Introduction Textbook

• Bioelectromagnetism : Principles and Application of Bioelectric and Biomagnetic Field

– Jaakko Malmivuo/Robert Plonsey Jaakko Malmivuo, PhD Professor, Aalto University – Oxford University Press/1995 Department of Electronics AALTO, FINLAND

• Bioelectromagnetism Portal – http://www.bem.fi/ – Textbook & Related information Robert Plonsey, Ph. D. Professor Emeritus, Duke University Biomedical Engineering Bioelectromagnetism

• Discipline examining electric, electromagnetic, & magnetic phenomena in biological tissues – Behavior of excitable tissue(the sources) – Electric currents and potentials in the volume conductor – Magnetic field at and beyond the body – Response of excitable cells to electric and magnetic field stimulation – Intrinsic electric and magnetic properties of the tissue • cf: medical electronics: actual devices for this Related Disciplines

• Physics & Engineering  Biology & Medicine • Biophysics: biological problems with physics. • Bioelectromagnetism: biology + electromagnetic physics. • Biotechnology: microbiological process technology for agriculture, food and drug production. • Biomedical engineering: application of science and technology to biology and medicine. • Bioengineering: biomedical Eng. + biotechnology Related Disciplines

• Physics & Engineering  Biology & Medicine • Medical physics: science based on physical problems in clinical medicine. • Medical electronics: electronic devices and methods in medicine. • Medical engineering: engineering + medicine • Clinical engineering: applying and implementing medical technology to optimize healthcare delivery BEM & Disciplines Subdivision

• Maxwell’s equation: electromagnetic connection – Bioelectric field  Biomagnetic field

Source Medium External

Electric Electric Bioelectricity

Electric Magnetic Bioelectromagnetism (Biomagnetism) Magnetic Magnetic Biomagnetism

Magnetic Electric - Subdivision • Principle of Reciprocity – Measurement, Stimulation, Impedance

Measurement Source Medium External

Source Medium External Stimulation

Measurement of Source External Medium Intrinsic Property Measurement

From neural cells From neural cells From other tissues - EEG, ENG, ERG - MEG, MNG, MRG - Magnetopneumogram From muscle cells From muscle cells - Magnetohepatogram - ECG, EMG - MCG, MMG From other tissues From other tissues - EOG, ENG - MOG, MNG electronystagmography Stimulation • Electric and magnetic stimulation

Transthreshold Stimulation Stimulation - CNS, - CNS, - Motor nerve/muscle - Motor nerve/muscle - Cardiac pacing - Cardiac pacing - Defibrillation - Defibrillation Therapy - Magnetotherapy Subthreshold Therapy Therapy - Electrotherapy - Electromagnetotherapy - Surgical diathermy Intrinsic Property • Electric and magnetic property measurement - with subthreshold stimulation

Impedance Magnetic Magnetic susceptibility - Cardiography, measurement of - Plethysmogrpahy - Peumography electric impedance Magnetic remanence - Tomography Impedance MRI Electrodermal tomography response

Chapter Organization - Measurement of Field -

(A) Bioelectricity (B) Bioelectromagnetism (C) Biomagnetism Electric field from bioelectric Magnetic field from Magnetic field from source bioelectric source magnetic material

04 Active behavior of the membrane 12 Theory of biomagnetic Not discussed 05 Physiology of the synapse and brain measurements 06 Bioelectric behavior of the heart 14 Magnetoencephalography 07 Volume source and volume 20 Magnetocardiography 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 Chapter Organization - Stimulation and magnetization-

(A) Bioelectricity (B) Bioelectromagnetism (C) Biomagnetism Electric stimulation Electric stimulation Magnetization of with electric field with magnetic field material

03 Subthreshold membrane 22 Magnetic stimulation Not discussed phenomena 21 Functional electric stimulation 23 Cardiac pacing 24 Cardiac defibrillation - Measurement of Intrinsic Properties- (A) Bioelectricity (B) Bioelectromagnetism (C) Biomagnetism Electric measurement of Magnetic measurement of Magnetic measurement electric impedance electric impedance of magnetic susceptibility 25 Impedance plethysmography 26 Magnetic measurement of Not discussed 26 Impedance tomography electric impedance 27 Electrodermal response tomography Why bioelectromagnetism?

