http://exhibits.library.stonybrook.edu/mfp/files/original/18207735ad5546b08aac89618232e7bc.pdf 66f756c9dd21d0500a4b4e9773773d3e PDF Text Text �������Wm « . . ”1%! W3 l/W W "79"! - duh [cow ~ 4444...; n— wlamaZu-fl nag ‘3 073 /3 W _———_—_é¢%0u_LL__p_J_ 1w... mug: . j” / 3 H4 Ito :98 ��'VfJii MMud‘vue I7M¢2+ ? la Mal. .max Q ,4”; . 9:19 M00 4/73 ,“ K We; /a¢/If ,, (14.2...e‘23m,“ L DF/Wdfi flan" 714 - “7‘ 44.4.5 44W r M , %W(“ W77 27/56:.) xéa/av-p 2/3“; 413»; Ma... 7w,» #1W 1‘ I; a.“ me: ‘M‘M w 4‘ 7‘ WWW/3,1:I/7 w»! AWL—«awe; CK’S") mm) M �7 7 4%? % ,4» 014/.- a‘,‘” __n ”ViV W ,, (A. 2‘ MW "5 11M; r W ��‘ WMA (“Av/Jaw AJa—lnw.m.5¢nfi¢ �������M Wf - I7 ‘70 [Lav/2.». 5’52 31 ,9: d3: ���������fibrw Dr? ' D.- £44415" Iv ~43 VP-’YV MED-thaw Masha“. -6” 'DFP- m 51am JV 1 ‘ ��\ \-_' <f/ e4 AM (3 �����73/4 r 4/»! / 4? ��" ,; . “A; 7 m 7V ����Ph. i74800 MECHOIYI® CHLORIDE (METHACHOLINE CHLORIDE U.S.P., MERCK) a SHARP DOHME MECHOLYL* Chloride produces the same physiologic response as does acetylcholine, which, when released at nerve endings, produces parasympathetic stimulation. In therapeutic doses, MECHOLYL slows the heart rate, lowers blood pressure, constricts the bronchioles, dilates the peripheral blood vessels, constricts the pupils, Increases intestinal tone and peristalsis, causes salivation and flushing, and stimulates the detrusor muscle of the bladder. In general its efiects are the opposite of those produced by epinephrine. Its action is much more prolonged than that of acetylcholine and it is, moreover, devoid of the nicotine-like effect of that substance. METHODS OF ADMINISTRATION MECHOLYL Chloride is a potent substance and careful consideration should be given to Its dosage and method of administration. For *MECHOLYL is the registered trade-mark of MERCK & CO., Inc., for its brand of methacholine. [i] stopping an attack of paroxysmal auricular tachycardia it should be given by subcutaneous iniection (never by intravenous or intramuscular injection), and the same method of administration may be used in treating scleroderma, chronic ulcers, Raynaud's disease and other vasospastic states, although in the latter conditions better and more prolonged efiects are obtained when it is administered by the method of ion transfer For administration by mouth (iontophoresis). the less hygroscopic MECHOLYL Bromide is supplied in tablet form. Atropine intravenously immediately terminates the action of MECHOLYL. A syringe containing a suitable dose of atropine sulfate [0.6 milligram (l/iOO grainI] should be available for immediate intravenous iniection if the dose of MECHOLYL Chloride causes undesirable symp- MECHOLYL Chloride is supplied in ampuls Since MECHOLYL constricts the bronchioles containing 25 milligrams (0.025 gram) of the powder. Solutions for subcutaneous iniection are prepared by dissolving the drug in sufficient sterile distilled water to make it possible to measure accurately and administer easily the dosage desired. WARNING Injections of MECHOLYL Chloride should be given subcutaneously only. lniections should never be given in- travenously or intramuscularly. PRECAUTIONS The patient should be lying down during the administration of MECHOLYL Chloride to minimize the effects of lowered blood pressure. [2] toms. Overdosage of MECHOLYL may produce momentary cardiac arrest. The Trendelenburg position, to give the cardiac center the benefit of any circulation present, is sometimes beneficial in such an emergency. and may produce an asthmatic attack in those subiect to this condition, it should be used with extreme caution, if at all, in cases where there is a history of asthma or hypersensitivity. Substernal pain following the administration of MECHOLYL is said to be rare. However, the use of this drug in patients subiect to angina pectoris is not recommended. USE IN PAROXYSMAL AURICULAR TACHYCARDIA One of the most efficacious uses of MECHOLYL Chloride is in terminating attacks of paroxysmal auricular tachycardia. It is, however, not effective for prophylaxis or for continued treatment in cases of frequent recurrence of the arrhythmia. [3] �not recommended for the treatment of auricular fibrillation, auricular flutter, or paroxysmal ventricular tachycardia. It is DOSAGE The initial subcutaneous dose of MECHOLYL Chloride should be limited to IO milligrams (0.01 gram) to test the patient's tolerance. Careful preliminary testing of the patient with a small dose will not nullify the effect of a subsequent dose, and is advisable if there is any doubt of the patient's ability to tolerate the drug. treating paroxysmal auricular tachycardia in patients under twenty years of age, IO milligrams given subcutaneously usually terminates an attack. In older patients, 20 to 40 milligrams may be required; obese patients sometimes require more. In Slow absorption of the drug due to inadequate local circulation may interfere with the therapeutic response. If the attack is not terminated in two minutes, compression of the vagi, together with gentle massage at the site of iniection to promote absorption, is suggested. Conversely, if absorption is found to be too rapid, further absorption may be retarded by applying a tourniquet above the site of iniection. The efiects of MECHOLYL may be terminated immediately by atropine. [4] and larger dose (if that given first fails to interrupt the attack) may be given 20 to 30 minutes later, providing no severe reaction has occurred following the first dose. Quinidine in moderate doses (not more than 0.2 gram four times a day) usually does not impair the MECHOLYL effect. Larger doses tend to inhibit its action, although MECHOLYL has been known to “break through" the depresr slon of quinidine. 174800 For oral administration or administration by the method of ion transfer (iontophoresls)—Ph. A second I Gm. bottles. 10 Gm. bottles. MECHOLYL BROMIDE (for oral administration only) is supplied in Boxes of 24—200 mg. (0.2 Gm.) tablets Bottles of 500—200 mg. (0.2 Gm.) tablets OTHER USES OF MECHOLYL CHLORIDE been used (by suba number of other condi- MECHOLYL Chloride has cutaneous iniection) in tions, particularly in certain vasospastic diseases, such as Raynaud’s disease, in chronic ulcers, and in scleroderma. If a test dose of IO milligrams of MECHOLYL Chloride has been well tolerated, the subsequent dose may be increased cautiously up to 25 milligrams (0.025 gram). In these conditions, however, the much more prolonged efiect produced by MECHOLYL Chloride administration by the method of Iontophoresis (ion transfer) or by the oral administration of MECHOLYL Bromide Tablets is preferred. MECHOLYL CHLORIDE is supplied ,snm DOHME SHARP 8: DOHME as follows: Philadelphia, U. S. A. For subcutaneous iniection— DIVISION OF MERCK a: CO. Inc. Boxes of 6 ampuls each containing 25 mg. (0.025 Gm.) of the dry powder. I 5 I P- IB-413 [6] Printed in U.S.A. �For the Medical Profession only ‘ANECTINE’® CHLO RIDE BRAND SUCCINYLCHOLINE CHLORIDE INJECTION 20 mg. in each cc. Multiple-dose vials of IO cc. (for intravenous use) ; n’l ' ix, use 'v 6’ ‘ " ' e .,'alysis. While respiratory depression is usually a r single dose of the drug, or following ’M‘uV-r-mtous administration, cessamore prolonged respiratory there may on occasion be depresoion requiring adequate respiratory exgen by the administration of supplemental or controlled . - -. . ‘ANECTIN E’ Chloride brand Succinylcholine Chloride Injection is an ultra-shortactmg skeletal muscle relaxant; that is, following intravenous injection of small procedures. The quick return of spontaneous respiration is a definite For more prolonged relaxation advantage. ‘ANECTINE’ may be given by continuous intravenous drip; tachyphylaxis does occur and cumulative action is not seen. The degree of relaxation not be ordinarily may controlled by the solution. Upon stopping the intravenous drip, adjusting the rate of flow of narily resumes within a minute and spontaneous respiration ordirecovery is complete within 5 minutes. CHEMICAL PROPERTIES Succinylcholine chloride, also to as diacetylcholine chloride, is odorless, crystalline substance referred a white, which'is readily soluble in succmic acid bis (fl-dimethyl—aminoe‘thyl) water. Chemically it is ester dimethochloride, and its formula is as follows: i ' ' ’ Cl CH2COOCH2CH2iV(CHa)3 CH2COOCH2€H2N(CH3)3 :I'he ester linkage is rapidly hydrolyzed in alkaline solutions but is in acrd solutions. In order to relatively stable promote stability, solutions should be refrigeration. It appears that succinylcholme is rapidly hydrolyzed kept-under followmg its PHARMACOLOGICAL ACTION ‘ANECTINE’ causes muscular transmission at the myoneural paralysis by producing a blockage of nervous junction.This action was first reported et al.1 Independent studies by Bovet The at Wellcome Research Laboratories have been conducted on the synthesis2 and pharmacology“7 of the drug. de Beer and his associates3-7 have found that doses as low as 0.05 mg./Kg. given cats are effective in producing