sensitivity distribution of electric impedance measurements are the same. This is also true for the corresponding bioelectromagnetic and biomagnetic methods, respectively. Depending on whether we discuss the measurement of the field, of stimulation/magnetization, or the measurement of intrinsic properties of tissue, bioelectromagnetism may be divided within this framework (vertically in Figure 1.2) as follows:.

(I) Measurement of an electric or a magnetic field from a bioelectric source or (the magnetic field from) magnetic material.

(II) Electric stimulation with an electric or a magnetic field or the magnetization of materials (with magnetic field)

(III) Measurement of the intrinsic electric or magnetic properties of tissue.

Fig. 1.2. Organization of bioelectromagnetism into its subdivisions. It is first divided horizontally to:

A) bioelectricity

B) bioelectromagnetism (biomagnetism), and

C) biomagnetism.

Then the division is made vertically to:

I) measurement of fields,

II) stimulation and magnetization, and

III) measurement of intrinsic electric and magnetic properties of tissue.

The horizontal divisions are tied together by Maxwell's equations and the vertical divisions by the principle of reciprocity.

Description of the Subdivisions

The aforementioned taxonomy is illustrated in Figure 1.2 and a detailed description of its elements is given in this section.

(I) Measurement of an electric or a magnetic field refers, essentially, to the electric or magnetic signals produced by the activity of living tissues. In this subdivision of bioelectromagnetism, the active tissues produce electromagnetic energy, which is measured either electrically or magnetically within or outside the organism in which the source lies. This subdivision includes also the magnetic field produced by magnetic material in the tissue. Examples of these fields in the three horizontal subdivisions are shown in Table 1.1.

Table 1.1   I ) Measurements of fields

(A) Bioelectricity (B) Bioelectromagnetism
     (Biomagnetism) (C) Biomagnetism

Neural cells

electroencephalography (EEG)    magnetoencephalography (MEG)

electroneurography (ENG) magnetoneurography (MNG)

electroretinography (ERG) magnetoretinography (MRG)

Muscle cells

electrocardiography (ECG) magnetocardiography (MCG)

electromyography (EMG) magnetomyography (MMG)

Other tissue

electro-oculography (EOG) magneto-oculography (MOG)

electronystagmography (ENG) magnetonystagmography (MNG)

magnetopneumogram

magnetohepatogram

(II) Electric stimulation with an electric or a magnetic field or the magnetization of materials includes the effects of applied electric and magnetic fields on tissue. In this subdivision of bioelectromagnetism, electric or magnetic energy is generated with an electronic device outside biological tissues. When this electric or magnetic energy is applied to excitable tissue in order to activate it, it is called electric stimulation or magnetic stimulation, respectively. When the magnetic energy is applied to tissue containing ferromagnetic material, the material is magnetized. (To be accurate, an insulated human body may also be charged to a high electric potential. This kind of experiment, called electrifying, were made already during the early development of bioelectricity but their value is only in the entertainment.) Similarly the nonlinear membrane properties may be defined with both subthreshold and transthreshold stimuli. Subthreshold electric or magnetic energy may also be applied for other therapeutic purposes, called electrotherapy or magnetotherapy. Examples of this second subdivision of bioelectromagnetism, also called electrobiology and magnetobiology, respectively, are shown in Table 1.2.

Table 1.2   II ) Stimulation and magnetization

(A) Bioelectricity (B) Bioelectromagnetism
     (Biomagnetism) (C) Biomagnetism

Stimulation

  patch clamp, voltage clamp

  electric stimulation of
the central nervous system
or of motor nerve/muscle
magnetic stimulation of
the central nervous system
or of motor nerve/muscle

  electric cardiac pacing magnetic cardiac pacing

  electric cardiac defibrillation magnetic cardiac defibrillation

Therapeutic applications

  electrotherapy electromagnetotherapy magnetotherapy

  electrosurgery
(surgical diathermy)

Magnetization

magnetization of
    ferromagnetic material

(III) Measurement of the intrinsic electric or magnetic properties of tissue is included in bioelectromagnetism as a third subdivision. As in Subdivision II, electric or magnetic energy is generated by an electronic device outside the biological tissue and applied to it. However, when the strength of the energy is subthreshold, the passive (intrinsic) electric and magnetic properties of the tissue may be obtained by performing suitable measurements. Table 1.3 illustrates this subdivision:

Table 1.3   III ) Measurement of intrinsic properties

(A) Bioelectricity (B) Bioelectromagnetism
     (Biomagnetism) (C) Biomagnetism

electric measurement of
  electric impedance magnetic measurement of
  electric impedance measurement of magnetic
  susceptibility

impedance cardiography magnetic susceptibility
  plethysmography

impedance pneumography magnetic remanence measurement

impedance tomography impedance tomography magnetic resonance imaging (MRI)

electrodermal response (EDR)

Lead Field Theoretical Approach

As noted in the beginning of Section 1.2.1, Maxwell's equations connect time-varying electric and magnetic fields, so that when there are bioelectric fields there are also biomagnetic fields, and vice versa. This electromagnetic connection is the universal principle unifying the three subdivisions - A, B, and C - of bioelectromagnetism in the horizontal direction in Figure 1.2. As noted in the beginning of this section, the sensitivity distribution in the detection of bioelectric signals, the energy distribution in electric stimulation, and the sensitivity distribution of the electric impedance measurement are the same. All of this is true also for the corresponding bioelectromagnetic and biomagnetic methods, respectively. The universal principle that ties together the three subdivisions I, II, and III and unifies the discipline of bioelectromagnetism in the vertical direction in Figure 1.2 is the principle of reciprocity.

These fundamental principles are further illustrated in Figure 1.3, which is drawn in the same format as Figure 1.2 but also includes a description of the applied methods and the lead fields that characterize their sensitivity/energy distributions. Before finishing this book, the reader may have difficulty understanding Figure 1.3 in depth. However, we wanted to introduce this figure early, because it illustrates the fundamental principles governing the entire discipline of bioelectromagnetism, which will be amplified later on..

Fig. 1.3. Lead field theoretical approach to describe the subdivisions of bioelectromagnetism. The sensitivity distribution in the detection of bioelectric signals, the energy distribution in electric stimulation, and the distribution of measurement sensitivity of electric impedance are the same, owing to the principle of reciprocity. This is true also for the corresponding bioelectromagnetic and biomagnetic methods. Maxwell's equations tie time-varying electric and magnetic fields together so that when there are bioelectric fields there are also bioelectromagnetic fields, and vice versa.

1.2.2 Division on an Anatomical Basis

Bioelectromagnetism can be classified also along anatomical lines. This division is appropriate especially when one is discussing clinical applications. In this case, bioelectromagnetism is subdivided according to the applicable tissue. For example, one might consider

a) neurophysiological bioelectromagnetism;

b) cardiologic bioelectromagnetism; and

c) bioelectromagnetism of other organs or tissues.