• Vital function of living organism. – Membrane potential • Life begins with a change in membrane potential – Fertilization of egg with sperm • Change in membrane potential prevent further accesses. • Easily & simply measured – Directly with electrode/magnetometer – Real-time by noninvasive methods Why bioelectromagnetism? • Signal transmission for information & control – Sensory, motor, and for regulation • Basis for electronic implementation – Diagnostic devices, implantable devices – Rapidly developing in medical diagnosis & therapy • Behavior in living tissue – Cellular, organic & subcellular level • Current through single channel: Patch clamp – Application to molecular biology • Development of pharmaceuticals History: Electric fish

• 1st document & experiment 메기 – Electric sheatfish(catfish) 상형문자 • Egyptian hieroglyph: 4000BC 무덤벽화 • Sepulcher fresco: 1868 • Electric shock: 450V – 1st medical application • With torpedo fish: AD46 • Headache and gout arthritis • Unique way to get electricity until 17th century History: Amber

• Amber: attract light substance – Arostotle(384-22BC), – Thales(625-547BC) – Smith(1931) • Electroscope: Gilbert(1600) – Turn toward the substance of attracting power (Electriks)  the Greek name for amber – Published in “De magnete” Muscle contraction

• By “animal spirit”, “nervous inflow”?

water • Experiments for volume change droplet – Swammerdam(1664)

• No movement of water droplet silver • No inflow of nervous fluid ! wire

st copper • 1 motor nerve stimulation loop – By emf from bimetallic junction • Current flow within muscle after 1st stimulation: biological origin – Electrical or mechanical stimulation? 1st Electric Machine

• Generate static electricity – Otto von Guericke(1672) : By rotation – Sphere of sulfur + Iron axle in wooden framework • Rotating glass wheel: Francis Hauksbee(1709) – Evacuating glass  Brilliant light  Cathode ray, x-ray, electron • Electricity has usefulness only for medicine – Johan G. Kruger(1743) Electromagnetic Stimulation

• 4 different historical period – Static electricity: Benjamin Franklin(1706-1790) – Direct current: Luigi Galvani (1737-1798) – Induction coil shocks: Michael Faraday(1791-1867) – RF current: Jacques d'Arsonval (1851-1940) Metal foil on inner & outer • Leyden jar: capacitor surfaces – Kleist: 1745 – Musschenbroek: 1746 • Leyden U. Netherlands – Ramsden: 1768, 1st practical generator Benjamin Franklin

• Founding Fathers of the United States, 박식가 • “The 1st American“ & Polymath: – Author, printer, political theorist, politician, scientist, postmaster, inventor, civic activist, statesman, diplomat. • Concept of +/- electricity • Atmospheric electricity – Kite experiment: 1752 • Lightning: electricity • Collecting into Leyden jar • Invention of lightning rod Portraits in US Dollars George Andrew Washington Jackson 1st President 7th President

Ulysses S. Thomas Grant Jefferson 18th President 3rd President

Abraham Benjamin Lincoln Franklin st 16th 1 US President Ambassador to France 1st American

Alexander Hamilton 1st US Secretary of the Treasury Muscle Stimulation

• Jean Jallabert: 1747 – Prof. in mathematics in Genova – Electrical stimulation to hand paralyzed patient • For 3 months & successful • Beginning of therapeutic stimulation of muscle by electricity • Lugi Galvani: Jan. 26. 1781 – Prof. in anatomy, U. of Bologna • Electrical stimulation of femoral nerve of frog • Violent muscular contraction – 1st neuromuscular electric stimulation Lugi Galvani

• Study with atmospheric electricity zinc – Frog leg contraction on lightning • Study on calm weather – Iron railing in garden cooper – Brass hook inserted in spinal cord – Contraction on contacting • Stimulation by bimetallic arch – Did not understand mechanism of bimetallic voltage • Just discharging the animal bioelectricity Alessandro Volta

• Physicist, Univ. of Pavia • Current not from animal – “Metallic current” • metals muscle – Electricity can be a powerful stimulus for nerves and muscles • Volta bimetallic pile – 1st battery: 1800 – “Artificial electrical organ” • In contrast to torpedo fish – Q=CV, capacitor Animal or Metal Current