intravenously to muscular relaxation, and that intravenous doses of 0.1 mg./Kg. or more produce and complete muscular characterized by short durationprompt paralysis which is of and action extremely rapid recovery. Repeated injections produce reproducible and phylaxls nor significant cumulative predictable muscular paralysis, neither tachyeffects being seen. When given by intravenous drip, a predetermined degree (scratic of relaxation in a cat nerve-gastrocnemius muscle) could be closely approxrmated by adjusting �The administration of doses of ‘ANECTINE’ sufficient to produce complete neuromuscular blockade has not caused any significant. ghange in blood pressure (except for the typical asphyxial pressor response in the absence of adequate respiration). No,evidence of any histamine-like depressor action has been found, thus differing from observations with d-tubocurarine. The ECG of the cafi was unchanged during a 2-hour infusion maintaining complete paralysis. ' ‘ ‘ Acute toxicity studies in albino mice showed the intravenous L.D.5o to be 0.55 to 0.59 mg./Kg. Complete paralysis resulted, with marked dySpnea and anoxia; death was apparently due to respiratory failure. Those mice which survived the initial symptoms exhibited disappearance of anoxia and dyspnea in 2 minutes and had completely recovered within 30. minutes. Chronic toxicity studies on albino rats showed that the intraperitoneal injection of -1' mg./Kg. or less, twice daily over a period of 4 weeks, produced no evidence of toxicity. important.difl‘erence‘between ‘ANECTINE” and d-tubocurarine is that the former is not antagonized by anticholineste'rases. On the comrhlti’, 5.14.911 drugs as physostigmine, lThis rostigmine (neostigmine) and procaineaapnoli‘asgmthg 5;th 1:8 :11 would support the theory that syuccinylcholine'is hydrogze succinylcholine. by cholinesterases and that interference with this enzyme actiOn results in per- -. sistence of activity of the drug. Edrophonium (Tensilon) also prolongs the action of succinylchohne. An- ' ,. ' CLINICAL INDICATIONSUKNI) DOSAGE ‘ 1 Short Duration: ‘ANECTINE' Chloride brand Succinylcholine Chloride Injection is indicated for the production of muscle relaxation during surgical procedures, 3,9,13il5-17 and in conjunction with electroshock therapy.13,14,16 In view of its very short duration of action (usually about 3 minutes following a single intravenous injection) succinylcholine is ideally suited for procedures ;requiring 'only brief relaxation, .such as endotracheal intubation, endoscopic examinations, orthopedic manipulations, short surgicalvprocedures such as tonsillectomies, and electroshock therapy. As described previously, intravenous administration of the drug produces relaxation within a minute, which lasts about 3 minutes and is quickly followed by recovery of spontaneous respiration in those cases where apnea hasoccurred. Dosage for. Short Procedures: The average dose for’relaxation of short duration is 20 mg. (1"cc.) ‘ANECTI‘NE’ Injection given intravenously (Foldess)... The optimum'doSe will vary among individuals and may vary from =10 to 30 mg." for adults (0.5 to 1.5 cc.). Following administration of doses in this range, relaxation develops in about 1 minute; maximum muscular paralysis may persist for about 2 minutes, after which recovery rapidly takes place within the next few minutes. However, very large doses may result in more prolonged apnea. ”-21 Obviously, facilities for supplemental or controlled respiration with ,adequate exchangeoi oXygen should be available at all times. In order. to'avoid carbon dioxide accumulation and hypoxia, supplemental or controlled respirationgshould b? provided during respiratory depression without waiting for the development 0 apnea.. , Prolonged Relaxation: Although ‘ANECTINE’ isfshort—acting, prolonged relaxation may be obtained by repeated injections or, preferably, by maintaininga continuous intravenous drip.8,3o By adjusting. the rate of flow, the desired degree of relaxation may be obtained and maint‘air‘ie'd‘, and the degree of relaxation can be changed within 30 seconds by changing the rate of flow. Upon stopping the flow of the intravenous drip solution, relaxation. quickly disappears. In those cases where respiration has been depressed it usually returns to normal_within a. few minutes upon stopping the intravenous drip, V. Dosage for Long Procedures: The-'aVerage dose for continuous intravenous infui‘ sion is 2.5 mg. per minute for adult patients. For convenience'in preparingsolutions for intravenous drip there are available ‘Anectine’ Chloride Solution, 50 mg. per cc., 10 cc. ampuls and 100 mg. per cc., 10 cc. ampuls. The, contents of one 500 in mg. 10 cc. ampul may be added to SOD-ecstetileiisotonic saline solution to an prepare (1 0.1% mg. per cc.) ‘Anectine’ Chloride Solution; the contents of one 1 Gm. in ’0 cc. ainpul‘maybe added to 1,000 cc. to prepare an 0.1% ‘Anectine" Chloride Solution. This concentration is suitable for continuous intravenous infusion, See literature accompanying ‘A‘u‘ectine' Chloride Solution,’5_0fn‘1g./cc., 10 cc. ampuls, and 100 mg:‘]cc.,«10 c‘c‘. animals for details regarding use of'r'this‘product for obtaining ' ' r‘elaxatiOn. Solutions for prolonged intravenous drip jay also be‘ prepared. for a dilution of‘An‘e’ctine’ Injection, 20 mg./cc. in appioprrate proportions. ‘ NOTE: Succinylcholine is rapidly hydrolyzed by alkaline'solutions and therefore loses potency rapidly. it mixed with thiopental sodium (pentot‘hal sddium). Such mixtures, if used at all, must be used within a few minutes ofvprepatationq however, separate injection of ‘ANECTINE’ is preferable. Succinylcholine chloride is quite stable when storedqunder refrigeration. 0n long standing at room temperature potency gradually decreases; however; solutions may be kept as long as 3 months at room, temperature without significant loss of potency as determined by biological assay. , , ' !~- ‘ �.m . . CONTRAINDICATIONS AND PRECAUTIONS The drug should be used only by those skilled in‘ the administration of sppplemental *oecontrolled. respiration and facilities for this procedure, including adequate respiratory exchange with oxygen, should always be immediately .. available. “'V ' 'ANECTINE’lis not an anesthetic agent and should not be regarded as a substitute for anesthesia; 'its‘Ause“ does not take the place of givmg an adequate amount of anesthetic agent. Some anesthesiologists believe that rapid injection is responsible for the muscular twitching that is seen just prior to relaxation. These fascrculations may be due to the‘rate’of injection of the drug, and may be minimized or avoided ‘by giving the injection more slowly/,8,”8 While respiratory depression is usually of very short duration following a 'single dose of the drug, d" following cessation of continuous intravenous administration, ‘LiiCl‘C may‘e..-.§ribcc{i.iongespeaially with excessive doses, more prolonged respiratory depression 1.9-2]- requiririg controlled respiration and the administration of oxygen. The duration of the effect of ‘ANECTINE’ may depend on plasma-cholinesterase activity.94,2°,27 Patients’with severe'liver disease, severe anemia, severe malnutrition, and possibly those suffering from' polyphosphate insecticide poisoning may have a decreased plasma-cholinesterase activity which may intensify and prolong the action of ‘ANECTINE’, especially if large'doses are used.23,29 In such cases, in addition to the usual measures of controlled respiration and administration of oxygen, it may be desirable to administer plasma or whole blood for the purpose of restoring cholinesterase activity,” Neostigmine and other anticholine’sterases, as well as edrophonium (Tensilon), do not antagonize the action ,of~‘ANECTINE’, but on the prolong its contrary efi'ect. They are therefore contraindicated as antidotes for ‘ANECTINE’. Intravenous injections of proCaiiie likewise may prolong and intensify the action of ‘ANECTINE’. There is evidence that intraocular pressure is increased slightly following injection of ‘Anectineflfl “This effect is seen immediately after the injection and during the fasciculatory phase; it' subsides as complete paralysis supervenes; it appears to be the result of brief contraction of the extraocular muscles. This suggests that ‘Anectine’ should ’be usedl‘with caution, if at all, in intraocular surgery. The opinion is expressed that the effect is probably not sufficient to contraindicate the drug in general, surgery or electroshock therapy for patients with "' glaucoma. ‘ r‘ .- .KBIBIZIOGRAPHY 1. 2. Bovet, D., Bovet—Nittl, F., Guarino, 3., Longo, V.G., and Marotta, M.: Pharmacodynamical property of certain derivatives of suc’cin'ylcholine with curate-like action: esters of trialkylethanolamine of dicarboxylie aliphatic acids. Rendieonti Istituto Superiore di Sanita 12:106, 1949. Phillips, A.P.: Synthetic curate substitutes from aliphatic dicarboxylic acid aminoethyl esters. J. Am. Chem. Soc. 71:3264, 1949. Castillo, J.C., and de Beer, E.J.: Poteii‘tiationbl' curarizing action of diacetylcholine (succin lcholine) by aliphatic dicarboxylic acid aminoethyl amides. Federation Proceedings 9:262, 19 0. Castillo, J.C. and de Beer, E.J.:_The neuromuscular blocking action of succinylcholine (diacetylcholine). J. Pharmacol. 