1.2.3 Organization of this Book

Because it is inappropriate from a didactic perspective to use only one of the aforementioned divisional schemes (i.e.,division on a theoretical or an anatomical basis), both of them are utilized in this book. This book includes 28 chapters which are arranged into nine parts. Table 1.4 illustrates how these chapters fit into the scheme where by bioelectromagnetism is divided on a theoretical basis, as introduced in Figure 1.2.

Part I discusses the anatomical and physiological basis of bioelectromagnetism. From the anatomical perspective, for example, Part I considers bioelectric phenomena first on a cellular level (i.e., involving nerve and muscle cells) and then on an organ level (involving the nervous system (brain) and the heart).

Part II introduces the concepts of the volume source and volume conductor and the concept of modeling. It also introduces the concept of impressed current source and discusses general theoretical concepts of source-field models and the bidomain volume conductor. These discussions consider only electric concepts.

Part III explores theoretical methods and thus anatomical features are excluded from discussion. For practical (and historical) reasons, this discussion is first presented from an electric perspective in Chapter 11. Chapter 12 then relates most of these theoretical methods to magnetism and especially considers the difference between concepts in electricity and magnetism.

The rest of the book (i.e., Parts IV - IX) explores clinical applications. For this reason, bioelectromagnetism is first classified on an anatomical basis into bioelectric and bio(electro)magnetic constituents to point out the parallelism between them. Part IV describes electric and magnetic measurements of bioelectric sources of the nervous system, and Part V those of the heart.

In Part VI, Chapters 21 and 22 discuss electric and magnetic stimulation of neural and Part VII, Chapters 23 and 24, that of cardiac tissue. These subfields are also referred to as electrobiology and magnetobiology.

Part VIII focuses on Subdivision III of bioelectromagnetism - that is, the measurement of the intrinsic electric properties of biological tissue. Chapters 25 and 26 examine the measurement and imaging of tissue impedance, and Chapter 27 the measurement of the electrodermal response.

In Part IX, Chapter 28 introduces the reader to a bioelectric signal that is not generated by excitable tissue: the electro-oculogram (EOG). The electroretinogram (ERG) also is discussed in this connection for anatomical reasons, although the signal is due to an excitable tissue, namely the retina.

The discussion of the effects of an electromagnetic field on the tissue, which is part of Subdivision II, includes topics on cellular physiology and pathology rather than electromagnetic theory. Therefore this book does not include this subject. The reader may get an overview of this for instance from (Gandhi, 1990; Reilly, 1992).

Table 1.4 Organization of this book (by chapter number) according to the division of bioelectromagnetism on a theoretical basis.

(A) Bioelectricity (B) Bioelectromagnetism
(Biomagnetism) (C) Biomagnetism

(I) Measurement of fields

Electric field from
bioelectric source Magnetic field from
bioelectric source Magnetic field from
magnetic material

04 Active behavior of the membrane
05 Physiology of the synapse and brain
06 Bioelectric behavior of the heart
07 Volume source and volume conductor
08 Source-field models
09 Bidomain model
11 Theoretical methods
13 Electroencephalography
15 12-lead ECG
16 Vectorcardiography
17 Other ECG systems
18 Distortion in ECG
19 ECG diagnosis
28 Electric signals of the eye

12 Theory of biomagnetic measurements
14 Magnetoencephalography
20 Magnetocardiography Not discussed

(II) Stimulation and magnetization

Electric stimulation
with electric field Electric stimulation
with magnetic field Magnetization of material
03 Subthreshold membrane phenomena
21 Functional electric stimulation
23 Cardiac pacing
24 Cardiac defibrillation
22 Magnetic stimulation Not discussed

(III) Measurement of intrinsic properties

Electric measurement of
electric impedance Magnetic measurement of
electric impedance Magnetic measurement of
magnetic susceptibility
25 Impedance plethysmography
26 Impedance tomography
27 Electrodermal response
26 Magnetic measurement of
electric impedance tomography Not discussed

Because discussion of Subdivision C would require the introduction of additional fundamentals, we have chosen not to include it in this volume. As mentioned earlier, Subdivision C entails measurement of the magnetic field from magnetic material, magnetization of material, and measurement of magnetic susceptibility. The reader interested in these topics should consult Maniewski et al. (1988) and other sources. At the present time, interest in the Subdivision C topic is limited.

1.3 IMPORTANCE OF BIOELECTROMAGNETISM

Why should we consider the study of electric and magnetic phenomena in living tissues as a separate discipline? The main reason is that bioelectric phenomena of the cell membrane are vital functions of the living organism. The cell uses the membrane potential in several ways. With rapid opening of the channels for sodium ions, the membrane potential is altered radically within a thousandth of a second. Cells in the nervous system communicate with one another by means of such electric signals that rapidly travel along the nerve processes. In fact, life itself begins with a change in membrane potential. As the sperm merges with the egg cell at the instant of fertilization, ion channels in the egg are activated. The resultant change in the membrane potential prevents access of other sperm cells.

Electric phenomena are easily measured, and therefore, this approach is direct and feasible. In the investigation of other modalities, such as biochemical and biophysical events, special transducers must be used to convert the phenomenon of interest into a measurable electric signal. In contrast electric phenomena can easily be directly measured with simple electrodes; alternatively, the magnetic field they produce can be detected with a magnetometer.

In contrast to all other biological variables, bioelectric and biomagnetic phenomena can be detected in real time by noninvasive methods because the information obtained from them is manifested immediately throughout and around the volume conductor formed by the body. Their source may be investigated by applying the modern theory of volume sources and volume conductors, utilizing the computing capability of modern computers. (The concepts of volume sources and volume conductors denote three-dimensional sources and conductors, respectively, having large dimensions relative to the distance of the measurement. These are discussed in detail later.) Conversely, it is possible to introduce temporally and spatially controlled electric stimuli to activate paralyzed regions of the neural or muscular systems of the body.

The electric nature of biological tissues permits the transmission of signals for information and for control and is therefore of vital importance for life. The first category includes such examples as vision, audition, and tactile sensation; in these cases a peripheral transducer (the eye, the ear, etc.) initiates afferent signals to the brain. Efferent signals originating in the brain can result in voluntary contraction of muscles to effect the movement of limbs, for example. And finally, homeostasis involves closed-loop regulation mediated, at least in part, by electric signals that affect vital physiologic functions such as heart rate, strength of cardiac contraction, humoral release, and so on.

As a result of the rapid development of electronic instrumentation and computer science, diagnostic instruments, which are based on bioelectric phenomena, have developed very quickly. Today it is impossible to imagine any hospital or doctor's office without electrocardiography and electroencephalography. The development of microelectronics has made such equipment portable and strengthened their diagnostic power. Implantable cardiac pacemakers have allowed millions of people with heart problems to return to normal life. Biomagnetic applications are likewise being rapidly developed and will, in the future, supplement bioelectric methods in medical diagnosis and therapy. These examples illustrate that bioelectromagnetism is a vital part of our everyday life.

