April Z6, 1966 Dear Dr. The program to evaluate various electrical combinations for their potential for producing anesthesia has been designed and is enclosed. An effort has been made to include as many of the parameters we prev-ionsly discus&ed and work out the details as soon as possible. After your review of the progralm, deletions or additions can be made if necessary. This study does not go into the specific details of the basic principles as much as I would like to investigate at some time. I think it best to look at that phase of study after we complete this study and know the current 2 combination that gives the best results. I would anticipate doing some microelectrode work for more specLfic information on the amount of current in specific brain area3 at a later date. I will complete r-iy training program -,t Thi s wiU work very well with yot, July I - June 30 fiscal year. I had 2anticipated being committed until S,@pternber 1, but have been able to arrange to start on this prograni July Ist instead. One part of the budget was somewhat uricartain. This is in regard to the i--istitutional ove."head. After checking with the people at II find that the overhead charges are 2019 on N. 1. H. or N. S. F. type grants or 40'Yo of salaries on other t7ypes. Since you mentioned a number of groups in Washington were interested in the program. I have assumed that a.Ll involved fit into the same bracket. 2 April Z6. 1966 Our plans are to devote full time to this program. The only exception to this for which I would like approval is to spend 9-17. days per year to pro- vide tha necessary surgical and anesthetic procedures for the kidney transpla-YAt -n at the 2 progra. I Electroanesthesia is used in these procedures on tw:bi calves and the very valuable data on electreanesthesia in twins of known corii- patibility would be included in the reports. No grant funds from the program would be iised in the ki4ney program. In discussing the anest2hesia program with Dr. it was of con- siderable interest to note the suggested possibility of hi@man application after completion of the animal program. 1 felt you would like to know of this in the event it is desirable to co-ordinate a human experimental program at a later date. Let me know if I need to make any changes in the prog2ram enclosed. I am looking forward to getting started on our program and see if we can't find out what the potential of electroanesthesia really is. Thank you for your continued interest. Your s truly, Enclosure ^--47 -4* PROJECT PROPOSAL Title: "Effects of Combinations of Waveforms and Frequencies of Electrical Currents Applied to the Head to Produce Anes:he3ia" Inve s tig ator Department and Location: Director: objectives and Procodures: 1. Determination of the most effective combinations af electrical current 2 producinz,r anesthesia A. Combinations of sine, saw tooth, square, triangle, white noise, pulse D,, C. and D.C. signals will be employe:i in combinations to achieve this objective. Both two and three wave combinations Will be employed with variable frequencies. Bas@d on the published experience 2of others and my own personal experience, it is not anticipated that anesthesia wi-U be produced by all currents. Some will produce convulsions, tonic muscle spasms, and/or respiratory- cardiac distress without anesthesia. From published data, these complications have been more evident with certain waveforms and cu.rzent combinations than with othe2rs. This sttidy proposes to de- termine in a systematic fashion which wave-forms and frequency c,omt>inations produce acceptable anesthesia with minimal undesirable side effects. Tne equipment has been desigr* d to permit invest7i- gation df over two hundred combinations of waveforms and frequencies which will be rated ac2cording to desirable and undesirable charac- teri,stics produced. B. Cornbination waves will be applied to the head by two techniques: 1. Summation of the current before it enters the head. (Two eleclrodes-Americ&n technique) 2. Summaticn of the current in the head. (Your and six electrode 7 combinations with separate leads to the generators producing the combination-Russian technique). Combinations of waveforms and frequencies which are obviously not satisfactory due to severe respiratory or circulatory distress, convulsions, cardiac difficulties or other unforeseen problems will be recorded as such, and will not be evaluated more extensively. .. ..... ..... 2 Combinations which show promise for'anesthesia will be evaluated further as outlined in objective 11. Ti@e effect of anesthetic currents on resplr circulation and depth 2 ątion, of anesthesia When a combination of electrical currents appears to have potential as an anesthetic agent. the following procedures will be followed. Pre- anesthet:%; measurement of all pertinent parameters will be made (see ty-pica.1 experimen-@ below). The cardiac an:i respirato y al2terations will be monitored during and after induction. If successful, a surgical procedure will be carried out to evaluate the effectiveness of the com- bination of current to produce anesthesia and muscle relaxation. Since it is possible with electrical current to pro!:Lcations to cats. K--iutsonl3-16 conducted most of his work with 700-1500 cycle per second sine wave currents in dogs and man. Hyperglycernia 2occurred during the pass- age of electrical currents. Knutson found no evidence c.,f brain damage from the current levels used in his experiments, but cites work done by other investigatoys with higher voltage le,.els which produced hemorrhages in the brain. At the loswer 2.