6: Exper. Therap. 99:458, 1950; de Beer, E.J., Castillo, J.C.,1.Phillips, A.P.,3Fanelli, R.V., Wnuck, A.L., and Norton, S.: Synthetic drugs influencing neuromuscular activity. Ann. New York Acad. Sci. 541362, 1951. Wnuck, A.L., Norton, 5., Ellis, C.H;, and- de Beer, E.J.: Production of controlled neuromuscular block by infusion of diacetylcholine. Federation Proceedings 11:403, 1952. Ellis, C.H., Norton, 3., and Morgan, W.V.: Central depression by drugs which block neuromuscular transmission. Federation Proceedings “11:42, 1952. Foldes, F.F., and McNall, P.G.: Succinylchélinei A new’a‘ppréach to muscular relaxation in anesthesiology. New England J. Med. 247596, 1952. Brucke, H., Ginzel, K.H., Klupp, H., Piaffenschlager, F., andWerner, 6.: Muscle relaxing effect: of bis'echoline e'sterof dicarboxylic‘acid in narcosis. Wien. klin. Wchnschi‘. 63 :464, 1951. Ginaiel, K.H., .Klupp,.H.,; and Werner, G.: Pharmacology of ”bis—quaternary Yammonium a, compounds. Comparative tests withisome aliphatic dicarboxylic acid esters. Arch. int. Pharmacodyn. and Therapy. 87:79, 1951. 7Gi'7nzzei,9§(l‘.H, Klupp, H., and Werner, G.: A‘dicholine ester with greater curare effect. Experentia . a. Arnold,‘0.H., Bock-Greissau, W., and Ginzel, K.H.: Wien. med. Wchnschr. 101:492, 1951. Theslefi‘, S.; Pharmacological and clinical tests with LT 1. (0.0—succinylcholine iodide). Nordiak ’ Med. 46:1045, 1951. Holmberg, G., and Thesleff, S.: Succinylcholine iodide as a muscle relaxant in electro—shock treatment. Nordisk Med. 4621567, 19SL‘Abst. in J.A.M.A. 14821064, 1952. Dardel, 0.37., and Theslefi, 8.: Clinical results with succinylcholine iodide, a new muscle relaxant. Nordisk Med.‘46:1308. 1951. Theslefi‘, 5., and Dardel, O.V.:'Clinical report on succinylcholine iodide. Presented at 26th International Congress of Anaesthetists, London, September 3—7, 1951. Abstracted in J. Am. MJWom. Assn. 7:58, 1952. " 3. 4. 5. 6. 7. 8. 9.' 10. 11. : 12. 13. . - , ‘ 14. 15. ‘ 16. ~ ' �I7. Mayrhofer, 0., and Hassfurter, M.: Surgical risks in patients with cardiac and vascular disorder. Wien. klin. Wchnschr. 63:88.5, 1951. 18. Holzer, 1-1.: Wien. med. Wchnschr. 102:112, 1952. 19. {IggerfgIséKd Prolonged respiratory paralysis after succinylcholine. Correspondence. Brit. MJ. 20. Love, S.H.S.: Prolonged apnea following scoline. Correspondence. Anesthesia (London) 7:113, 1952. 21. Gould, R.B.: Succinylcholine. Correspondence. Brit. MJ. 1:440, 1952. 22. Bovet, D., Bovet—Nitti, E, Guarino, S., Longo, V.G., and Fusco, R.: Investigations on synthetic 23. 24. 25. 26. 27. 28. 29. 30. 31. curarizing drugs. III. Succinylcholine and its aliphatic derivatives. Arch. int. Pharmacodyn. and Therapy 88:1, 1951. Poulsen, H. and Hougs, W.: Letters to the Editor, Lancet 2:199, 1952. Foldes, F.F.: Letters to the Editor, Lancet 2:245, 1952. Kay, H.T.: Letters to the Editor, Lancet 2:200, 1952. Evans, F.T., Gray, P.W.S., Lehmann, 1-1., and Silk, E.: Sensitivity to Succinylcholine in Relation to Serum-cholinesterase, Lancet 1:17.29, 1952. Bourne, J.G., Collier, H.O.J., and Somers, G.E-:ASuccinyIchoIine (Succinoylcholine)—MuscIe »S[« Relaxant of Short Action, Lancet 1'§2.£5, 1952. Lehmann, 1-1.: Letters to the Editor, Lancet 2:199, 1952. Hampton, L.J.: Personal communication. .L . ,r .:l Diacétiyilchdlihe I" and Little. M., Jr , Hampton, L.]., Grosskreutz, D.C.'. (Succin’yIcIroIine): A Controllable Mu'scIe Rel’axant. Presented before the Twenty-seventh Annual Cpnzress of Anes‘ ” ‘h thetistSyVirginia Beach, Virginia, Septemher 22-15,..1952. " " ‘1 ' Lincoff, H.A., Ellis, C.H., DeVoe, A.G., de Beer, E.J., Impastato, D._I., Berg, 5., Orkin, L., and Magda, 1-1.: The EEect of Succinylcholine on Intraocular Pressure. Am. J. Opth. 40:501,1955. — PREPARATION FOR IMMEDIATE INJECTION OF SINGLE DOSES FOR SHORT PROCEDURES ‘ANECTINE’ CH LORIDE mo SUCCINYLCHOLINE CHLORIDE INJECTION 20 mg. in each cc. multiple-dose vial: of IO cc. For intravenous i'nieetion V Also available: FOR PREPARATION OF INTRAVENOUS DRIP SOLUTIONS ONLY ‘ANE CTINE ’ C H LO R I D E m SUCCINYLCHOLINE CHLORIDE STERILE SOLUTION 50 mg. in each cc. IO cc. ampuls (Total contents 500 mg. Succinylcholine Chlorlde) To be diluted before using FOR PREPARATION OF INTRAVENOUS DRIP SOLUTIONS ONLY HIGH POTENCY ‘A N E C T I N E ’0 CHLORIDE SUCCINYLCHOLINE CHLORIDE STERILE SOLUTION 100 mg. in each cc. 10 cc. ampuls (Total contents I Gm. SuccinyIchoIine Chloride) To be diluted before using ‘Aneetine’ Injection is supplied in the form of a sterile isotonic aqueous .rolution. ImtoniCity 15' achieved by the addition of a :uitable quantity of sodium chloride. \\ .” p,“ BURROUGHS WELLCOME & CO. (U.S.A.) INC.,TUCKAHOE, N.Y. Associated Houses: LONDON BOMBAY by 731 MONTREAL BUENOS AIRES Printed in u.s.A. SYDNEY CAIRO JOHANNESBURG DUBLIN AUCKLAND 41 I o o 6 �Poloni, A.: L'Acetilcolina nel liquor dei malati di mente. Hancenze di effetto curarosimile del liquor di echizophrenici sul mnecolo acetilcolina e en dorsale dell: saga, I1 Gervello g1: 81-1oh, 1951. Translation of EEEEEEE‘ author, using the method of Tower for the conservation of acetylcholine in spinal fluid, and the dorsal muscle of the leech for the test, has made the fol» lowing observations in several trials, making use of the spinal fluid of 10 normal subjects and 110 mental patients, of whom 50 were schizophrenics, 10 progressive paralytica and 50 subjects with other forms of mental disease: The (1) That the spinal fluid of normalaubjects cistains acetylcholine in a to 1:1G' concentration varying from 1:1 (2) That the spinal fluid or schiaophrenice in 9h$ of the case: does not contain ecetyloholine bet a substance which produces an action antagoMstic to acetglgholine, 7; weble to that of ”curare", in a concentration of 1:1 to 1:1' .... (3) In the spinal fluid‘of the progressive paralytic: one encounters the some curare-like subetance nut in a lower concentration than in that of schizophrenics. (h) The spinal fluid of persons affected with other forms of mental sick— ness, as well as that of normal subjects, did not contain the curerelike substance in a discernible quantity, but only acetylchcline, which was found in greater concentration in the hystericale and epileptice, in lower concentration in senile psychotics and alcoholics. This emphasizes the pathologic vale of the report obtained from the spinal fluid of schizophrenics and progressive parelytics and suggests the hypothesis that the curare-like substance is trimethylamine, product of the excessive catabol~ ion of choline, of which the author has found an abnormal urinary excretion in schizophrenics; (In the some paper, in a footnote, the author eliminates trimethylamine, since does not have aurora-like properties.) it �CHOLINERGIC ASPECTS OF CONVULSIVE THERAPY Max Fink, M'.D. �\ From ‘ the Department of Psychiatry, Washington University School of Medicine and the Department of Psychiatry at the Missouri Institute of Psychiatry, University of Missouri School of Medicine, SUOO Arsenal St., St. Louis, Missouri 63139. MH-072u9 and MH—2715, MH—927, grants part, IVE-11380; and the Psychiatric Research Fomdation of Missouri. Aided, in IX: 65-8 2-25-66 by USPHS Revised for the Jowmal. 06 vaouA and Manta! Disease. �CHOLINERGIC ASPECTS OF CONVULSIVE THERAPY While the mode of action of convulsive therapies remains enigmatic, one theory holds that the early development and persistence of changes in brain function are requisite to changes in behavior.“3’21,22 useful index of neurophysiological change is the appearance of high voltage electroencephalographic slow wave activity.22 '23 While the biochemistry of this activity is A poorly understood, demonstrations that it is inhibited by anticholinergic corrxpoundsl9920’3""56 suggest that cholinergic systems may play an active part. The EEG patterns and the response to anticholinergic drugs in convulsive therapy are similar to experimental and clinical head trauma and to a lesser extent, to spontaneous seizures. impulses has been extensively studied since the early descriptions by Dale12 and Loewi.38 A constituent of nervous tissue in a acetylcroline is liberated during the excitation process. It is rapidly hydrolyzed through the mediation of aoetylcholinesterase and is rapidly reconstituted by the bound form, �choline—acetylase system.‘+5 Free acetylcholine has not been measurable in normal cerebrospinal fluid despite the rapid breakdom of bound acetylcholine during periods of activity and excitement.63 But the normal have measurable cholinesterase cerebrospinal fluid does activity.