Bioelectromagnetism makes it possible to investigate the behavior of living tissue on both cellular and organic levels. Furthermore, the latest scientific achievements now allow scientists to do research at the subcellular level by measuring the electric current flowing through a single ion channel of the cell membrane with the patch-clamp method. With the latter approach, bioelectromagnetism can be applied to molecular biology and to the development of new pharmaceuticals. Thus bioelectromagnetism offers new and important opportunities for the development of diagnostic and therapeutic methods.

1.4 SHORT HISTORY OF BIOELECTROMAGNETISM

1.4.1 The First Written Documents and First Experiments in Bioelectromagnetism

The first written document on bioelectric events is in an ancient Egyptian hieroglyph of 4000 B.C. The hieroglyph describes the electric sheatfish (catfish) as a fish that "releases the troops." Evidently, when the catch included such a fish, the fish generated electric shocks with an amplitude of more than 450 V, which forced the fishermen to release all of the fish. The sheatfish is also illustrated in an Egyptian sepulcher fresco (Morgan, 1868).

The Greek philosophers Aristotle (384-322 B.C.) and Thales (c.625-547 B.C.) experimented with amber and recognized its power to attract light substances (Smith, 1931). The first written document on the medical application of electricity is from the year A.D. 46, when Scribonius Largus recommended the use of torpedo fish for curing headaches and gouty arthritis (Kellaway, 1946). The electric fish remained the only means of producing electricity for electrotherapeutic experiments until the seventeenth century.

William Gilbert (1544-1603), physician to Queen Elizabeth I of England, was the first to subject the attractive power of amber to planned experiment. Gilbert constructed the first instrument to measure this power. This electroscope was a light metal needle pivoted on a pin so that it would turn toward the substances of attracting power (see Figure 1.4). Gilbert called the substances possessing this power of attraction electricks, from the Greek name for amber (elektron). Thus he coined the term that eventually became the new science of electricity. Gilbert published his experiments in 1600 in a book entitled De Magnete (Gilbert, 1600). (The reader may refer to Figure 1.20 at the end of this chapter. It presents a chronology of important historical events in bioelectromagnetism from the year 1600 until today.)

Fig. 1.4. The first instrument to detect electricity was the electroscope invented by William Gilbert. (Gilbert 1600).

The first carefully documented scientific experiments in neuromuscular physiology were conducted by Jan Swammerdam (Dutch; 1637-80). At that time it was believed that contraction of a muscle was caused by the flow of "animal spirits" or "nervous fluid" along the nerve to the muscle. In 1664, Swammerdam conducted experiments to study the muscle volume changes during contraction (see Figure 1.5). Swammerdam placed a frog muscle (b) into a glass vessel (a). When contraction of the muscle was initiated by stimulation of its motor nerve, a water droplet (e) in a narrow tube, projecting from the vessel, did not move, indicating that the muscle did not expand. Thus, the contraction could not be a consequence of inflow of nervous fluid.

Fig. 1.5. Stimulation experiment of Jan Swammerdam in 1664. Touching the motoric nerve of a frog muscle (b) in a glass vessel (a) with silver wire (c) and a copper loop (d) produces stimulation of the nerve, which elicits a muscular contraction; however, it is uncertain as to whether the stimulation was produced as a result of electricity from the two dissimilar metals or from the mechanical pinching. See also text. (Swammerdam, 1738.).

In many similar experiments, Swammerdam stimulated the motor nerve by pinching it. In fact, in this experiment stimulation was achieved by pulling the nerve with a wire (c) made of silver (filium argenteum) against a loop (d) made of copper (filium aeneum). According to the principles of electrochemistry, the dissimilar metals in this experiment, which are embedded in the electrolyte provided by the tissue, are the origin of an electromotive force (emf) and an associated electric current. The latter flows through the metals and the tissue, and is responsible for the stimulation (activation) of the nerve in this tissue preparation. The nerve, once activated, initiates a flow of current of its own. These are of biological origin, driven from sources that lie in the nerve and muscle membranes, and are distinct from the aforementioned stimulating currents. The active region of excitation propagates from the nerve to the muscle and is the immediate cause of the muscle contraction. The electric behavior of nerve and muscle forms the subject matter of "bioelectricity," and is one central topic in this book.

It is believed that this was the first documented experiment of motor nerve stimulation resulting from an emf generated at a bimetallic junction (Brazier, 1959). Swammerdam probably did not understand that neuromuscular excitation is an electric phenomenon. On the other hand, some authors interpret the aforementioned stimulation to have resulted actually from the mechanical stretching of the nerve. The results of this experiment were published posthumously in 1738 (Swammerdam, 1738).

The first electric machine was constructed by Otto von Guericke (German; 1602-1686). It was a sphere of sulphur ("the size of an infant's head") with an iron axle mounted in a wooden framework, as illustrated in Figure 1.6. When the sphere was rotated and rubbed, it generated static electricity (von Guericke, 1672). The second electric machine was invented in 1704 by Francis Hauksbee the Elder (British; 1666-1713). It was a sphere of glass rotated by a wheel (see Figure 1.7). When the rotating glass was rubbed, it produced electricity continuously (Hauksbee, 1709). It is worth mentioning that Hauksbee also experimented with evacuating the glass with an air pump and was able to generate brilliant light, thus anticipating the discovery of cathode rays, x-rays, and the electron.

Fig. 1.6. Otto von Guericke constructed the first electric machine which included a sphere of sulphur with an iron axle. When rotating and rubbing the sphere it generated static electricity. (Guericke, 1672).

Fig. 1.7. Electric machine invented by Hauksbee in 1704. It had a sphere of glass rotated by a wheel. When the glass was rotated and rubbed it produced electricity continuously. If the glass was evacuated with air pump it generated brilliant light. (Hauksbee, 1709).

At that time the main use of electricity was for entertainment and medicine. One of the earliest statements concerning the use of electricity was made in 1743 by Johann Gottlob Kr�ger of the University of Halle: "All things must have a usefulness; that is certain. Since electricity must have a usefulness, and we have seen that it cannot be looked for either in theology or in jurisprudence, there is obviously nothing left but medicine." (Licht, 1967).

1.4.2 Electric and Magnetic Stimulation

Systematic application of electromedical equipment for therapeutic use started in the 1700s. One can identify four different historical periods of electromagnetic stimulation, each based on a specific type or origin of electricity. These periods are named after Benjamin Franklin (American; 1706-1790), Luigi Galvani (Italian; 1737-1798), Michael Faraday (British; 1791-1867), and Jacques Ars�ne d'Arsonval (French; 1851-1940), as explained in Table 1.5. These men were the discoverers or promoters of different kinds of electricity: static electricity, direct current, induction coil shocks, and radiofrequency current, respectively (Geddes, 1984a).

Table 1.5. Different historical eras of electric and
electromagnetic stimulation.