• Galvani vs. Volta • Giovanni Aldini – Assistant & Nephew of Galvani – Physicist, Univ. of Bologna – Strong supporter of Galvani • Series of experiment without using two metals: 1804 – Stimulation with voltatic piles – Water filled vessel as electrodes Giovanni Aldini • Muscle contraction on cadavers – By electrical stimulation – Facial contraction by brain stimulation – Not successful with heart muscle Giovanni Aldini • Mental disorder treatment: Depression – 1st brain stimulation • Reanimation(?) on drowned person – Inspired electrical stimulation in heart failure – Cardiac pacemaker & defibrillator Cardiorespiratory Resuscitation

• T. Green: 1872 • Resuscitate surgical patient – Anesthetized with chloroform • depressing respiration and cardiac pulse – With battery of 300volts • Btw neck and lower rib on the left – Successful on 5~7 patients • On subject with sudden respiratory arrest, without pulse Induction Coil

• High voltage of alternating current in 2nd coil • Invented by Michael Faraday : 1831 • 1st Medical application: 1834 – By Bois-Reymond: 1846 • Cerebral cortex stimulation – By Robert Bartholow: 1874 – On exposed cortex – Movement of opposite side – Turning of head Induction coil with hammer break Magnetic Stimulation

• Jacques Arsene d’ Arsonval: 1893 • Heated living tissue – Diathermy by HF current – With electrodes or large coil • Flickering visual sensation – With 32A at 42Hz – Magnetophosphenes – Retina stimulation by magnetic field • 1st transcranial magnetic stimulation: 1985 – On motor cortex Direct Cardiac Pacing

• F. Steiner: 1871, In anesthetized dog • Hugo W. Ziemssen: 1882 – Experiment in human • Albert Salibury Hyman: 1932 – Clinically to atrial pacing • Paul Maurice Zoll: 1952 – Cardiac pacing for 20 min • Furman & Schwedel: 1958 – Supporting 96 day with cardiac pacing Pacemaker Implantation

• In Karolinska instutute, Sweden 1958: – Made by Engineer Rune Elmqvist • Invention of transistor (1948) – Implanted by surgeon Ake Senning Cardiac Defibrillation

• Prevost(Swiss) & Battelli(Italy): 1899 • In animal experiments – Low voltage electronic shock • Induce ventricular fibrillation – High voltage shock • Defibrillate a fibrillating heart • Kouwenhoven(US): 1930 – Modern defibrillators: 60Hz in dog’s heart • 1st human defibrillation : 1947 Electromagnetic Connection

• Connection btw electricity and Magnetism • Hans Christian Orsted(Danish): 1819 – Experiment of electric current over compass • Deflection in perpendicular position • Deflection direction change by current direction change

Compass: 1st magnetic field detector Invented about AD100 in China Galvanometer

• Instrument detecting weak electric current – Multiplikator by Schweigger(German, 1821) • Increased magnetic field with multiple loops • Astatic galvanometer: Nobili(Italy, 1825)

1 needle for detecting 2 needles 1 needle for 8-shape coil indicating Bioelectric Current Measurement

• 1st muscle impulse – By Matteucci(Italy,1838) in frog muscle • 1st nerve impulse – By du Bois-Reymond(German, 1843) in frog • 1st electric activity of brain – Caton(British, 1875) – In rabbit and monkey du Bois-Reymond’s • Nerve potential propagation apparatus – Beck(Polish, 1888) – Along the nerve without attenuation EEG

• 1st recording – By Hans Berger • German, 1924 – Identified major rhythms • α rhythms • β rhythms • In 1929

Berger’s notebook ECG

• 1st recording : Waller (British, 1887) – Using capillary electrometer • Photographic film + capillary filled with sulfuric acid and mercury • Interface move in response to electric field • 1mV sensitivity, poor time response

Apexcardiogram: Mechanical movement of apex ECG Dipolar Nature

• Cardiac generator has dipolar nature – Need 5 measurement points • Hands, legs, mouth • 10 bipolar leads – 3 almost orthogonal leads • Mouth - left arm • Mouth - left leg • Back - front Willem Einthoven

• 1st high quality ECG recorder: 1908 – Based on string galvanometer – Possible to clinical application – Summarized results in 1908 & 1913 – Nobel prize in 1924 Vectorcardiography