“1 ChoLéneILgic Mme/ta 06 CILanLoce/Lebm mena. Free acetylcholine was found in the cerebrospinal fluid of cats within a few minutes after experimental head trauma and persisted for varying periods up to 1+8 hours. The quantity of free acetylcholine varied between 2.7 and 9.0 gamma/ 100cc and the amount was related to the degree of induced trauma.6 Concurrent electroencephalogram first demonstrated high voltage fast activity, interpreted as evidence of an intense neuronal discharge, which was succeeded by-a short period of flattening of all recorded electrical activity. These phases were followed by prolonged periods of high amplitude sharp waves in the delta frequencies. The behavioral changes related to the degree of induced trauma and to the amount of measured free acetylcholine. With higher levels of acetylcholine, Bornstein reported greater degrees of EEG abnormality and greater changes in consciousness. Spontaneous post-traumatic seizures were also amount related to the of free acetylcholine measured in the cerebrospinal fluid. �Bornstein applied acetylcholine to exposed cat cerebral cortex. When the concentration of acetylcholine was or less, high amplitude sharp the electroencephalogram. to 2 waves When of low frequency appeared in the concentration gamma/100cc, the electroencephalogram parallel to the post-traumatic records. Investigations in neurological patients McEachern demonstrated 1 gamma/10000 was increased flattened in a fashion by Tower and free acetylcholine in the cerebro- spinal fluid only in patients with recent head trauma, recent grand—Hal seizures or after electroconvulsive therapy.63 Free acetylcholine varied from 0.2 to 100 gamma/ 100cc. In assaying spinal fluid cholinesterase activity, they noted a sharp rise in the butyrylcholinesterase fraction and a fall in the acetylcholinesterase fraction in patients with head trauma and following convulsive therapy. however, the cerebrospinal although it ' After spontaneous seizures, fluid did not exhibit such inversion contained free acetylcholine. They concluded that the level of free acetylcholine varied directly with the degree of cerebral damage and that reversal of cholinesterase fractions was a more sensitive indicator of cerebral damage. Electroencephalograms taken at varying intervals following trauma also indicated a relation between the degree of EEG abnormality and the appearance of free acetylcholine in the cerebrospinal fluid. �Increased acetylcholine in rat brain after traumatic shock was also reported by Kbvach, at a£.35 This acetylcholine activity vitae. was inhibited by the administration of atropine tn electrographic, behavioral and neurologic signs of head trauma were blocked by the parenteral administration of The atropine, as were similar clinical changes occurring after the intracisternal addition of acetylcholine.6 0.5—1.0 mg/kg applied these observations to the treatnent of closed head injuries. In 20 patients with varying degrees of trauma, he administered atropine subcutaneously in doses of 0 .1 mg/kg, Ward noting clinical improvement in some and electrographic effects in others.67 a reversal of the The same changes in the' .*-‘_ post-traumatic electroencephalogram were reported by Jenkner and Lechner in a study of diethazine, another anticholinergic single intravenous dose in forty patients resulted in nornalizing the abnormal electroencephalogram in twenty—two drug. A and marked improvement in six others.33 Similarly, in experiments of post—traumatic shock and cerebral edema in animals, Denisenko reported a blocking of the clinical changes by such anticholinergic compounds as methylbenactyzine and adiphenine (Trasentin).13 ThuA, the amount 06 Mae acetytchloune may tamed/52 éptnat fluid 60110“)th cmtnocuebaat mama and the tn the, amount 06 - ‘ -A,‘r �ghee acety£cho£ine, the degnee and type 05 e£ecthoencepha£nghaphie in carded/C behavion abnolzmablty, and changed phenomena, which may be deduced by appear/L aA the adminibtnation Lute/mutated anti- 06 chounugie daugb. Bluuln acetylchofléne and antéehounugic dhugb. The effects of the direct application of acetylcholine to the central nervous system may also be blocked by anticholinergic drugs. The administration of the cholinesterase inhibitor di—isopropyl fluorophysphate (DFP) elicited high amplitude rapid frequency patterns similar to status epilepticus and some posttraumatic states.2'*’31a32a68 These EEG effects were blocked by small doses of parenteral atropine and scopolamine. The' EEG geat increase in acetylcholine after tetraethyl (TEPP) was measured and pyrophosphate related to the toxic effects and the induced convulsions .29 ’59 Chatfield and Dempsey prepared exposed animal cortex with prestigmine and evoked electroencephalographic spike activity. prior administration of atropine blocked the appearance of spiking, or if present, this electrical activity could be The eliminated by atropine.9 In contrast to these findings, Brenner and Merritt applied topical acetylcholine in concentrations of 2—1/2 to 1096 to the exposed cortex of cats and noted no effect. on the electro— encephalographic changes after intravenous atropine (1 mg/kg) .7 �The concentrations of acetylcholine in these experdnents, however, were higher than the topical applications (1-H gamma/1000c) and the intracisternal (0.2-10 gamma/10000) injections of Bornstein.6 Brenner and Merritt also noted electroencephalographic effects similar to acetylcholine after methacholine (Mecholyl) and carbamylcholine (Doryl) in concentrations much lower than the acetylcholine concentrations. They ascribed the increased effectiveness of these cholinergic drugs to their lack of sensitivity to cerebral cholinesterases. 6mm Atady a necuAa/Lg Ceaebao¢pina£ Fluid Acetyfichofiine and Seizuneb. One view Thug data M9, confiuwxg and to quaiifiy thié iAAue. of acetylcholine metabolism finds it in nervous tissues in an inactive and bound form. During periods of activity, acetylcholine is liberated at the cell membrane where it is rapidly deactivated by cholinesterases. The amount of bound acetylcholine is the resultant of the continuous processes of synthesis, liberation 'u and breakdown.15 It has been postulated that the level rises falls during waking activity.15’29’“5’6° at al. reported increased free and total acetylcholine during sleep and Tbbias after chlorofornland pentobarbital anesthesia in rat and frog brain but no changes after strychnine or picrotoxin convulsions.5° �(microacetylcholine of level the neasured Richter and Crossland in and rat sleep anesthesia during tissue) brain gamma per mg. brain to be 300% The difference levels. post—seizure than higher rate resynthesis the as however, transient, in tissue levels is gamma/gm/minute).“5 (7 high is brain in rat for acetylcholine Crossland a£.16 and at Elliott confirmed by These observations were and Merrick.11 Giarman and Pepeu reported the increase in be roughly to various depressants following acetylcholine nervous central the of of depression the degree proportional to Buck, and Maynert activity.29 motor in system and the reduction sedation during levels acetylcholine brain however, studying elevated with associated were sedatives concluded that some existed.39 relationships rigorous brain acetylcholine but that no of. observations In part, this may be related to the earlier in measured synthesis acetylcholine McLennan and Elliott that narcotic of low dosages by accelerated rat brain slices is dosages.”° by-high inhibited but drugs, in fluid the in spinal Free acetylcholine was reported an patients, epileptic patients with epilepsy.1°’63 5.0 0.02 to of in quantities demonstrated free acetylcholine Of 56 Acetylcholine gamma/100cc. 1.0 of with an average gamma/100cc extent the seizures, of the frequency to related levels were since time the and to abnormality, of electroencephalographic �the last seizure but bore no relation to medication, type of epilepsy or level of cholinesterase activity. Elliott at al. also noted free acetylcholine in the spinal fluid in concentrations up to 3 gamma/100cc after pentylenetetrazol (Metrazol) convulsions.16 Tower and McEachern viewed the increased acetylcholine as a by—product of the seizure and not causal.63 Studying the hypothesis that seizures were induced by the accumulation of acetylcholine, Tbrda neasured the level of acetylcholine in brain tissue after pentylenetetrazol convulsions. She noted a rise in the acetylcholine content of brain before and a fall during the convulsion. Below certain levels of acetylcholine, convulsions failed to occur. She suggested that the fall in . tissue acetylcholine during a convulsion was due to the inhibition of acetylcholine synthesis by increased concentra-’ tions of metabolites such as annenium ions.51:62 Giarnen and Pepeu also measured changes in central nervous system acetylcholine following various stimulants.29 Only after nethacholine and 3, 5—dimethylbutylethyl-barbiturate was there a significant change in the acetylcholine level. They noted a decrease in association with induced convulsions. With other drugs which they classified as stimulants (LSD, iproniazid, iproniazid + hydroxytryptophan, and iproniazid were no changes in the acetylcholine level. + DOPA) there They concluded that �despite intense excitation produced by these compounds, there were no changes in acetylcholine levels unless these were accompanied by convulsions. (The between these observers and Cone may be differences in observations at at. related to the differences in measurenents, fOr the latter and Tower and McEachern methods measured changes of biochemical reflecting free acetylcholine only, while Giarman and Pepeu measured total acetylcholine including bound and free forns of acetylcholine.