Scientist Lifetime Historical era

Benjamin Franklin 1706-1790 static electricity

Luigi Galvani 1737-1798 direct current

Michael Faraday 1791-1867 induction coil shocks

Jacques d'Arsonval 1851-1940 radiofrequency current

The essential invention necessary for the application of a stimulating electric current was the Leyden jar. It was invented on the 11th of October, in 1745 by German inventor Ewald Georg von Kleist (c. 1700-1748) (Krueger, 1746). It was also invented independently by a Dutch scientist, Pieter van Musschenbroek (1692-1761) of the University of Leyden in The Netherlands in 1746, whose university affiliation explains the origin of the name. The Leyden jar is a capacitor formed by a glass bottle covered with metal foil on the inner and outer surfaces, as illustrated in Figure 1.8. The first practical electrostatic generator was invented by Jesse Ramsden (British; 1735-1800) in 1768 (Mottelay, 1975).

Benjamin Franklin deduced the concept of positive and negative electricity in 1747 during his experiments with the Leyden jar. Franklin also studied atmospheric electricity with his famous kite experiment in 1752.

Soon after the Leyden jar was invented, it was applied to muscular stimulation and treatment of paralysis. As early as 1747, Jean Jallabert (Italian; 1712-1768), professor of mathematics in Genova, applied electric stimulation to a patient whose hand was paralyzed. The treatment lasted three months and was successful. This experiment,which was carefully documented (Jallabert, 1748), represents the beginning of therapeutic stimulation of muscles by electricity.

Fig. 1.8. The Leyden Jar, invented in 1745, was the first storage of electricity. It is formed by a glass bottle covered with metal foil on the inner and outer surfaces. (Krueger, 1746).

The most famous experiments in neuromuscular stimulation were performed by Luigi Galvani, professor of anatomy at the University of Bologna. His first important finding is dated January 26, 1781. A dissected and prepared frog was lying on the same table as an electric machine. When his assistant touched with a scalpel the femoral nerve of the frog sparks were simultaneously discharged in the nearby electric machine, and violent muscular contractions occurred (Galvani, 1791; Rowbottom and Susskind, 1984, p. 35). (It has been suggested that the assistant was Galvani's wife Lucia, who is known to have helped him with his experiments.) This is cited as the first documented experiment in neuromuscular electric stimulation.

Galvani continued the stimulation studies with atmospheric electricity on a prepared frog leg. He connected an electric conductor between the side of the house and the nerve of the frog leg. Then he grounded the muscle with another conductor in an adjacent well. Contractions were obtained when lightning flashed. In September 1786, Galvani was trying to obtain contractions from atmospheric electricity during calm weather. He suspended frog preparations from an iron railing in his garden by brass hooks inserted through the spinal cord. Galvani happened to press the hook against the railing when the leg was also in contact with it. Observing frequent contractions, he repeated the experiment in a closed room. He placed the frog leg on an iron plate and pressed the brass hook against the plate, and muscular contractions occurred.

Continuing these experiments systematically, Galvani found that when the nerve and the muscle of a frog were simultaneously touched with a bimetallic arch of copper and zinc, a contraction of the muscle was produced. This is illustrated in Figure 1.9 (Galvani, 1791). This experiment is often cited as the classic study to demonstrate the existence of bioelectricity (Rowbottom and Susskind, 1984 p. 39), although, as mentioned previously, it is possible that Jan Swammerdam had already conducted similar experiments in 1664. It is well known that Galvani did not understand the mechanism of the stimulation with the bimetallic arch. His explanation for this phenomenon was that the bimetallic arch was discharging the "animal electricity" existing in the body.

Alessandro Volta (Italian; 1745-1827), professor of physics in Pavia, continued the experiments on galvanic stimulation. He understood better the mechanism by which electricity is produced from two dissimilar metals and an electrolyte. His work led in 1800 to the invention of the Voltaic pile, a battery that could produce continuous electric current (Volta, 1800). Giovanni (Joannis) Aldini (Italian; 1762-1834), a nephew of Galvani, applied stimulating current from Voltaic piles to patients (Aldini, 1804). For electrodes he used water-filled vessels in which the patient's hands were placed. He also used this method in an attempt to resuscitate people who were almost dead..

Fig. 1.9. Stimulation experiment of Luigi Galvani. The electrochemical behavior of two dissimilar metals [(zinc (Z) and copper (C)] in a bimetallic arch, in contact with the electrolytes of tissue, produces an electric stimulating current that elicits muscular contraction.

In 1872, T. Green described cardiorespiratory resuscitation, a method used to resuscitate surgical patients who were anesthetized with chloroform, an anesthetic with the side effect of depressing respiration and the cardiac pulse. Using a battery of up to 200 cells generating about 300 volts, he applied this voltage to the patient between the neck and the lower ribs on the left side. It is documented that T. Green used this method successfully on five or seven patients who suffered sudden respiratory arrest and were without a pulse (Green, 1872).

Michael Faraday's invention of the induction coil in 1831 initiated the faradic era of electromedicine (Faraday, 1834). However, it was Emil Heinrich du Bois-Reymond (German; 1818-96), who in 1846 introduced the induction coil to medical applications (du Bois-Reymond, 1849). This was called the Faraday stimulation. An induction coil with hammer break is shown in Figure 1.10. An early experiment of Faraday stimulation of the cerebral cortex was made in 1874 by Dr. Robert Bartholow, a professor of medicine in Cincinnati (Bartholow, 1881). Robert Bartholow stimulated the exposed cerebral cortex with faradic currents and observed that they would elicit movements of the limbs of the opposite side and also the turning of the head to that side (York, 1987).

In the late 1800s, Jacques Ars�ne d'Arsonval heated living tissue by applying high-frequency electric current either with an electrode or with a large coil (see Figure 1.11) (d'Arsonval, 1893). This was the beginning of diathermy.

Jacques d'Arsonval (1896) reported on a flickering visual sensation perceived when an individual's head was placed within a strong time-varying magnetic field. This was generated with a large coil carrying 32 A at 42 Hz. He called this phenomenon "magnetophosphenes." It was caused by the stimulating effect of the magnetic field to the retina, which is known to be very sensitive to it. This was the first experiment on magnetic stimulation of the nervous system. The first transcranial magnetic stimulation of the motor cortex was achieved in 1985 (Barker, Jalinous, and Freeston, 1985)..

Fig. 1.10. Induction coil with hammer break. Electric current from the battery (E) is fed to the primary circuit of the induction coil (A). This current pulls the hammer with the magnetic field of the solenoid (close to G) and breaks the circuit with the contactor (D). Through the vibration of the hammer this breaking is continuous and it induces a high voltage alternating current in the secondary circuit in (A). This current is applied to the patient with electrodes (H)..

Fig. 1.11.

The first scientist to report direct cardiac pacing was F. Steiner (1871), who demonstrated this method in a dog anesthetized with an overdose of chloroform. In 1882, Hugo Wilhelm von Ziemssen (German; 1829-1902) applied this technique to a human (Ziemssen, 1882). It was only in 1932, when cardiac pacing was reported by Albert Salisbury Hyman (American; 1893-1972), that this method was applied clinically to atrial pacing (Hyman, 1932).