@@v@-Is of current ap?lication, tie principal daneer of brain cell damage w2as fron-I inadequate oxygen, due to depression of the respiration by physical interference from muscle contractions. Knutson controlled convulsions by *.he use of muscle relaxants or by adjustments in the current applied to the head. Knutson found ttiat serum potassium, calcium, chloride and sodium did not change during three hours of continuous electro-aresthesia. Blood urea nitr.ogen levels indicated a decrease in kidney function. By using techniques of modern anesthesia. Knutson was able to eliminate or modify the complication?g of cyanosis, bradycardia, cardiac irregularities and severe muscle contractions. Pricel7 reported muscle spasms, elevation in blood pressure and tachycard---a as the principal disadvantages. His experience indicalted 2that children and elderly patients tolerated electro-anesthesia especially well. The responses to electro-anesthesia could indicate potential use in patients with low blood pressure or bronchial infections, according t-o Price. The wave form used was sine wave at 700 cycles per second. Po-wersl8, 44 reported diverse effects he observed in dogs using 700 2 c. p. 9. since wave current. Current of l'OO milliamperes for one-half hour pro- duced increases in the hernatocrit unless dogs weri splenectomized. A significant increase in the myocardial contractile force was recorded using a Walton-5zodie strain gauge sutured to the right ventricle and recorded on a Model 5,c Grass polygraph. 2 Sancesl9-26 used rectangular electrical wa-.res and made studies oa- conduction over cortical pathways. Evoked potentials were recorded in Macaque monkeys during electro-anesthesia. 'Alith electrical stimulation of the sciatic nerve, the evoked response recorded from the medial lemniscus was minimally affected, that recorded from the nucleus ventralis posterior 1 was moderately reduced in amplitude, while the evoked potential recorded from the post central gyrus was abolished. 4 Srnith32-36 used a number of different currents in his research. In dogs subjected to 20 milliamperes of DC and 20-30 milliamperes of square wave AC, there was a temporary but consistent c@ange in amplitude and frequency of the EEG. The post-electro-anesthesia EEG pattern returned to 2 normal within 30 minutes. Histo-pathology studies revealed no neuronal changes other than agonal swelling, without areas pf hemorrhage or necrosis in the eight brains evaluatet3-. In clinical studies on dogs, respiration was slowed, but the arterial oxygen saturatior- did not fall below 91 per cent. The pCO2 levels did not rise abo2ve normal. Body temperature rises were detected, but could be reduced if the animal was not intubated and had the tongue exposed to the air. Turbes37-39 used a variety of currents and studied the effects on th@ EEG, reflexes, pain and maintance of electro-anesthesia. Slow induction was found to give a more acceptable physiological state and thus give more reliable r2esults for aU parz-rneters evali-,ated. Fast inductions gave cardic-pulmonary difficulties which were fatal if not treated promptly,. Va,nHarreveld4O-43 using 60 cycle currents observed respiratory arrest durirlg ingiuction with 300 milliamperes of current. After this inilial period, he reduced the current sufficient to restore respi4rati.c-n. No mention was made of the number of animals that had perma-nent respiratory arrest. Increases in blood pressure were observed. The material published by Van Harreveld indi- cated respiratory difficulties were present throughout his procedures. Many of the difficulties reported with tle use of eiectro-anesthesia can be controlled by the application of proper principles. as Knutson indicates. Cardiac and respiratory difficulties will frequently occur if these are not observed. The two most important principles of salfe anesthesia which should be observed during clectro-anesthesia are the maintenan@e of respiration and circulat;.on. Most of the problems encountered are related to one or both of these systems. Maintaining proper ventilation for appropriate oxygen supply to the cells, adequate elimination of carbon dioxid-e and normal blood pH is essential. Equally important is the maintenance of a safe blood pressure, 2 sufficient cardiac output, and a proper blood supp:y to all vital body tissues.. It is important to consider the comfort of the patient and avoid undue stress, injury and discomfort. The anesthesia should be controlled to assure adequate depth for the surgical procedures that are to be performed. The conscientious anesthesiologist never relinquishes the immediate 2 care of his patient until he is certain that he is no longer needed for the support of the patient's normal physiologic-.al sta*,e. He is responsible, from the administration of the preanesthetic drugs until the completion of the post- anesthetic care, for the needs of his patient,' The investigator in electro- anesthesia should be expected to maintain the same degree of 1responsibuity. He must rnaintain a physiological state that is as rear normal as possible throughout the application of the electrical currents for anesthesia. 