“°). Thane btudieb Auggebt that aae accompanied by an tncteaee tibeaated 6aom tté Apontaneoub on tnduced 4etzune¢ tn tnteaeettutaa finee aeetytchottne bound fionm whtch may be aefiteeted tn the Aptnat staid. Ceaebnat activity and eetzuneé enhance aeetytehottne deatAuction, toweatng txnbue teveZA 06 aeetytehottne, white eteep and anebthebta augment aeetytehatine paoduetion ineaeaetng ttbbue tavetb. ' Centaat Menuoue SyAtem Cholineeteaaeee. Tower and McBachern also measured spinal fluid cholinesterase activity.63’5“’65 By reporting cholinesterase activity as a ratio of the rate of hydrolysis with two substrates compared to an acetylcholine substrate, acetylcholinesterase/acetylcholine and butyrylcholinesterase/ acetylcholine ratios are derived. Normal cerebrospinal fluid contains these esterases in the ratio of 33:17. �-10In patients with head trauma, Tower and MCEachern reported an inversion of the cholinesterases with an increase in the butyrylcholinesterase of the spinal fluid and a decrease in acetylcholinesterase activity. The extent of the cholinesterase related to the severity of trauma and to the degree abnormality. A similar reversal was observed in patients reversal of EEG was undergoing convulsive therapy. In patients with elevated spinal fluid acetylcholine spontaneous seizures, however, no change in the after ratio of cholinesterases or total cholinesterase activity was found. Changes in cholinesterase activity may be related to changes in cell membrane permeability. Acetylcholinesterase is found in highest concentration in the central nervous system while butyrylcholinesterase predominates in other tissues, especially blood serum. With increased cerebral acetylcholine, vasodilation predicted, with vascular fluid transudation varying with the extent and duration of the vasodilation.35 Spiegel, Spiegel—Adolf, and their and increased cellular perneability may be co-workers demonstrated such perneability changes and increased conductivity of the tissues associated with the appearance of various ions (as potassium and phosphate) in the spinal fluid following electrically induced convulsions.5"'58 electrolytes as nucleic-acid splitting enzymes Such non- also increased. �-11- Changes in cellular permeability may be the basis for the high concentrations of acetylcholine and increased concentrations of butyrylcholinesterase after induced seizures or head trauma.65 That changes in cholinesterases may be large and measurable is suggested tte recent demonstrations that neural stimulation by and learning produces changes in brain weight and acetylcholinesterase reports, Pryor and Otis studied the effects of repeated induced seizures in Wistar rats.“3 After Following these activity.37’“9 as little as u weeks they observed increases in brain weight and in acetylcholinesterase activity which was related to decrements in behavioral perfornance. persistance of acetylcholine in spinal fluid after head trauma and after seizures despite increased cholinesterase The activity may be acetylcholine— the of the related to sensitivity acetylcholinesterase system to concentration relationships.8’“1’55 At "physiologic" concentrations, hydrolysis of acetylcholine is rapid (3—H ndcmoseconds) but at higher and lower concentrations, the activity falls off quickly. In contrast, the butyryldholinesterase~acetylcholine relationship is non—specific rate of hydrolysis increases with increased concentration. These relationships relate to theories of the induction of seizures. While the usual concentrations of acetylcholine at and the cell membranes are destroyed by the specific activity of acetylcholinesterase in a few microseconds, an excessive concentration following excitation may exceed its rate of �-12- hydrolysis. The seizure threshold induced, with the seizure itself may be reached and a seizure adding to the amount of free acetylcholine. Increased acetylcholine affects vascular and cellular perneability altering the concentrations of various ions, including butyrylcholinesterase in tissues and in the cerebrospinal fluid. Through the activity of this esterase, though of low efficiency and depending on concentration acetylcholine is reduced in tissues to levels for the action of acetylcholinesterase. ChoZanAzcnaAeA appcanb in the Apina£ 6£uid kinetics. more direct a4 a ncfiflcction 06 theta incncaAc in inzcnchZuzan gluidb ac6u£xing diam changcb in cc££ mcmbnanc pcnmcabizity accompanying incncabcd EEG Hypcnbynchnony and Induced Convu£5ion4. of high voltage EEG slow wave The acctchhoanc. significance activity for the convulsive therapy process has been repeatedly described."’?-’23’50,51 In the usual course of convulsive therapy, interhtreatment electroencephalograms record progressive increases in amplitude and in theta activity and a reduction in beta activity. As treatment continues, delta activity appears in bursts and eventually is the dominant activity in all leads. These changes are directly related to the number and rate of induced convulsions, and is not specific for a method of induction. While some relationships to type of electrical current has been observed, all seizure inducing methods —- electrical, intravenous chemical or inhalant -— exhibit the same type of EEG pattern changes.21’22a23:3° �-13The early appearance of high degree hypersynchrony and its persistence throughout a treatment course has been found to be prerequisite to improvement. Both the electrographic and the behavioral changes of induced convulsions are transiently reversed by the acute administration of experimental anticholinergic compounds.19’2° The intravenoue injection of diethazine, bonactvzine, the piperidylbenzilates JB—318, JB—336 and JB—329 (Ditren), and subjects. WIN-2299 induced EEG These EEG desynchronization in psychiatric changes were associated with behavioral alerting, anxiety, tremors, illusions and hallucinations. In patients who had recently received electroconvulsive therapy there was a reduction in slow wave activity and a reversal of euphoria, denial and confusion. Atropine, in low doses, was also associated with EEG desynchronization accompanied by tachycardia, nervousness and tension. At higher dosages, hypersynchronous slow waves followed by lower voltage, poorly organized delta activity with superimposed beta activity was accompanied by progressive confusion and disorientation. effect of anticholinergic drugs on the slow wave activity of convulsive therapy was also assessed by the chronic administration of atropine (5 mgm per day) and scopolamine (1-3 The during the weeks of treatment. The amount of EEG slowing was significantly less than in a control group.66 The samples were too small for a clinical correlation but the data is consistent mg) �-1uwith blocking of the clinical effects of electroconvulsive therapy. Marked improvement was reported in treated, none of scopolamine-treated and in 5 controls receiving unmodified replicated ECT. of 2 1+ 7 atropine— of the 6 This study was not by the authors who suggest or population changes may have results in a second study.“ that dosage factors contributed to the different - AA tn cueblcat tJLauma, the demographic changes induced convuutoms may be modified by the 06 antichounugtc dlLugb Auggebting 06 Want/cation that tncneeued amounts acetytchoune on tncneated chounugtc aecepttvity ts amounted with the htgh voltage Atow wave activity. 