• Williams: 1914 – Sequence of instantaneous vectors • Clinical tool: by Mann(1916) – 2D VCG based on Einthoven triangle – “Monocardiogram” • Display in real-time vector form – Amplification by electron tube: Forest, 1906 – Low voltage CRT: Johnson, 1921 – Transistor: Bardeen & Brattain, 1948 Electrophysiological Studies

• Neuron as functional unit of nervous system – Forel, His, Cajal in 1871 • Neuron for neural cells: Waldeyer(German, 1891) • Concept of synapse & reflex arc – Sherrington (British, 1897) • All-or-nothing law: Adrian(British, 1912) – Measurement of single nerve impulse: 1926 – Nobel prize in 1932 with Sherrington Membrane

• Membrane theory by Berstein(German) – Membrane potential by ion distribution ratio – Selective permeability • Impulse transmission over Axon – Gasser & Erlanger: 1922  Nobel prize in 1944 – Time course of nerve impulse & thicker fiber transmit faster • Accurate mathematical membrane model – Hodgkin & Huxley: (English,1952) – Nobel prize in 1963 • Synaptic transmission: Eccles(Australia, 1950) Retina & Nervous System

• Granit(Finland) – Inhibitory synapse in retina: 1935 – Color vision experiments: 1937 • With ERG to confirm spectral differentiation – 3 types of color cells: red, green, blue • With microelectrode inside the cell – Nobel prize in 1967 • With H. Keffer, George Wald Patch Clamp

• Behavior of ion channel in greater detail – Electric current from single ion channel – Neher and Sakmann: 1976 – Nobel prize in 1991 • Origin of biomagnetism into molecular level – Useful also for developing new pharmaceuticals Electricity & Magnetism

• Oersted, Biot, Savart: 1819 – Force btw magnetic pole & current carrying wire • Ampere: 1820, 1827 – Solenoid behave magnetically like permant magnet – Mathematical theory of electrodynamics • Maxwell: 1864, 1865 – Electromagnetic connection – Equations for time varying electricity & magnetism • Devices – Galvanometer, electric generator, electric motor… Biomagnetic Signal

• Not detected for long time by extremely low amplitude • Magnetocardiogram(MCG) – Baule & MacFee: 1963 – Magnetometer: 2M turns of wire around ferrite-core – 2 detectors • Opposite sensing • To cancel noises – SQUID at working at -269C • Superconducting QUantum Interference Device Magnetoencephalogram

• David Cohen – 1st alpha rhythm recording with induction coil magnetometer(1968) – 1st MEG with SQUID(1970) • Practical detection only by SQUID

• Magnetic field of frog’s nerve bundle – Wikswo: 1980 Electric or Magnetic

• Bioelectric signal measurement – Current source: Detection by magnetized needle – 1st measurement was “flow source” – Conversion into magnetic signal out of body – Replaced by use of amplifiers and electric devices • Magnetic source : magnified by multiple turns – Conversion into magnetic signal within the body – 1st measurement was “Vortex source” Electric vs Magnetic

• Theoretical electromagnetic connection – Electric signal ↔ magnetic signal – No additional information from magnetic measurement theoretically • Difference in sensitivity distribution – Between electricity and magnetism • Diverse technical properties of instrumentation – Specific advantages in certain applications Helmholtz(1821-1894)

• Earliest contribution on bioelectromagnetism – Experimental and theoretical 1. Axons are processes of nerve cell bodies(1842) 2. 1st law of thermodynamics(1847) 3. 1st myograph & nerve conduction velocity(1850) 4. Double layer concept(1853) 5. Solid angle theorem for electrical signal 6. Principles of superposition(1853) 7. Reciprocity theorem(1853) 8. Insolvability of the inverse problem(1853) Helmholtz(1821-1894)