6 Proper attention to the principles of anest--iesiology in the calf and other &nimals has made it possible to produce adequate anesthesia for surgery without cardiac and respiratory arrest and related difficulties. Higher frequencies are needed to eliminate these problems and applications need to 2 be made with a slower induction than routinely used by many investigators. Investigations at Oak Ridge, Tennessee 27- 31 proved it was not necessa-r-y to use techniques which interfer with the normal function of the animal. These applications of electrical anesthesia were sufficient to produce anesthesia for surgery. Later the same results were accomplished in other2 environments. PURPOS.E OF THE PROPOSED RESEARCH PROC-RAM Ntu--nerous invest,'-gators since 1902 have attempted to produce anesthi sia with the use of electrical currents. Many types of current and methods of applying them have been tried, Some of these have been moderately successful in producing an anesthetic state. Even with su2ccessful applications, however, unwanted side-effects were usually prese--it and resulted from the application of electrical current to the brain as a wholn. Indiscriminate application of electrical currents to the head accounted for the severe unwanted actions. It is not known if electrical currents -sufficient to produce a@nesthesia can be di6rected to specific areas of the brain through external electrodes. Neither do we know if this would eliminate all unwanted side-effects. There is also a lack of s-.ifficient evidence to distinguish between anesthesia and paralysis pro- duced by electrical currents in animals. AMIN,, Ask qp 7 The uriderstanding of the mechanisms by which electro-anesthesia is produced could make it possible for this rnethod o.' anesthesia to become clinically acceptable. Therefore. the propose-I p2r:)gram to determine the inforrnatidn necessary to justify the extension of the use of electrical current for clinical anesthesia is submitted. OBJ'ECTIVES OF TH& PROPOSED RESEARCH PPOGRAM The objectives of this proposal are to answer three major questions. 1. Where does the current go when it is applied to the cranium? 2 2. When is anesthesia present and at what depth? 3. What are the undesirable side effects of various currents and can they be eliminated? PROPOSED STUDIES TO ACHIEVE OBJECTRVES 1. Electrical Mechanisms A. Determination of the frequency response curves and the external impedance levels of cran2ium. B. Determination of the degrees of linearity of these electrical respon-ses. C. Determination of the impedance of the tissues of the brain. D. Determination of tissue voltage levels in the brain. E. Determination of the distributiorl of total electrical current 1 in the cranium. 8 F. Determination of the convolution of dual electrical currents in the brain. 0. Determination of the role of the cerebral spinal fluid as a conductor of electrical currents. R. Determination of the effects of induced brain lesions on the capability to produce electro-a-nesthesia. 1. Determination of methods to focus current to specific locatione; in the brain. II. Biological Responses A. Determination of the level of anesthesia. 2 5. Determination of the effect of electro-ar-esthesia on blood gases and blood pH. C. Determination of the effect of electro-anesthesia on the cir- culatory system, including blood glucose levels. METI-IODS 1. Animals to be Use2d A. Calves. B. Primates. The calf has been selected as the experimental animal in the initial studies. Primates will be used after the evaluiltions are complete in the calf. For this purpos-e. the Rheus monkey and th-e 5 Chimpanzee have been selected. In vitro studies will be done on cadaver heads of calves, pri- mates and humans in a related sequence to the in vivo studies. 9 C. Justificatioa of Animal Selection. The most repeatable results the most stable level of anesthesia from the use of electrical currents have been achieved during bovine applicatio:ns. There are specific prob2lems associated with each of the other species as experienced by this investigator in studies on horses. s@,,eep. pigs, dogs, cats, rabbits, rats, goats, and monkeys. The most accurate informatior. on the mechanisms of clectro- anesthesia can be obtained from animals that respond most 2 favorable to electrical currents. Therefore. the calf was selected as the experimental animal for the first phase of the program. Calves are available in adequate numbers and the facilities for handling them are adequate. Calves of a 175-200 pound weight range would be used. Twenty2-five calves per year would be needed. Primates are considered essential to the program, after completion of calf studies, since the a-natomical structure of the head and the reactions io electro-anesthesia rnore closely resembles those of the human. Thus a link betwee3n bovine and humar, applications is formed to more clearly define the mechanisms involved. -10- 11. Currents to be Used A. Pulsed direct current with variable pulse duration, frequency of piilse and amplitude. B. Sinusoidal alternating current with variable frequency and amplitude. 2 C. Dual sinusoidal with summation in the generator. 0. Dual sinusoidal with summation in the head. E. Justification of Current Selections. The review of the literat7ure reveals that by-pertension, cardiac and respiratory arrest and strong muscle contrac2tions can occur. The cardiac and respiratory arrest can be perma- nent if the electrical currents are rlot properly applied. 1. Sinusoidal currents can be varied to produce a wide range et responses in the animal. These i-nclude cle-.tro-sleep 2 with high-frequency-low amperage, electro-anesthesia with mid-frequency and amperage, and electro-conv-,,tlsion with low-frequency-high amperage application. Thus by adjustment of the relationships between currezit amplitude and frequency, the dlffere:nce s in responses of the electro- biological pa-ra=eters can be evaluated for the corresponding states of consciousness. 2. The sinusoidal waveform is a clean electrical wave unlil,,e a number of other types, such as square and triangle waves which are composed of a number of sinusoidat waves at various frequencies in 2the harrnc-nic mechanism. There- fore, less distortion should occur in sinusoidal application-a. 3. Dual sinusoidal with summation in the generator produces superficial analgesia without sufficient depth in the deep tissues. It 2has the reverse eifect of single sinusoidal, therefore the response of the rnechanisms involved are changed. 