The modern era of cardiac pacing started in August 1952, when Paul Maurice Zoll (American; 1911- ) performed cardiac pacing for a duration of 20 min (Zoll, 1952). In 1958, Furman and Schwedel succeeded in supporting a patient for 96 days with cardiac pacing (Furman and Schwedel, 1959).

The first implantation of a cardiac pacemaker, a milestone in the history of bioelectromagnetism, was accomplished in Stockholm by the surgeon �ke Senning (1915- ). On October 8, 1958, at the Karolinska Institute, he implanted the pacemaker made by engineer Rune Elmqvist. The development of the implantable pacemaker was made possible by the invention of the transistor by Bardeen and Brattain in 1948.

The first report on cardiac defibrillation, in 1899, is that by Jean Louis Prevost (Swiss; 1838-1927) and Fr�d�ric Battelli (Italian; 1867-1941) (Prevost and Battelli, 1899). They found, in animal experiments, that low-voltage electric shocks induced ventricular fibrillation whereas high-voltage shocks did not. Instead, the latter defibrillated a fibrillating heart.

Modern ventricular defibrillation started with the famous work of William B. Kouwenhoven (American; 1886-1975) and his colleagues who, in the 1930s, used 60 Hz current to defibrillate a dog heart (Geddes, 1976). The first human defibrillation was accomplished by Beck and his colleagues in 1947 (Beck, Pritchard and Feil, 1947).

1.4.3 Detection of Bioelectric Activity

The connection between electricity and magnetism was discovered in 1819 by Hans Christian �rsted (Danish; 1777-1851). �rsted conducted his first experiment during his lecture at the University of Copenhagen. Passing an electric current through a wire above a magnetic needle, he forced the needle to move to the direction normal to the wire (see Figure 1.12) (�rsted, 1820a,b,c). By reversing the direction of the electric current, he reversed the direction of the needle deflection. (The magnetic needle, i.e. the compass, was invented in China about A.D. 100 and is the first detector of magnetic field.)

Fig. 1.12. Reconstruction of the first demonstration of the electromagnetic connection by Hans Christian �rsted in 1819. The battery generates an electric current I to flow in the circuit formed by a metal wire. This current induces a magnetic induction around the wire. The magnetic needle under the wire turns parallel to the direction of the magnetic induction demonstrating its existence. (�rsted, 1820a,b,c).

After this discovery, it was possible to devise a galvanometer, an instrument detecting weak electric currents. Invented by Johann Salemo Christopf Schweigger (German; 1779-1875) in 1821, it is based on the deflection of a magnetized needle in the magnetic field inside a coil, into which the current to be measured is introduced. Because he increased the magnetic field by using multiple loops of wire forming the coil, Schweigger called his instrument multiplikator (Schweigger, 1821). In 1825, Leopold Nobili (Italian; 1784-1835), a professor of physics in Florence, invented the astatic galvanometer (Nobili, 1825). In its construction, Nobili employed a double coil of 72 turns wound in a figure eight (see Figure 1.13A). One magnetic needle was located in each of the two openings. The needles were connected on the same suspension. They were parallel, but of opposite polarity. Since the current flowed in opposite direction in the two coils, both needles moved in the same direction. Because of their opposite direction, the needles did not respond to Earth's magnetic field. Another version of the astatic galvanometer is illustrated in Figure 1.13B. This construction includes only one coil around one of the two magnetic needles. The other needle (identical but opposite in direction), provided with a scale, serves also as an indicator..

Fig. 1.13. (A) Astatic galvanometer invented by Nobili in 1825. He compensated for the effect of the Earth's magnetic field by placing two identical magnetic needles connected on the same suspension in opposite directions in the openings of a coil wound in the form of figure eight. (Nobili, 1825.) (B) A technically more advanced version of the astatic galvanometer. Only one of the two identical (but opposite) needles is surrounded by a coil. The other needle serves as an indicator.

Carlo Matteucci (Italian; 1811-65) was the first to measure a bioelectric current. Using the astatic galvanometer, he made his first measurement of muscle impulse in frog muscle in 1838 (Matteucci, 1838), although the report did not appear in print until 1842.

In 1841, the German physiologist Emil du Bois-Reymond had received a copy of Matteucci's short essay on animal electricity, and thus was aware of the experiments of Matteucci. He repeated the studies with improved instrumentation. Besides detecting the bioelectric current from frog muscle, du Bois-Reymond, in 1842 (shortly before Matteucci's paper was published), measured the current arising from a frog nerve impulse (du Bois-Reymond, 1843). One of his experiments is shown in Figure 1.14.

The English school of neurophysiology began when Richard Caton (British; 1842-1926) became interested in the recording technique of du Bois-Reymond and applied it to the measurement of the electric activity of the brains of rabbits and monkeys. The first report of his experiments, published in 1875 (Caton, 1875), is believed to constitute the discovery of the electroencephalogram (EEG). In 1888, a young Polish scientist Adolf Beck (1863- 1942), working for the great physiologist Napoleon Nicodemus Cybulski (1854-1919) at the University of Krakow, succeeded in demonstrating that the electric impulse propagated along a nerve fiber without attenuation (Beck, 1888). Without knowledge of the work of Caton, Beck studied the electric activity of the brain in animal experiments and independently arrived at many of Caton's conclusions (Beck, 1891). The German psychiatrist Hans Berger (1873-1941), made the first recording of the EEG on a human in 1924, and identified the two major rhythms, and (Berger, 1929). Berger's recordings on EEG are illustrated in Figure 1.15.

Fig. 1.14.

Fig. 1.15.

The tracings of the electric activity of the human heart, the electrocardiogram (ECG), was first measured in 1887 by Augustus Waller (British; 1856-1922) using capillary electrometer (Waller, 1887; see Figure 1.16). In a capillary electrometer a moving photographic film is exposed along a glass capillary tube filled with sulphuric acid and mercury. Their interface moves in response to an electric field. The sensitivity of the capillary electrometer is about 1 mV, but its time response is very poor. The capillary electrometer was invented in 1873 by Gabriel Lippman (1873), and the photographic technique by which the signal was recorded by E. J. Marey and G. J. Lippman (1876).

Waller found that the cardiac electric generator has a dipolar nature (Figure 1.17) and suggested that the ECG should be measured between the five measurement points formed by the hands, legs, and mouth (a total of 10 bipolar leads). He was also the first to record a set of three nearly orthogonal leads, including mouth-to-left arm, mouth-to-left leg, and back-to-front.

A pioneer in modern electrocardiography was Willem Einthoven (Dutch; 1860-1927) who, at the beginning of this century, developed the first high-quality ECG recorder based on the string galvanometer (Einthoven, 1908). Though Einthoven is often credited with inventing the string galvanometer, that honor actually belongs to Cl�ment Ader (1897). However, Einthoven undoubtedly made important improvements in this device such that it was possible to apply it to clinical electrocardiography. Einthoven summarized his fundamental results in ECG research in 1908 and 1913 (Einthoven, 1908; Einthoven et al., 1913), and received the Nobel Prize for his work in 1924.