06 Acetytchoune and Induced Convutbtont . Despite a constant application of treatments, however, there is great variability in the time of appearance, the duration, anount, and sensitivity to modification by alerting, hyperventilation and barbiturates of the electrographic slow activity in psychiatric populations.30 These differences relate to differences in central cholinergic activity. The failure of certain patients to develop hypersynchrony may be associated with the absence of free acetylcholine and with minimal changes in cerebral function, wave �-15thus precluding a clinical response to induced convulsions. Tower and McEachern in their study of craniocerebral trauma, included observations of six psychiatric patients undergoing convulsive therapy.63 Studying the patients ments they reported free spinal after 3-7 fluid acetylcholine in treattwo patients; and an increase in butyrylcholinesterase and a decrease in acetylcholinesterase with a reversal of the ratio of cholinesterases in five of the six patients. Concerning the one patient in the series who failed to show either free acetylcholine or a cholinesterase ratio reversal in the spinal fluid, the authors stated; "It is interesting that this patient was the only one of the six to show no response to treatment." From these observations they concluded that the spinal fluid' <3; changes in induced convulsions were more like those of 4 ‘4‘ craniocerebral trauma than those of spontaneous epilepsy. «3-.3‘ Other evidence of alterations in the perneability barrier may be seen in the demonstrations of an increaSed concentration of cocaine in brain tissues three days after a series of induced convulsions.1 The change 12 in concentration of this large molecule, ordinarily absent in brain tissue, was associated with the appearance of hypersynclu'ony (delta bursts) in the electroencephalogram, �1 -.,,-_..._. -15Fhom theae oboehvationb we would conclude that induced convuibioni, like chaniocehebhai thauma and Apontaneoui Aeizuheb, ane aAAociated with an incheaie in ghee acetyichoiine in inten- cebtuiah 6iuidA, attuing cuebhai pumeabifity and enhancing the appeahance is maintained Lb . one 05 cholinebteJLaAeA. The Level 06 ghee by hepeated induced Aeizunei . hefiiection ieveu 06 aLCULed aitehed pehmeabiiity 06 06 EEG acetyichoiine hypmynchlwny acetyichoiine and the eiecthoiyteb and otheh Aubitanceé, inciuding choiineAtULaAeAs. The changeé in intuceuuiah elect/w- .oi.m_m_._._.. _ ..l.__a u.- iyteé, inciuding aeetuichoiine phovide the biochendcai AubAthate 601:. the pelwibtent behaviouai changed and EEG hypwynchnony fioaowing induced convuibianb. An ww...-._.~__.-m~ 06 application the phedietion o6 06 these conciuiioni is been in the btudieb the convuiAive thehapy heéponbe and the ctaiiisication as psychoaei. ~--....-_ Choiineétehabei and the Ciaibiflicatian 06 PAychOAeb. ._‘ 4» .. V Punkenstein at at. reported a relationship between the blood pressure response to methacholine and the clinical response to convulsive therepy.25'27 Immediately after the injection the blood pressure falls, usually returning to the baseline within 5-20 minutes. A return within 5 minutes Of methacholine places the patients in Groups after- 20 minutes \‘ \e I, II or III; places'the patient in while a return Groups VI and VII. �-17Group I and Group II-III respectively, while and 97% have a 9% and a 35% Gkoup VI and Group VII recovery rate, subjects have 89% recovery rates to induced convulsions.27 Group I to III reactors may be looked upon as patients in whom is rapidly hydrolyzed; while Groups VI and VII have a slow hydrolysis rate. (The response to injected epinephrine was suggested as a second criteria in the classification, but is of limited discriminating value.”8) methacholine While we have no biochemical explanation fbr the differences in the metabolism of methacholine in these psychiatric groups, it is possible that the blood and tissue cholinesterase activity levels of Groups I—III is high while that of Groups VI-VII is The low compared to general psychiatric populations. differences in blood cholinesterase levels in normal and mentally ill subjects have been extensively studied. Despite differences in nethods,“’5 elevated cholinesterase levels compared to normal populations have been reported for depressive subjects,"""’5"‘7952 schizophrenic subjectslh’28’53 and a mixed psychiatric populations .“2 Alpern reported lowered cholinesterase levels in schizophrenic subjects.2 While these studies appear inconclusive, they provide data that the variations in blood cholinesterase levels are generally greater and frequently elevated in the mentally ill. Negative reports include the failure by Ellman and Callaway” to confirm Rubin's study; and Altschule's review of the data suggesting �-13no abnornality ' of cholinesterase levels in the mentally ill.3 that cholineAth play These Atudteb AuggeAt meaAuAeA may a significant note. in the thuapeutéc aupome to canvutatve the/mpg and in the pathoggnebta 06 paychobu. �-19; CONCLUSIONS This review summarizes some of the available data suggesting that cholinergic mechanisms may be central to the convulsive therapy process. Induced convulsions are associated with cerebral vasodilaticn and increased cellular permeability, followed by the appearance of increased amounts of enzymes and electrolytes in intercellular and cerebrospinal fluids . The increase in acetylcholine, vasodilation and increased permeability appear as interrelated phenomena associated with ' trauma, seizures and induced convulsions. These biochemical changes acconpany increased hypersynchrony which is recorded as EEG slow wave electrical activity in scalp electrodes and which can be nodified by the acute and ' chronic administration of anticholinergic drugs as atropine, benactyzine, diethazine, procyclidine and various piperidyl— benzilates . In these regards, induced convulsions are more similar to cerebral trauma than to spontaneous seizures. in cerebral biochemistry alter cellular activity sufficiently to affect consciousness and the behavior of subjects . Failure to induce persistent biochemical changes, including the The changes concentration of acetylcholine, results in failure to produce behavioral change. �-20There is, as yet, no consistent evidence for differences in the sensitivity or dependence of populations on cholinergic mechanisms. Differences in the rate of development of cerebral changes to the sane number and frequency of induced convulsions classifications of the nentally ill based on the blood pressure response to methacholine suggest, however, that such differences may be significant in the pathogenesis of different and .._..__...V ___,‘~,‘....____... ' «uAW—‘wflflw ,1“ psychoses . �REFERENCES 1. Aim, B., Strait, R. L. A., Pace, J. W., Hnenoff, M. K. and Neumphysiological effects of electrically Bowditch, S. C. indnced convulsions. Arch. Neurol. Psychiat., 75: 371-378, 1956. 2. Alpern, D. O. i kholinergicheskaya Aktivnost kholinesterasy reaktsiya kmvi pri shizofrenii. [Cholinesterase activity and cholinergic reaction of the blood in schizophrenia.] Fiziol. Zh. , 4: 87-90 , 1956 . 3. Altschule, Vitamins, enzyme systems, and trace elements. M. D. Bodily Physiology Grune '+. Stratton, 8 in Mental; and Emotional. New Augustinsson, K.-B. . 04143on, pp. 169-172. York, 1953. The normal variation of human blood cholinestenase activity. ‘Acta Physiol. Scand., 35: ‘40-52, 1955. 5. Augustinsson, K.-B.. Glick, ed., Method. Assay methods Bernstein, M. D. New Brenner, ‘C. and York, 1957. Presence and action of acetylcholine in experimental brain trauma. 7. D. vol. 5, pp. 1-63. 05 Biochemical mug/6416, Interscience Publishers, 6. for cholinesterase. In Merritt, J. Neurophysiol., H. H. 9: 3&9-366, 19146. Effect of certain choline derivatives on electrical activity of the cortex. Arch. Neuml. Psychiat., 48: 382-395, 8. 19‘62. Burgen, A. S. V. and MacIntosh, F. C. significance of acetylcholine. and J. H. In The K. A. C. physiological Elliot, I. H. Page Quastel, eds.. Numchomw, pp. avu-375. Thomas, Springfield, Illinois, 1955. �9. Chatfield, P. 0. and Dempsey, E. W. Effects of prostigmine and acetylcholine on cortical potentials. Amer. J. Physiol., 135: 633-940, 19142. 10. mne’ W. Va, and neuronal 11. and MCEaChem, D. B. >125: A. J. 73: 59-63, 19%. effect of anaesthesia The acetylcholine content of the brain. J. Physiol. , 56-66, 195a. The Dale, H. H. and AcetYIChOlele Do activity in epilepsy. J.A.M.A., Crossland, J. and Merrick, on the 1.2. mer, action of certain esters and ethers of choline, their relation to nmscarine. J. Pharmacol. Exp. Ther., 6: 1u7. 191a. 13. Phamacological blocking of central cholinoreactive Denisenko, P. P. systems and the possibilities of its therapeutic application. In G. B. 05 Chounugic and Addenugic Tamwiuion. Vol. Koelle, W. W. Douglas and A. Carlsson, general ed. , leceedéngb Meeting, pp. 1u7-152. l“. 05 «the. Second Macmillan, New eds., 3 Phanmacalagy of Intunatéand H. Rascova, Phamnacologicat York, 1965. F., Hemphill, R. E., Reiss, M. and Brunmel, E. Investigations into cholinesterase levels in serum and cerebroepinal fluid of psychotic patients. Biochem. J. , Early, D. 45: 552-556, 19u9. 15. Bccles, J. C. The Phyuozogy 06 Synapbu, Press, New York, 196“. 316 pp- Academic �16. Elliott, K. A. C., Swank, R. L. and Henderson, N. Effects of anesthetics and convulsants on acetylcholine content of brain. Amer. J. Physiol., .162: neg-um, 1950. 17. Ellman, G. L. and Callaway, E. Erythrocyte cholinesterase—levels in mental patients. Nature (London), 18. Pink, M. A J. Hillside 19. 192: 1216, 1961. unified theory of the action of physiodynamic therapies. Hosp. (Glen Oaks), 6: 197-206, 1957. Effect of anticholinergic agent, diethazine, on EEG and behavior: significance for theory of convulsiVe therapy. Pink, M. Arch. Neurol. Psychiat., 80: 380-387, 1958. 20. Pink, M. Effect of anticholinergic compounds on post convulsive electroencephalogram and behavior of psychiatric patients. Electroenceph. Clin. Neurophysiol., 21. 