4. Dual sinusoidal with su.-nmation in the head is a technique that opens new approaches to electro- anesthesia. As the2 two currents are brought together inside the head, a number of possibilities exist which affects the response to currenl. If the p'nase angles are the same, the currents wiU com- bine in a true sumrnatio-i. However, variatiors in 5 the relationqhip of phase angles of the applied currents can cause summation at locations in the brain and cancellations of the current in other areas, -Thus if we can learn how to control this lz rnechanist-n to focus the current to specific locations in the brain rather than total brain stirnulation, many of the unw"ted side effects could possibly be elimi- 2 nated. al. Methods to be used in each Proposed Study A. General Statement for All Studies: Statistical consultation will be obtained for aid in the design of experiments and in the evaluation of data gen- erated. B. Specific Studies (E2lectrical) 1. Determination of the frequency response curves and external impedance levels of the cranium. In vitro studies will be made in cadaver calf heads and in vivo studies in calves of same size. The technique to be used consists o2f: a. Applying electrodes to the head of the calf for current application. Both bitemporal and a.nterior-posterior types are to be used. b. Placement of recording electrode by steroto)dc adjustment into0 the tissues of the cra-,iium. -i3 Electrodes can be adjusted for depth and location in the tissues from skin levels to the dura mater. Trephine openings in the skull will be made. c. Connect2 anesthesia-current generator in series with animal head aad impedance bridge for input. d. Connect out-out of impedance bridge and re- cording electrode in head in series to the oscilliscope. 2 e. Current is applied through the head at desig- nated frequencies and amperage and recorded on oscilliscope, The same current is applied through the irnpeda-ice bridge and it is adjusted to give same output to the scope. The impedance 2 levels ga the bridge then correspond to those of the animals head. Thus the total impedance met by the current applied through external electrodes is determined. i. By determining the impedance of the head and 9knowing the current input to the head, the current flow in the brain can be determined. g. By adjusting the frequencies and amplitude in an interval method. the response curves can be 14 determined. ;ive milliampere and 100 cycles per second or pulses per second intervals wiU be used at ranges up to 2000 cycles per second. Above this, 500 cycles per second intervals will 2 be used. 2. Determination of the degree of linearit7y of these electrical responses. This study is closely associated with Study A. It does not require additional measurements, but a mathamatical analysis &nd.graphing of the responses exhibit2ed for frequency and impedance to determine the degree of linearity of the system. 3. Deterrnination of the impedance of the tissues of the brain. 54, 55 s6 a. Theory: Investigations by AArey Nicholson 2 57 58, 59, 60 62 RaU , Ranch ,and van Harreveld illustra!,t*- the variations in impedance levels in the segments of the brain and changes that take place under changing behavi'or patterns. Willen2k-iu 65 found that'the impeda@nce levels in the brain stem changed in relation to the level of anesthesia from methoxyflurane. Since'the brain and surrounding tissues behave like a series of paraue"& resistors and capicators, it is reasonable to 3 theorize that the impedance responses will vary in relation to the frequency of current applied to the brain. 1 5 b. Method of Conducting Study This study will follow the frequency response curve and external irnpedarc-e study. The same equipment and procedures are Lsed, The primary difference is in the tissues to be studieti. This study evaluates the impedance levels at var)ring frequencies in the brain tissue. Areas of the brain to be studied are: 1) Cerebral Cortex Z) Thalmus 3) Hypothalmus 2 4) Brain Stem 5) Cerebellum C. Special Techniques - The study of external impedance required a maximum depth to the dura for recording electrodes. In this study, the electrodes must be placed in specific locations of the brai2n. Electrodes will be of minimum size to prevent excess damage to the brain tissue and will have a I rn. m.. uninsulated point for recording. The insulation will be n@.)n-me.tallic to prevent error in results. Metallic coating produces 0 extra capacitance values. The principal investigator has placed acute and chronic electrodes in the brain of large animals. Problems encountered will be solved by consultation with neuroanatorny and neurosurgery staif personnel. 16 4. Determination of tissue voltage levels in the brain. a. Theory: The various types of brain cells and nerve fibers have specific voltage potentials. It is also known that the voltage changes with the state of the 2 cells, i. @-. resting, during depolarization or re- polarization. 64. 65 It is reasonable to predict that the induct,.on of additional voltage of electrical currents into the brain will interfer with the normal 2 voltage potentials of Lie cells. thus affecting their usual function. b. Method to Complete Study. 1) Equipment a) Electro-anesthesia generators. b) Oscilliscope with differential amplifi2er. c) Double recording electrodes with I m.m. non-insulated tips I m. rn. apart. d) Electrodes controlled by-sterotaxic adjustment. 2) Procedures a) Cadaver heads will2 be used to perfect techniques arld then live calves. b) Electrodes will be worked through L-ephine openings in the skull. 