Horatio Williams, who was the first to construct a sequence of instantaneous vectors (Williams, 1914), is usually considered to be the inventor of vectorcardiography. Hubert Mann made further studies in vectorcardiography to develop it as a clinical tool. He published his first two-dimensional vectorcardiogram based on Einthoven's triangle in 1916 (see Figure 1.18) and called this construction the "monocardiogram" (Mann, 1920). After J. B. Johnson (1921) of the Western Electric Company invented the low-voltage cathode ray tube, it became possible to display bioelectric signals in vector form in real time. This invention allowed vectorcardiography to be used as a clinical tool.

The invention of the electron tube by Lee de Forest (American: 1873-1961) in 1906 allowed bioelectric signals to be amplified, revolutionizing measurement technology. Finally, the invention of the transistor by John Bardeen and Walter Brattain in 1948 marked the beginning of the semiconductor era. It also allowed the instrumentation of bioelectromagnetism to be miniaturized, made portable and implantable, and more reliable.

Fig. 1.16. The first recording of the human electrocardiogram by Augustus Waller (1887). The recording was made with a capillary electrometer. The ECG recording (e) is the borderline between the black and white areas. The other curve (h) is the apexcardiogram, a recording of the mechanical movement of the apex of the heart.

Fig. 1.17. Electric field of the heart on the surface of the thorax, recorded by Augustus Waller (1887). The curves (a) and (b) represent the recorded positive and negative isopotential lines, respectively. These indicate that the heart is a dipolar source having the positive and negative poles at (A) and (B), respectively. The curves (c) represent the assumed current flow lines..

Fig. 1.18. The monocardiogram by Mann. (Redrawn from Mann, 1920).

1.4.4 Modern Electrophysiological Studies of Neural Cells

The term neuron was first applied to the neural cell in 1891 by Heinrich Wilhelm Gottfried Waldeyer (German; 1837-1921). Basic research into the study of neurons was undertaken at the end of the nineteenth century by August Forel (Swiss; 1848-1931), Wilhelm His, Sr. (Swiss; 1831-1904), and Santiago Ram�n y Cajal (Spanish; 1852-1934). According to their theory, it is the neural cell that is the functional unit in the nervous system. (In 1871, Santiago Ram�n y Cajal also discovered that neurons could be selectively stained with a special silver preparation.)

Sir Charles Scott Sherrington (British; 1856-1952) introduced the concept of the synapse (Sherrington, 1897). He also contributed the concept of the reflex arc. Lord Edgar Douglas Adrian (British; 1889-1977) formulated the all-or-nothing law of the neural cell in 1912 (Adrian and Lucas, 1912; Adrian, 1914) and measured the electric impulse of a single nerve 1926. Adrian and Sherrington won the Nobel Prize in 1932.

The founder of membrane theory was Julius Bernstein (German; 1839-1917), a pupil of Hermann von Helmholtz. Bernstein stated that the potential difference across the membrane was maintained by the difference in concentration of potassium ions on opposite sides of the membrane. The membrane, which is selectively permeable to all ions, has a particularly high permeability to potassium. This formed the basis for an evaluation of the transmembrane voltage as proportional to the logarithm of the concentration ratio of the potassium ions, as expressed by the Nernst equation.

Herbert Spencer Gasser (American; 1888-1963) and Joseph Erlanger (American; 1874-1965) studied nerve impulses with the aid of a cathode ray tube. Because they could not get a cathode-ray oscilloscope from the Western Electric Company, which had recently invented it, they built such a device themselves from a distillation flask. Linking the device to an amplifier, they could record the time course of nerve impulses for the first time (Gasser and Erlanger, 1922). With their experiments they were also able to confirm the hypothesis that axons of large diameter within a nerve bundle transmit nerve impulses more quickly than do thin axons. For their studies Gasser and Erlanger received the Nobel Prize in 1944.

Sir Alan Lloyd Hodgkin (English; 1914- ) and Sir Andrew Fielding Huxley (English; 1914- ) investigated the behavior of the cell membrane in great detail and developed a very accurate mathematical model of the activation process (Hodgkin and Huxley, 1952). Sir John Eccles (Australian; 1903- ) investigated synaptic transmission in Canberra, Australia, in the 1950s. Eccles, Hodgkin, and Huxley won the Nobel Prize in 1963.

Ragnar Arthur Granit (Finnish; 1900-1991) undertook fundamental research in the bioelectric phenomena of the retina and the nervous system in the 1930s and 1940s. In 1935, he could show experimentally that inhibitory synapses are found in the retina. Hermann von Helmholtz had proposed that the human ability to discriminate a spectrum of colors could be explained if it could be proven that the eye contains receptors sensitive to different wavelengths of light. Granit's first experiments in color vision, performed in 1937, employed the electroretinogram (ERG) to confirm the extent of spectral differentiation. In 1939, Granit developed a microelectrode, a device that permits the measurement of electric potentials inside a cell. With this technique Granit further studied the color vision and established the spectral sensitivities of the three types of cone cells - blue, green, and red. Ragnar Granit shared the 1967 Nobel Prize with H. Keffer Hartline and George Wald "for their discoveries concerning the primary physiological and chemical visual processes in the eye." (Granit, 1955)

The behavior of ion channels in the biological membrane has been described in greater detail through the invention of the patch clamp technique by Erwin Neher (German; 1944- ) and Bert Sakmann (German; 1942- ) (Neher and Sakmann, 1976). With the patch clamp method it is possible to measure the electric current from a single ionic channel. This extends the origins of bioelectromagnetism to molecular biology so that this technique can also be used, for instance, in developing new pharmaceuticals. Neher and Sakmann won the Nobel Prize in 1991.

1.4.5 Bioelectromagnetism

As mentioned in Section 1.4.3, the connection between electricity and magnetism was experimentally discovered in 1819 by Hans Christian �rsted. French scientists Jean Baptiste Biot (1774- 1862) and F�lix Savart (1791-1841) proved that the force between a current-carrying helical wire and a magnet pole is inversely proportional to the distance between them (Biot, 1820). Andr� Marie Amp�re (French; 1775-1836) showed that a current-carrying helical wire, which he called the solenoid, behaved magnetically as a permanent magnet (Amp�re, 1820), hence linking the electric current to the production of a magnetic field. Amp�re also developed the mathematical theory of electrodynamics (Amp�re, 1827). The electromagnetic connection was theoretically formulated in 1864 by James Clerk Maxwell (British; 1831-79), who developed equations that link time-varying electricity and magnetism (Maxwell, 1865). Since �rsted's discovery, electromagnetic interdependence has been widely utilized in a large variety of devices. Examples of these include those used for the measurement of electric current (galvanometers and ammeters), electric generators, electric motors, and various radiofrequency devices. However, biomagnetic signals were not detected for a long time because of their extremely low amplitude.