22. 12 (2): 359-369, 1960. of action of convulsive therapy: the neurophysiologicadaptive view. J. Neumpsyclfiat. , 3: 231-233, Pink, Pink,- M. M. The mode 1962. and Kahn, R. L. Quantitative studies of slow wave activity following electroshock. Electroenceph. Clin. Neurophysiol. , s: 153, 1956. 23. Alan, B, and beflcowits, H. J. Inhalant-induced convulsions. Arch. Gen. Psychiat. (Chicago), 4: 259-266, 1961. �2“. Freedman, A. M., Bales, P. D., Experimental production of Amer. 25. J. Physiol., mstem’ Do Ho Willis, electrical major convulsiVe patterns. 156: 117-1214, 19%. . Gr‘eenblatt, J. New. mnto Dis. , [08: mnkenstein, changes J. 27. D. Rmkenstein, D. nervous system Autonomc shock treatment. M. and Solomon, H. C. in mentally Autonomic ill patients. 114: 1-18, 1951. H., Greenblatt, M. and Solomon, H. C. Autonomic test of prognostic significance in relation to electroshocktreatment. 28. electric psyChOIOgic changes Dis., Nerv. Ment. 301011011, H. C. HOQ-HZZ, 19.48. H., Greenblatt, paralleling and Mn nervous system changes following 26. A. and Hinwich, H. E. Psychosom. Med., 14: 3147-362, 1952. Cholinesterase activity of whole blood from healthy and schizophrenic individuals. Nature (London), 198: 1118-1119, Gal, E. M. . 1963. 29. Giannan, M. J. acetylcholine. 30. and Pepeu, G. Drug-induced changes Brit. J. Pharmacol., in brain 19: 226-2314, 1962. Significance of individual variability in EEG response to electroshock. J. Hillside Hosp. (Glen Oaks), Green, M. A. 6: 229-2H0, 1957. 31. Hampson, J. L., Essig, C. F., McCauley, A. and Himwich, H. E. Effects of di-isopropyl flnomphosphate (DFP) on electroencephalogram and cholinesterase activity. Electroenceph. Clin. Neurophysiol. , 2: ui-us, 1950. �32. E., Essig, Hinwich, H. Freedman, A. M. F., C. Hampson, J. L., Bales, P. D. and Effect of trimethadione (Tridione) and other drugs on convulsions caused by di-isopropyl fluorophosphate (DFPj . Amer. 33. J. Psychiat., 106: 816-820, 1950. effect of Diparool on the electroencephalogram in the normal subject and in those with Jenkner, F. L. and Lechner, H. The cerebral trauma. Eleotroenoeph. Clin. Neurophysiol., 7: 303-305, 1955. 3M. Johnson, L. c., Ulett, A., Johnson, M., Smith, G. K. and Sines, J. o. ElectroconvulsiVe therapy (with and without atropine); effect on electronically analyzed electroencephalogram. Arch. (Chicago), 2: 35. Gen. Psychiat. 32u—336, 1960. Kabat, E. A. , Glusman, of the albumin and and Knaub, V. M. ganma Quantitative estimation globulin in normal and pathologic cerebmspinal fluid by inmunochemioal methods. Amer. J. Med. , 4: 653—662, 1948. 36. Kovach, A. G. 3., Fonyo, A. and Halmagyi, M. Acetylcholine content of the brain in tratmatic shock. Acta Physiol. Acad. SCio Hung., 37. '3: 1-“, 1957. Krech, D., Rosenzweig, M. R. and Bennett, E. L. Effects of envirormental complexity and training on brain chemistry. J. 38. Carp. Physiol. Psychol., 53: 509-519, 1960. Loewi, 0. fiber hmmrale Ubertragbarkeit der Hemmemdirkxmg. Arch. Ges. Physiol., 1898 239-2‘J2, 1921. �39. Maynert, E. on H0. W. Effects of C.N.S. depressants and Buck, E. G. brain acetylcholine. Phamtacologist, 6: 191, McLennan, H. and Elliott, 196M. Effects of convulsant and K. A. C. narcotic drugs on acetylcholine synthesis. J. Pharmacol. Exp. “1. Ther., 103: 35-u3, 1951. Nachmansohn, D. and Rothenberg, on Specificity of enzymes M. A. Studies on cholinesterase: in nerve tissue. J. Biol. Chem., 158: 653-666, lSHS. M2. Plum, C. M. Study of cholinesterase mental disorders. #3. Pryor, T. and G. nervous and in activity Clin. Chem” 6: 332-3H0, 1960. Otis, Effects of chronic administration L. S. of electroconvulsive shock on behavior, brain weight and brain Presented chemistry. at the American Association for the Advanoenent of Science, Berkeley, 1965. an. Ravin, H. A. and Altschule, M. D. Serum cholinesterase activity in mental disease. Arch. Neurol. Psychiat., M5. Richter, D. and 58: 6‘45-650, 1952. Grassland, J. Variation in acetylcholine content of the brain with physiological state. Amer. J. Physiol., M6. 159: 2u7-255, 19u9. Richter, D. J. Sci... 88: I‘28-‘43“, Ment. and Lee, M. Serum choline esterase and anxiety. 19M2. �H7. “8. #9. Richter, D. J. Sci., Ment. and Lee, M. Serum 88: 1135-439, 19H2. Rose, J. Acta Psychiat. Scand., 38: T. Rosenzweig, The Funkenstein M. choline esterase and depression. test - a review of the literature. 12H—153, 1962. R., Krech, D., Bennett, E. L. and Diamond, M. C. Effects of environmental complexity and training on brain chemistry and anatomy: a replication and extension. J. Comp. Physiol. Psychol., 55: l4294437, 1962. 50. Roth, M. Changes in the EEG under barbiturate anaesthesia produced by electro-convulsive treatment and for the theory of ECI‘ their significance action. Electroenceph. Clin. Neurophysiol. , 3: 261—280, 1951. 51. Roth, M., Kay, D. W. K., Shaw, J. and Green, J. Prognosis and Pentothal induced electroencephalographic changes in electro-convulsive treatment. Electroenceph. Clin. Neurophysiol. , 9: 225—237, 1957. 52. Rowntree, D. W., Nevin, S. and Wilson, A. The effects of diisopropylflmrophosphonate in schizophrenia and manic depressive psychosis. J. Neurol. Neurosurg. Psychiat., 13: 53. 167-62, 1950. Rubin, L. S. Acetylcholine hydrolysis in psychiatric patients. Science, 128: 2510-255, 1958. . -1 �5Q. Spiegel, E. A. and Spiegel-Adolf, Permeability changes in M. the brain induced by Metrazol and insulin convulsions. J. New. Ment. 55. Dis., 93: 750-755, Spiegel, E. A. 191*1. and Spiegel—Adolf, Physicochemical effects M. of electrically induced convulsions (cerebrospinal fluid studies). W5. 56. A880, 70: 130-132, 19“”. AHEI‘. NeUI‘Ol. Spiegel, E. A. and SpiegeléAdolf, Physiological and M. physicochemical mechanisms in electroshock treatment. COnfin. Neum1., 13: 38-63, 1953. 57. 58. Spiegel, A., Spiegel—Adolf, E. and Henry, G. .M. Physicochemical changes in the brain accompanying electrically induced convulsive discharges. Trans. Ass., 68: Amer. Neurol. Spiegel-Adolf, M., Wilcox, P. H. and 171+, 19'42. Spiegel, E. A. Cerebrospinal fluid changes in electroshock treatment of 59. psychoses. Amer. J. Psychiat., Stone, role of acetylcholine in brain metabolism W. E. The and function. 60. Amer. J. 'IbbiaS, Jo Ml. Lipton, 104: 697-705, 19%. Phys. Med., 36: 222-255, 1957. Mo A. and Iepinat, A. A. Effect Of anesthetics and convulsants on brain acetylcholine content. Proc- $Co Exp. 61. Torda, C. B11010 Mdo, 6': 51'5“, 19145. Effect of convulsion inducing agents on the acetylcholine content of the brain. 173: 179-183, 1953. Amer. J. Physiol. , �62. Torda, Effects of single injection of corticotropin C. on ammonium ion and acetylcholine content 63. Tower, D. B. and McEachern, D. of brain. (ACTH) Amer. J. Acetylcholine and neuronal activity. I. Cholinesterase patterns and acetylcholine in the cerebrcspinal fluids of patients with craniocerebral tram. 616. Canad. Jo Researdl, Sect. E, 27: 105-119, lgugo \ Tower, D. B. and McBachern, D. of cholinesterases in human The content and characterization cerebrospinal fluids. Canad. J. Research, Sect. E, 27: 132-145. 1949. 65. Tower, D. B. and McEachern, D. II. Acetylcholine and neuronal activity. Acetylcholine and cholinesterase activity in the cerebmspinal fluids of patients with epilepsy. Canad. J. Research, Sect. 66. Ulett, G. A. E, 27: 120—131, 19u9. and Johnson, M. W. Effect of atropine and sc0polamine upon electroencephalographic changes induced by electro—convulsive therapy. Electmenceph. Clin. Neurophysiol., 9: 217-22u, 1957. 67. Ward, A. A... Jr. Atropine in the treatment of closed head injury. J. Neurosurg., 68. Wescoe, w. The 0., 7: 398-402, 1950. Green, R. E., McNamara, B. P. and Krop, S. influence of atropine and scopolamine on the central effects of DFP. J. Pharmacol. Exp. Then, 92: 63-72, 191.8. �for Ihe Bio Sciences Informgfion Exchange. . . . . NoI' for publlgnhon pubhcahon or Prepared j DEPARTMENT OF HEALTH, EDUCATION. AND WELFARE ——1 m”: PUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH "one: or ; . s SUBMITTED TO! ‘Public Hoalth Service. NeIionaI lnr+i+u+es of 'n-r OF Paganini “mmame ‘ and Give names. department. and official Win ‘l'ifles RESEARCH Hulfh. ' ‘ ' rnoJEcIr;”.-\ Div. of Research Grants. Bofhesda l4. Md. ' , in Spinal Fluid § 7 a—sm. (022 , ' , PROJECT NO. (Do no? use this space) and. U lemme} l Read" Injuries“ ' , I of PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIONAL PERSONNEL engaged on the proiecf. 11.9., Rmsurgem, mums: Gluing Instructor in NeuroIn. surgery. Dartmouth Radical School Smutfiadgs. i. . John P. Wilson, Ph.D., Assistant meensor 1n the Physiological Sciences, Dartmouth Medical School I NAME AND ADDRESS OF APPLICANT INSTITUTION: ' Hitchcock Fomdation Hanover , New Hampshire SUMMARY OF PROPOSED WORK — (200 words or less —- Omlf Confidential data.) In In Bio Sciences lnforrnafion Exchange summer!