4c) Readings wil'- be made in the major segments 0 of the brain F-t selected frequencies and amplitudes of input current. i7 3) Brain Areas to be Studied a) Cerebral Cortex b) Thalmus c) Hypothalmus d) Brain Stern 2 e) Cerebellarn 5. Determination of the distribution of total electrical current in the cranium. a. Object: How much of the total current applied to the head actually reaches the brain? This is &n in vi,#,ro study on cada,.rer heads. b. Procedure: Calf heads will be opened sufficie nily for the brain to be aspirated. Reco@rding electrodes will be placed in the cerebral cavity and it will be refilled with physiological saline. Electrical currents 2 will be applied to the head in the normal manner for anesthesia and the current amplitude in the homolog-is solution will be calculated from the osciuiscope readings. This value substracted fro--n the generator output should gi9ve the amount of current dissipated in the skinmuscle and bone of the head. 53 6. Determination of the convolution of dual electrical currents in the brain. a. Theory: The obseri@-ed responses of experimental animals under the influence of dual electrical currents indicate that ae effect on the central nervous system is not the same as single wave induced curr2ents. The responses a-re of a sleep- like nature rather than anesthesia if the combination is summated in the generator, but indicates deeper anesthesia if the summation is in the head. Since surnmation of two currents in a system does not 2 necessarily follow a nume-rically adding effect, it is logical to believe that the currents applied to the head frorn two sources are convoluting (passing one another) in such form that the phase angles determinl- if they are adding or canceuing in a particu2lar segment of the brain. Therefore, the determination of this theory would indicate the possibility of focusing current to specific locations of the brain. b. Animals - I in vitro studies in cadaver calf heads, 4 2) in vivo studies in calves. C. instrumentation 1) Current Generator!;. 2) Oscilliscope. 3) Recording electrodes and sterotaxic equipment. AM6 d. Procedure I Electrodes would be surgically placed in select locations in the cerebral cortex. thaimus, hypothal.-nus, brain stem, and 2 cerebellum. 2) External currents for anesthesia would be applied through external electrodes. 3) Reading will be made on the oscilliscope. 4) Using known input and observed output, the convo2lution of current in the system (brain) will be mathematically determined. 7. Determination of the role of the cerebral spinal fluid' as a conductor of electrical currents. a. Since the impedance of CSF is so little compared to the tissue of the2 head, there is evidence that this may be the medium through which much of the current flows. b An in vitro study is proposed in which the hea-d and neck of calves would be used as the container for the fluids. Currents will be applied to the head 8in the normal fashion for electro-anesthesia. Record- ing electrodes will be placed in the brain and connected to an oscilliscope. After recordings 20 of the voltage and current to the brain, the CSF will be replaced by electrolyte solutions'anci HZO. The conductance through each of these media will be determined for correlation. Thus the role of 2 conductance through the CSF can be made. S. Determination of the effects of indi-iced brain lesions on the capability to pfoduce electro-anesthesia. a. To provide additional evidence that specific areas in the brain are involved with the mechanism of electro2-anesthesia, lesions vrill be produced in live animals in select areas of the thalmus, hypo- thalmus, and cerebral cortex and thci-r effects on the capability to produce electro-anesthesia determined. b. Lesions will be sur2gically produced and consulta- tion with the staff neurosurgecns at 1'will be made in perfecting techniques. Current freq%2ency and amperage requirements will be compared with those of normal brains. C. The bradykinin test will be made to determ6ine depth of anesthesia. 9. Determination of the methods to focus current to specific locations in the brain. 21 a. Although this study is listed last it is one of the most important studies. However, the preceeding studies must be made to rnake it possible. b. Theory, It is desirable to only have the current 2 in the brai n where stirnulation to specific sites will produce anesthesia, thus reducing the unwanted side effects. The question to be answered is, "Can this be controlled by appiying currents at selected phase angles from speci-f-3Lc locations2 on the skuu to allow cancellation of current in aJI areas of the brain except those that need to be affected? C. In this study, the multiple inducing electrodes wbuld be placed in specific loc&tions enabling the phase &ngle to be controlled, 2giving the proper level of current in various areas of the brain. In the initial studies, the electrodes would be placed through the bone of the skull by surgical technique, thus eliminating the deflection of current by the bone. After determination 2of the proper effect by this technique, attempts to produce tb-e same effect with electrodes outside the skull would be made. Thus determination can be made by recording from the specific locations of the bra,'In. the amount of current present. 3 40 22 C. Specific Studies (Biological) 1. Determinati-on of the level of anesthesia. a. The bradykinin test as -described by Lim, et, al 45- 52 Will be used as an index to depth of anesthesia. 