The first biomagnetic signal, the magnetocardiogram (MCG), was detected by Gerhard M. Baule and Richard McFee in 1963 with an induction coil magnetometer (Baule and McFee, 1963). The magnetometer was made by winding two million turns of copper wire around a ferrite core. In addition to the detector coil, which was placed in front of the heart, another identical coil was connected in series and placed alongside. The two coils had opposite senses and thereby canceled the distributing common magnetic fields arising from distant external sources (see Figure 1.19). A remarkable increase in the sensitivity of biomagnetic measurements was obtained with the introduction of the Superconducting QUantum Interference Device (SQUID), working at the temperature of liquid helium (-269 C) (Zimmerman, Thiene, and Hardings, 1970; Cohen, 1972).

Although David Cohen succeeded to measure the magnetic alpha rhythm with an induction coil magnetometer (Cohen, 1968), the magnetic signal generated by the electric activity of the brain, measured in the magnetoencephalogram (MEG), is so low that in practice its detection is possible only by using the SQUID. With such a device the MEG was first detected by David Cohen in 1970 (Cohen, 1972). John Wikswo and his co-workers were first to measure the magnetic field of a frog nerve bundle in 1980 (Wikswo, Barach, and Freeman, 1980).

In this connection we want to draw the readers' attention to the fact that the difference between the measurement principles in the first measurements of the bioelectric and biomagnetic signals is surprisingly small:

In the first measurement of the bioelectric signal, Matteucci (1838) used a magnetized needle as the detector. (The bioelectric field is, of course, far too low to deflect the needle of an electroscope.) The biomagnetic field, produced by the bioelectric currents flowing in the frog leg, was too small to deflect the magnetic needle directly. It was therefore multiplied by feeding the bioelectric current to a coil of multiple turns and with placement of the needle inside the coil, an application of the invention of Schweigger (1821). The effect of the Earth's magnetic field was compensated by winding the coil in the form of a figure eight, placing two identical magnetic needles on the same suspension and oriented in opposite directions in the two openings of the coil. This formed an astatic galvanometer, as described earlier.

In the first measurement of a biomagnetic signal (the magnetocardiogram), the magnetic field produced by the bioelectric currents circulating in the human body was measured with a coil (Baule and McFee, 1963). Because of the low amplitude of this biomagnetic field, multiple turns of wire had to be wound around the core of the coil. To compensate for the effect of the magnetic field of the Earth and other sources of "noise", two identical coils wound in opposite directions were used (Figure 1.19).

Thus, in terms of measurement technology, the first measurements of bioelectric and biomagnetic signals can be discriminated on the basis of whether the primary loop of the conversion of the bioelectric current to a magnetic field takes place outside or within the body, respectively. Since the invention of the capillary electrometer by G. J. Lippman (1873) and especially after the invention of electronic amplifiers, electric measurements have not directly utilized induced magnetic fields, and therefore the techniques of bioelectric and biomagnetic measurements have been driven apart.

In terms of measurement theory, the first measurements of bioelectric signals were measurements of the flow source, and thus truly electric. The first measurement of the biomagnetic signal by Richard McFee was the measurement of the vortex source, and thus truly magnetic. It will be shown later that with magnetic detectors it is possible to make a measurement which resembles the detection of the flow source. However, such a measurment does not give new informaion about the source compared to the electric measurement.

This example should draw our readers' attention to the fact that from a theoretical point of view, the essential difference between the bioelectric and biomagnetic measurements lies in the sensitivity distributions of these methods. Another difference stems from the diverse technical properties of these instrumentations, which impart to either method specific advantages in certain applications..

Fig. 1.19.

1.4.6 Theoretical Contributions to Bioelectromagnetism

The German scientist and philosopher Hermann Ludwig Ferdinand von Helmholtz (1821-1894) made the earliest significant contributions of the theory of bioelectromagnetism. A physician by education and, in 1849, appointed professor of physiology at K�nigsberg, he moved to the chair of physiology at Bonn in 1855. In 1871 he was awarded the chair of physics at the University of Berlin, and in 1888 was also appointed the first director of Physikalisch-Technische Bundesanstalt in Berlin.

Helmholtz's fundamental experimental and theoretical scientific contributions in the field of bioelectromagnetism include the following topics, which are included in this book:

axons are processes of nerve cell bodies

conservation of energy (the First Law of Thermodynamics)

myograph

conduction velocity

double layer source

solid angle theorem

principle of superposition

reciprocity theorem

inverse problem

independence of flow and vortex sources

Helmholtz coils

Besides these, the contributions of Helmholtz to other fields of science include fundamental works in physiology, acoustics, optics, electrodynamics, thermodynamics, and meteorology. He is the author of the theory of hearing (1863) from which all modern theories of resonance are derived. He also invented, in 1851, the ophthalmoscope, which is used to investigate the retina of a living eye.

Until the end of the nineteenth century, the physics of electricity was not fully understood. It was known, however, that neither pure water nor dry salts could by themselves transmit an electric current, whereas in aqueous solution salts could. Svante August Arrhenius (Swedish; 1859-1927) hypothesized in his (1884) doctoral thesis that molecules of some substances dissociate, or split, into two or more particles (ions) when they are dissolved in a liquid. Although each intact molecule is electrically balanced, the particles carry an electric charge, either positive or negative depending on the nature of the particle. These charged bodies form only in solution and permit the passage of electricity. This theory is fundamental for understanding the nature of the bioelectric current, because it flows in solutions and is carried by ions. Svante Arrhenius won the Nobel Prize in Chemistry in 1903.

At the end of the nineteenth century, Walther Hermann Nernst (German; 1864-1941) did fundamental work in thermochemistry, investigating the behavior of electrolytes in the presence of electric currents. In 1889, he developed a fundamental law, known as the Nernst equation. Nernst also developed many other fundamental laws, including the Third Law of Thermodynamics. He was awarded the Nobel Prize in Chemistry in 1920.

Dutch scientists Hermann Carel Burger (1893-1965) and Johan Bernhard van Milaan (1886-1965) introduced the concept of the lead vector in 1946 (Burger and van Milaan, 1946). They also extended this to the concept of the image surface. In 1953, Richard McFee and Franklin D. Johnston introduced the important concept of the lead field, which is based on the reciprocity theorem of Helmholtz (McFee and Johnston, 1953, 1954ab). The invention of the electromagnetic connection in 1819 by �rsted tied bioelectric and biomagnetic fields together. The invention of the reciprocity theorem in 1853 by Helmholtz showed that the sensitivity distribution of a lead for measuring bioelectric sources is the same as the distribution of stimulation current introduced into the same lead. Furthermore, this is the same as the sensitivity distribution of a tissue impedance measurement with the same lead. All this is true for corresponding magnetic methods as well. These principles are easily illustrated with the concept of lead field.

Dennis Gabor (British; 1900-1979) and Clifford V. Nelson published the Gabor-Nelson theorem in 1954 (Gabor and Nelson, 1954). This theorem explains how an equivalent dipole of a volume source and its location may be calculated from measurements on the surface of a homogeneous volume conductor.