9. Helmholtz theorem • Independence of flow and vortex sources 10. Helmholtz coil • For biomagnetic instrumentation 11. Author of “Theory of hearing” 12. Invented Ophthalmoscope Theoretical contribution • No clear physics of electricity up to end of 19C – Pure water, dry salt conductive ? • Svante Augustus Arrhenius(1859-1927) – Molecular dissociation into particles(ions) in liquid – Particle carry an electric charge + or - – Current flow in solutions by ions • Nature of bioelectric current! – Nobel prize in 1903(chemistry) Theoretical contribution • Walther Hermann Nernst(1864-1941) – Fundamental work in thermochemistry – Behavior of electrolytes under electric current • Nernst equation(1889) – 3rd law of thermodynamics – Nobel prize in 1920(chemistry) • Burger, Milaan(1946): lead vector concept • McFee, Johnston(1953): lead field concept • Helmholtz(1853): reciprocal theorem • Gabor & Nelson(1954) – Equivalent dipole source from surface measurement History Summary History Summary

• History of electromagnetism=History of Bioelectromagnetism (Upto mid 19th C) – Leyden jar: produced static electricity to stimulate human – Voltaic pile: galvanic stimulation – Universal principles from BEM measurements • Principles of reciprocity and principles of superposition – Development of sensitive measurement instrument • Astatic galvanometer, string galvanometer, SQUID – Understanding nervous system • Development of computers & neurocomputers History Summary

• 17th C ~ early 18th C – Biomagnetism: basis for new invention & application – In different countries with limited communication • Leyden jar(1745, Germany), (1746, Netherlands) human stimulation(1747, Italy) • EM connection(1819, Denmark)Galvanometer(1821, Germany) Astatic galvanometer(1825,Italy) History Summary

• Forgotten for 100 years – Lead field theory 100 years after reciprocity theorem – Magnetic stimulation of motor cortex almost 100 years after 1st magnetophosphenes • 100 years difference in average – Between bioelectric measurement and biomagnetic measurement History Summary

• Date back to earliest development – 150 years back to astatic galvanometer • 1st MCG measurement • Gradiometer in multichannel MEG • SQUID  Compensation of magnetic noise – ECG limb leads: 100 years ago by Waller – Dipole model: still has strong role ECG & MCG Nobel Prizes in BEM

1. 1901 Jacobus van't Hoff (Netherlands) • Laws of chemical dynamics and osmotic pressure 2. 1903 Svante Arrhenius (Sweden) • Theory of electrolytic dissociation 3. 1906 Camillo Golgi(Italy), Santiago Ramón y Cajal(Spain) • Structure of nervous system 4. 1920 Walther Nernst(Germany) • Work in thermochemistry 5. 1924 Willem Einthoven(Netherlands) • Discovery of ECG mechanism 6. 1932 Edgar Douglas Adrian(Britain), Sir Charles Sherrington(Britain) • Discoveries regarding function of neurons 7. 1936 Sir Henry Hallet Dale(Britain), Otto Loewi(Germany) • Work on chemical transmission of nerve impulses 8. 1944 Joseph Erlanger (U.S.), Herbert Spencer Gasser (U.S.) • Differentiated functions of nerve fibers 9. 1949 Walter Rudolf Hess (Switzerland) • Discovery of function of middle brain Nobel Prizes in BEM 10. 1961 Georg von Békésy (U.S.) • Discoveries of the physical mechanism of the inner ear 11. 1963 John Eccles(Australia), Alan Hodgkin(Britain), A. Huxley(Britain) • Study of the transmission of nerve impulses along a nerve fibre 12. 1967 Ragnar Granit (Finland), Keffer Hartline(U.S.), George Wald(U.S.) • Discoveries about chemical & physiological visual processes in eye 13. 1968 Lars Onsager (U.S.) • Work on theory of thermo-dynamics of irreversible processes 14. 1970 Julius Axelrod (U.S.), Bernard Katz (Britain), Ulf von Euler(Sweden) • Discoveries concerning the chemistry of nerve transmission 15. 1981 David Hunter Hubel (U.S.), Torsten Nils Wiesel(Sweden) • Discoveries concerning information processing in the visual system 16. 1991 Erwin Neher(Germany), Bert Sakmann(Germany), • Discoveries concerning the function of single ion channels in cells 17. 1997 Paul D. Boyer(U.S.), John E. Walker (U.K.), Jens C. Skou (Denmark) • Enzymatic mechanism underlying the synthesis of ATP; • Discovery of an ion-transporting enzyme, Na+, K+ -ATPase 18. 2003 Peter Agre(U.S.),Roderick MacKinnon(U.S.), U.S. • Discoveries concerning channels in cell membranes