2 Either intra-arterial or intra-peritoneal injection of bradykininevokes a response if pain is perceived. There is no tissue damage by bradykinin, &nd the pa.in responses can be recorded in terms of blood pressure elevation. The test can be re2peated frequently. Pain is perceived 15 seconds after injection and lasts 30-40 seconds. b, By using this test at each of the frequency and arnplitude levels for the four types of current to be studied, the depth of anesthesia and at what current levels it occur3 can be determined. c. By correlating response 6@O bradykinin with the other physiological changes, an outline of the - signs of various levels of anesthesia can be drawn 4up for electro-anesthesia. d. Recordit@gs of responses will be made with a physiological recorder with blood pressure, ECO, and impedance pneumograph transducers and pre- amplifiers. Blood pressure rm asurements wiU 2 3 be made by direct cannulation of the external maxillary artery. 2. Determination of the effect of electro-anesthesia on blood gases and blood pH. a. Since proper oxygen suppl2y to the bra-in ceus must be maintained to prevent cell damage, the effects of the various types of current on these parameters must be made. b. Mgh amputude current5 at low frequencies produce definite respiratory 2distress. It is, therefore, important to 'know at wl-%at levels there is sufficie-it disturbance'of the blood gases and pH to be hazardous. C. Determination before, during, and after &nesthesia will be done for all four types of current at 100 cycles 2 per second and 5 milliamperage intervals. The range will extend from no detectable respiratory distress to obvious disturbance, d. Arterial sarnples will be collected through an im- planted carotid catheter and results dete4rmined immediately after sampling. Samples will be collected at 15 minute intervals and idontinue until the response is stable. Ask 0 24 - The instrument to be used is the blood gas and pH equipment produced by tnstz-urnentation Labs of 15oston, Massachusetts. 2 3. Determination of the effect of electro-anesthesia on the circulatory system, including blood glucose levels. a. Cardiac arrest can be produced by clectro-anesthesi;x. It is usually not fatal if the current is reduced promptly, allowing the hea2rt to rt:sume function. Cardiac arrest is not produced if higher frequencies of current are used. Therefore, it is important to know the range of currents which will produce cardiac difficulties. b. Three circulatory parar2neters that are knovm to be affected by clectro-anesthesia will be studied. 1) Blood Press@Lre. 2) ECG for heart rate and 6Aytbmids. 3) Blood Glucose. C. All four types of current to be s2tudied at the frequency and amplitudes ranges previously indicated. d. Equipment 1) Physiological recording equipment with trans- ducers and pream-.Dlifiers for blood pressure and ECC. 2) Bausch and Lornb Spectrometer for blood glucose determination will be used. ANTICIPATED PROGRESS in vitro studies can start two weeks after funding. It is anticipated that the first four electrical studies for the four types of current and the biological .studies for tw2o of the four types of current could be completed the first year. PERSONNEL IV. To be named. Will spend rninimum of 50'lo time on project. V. Aniynal Assistant - FuU time. VI. Technician for lab analysis Full time. Vil. Secretary - 501c of time. VM. Neurosurgery Assistance available in adv-isory capacity IX. Neurophysiology from these departments X. Neuroanatomy Xi. Radiology BUDGET FIRST YEAR PERSONNE'- SALARIES rnves tigator . . . . .Full time Technicians (2) 1. Assisting with animal procedures 2. Laboratory analysis Secretary part time (50@o) Engineering (systems electronics) 2 Consulting (Electronics, Neurosurgery, Neuroanatomey, 9-7 Neurophysiology) ANIMALS 25 calves @ $60 each $ Board.* $4. 00/da)r for 330 day9 $ Plan to reuse each animal as muct,. as possiltble. N,-,-.rb-er on hand at a given time will be two thus reducing board.-- EQUIPMENT I . Tektrc-nix Model R293 DC pulse generator and power supply. $ Hewl4@tt-Packard Model 3380 B Sine wave generator (can @e used in both sine wav0e analysis and external summation analysis, one sine wave generator is already available for use in dual wave convolution studi4ps). -2-7 - 3. Genera-I '-@-adio Impedance Bridge for measuring brain impedance levels, Model 1608-A 4. Motor drive unit for exact rate of curr,ent appli- cation in all cases 5. Simpson Voltmeter Model 312 6. Blood ga3 analysis equipment. Inst2rumentation Labs. NEcro-analysis system Gasses for caliberation of above 7. Bausch and Lomb Sepectrometer Model 20 for blood glucose determinations 8. Oscilliscope for monitoring waveform, rise t' distortion of waves, voltage levels and time irn e, intervals The Tek2tronix Model 561A with needed components lists for $1, 780. 00. The Hewlett-Packard Model 141A with similar components is $2, 075. 00. There is one advantage of the H-P model in that information can be stored on the screen. This would enable one to record frequency responses, rise time, voltage levels, f@t2c. , on the screen at specific intervals and &at dire(: t comparisons. Thus more accuracy can be obtained. The work can be done with either. More accuracy is preferred but can be sacrificed in this case if needed for budget purposes. 9. OscilliscQpe camera for permanent records of readings, (will work with either of the oscilliscope 5 models listed). 10. Sterotoxic apparatus by Universal- 610101 "HI' stand with adjustable horizontal bar 6101OZ Horizontal rider 610103 Carrier housing -28@- 610104 Micrometer carrier 613001 Micrometer 613510 Chuck, insulated Base plate and head holder will be constructed fit needs. The equipment listed can be used in either micro or macro-electrode applications. 11. Electrodes, connecting cables and 2electrical probes TOTAL EQUIPMENT SURGERY CRARGES These charges are f,)r surgical instruments, suture, operating room charges. Sinc,-- animals are to be reused the procedures will be made using aseptic techniques. 