1.4.7 Summary of the History of Bioelectromagnetism

The history of bioelectromagnetism is summarized chronologically in Figure 1.20. The historical events are divided into four groups: theory, instrumentation, stimulation, and measurements. This figure should serve as a useful overview for our readers and help them recognize how one contribution follows from an earlier one and how the development of an entire discipline thereby takes place. From this figure we may summarize the following thoughts.

1. Up to the middle of the nineteenth century, the history of electromagnetism has actually also been the history of bioelectromagnetism. The first electric machines and the Leyden jar were constructed to produce static electricity for a specific purpose: to "electrify" and to stimulate humans. The Voltaic pile was developed with the idea of galvanic stimulation. The universal principles of reciprocity and superposition were introduced in connection with their application to bioelectromagnetism. Bioelectric and biomagnetic measurements have also been the incentive for the development of sensitive measurement instruments. The latter include not only the astatic galvanometer, capillary electrometer, and string galvanometer of the nineteenth century but also the low-voltage cathode ray tube and the SQUID in the twentieth century. An understanding of the function of nerve cells and brain and their simulation with electronic models has led to the development of a new generation of computers: the neurocomputer. These events emphasize the importance of bioelectromagnetism.

2. In the seventeenth and early eighteenth centuries, it is surprising how quickly a new invention in the field of bioelectromagnetism became the basis for still further applications and new inventions, even in different countries, although travel and communication were limited to the horse. As examples one may mention the invention of the Leyden jar in Germany and the Netherlands in 1745 and 1746, respectively, and its systematic application to human functional electric stimulation in Italy in 1747. Another example is the invention of the electromagnetic connection in 1819 in Denmark and the development of the galvanometer in 1821 in Germany and the astatic galvanometer in 1825 in Italy.

3. On the other hand, some inventions have been rediscovered, having been "forgotten" for about 100 years. Exactly 100 years elapsed following the publication of the reciprocity theorem before the lead field theory was introduced. The magnetic stimulation of the motor cortex was developed almost 100 years after the observation of magnetophosphenes. The time span from the first bioelectric measurements to the first corresponding biomagnetic measurements has been, on average, 100 years - quite a long time!

4. Several fundamental techniques used today in bioelectromagnetic instrumentation date back to the earliest instruments. The astatic galvanometer of 1825 included an ingenious method of compensation for the magnetic noise field. This principle was applied to the first measurement of MCG in 1963. Actually the planar gradiometers, applied in the multichannel MEG-instruments using SQUID, are constructed exactly according to the same principle as the astatic galvanometer coil was more than 150 years ago. The basic clinical ECG leads - the limb leads - were invented 100 years ago by Waller. Similarly, Waller also introduced the dipole model to ECG, and it still has a strong role in electro- and magnetocardiology.

A more detailed review of the history of bioelectromagnetism can be found in the following references: Brazier (1988), Geddes (1984ab), McNeal (1977), Mottelay (1975), Rautaharju (1987, 1988), Rowbottom and Susskind (1984), and Wasson (1987)..

Fig. 1.20.

1.5 NOBEL PRIZES IN BIOELECTROMAGNETISM

The discipline of bioelectromagnetism is strongly reflected in the work of many Nobel laureates. It should be noted that 16 Nobel prizes have been given for contributions to the discipline of bioelectromagnetism and closely related subjects. Of these prizes, 12 were in physiology or medicine; four were in chemistry. Although some perhaps do not directly concern bioelectromagnetism, they are very closely related. Since several individuals may have shared an award, the actual number of Nobel laureates is 28. The large number of these Nobel laureates shows that bioelectromagnetism is recognized as a very important discipline. Nobel laureates associated with bioelectromagnetism are listed in Table 1.6.

One should probably add to this list the names of Gabriel Jonas Lippman and Dennis Gabor, although they did not receive their Nobel Prize for their work in bioelectromagnetism.

Gabriel Lippman received the Nobel Prize in physics in 1908 for his photographic reproduction of colors. But he was also the inventor of the capillary electrometer (Lippman, 1873). The capillary electrometer was a more sensitive measuring instrument than the astatic galvanometer and was an important contribution to the technology by which bioelectric events were recorded.

Dennis Gabor received the Nobel Prize in physics in 1971 from the invention of holography. He was also the senior author of the Gabor-Nelson theorem, which is used to ascertain the equivalent dipole of a volume source by measurements of the electric potential on the surface of the volume conductor (Gabor and Nelson, 1954).

One should also note that Georg von B�k�sy received the Nobel Prize for his discoveries of the physical mechanism of stimulation within the cochlea. His discoveries have, however, contributed most significantly to the analysis of the relation between the mechanical and the electric phenomena in the receptors involved in the transformation of sound into nerve impulses. Therefore, von B�k�sy's name is included in this list..

Table 1.6 Nobel prizes awarded in bioelectromagnetism and closely related subject areas

Year   Name of recipient Nationality Subject of research

1901 Jacobus van't Hoff *) The Netherlands      laws of chemical dynamics
and osmotic pressure

1903 Svante Arrhenius *) Sweden theory of electrolytic
dissociation

1906 Camillo Golgi
Santiago Ram�n y Cajal      Italy
Spain work on the structure of
nervous system

1920 Walther Nernst *) Germany work in thermochemistry

1924 Willem Einthoven The Netherlands discovery of electro-
cardiogram mechanism

1932 Edgar Douglas Adrian
Sir Charles Sherrington Britain
Britain discoveries regarding
function of neurons

1936 Sir Henry Hallet Dale
Otto Loewi Britain
Germany work on chemical trans-
mission of nerve impulses

1944 Joseph Erlanger
Herbert Spencer Gasser U.S.
U.S. researches on differentiated
functions of nerve fibers

1949 Walter Rudolf Hess Switzerland discovery of function of
middle brain

1961 Georg von B�k�sy U.S. discoveries of the physical
mechanism of the inner ear

1963 Sir John Eccles
Alan Lloyd Hodgkin
Andrew Fielding Huxley Australia
Britain
Britain study of the transmission
of nerve impulses along a
nerve fibre

1967 Ragnar Arthur Granit
Haldan Keffer Hartline
George Wald Finland
U.S.
U.S. discoveries about chemical
and physiological visual
processes in the eye

1968 Lars Onsager *) U.S. work on theory of thermo-
dynamics of irreversible
processes

1970 Julius Axelrod
Sir Bernard Katz
Ulf von Euler U.S.
Britain
Sweden discoveries concerning the
chemistry of nerve
transmission

1981 David Hunter Hubel
Torsten Nils Wiesel U.S.
Sweden discoveries concerning
information processing
in the visual system

1991 Erwin Neher
Bert Sakmann Germany
Germany discoveries concerning
the function of single
ion channels in cells

1997 Paul D. Boyer
John E. Walker
Jens C. Skou *) U.S.
U.K.
Denmark the enzymatic mechanism
underlying the synthesis of ATP;
discovery of an ion-transporting
enzyme, Na+, K+ -ATPase

2003 Peter Agre
Roderick MacKinnon *) U.S.
U.S. discoveries concerning
channels in cell membranes

*) Nobel Prize in chemistry. All other prizes were received in physiology or medicine.