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 Krüger 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 Arsène 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).

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 Arsène 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. d'Arsonval's great solenoid. (d'Arsonval, 1893).

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 Åke 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 Frédéric 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 Örsted (Danish; 1777-1851). Örsted 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) (Örsted, 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.)
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. 1.12. Reconstruction of the first demonstration of the electromagnetic connection by Hans Christian Örsted 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. (Örsted, 1820a,b,c).

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. Du Bois-Reymond's apparatus for studying effect of continuous current on nerve..

Fig. 1.15. A page from Berger's notebook illustrating early recordings of the human EEG.

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 Clément 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 Ramón 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 Ramón 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 Örsted. French scientists Jean Baptiste Biot (1774- 1862) and Félix 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). André Marie Ampère (French; 1775-1836) showed that a current-carrying helical wire, which he called the solenoid, behaved magnetically as a permanent magnet (Ampère, 1820), hence linking the electric current to the production of a magnetic field. Ampère also developed the mathematical theory of electrodynamics (Ampère, 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 Örsted'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. Detection of the first biomagnetic signal, the magnetocardiogram (MCG), by Baule and McFee. (Redrawn from Baule and McFee, 1963.).

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 Königsberg, 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:

1. The demonstration that axons are processes of nerve cell bodies (1842)
2. The establishment of the law of conservation of energy (the First Law of Thermodynamics) (1847)
3. The invention of the myograph and the first measurement of the conduction velocity of a motor nerve axon (1850)
4. The concept of double layer source (1853)
5. The solid angle theorem for electric potentials
6. The principle of superposition (1853)
7. The reciprocity theorem (1853)
8. The insolvability of the inverse problem (1853)
9. Helmholtz's theorem concerning the independence of flow and vortex sources
10. The Helmholtz coils (applied in biomagnetic instrumentation)

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 Örsted 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. Chronology of the history of bioelectromagnetism. The historical events are divided into four groups: theory, instrumentation, stimulation, and measurements..

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 Békésy 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 Békésy's name is included in this list..

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REVIEW ARTICLES

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Mottelay PF (1975): Bibliographical History of Electricity and Magnetism, 673 pp. Charles Griffin, New York.

Rautaharju PM (1987): A hundred years of progress in electrocardiography, 1: Early contributions from Waller to Wilson. Can. J. Cardiol. 3:(8) 362-74.

Rautaharju PM (1988): A hundred years of progress in electrocardiography, 2: The rise and decline of vectorcardiography. Can. J. Cardiol. 4:(2) 60-71.

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Rowbottom M, Susskind C (1984): Electricity and Medicine. History of Their Interaction, 303 pp. San Francisco Press, San Francisco.

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