50 days of surgery @ '.' Yday $ MISCEL2LANEOUS Physiological recording instrument paper Photography Travel Tubing, catheters, drugs, chemicals Computor time in data analysis Institutional Overhead: 401* of Salaries $ Total First Year $ Ask -29- Reductions in equipment cost the second year should offset any increases in other items for a second year budget of $ Detailed budgets for tirne periods after the initial year will be submitted at the requested time. AGMIL -30- REFERENCES FOR ELECTRO-ANF-STMESIA 1. LeDue, S. 1903. Llelectrisation cerebrale. Arch. Elect. Med. 11: 403-410. 2. Fabian, L. W., S. D. Hardy, M. Don Turner, P. S. Moore. 1961. 2 ElectricalanesthesiaV. Surveyofclinicalprogresswithinustrativecas,-S. Anesth. Analg. 40,653-661. 3. Geddes, L. A., C. C. Turbes, M 'Hinds, W. E. Barrows. 1965. The EEG during electronarcosis. Anesth. Analg. 44:305-312. 4. Geddes, L. A. , H. E. Hoff, and C. Voss. 1964. Cardiovascular respiratox-y studies during electronaxcosis in the dog. Cardiovasc. Research Center Bul:Letin 3:38-47. 1 5. Gowing, D., R. S. Underwood, F. P. Haugen. 1964. Electroca-rdiograpVjc studies during electronarcosis. Anesthesiology Z5:668-671. 6. Cowing, D. 1964. Electro2cardiographic studies during electro-anesthes5a. .First Symp, on Electroanesthesia. (Physiol. Dept. . Colorado State University, Ft. Collins, Colorado). pp 37-39. 7. Hardy, 1. D. , L. W. Fabian and M. D. Turner. 1961. Electrical anesthesi.@ for major surgery. ;. Amer. Med. Ass2n. 175:599-600. 8. Hardy, J. D., T. Carter, and M. D. Turner. 1959. Catechol &mine metabolism. Ann. Surg. 150:666-683. 9. Hardy, J. D., M. D. Turner, and C. D. McNeil. 1961. Electrical anesthesia. S. Surg. Res. 1.152-168. . 10. Herin, R. A. 1964. Induction techniq2ue changes and electroencephaiogi;aphic body temperature, and pupillary light reflex studies in dogs anesthetized 'th electric current. Amer. S. Vet. Res. Z5:739-746. wt . 11. Klemm, W. R. 1964. A square-wave elect:rical anesthesia current gerlerator. Ay,esthesiology 25:718-719. 2 1.2. K-lemm, W. R. & R. O'Leary. L964. Comparison of electrical pararhetexs and the quality of electroanesthesia. Anesthesiology 25:776-780, 13. Knatson, Robert C. 1954. Experirnents in electronarcosis: a prelirnina-,ry study. Anesthesiology 15:551-558. 14. Knutson, 2Robert C., F. Y. Tichy, and J. M. Reitman. 1956. The use of electrical current as an anesthetic agent. Anesthesiology 17:815-825. 15. Knutson, R. C., N. R. Magfors, and J. H. Matthews. 1965. Modification of -epileptic adter-discharges by electroanesthesia currents. Presented at Znd Ann. Symp. on Ele3ctroanesthesia. Univ. of Tenn. , Kn-.)xville. Ap-ril, 1965. 31 i 6, Knutson, R. C. 1964. The electroencephalograin in electroanesthesia. Proc. Lst Symp. Electroanesthesia. Et. Collins, Colorado. 17. Price. J. H. and W. H. L. Dornette. 1963. Clinical experience with electroanesthesia. Anesth. Analg. 42:487-495. is. Powers, M. F. and W. B. Wood. 1964. Electrical anesthesia studie---, di-.rerse effects. Ane3th, Analg. 43-.385-392. 19. Sances, A. , Jr. . and S. T. Larson. 1963. Electrona-rcosis and evoked brain potentials. Science 141:733-735. zo. Sances, A. 2, Jr. . S. J. Larson and S. L. Tacobs. 1963. Recording of brain potentials during electronarcosii. 16th Ann, Conf. on Eng. ia Med. and Biol. Harry S. Scott, Baltimore. p. 68-69 (266 pp). 21. Sances, A. , Tr. 1964. Effects of electrorarcosis on evoked,responees in the brain, A dis s ertation in partial2 fulfillment of the r equirerr* nts for Ph.D. Bio-medical Eng. Center, Northwestern Univ., Evanston, W. Z2. Sances, A. , Jr. , and S. J. Larson. 1964. Sensory and motor function during electroanesthesia. Proc. 17th Ann. Conf. on Eng. in Biol. and baed. in Cleveland. Ohio. MacGregor an2d Werner, Washington, D.C. 127 pp. 23. Sznces, A. , Jr. , and S. T. Larson. 1964. Mathematical representatic-n of classical sensory pathway as a function of electro-marcosis. Abstract WGt. Biophysical Soc, 8th Ann. Meeting. 24. $ances, A. , Jr. , and S. J. Larson. 1965. Neuro2physiological effects of electroanesthesia. Exp. Neurol. 13: <>.-t. 1965. 2 5. $ances, A. , Jr., and S. J. Larson. 1965. Evoked potentials " motor response determin&tions in the presence of Anan'ev type currents. Znd Ann. Coni. on Electroanesthesia, Knoxville, Tenn. April, 1965. 2 26. $ances, A., Jr. , and S. J. Larson. 1965. Transient and steady state response of soma-dendrite neuron model to step and rectangular current. Abstract. Proc. 9th Ann. Meeting Biophysical Soc. 27. $hort, Charles E. 1965. The physiological effects of electroalnesthesia @n domestic animals. Presented at 72nd Ann. Symp. on Electroanesthesia, Univ. of Tenn., Knoxville, Tenn. April, 1965. ZS. S-iort, C. E., C. C. Turbes, and 3@. S. Snyder. 1964. Large animal electroanesthesia. Proc. Ist Ann. Rocky Mt. Bioengineering Syrnp. 'LT. S. Air Force Academy, Colorado. p 231-286. -32 29. Short, C. E. 1964. The application of electroanesthesia on large animals: a report of 100 administrations. S. Amer. Vet. Med. Assoc. 145;1104-1106. 30. Short, C. E. 1964. Experiences in the applications of electroanestheria 2 to equidae. Agricultural Research Lab. UT-AEC, Oak Ridge, Tenn. Proc. 10th Ann. Conv. Amer. Assoc. Equine Fractit. Denver, Colo. December 1964. p 158-166. 3i, Short, C. E. 1965. Clinical effects of anesthesia produced by alternating electrical current. Anesth. d-nalg. 44:517-SZI. 2 32. Srnith, Robert H. and Stuart C. Cullen. 1962. Electrorkarcosis - A progress report. Amer. J. Med. Electronics S:308-313. 33. Smith, Robert H. and Stuart C. Cullen. 1962. Electronarcosis by -combination of direct and alternating current. 3. Electrodes and electrode holders. Anesthesiology 23:68Z-2686. 34. Smith, Robert H. , Robert R. Hylton, and Stuart C. Cullen. 1965. Electronarcosis by a combi'nation of direct and alternating current.' Arner. J. Med. Electr. Jan. -March, 1965. p 38-41. 35. -Smith, Robert H., Robert R. Hylton, Sohn R. McCabe, and Stuart C. Cullen. L965. Electr2ical anesthesia produced by a combination of direct and alternating current: technical studies in the Macaque monkey. Anesthes. Analg. 44:275-279. 36. Smith, Robert H., Richard K. Richards, Ward R. Richter, Robert R. Hylton, John R. McCabe, Stuart C. Cullen. 1965. Electrical anesthesia produced by combining di2rect and alternating currents: electronrnicroscopy of the dog brain. Anesthesiology Z6:607-614. 37. Turbes, C. C. and L. A. Geddes. 1964, Central nervous system activity associated %vith electronarcosis. First Sy-rnp. Electroanesth. Physiol. Dept., Colo. State Univ. . Ft. Collins, Colo. p 52-67. 2 38. Turbes, C. C. and L. A. Geddes. 1965. Studies on cerebral cortical and subcortical activity during electroanesthesia. In Proc. 2nd Ann. Rocky Mt. Bioengin. Symp., USAF Academy, Colorado. p 111-113. 39. Turbes, Calvin C. L965. Electrode placements and the neurophys- 9 iology involved. Presented at the Second Ai-in. Syrnp. on Electro- ELnesthesia. Univ. of Tenn., Knoxville. April, 1965. 33 - 40. Van Harreveld, A. , M. S. Plesset, and C. A. Wiersrna. 1942. Relation between the physical properties of electric-currents and their electronarcotic action. Amer. J. Physiol. 137:39-46. 41. Van Harreveld, A. , D. B. Tyler, and C. A. Wiersma. 1943.2 Brain metabolism during clectronarcosis. Amer. S. Physiol. 139:171-177. 42. Van Harreveld, A. 1947. On the mecha-aisrn and localization of the symptoms of electroshock and electronarcosis. S. Neuropath. Exp. Neurol. 6:177-184. 43. Van Harreveld, A. and W. B. Dandiliker. 1945. Blood pressure changes during electronarcosis. Proc. Soc. Exp. Biol. Med. 60:391-394. 44. Wood, W. B., M. F. Powers. W. H. L. Dornette, and S. Price. 1964. The cardiovascular effects of cra-nially impressed electric ,currents of anesthetic intensity. Anesth. Analg7. 43-313-323. -,36- RELATED REFERENCES BRADYKININ .45. C. Braun, F. Guzman, E. W. Horton, R. K. S. Lim and G. D. Porter. Visceral Recepters Pain, Bradyk:.nin, and Analgesic Agents. Proceedings of the Physiological Soc:-ety 4-5 Nov. 1960. Journal of Physiology, 155, 13-14p. 46, G@ D. Dickerson, R. S. Engle, F. Guzman, D. W. Rodgers, and R@ K. S. Lim. The Intraperitoneal Bradykinin - Evoked Pain Test for Analgesia. Life Science, 4, pp 2063-ZO69. 1965. Pergamori Press, Ltd. 47@. Frank Guzma2n, C. Braun, and Robert K. S. Lirn. Visceral Pain and the Pseudaffective Responses to tntra-arterial Injection of Bradykinin and other Algesic Agents. Arch. int Pharmacodyn, t962, CXXXVI, pp 3=4. 48. F. Guzman, C. Braun, R. K. S. Lim, G. D.. Porter and D. W. Rodgers. Narcotic and Non-narcotic Analgesia 2which Block Visceral Pain Evoked by rntra-Arteria-1 injection of Bradykinin and other Algesic Agents. Arch. int. Pharmacody-n, 1964, 149, pp 3-4. 491. Robert K. S. Lirn. Visceral Receptors and Visceral Pain. Annals of the New York Academy of Sciences, 86, Article 1, pp 73-89. March 320, 1960. 50. R. K. S. Lim, F. Cruzrnan, D. W. Rodgers, K. Coto, C. Braun, 0. D. Dickerson and R. 1. Engle. Site of Action of Narcotic and Non- narcotic Analgesics Determined by Blocking Bradykinin Evoked Visceral Pain, Arch. int. Pharmacodyn. 1964, 1SZ, pp I-Z. 5 I. Robert K. S. Lim, Cha Nao Lin, Frank Gazman, and Christian Braun. Visceral Receptors Concerned in Visceral Pain and the ?seudo- affective Response to tntra-arterial Inject4on of Bradykinin and other Algesic Agents. Journal of Comparative Anatomy, 118, p. 3, Tune, '.962. 52. I:L. K. S. Lim, F. Guzma9n, and D. W. Rodgers. Note on the Muscle R.eceptors Concerned with Pain. Symposium on Muscle Receptors, Ed, by Barker, Davi d. University of Hong Kong. Golden Jubilee Congress, September 11-16, 1961. ELECTRECAL DISSECTION 53, L, A. Geddes. Unpublished data from 3rd Symposium on Electro- anesthesia. St. Louis University School of Medicine. May, 1966. IMPEDANCE CHANGES 54. W. R. Adey, R. T. Kado, 1. Didio, and W. J. 2Schindler. "Impedance Changes in Cerebral Tissue Accompanying a Learned Discriminative Performance in the Cat. 11 Experimental Neurology, 7, pp Z59-281. ('- 9 6 3). Ss.. W, R. Adey, R. T. Kado, and D. 0. Walter. "Impedance Characterisf2xcs of Cortical and Sijb-cortical Structures: ]Evoluation of Regional Specificity in Hypercapnea and Hypothermia!! Experimental Neurology, 11, pp 190-216. (1965). 56. Paul W. Nicholson. "Specific Impedance of Cerebral White Matter".2 Experimental Neurology, 13, pp 386-401 11965). 57. Wilfrid RaU. "Membrane Potential Transients and Membrane Timq Constant of Matoneurons". ExperL-iiental Neurology, 2, pp 503-537 (1960). 58. James B. Ranck, Jr. and Spencer L. BeMent. "The Specific Impedanr-e of the Dorsal Columns of Cat: An Anisotropic ',%4edium ". Experimental Neurology, It. pp 451-463 (1965). 59. James B. Ranck, Jr. "Specific Impedance of Rabbit Cerebral Cortex". 2 Experimental Neurology, 7, pp 14-4-152 (1963). 60. James B. Ranck, Jr. Analysis of Specific Impedance of Rabbit Cerebral Cortex. Experimental Neurology, 7, pp 153-174 (1963). 61. tchiji Tasaki. Conduction of Nerve Impulse. Handbook of Physiology 2 or Neurophysiology, I, pp 75-121. 62. A. van Harreveld and Sidney Ochs. "Cerebral Ernpedance Changes After Circulatory Arrest". American IJournal Physiology, 187:180-19a, 1956. 63. Robert L. Willenkin. Anesthetic Level and 8Electrical Resistance of the Brain Stem. Anesthesiology, 27-2, 1966, p. 231. 64. Barry Wyke. General Anesthesia, lp pp 157-300. Washington Butterworths, 1965. 65. Sidney Ochs. Elements of Neurophysiology. John Wiley & Sons. tnc. , New York, 196 5.