“ of work In progrcss are exchanged wlfln qovernmonf and privan agencies supporfing research In modiul and rant-d fields and an forward“ to invosflqaton such informnfion. Your summary Is to be usod for rhese purposes. vbnqm study of in. neq'tylnholine MW: of spinal fluid mama“ in hudinjxafiu, utilizing the biéh'nsa'y author! am! Young; Mariana, has A, bun Wt“ tale .mn. In! study Indiana the presence put of «cannon», smtonin.‘ and one. unidentified in the period following head injury. mezpmponod “any: is an extension of this Mainly ml: u.m1n tissue as will as tpifail fluid. and ~11; aging. in addition chain: 'analysis for these one 3mm” (spectrephntnnuomter). during tha We“ f.‘ Silbmitted beginning SIGNATURE OF PRINCIPA INVESTIGATOR for periOd I. September 1956 A , ldenfify fhe Professional SchooI (medical, dental; public healfh. graduafe. or ofher) wifh which this proiecf should b idenfified: mm, INVESTIGATOR —— mm Romanian .. Do NOT um:- Ti—u: :nnn'n- I 11 ed. �12/17/56 smmc comm wanes WW3 rwml :5an or ~ may mam Acrmr! IN BLOOD ml mm... m) mma: )5.“th for the at mum of t papa-1m mutation mod for): Gil-13:1 mm th Mien, in Matt“, Mm mum Samar, Brooklyn, «.2... Pom-my 15, 1957. A with. m mom-mm nth-ad in ”portal for tho «5mm; a! W My W m W tar um» 91' m «mu-cm» Minty. Though of W31. “14 «mm-nan (2.39) and on m thalliutan» in min-.1 fluid. the mum. in nanny applaud. to the may.“ of and and «11:, um mm, m. on» biological num. Only 0.3 um, :1. of 13311:]. fluid at 0.001 I1. at m mu «um: knyltuooblno 10 why-d a lmdng incubation, m um is nquirod for a in dnmtion. W but”, pa 8. 1! “Situated by am“ 51 tol- trickle”— mm into a calorimeter tube. notummm¢1smwwnmmrm~wmmm «.1331. uotio acid, cum-1mm, ind daunting m thus Whom. Thu than that map mu :m an: m mt: with ”Miami” to product Absorption mm a. 510 tho a. ma to format ton, color with an New”. want, m m M. or new in. y. an be both may.» mum the cam in not by Adding *Mn 1397" u in spin]. fluid, um sham-mu 1: n «1mm Wu: mum-m), (lawnmmmwmmm dot-ruin“ 0! W “machinist-mu. mm of mm in various Mansion. fluids at. amounts-nod and coup-rd to tho findings in pun-nu with mm dim». Th. nor-:1 W “01ka Yb Ind!!! W10»). alto mu .ployd to “My «batman. that action, no): u LSD, which is a mum inhibitar of 10 �WW. Wham” mtahmtortothnmnmwwwcm hr this mu the awyummm - hm“: - WOJn1¢romoerquythu¢ummmmmtof tm»mmlibcatdhyumc lauwrkmwamwmawmmmnmm mum at m mm, 9.3. mm mu m... 3 601m, 3., m4 Gold-abut, m, a. 3mm. My», 1, 21.6 (1956). �we «mwmman. m: 31.3mm, wmmmc cmmms, m 1'3ch W W, W W. 'm .m no Magnum - Lon; Inland for of a n.‘., 3661“,, 1) m ”may, not M1» on an. ”WW- mm» harm), and for tho Illa; than 111:“ mu u spam. mum mum“ of and and ”both“!— mum.» 1mm in fan madman. a: aninitiou 1: Mm a. "mm m mm and tin-Sr to u» » W in mu W. W]! ma ‘ wat u Wtimflu York Mm, 11.0%ch cm 15, 19,7! “W nautical mm: m mm. mu that: m s: muons; mm; (nmalm, mom. mm of atypical alkaloid- m- mm», mthmuumbounafmuc mp: mkummcut 1n thiamine, and Wow. I'm: sum in : Mia «fat mm, 2) awn-s in ”WM 111le 20mm rm- the 91‘ m from macros! M Marina. municidanflmdtmmdwmfikh wish alkaloid! W I” be much. duration at diam-ranting nut-win 1:: tbs who «Wu. to We 03:10:13.1" I couple“ uh“ for henna; m6. mutating than and hack «mm ma mum-1a, «man. um, mad tmtm into a. null value at cthylm mum“. Tho aim a truncated m M Wu to dryness, thin upon-d out on mt» pupa. Separates: of tho 1: want either by handing cur-anaemia an; Mme).- 1anmmppmu1n mmmnarmmuostmtmamm mum. at mun, ms. mu. am.» 3min. m �“ cam mum «an an a! mt thomh with H» (521:1), or by in 1n 1:: m3. m- petition :5me“ W (m bola). At oommdm mum m «a «a: 1m puma). um flax-1p: , the. club“ with 1106M, tht «ma by mpontm in «11filth flaking. mud tub», than mm. arms. and Wm mama. m this point than W WI m MinnafiyotwlwtomdbthnMaunm«maintain-momma mummuawxomumqmmutmmmu W. M Mal-Influx com-mm; 1m «mum at out amen my be gland mm, thmhthMmWw5uw, mat. mad ”imam, mmtmu, WWI» W mama. W W bah structural {mm at th- '13., and to! 16 drug: tar in pasture m dam-trusting the with ml: w. metric Rub dag mhmtmthmmmofihmcamwath WWIMtMO. Amioutm of tin mm to flu arm. a! “Mum“ prior to m {allowing 4mg than” will I» mean“. �(Effect a! In a Was Mona an 3% Theory of convulsion for amriigmflme report to this society we noted the relational” between the degree of induced delta eetidw during the course or therapy and the behavioral response to electroshock. Thane patients, in when big: éegreee of delta nativity were induced early, and were sustained, miteeted the greatest. degree: at helmvieral change, as well as a significantly greater percentage of inprovemrt. and recovery than these patients in when only law degree: a: delta activity were We (Fm: m: m. 1957). In the past few years, a variety of reports relating changes in £me( 1‘) leetylchoum and oholineeternae in the spiral fluids of patients (Subs, Herd) 1rd minis 0 (Bernstein, Teller and HeEnohern) following head the obsem’cime that cholixm'wbic agents may by trauma (32mm, Bard, Jemmr) alter the EEG m; putterne induced and by electreeheck (Inuit), led us to investigate the role of autylcholine-eholinestemee metabolism in acctroeheck therapy. In 1956 Ulett reported that atropine or schpclmne, when administered row! the clock schedule blocked the appurme of the delta activity on a. we hm com to mandate with electroshock therapy. meet. noted, however, �that his patients nurtured numerous madcaiubla aide effecta during these mutations. (19%) had Previously, mm (1950 ramming the suggestion of Bernstein new that atmpine mama bath the EEG patterns and the mumlogm signs induced in an by head trauma. Here, too, the side effects wen marked. In 1953. W:- md Lechmr ropertad that mum-a1 effects similar to atropine mm intend in patients with 610W 11-. in tram, head on also reported the effect at normal subjects. the EEG hypothesis of the we of nation lanthanum is a soluble We: Wr “was: dry with. at“ comlaiva mama» aethnsm the bmdyoardia, «11m: moment neumplvuiolagicnqdapflva than”. coupow with Wologic to atropine. In maximum animals. hymns 335; Media 1.1m. and 111mm: of patients flaring electroshock Warsaw; and to relate than them findings to the ham and whim by Maine min- we purpose of this repwt to describe the effects of is dicthuine um; Thcy EEG blocks slowing of the heart; Wasp-m, «flatten. induced by ucatylcholme, main ugal uni hypotenaion. m ma fasciculation e and pilocarpmfi and induces �~3- m: shock firefly-two paymttric patients, in-vurioua stages of electron- treatmnt in an studied. the EEG these 351 upon-ward. voltm’ury purchiatric hospital have been WW Follow laboratory. Wtemd intmmny at a routino amtration, 4mm” both the were 25 mm the habtwioral m per minute, for a total errata. Prior and a to the W Mahatma, period were upeonaordad. Running 'dmg record again tested in recording, diamante unstmtured historical intervicw regarding, and meordefi EEG EEG an BEG at the rate or 290 to 250 nan, depending upcn drug maximum, aubjoots Imam periods were mntinued until mummm Wanna patterns on visual \. inspe ction. m m: (a) Neal: follwed by n fooling of Q. 11!. subject; manifested spontaneous gouging initially; dryness of the mouth and, a thickmsa of speech. They nohd heaimde and makneu of the increased mathsmou and difficulty in W were Psychiatnc/cleafly mnifoctad in between 13 and 30 mm attaining mm am noon rammed by eyelid closure. subjects. In the not. pound titer drug mutation, ax subjects spontan- �.3. 0011333” med fouling: of «mm mums mm amnion illusions, about than" 111mm, the setting of the «auras or our icientity. by the um: and Myrtle Such and m: pm- patterns were transient and had diaappuamd‘ of the expat-meat, usually vitiun three hours. In um subjects, mesing august-loan and panic led to, a «mum at an wrung. amt Hero, too, mummm at minimisation War was mum: tune hours. (b) In previous studies, we had noted the intimate rolafiommP hem ehangan in syntactic language 1:3th with mmm induced by allotmm. changes diothaaino inflamed In In subjects alteration in mm prior to abatmshook, in syntactic pattern at an “lurking” musty. 3&3er with tielta activity, We}: clinical amnesia {anthems of an ”alteration in cerebral function, diathaninu induced a appearance or animation of amt: languaga ambnl patterns. indicative tmient. dis- The pct-5.06 01' ohms” in language in mum-rent with 63mm in eloetmmephalom. (a) Patterns: In all words, than dosymhmiaaum or fmqmneics. Them m. M 15 in 3. MW in wltage and a decrease in pruinamo at In patients without. delta activity (magmas), �.5. me «mum ‘ppannoa or small by the T123543 5.- W8 of 198 voltage 6-? cps uctivity. are Monstmtcé in Slidoa 1, not. appear slower to be alterad. 0131.2. The basic alpha rate does Mishap in voltags and appaamnoe of The fmuweies with mwmtmtion in blockad. In patients with vu'ying ”thaw waiting voltages: W 1m voltage m and burst «halite. in 3 is a decrease ntdxitw diuppoun; and 31m and am Wotan hem This change It wants times {bits or Maud high voltage dean from convulsive urea-am, them are now: in Sudan ham. «W «mm Manny and voltage 1m, 15mm. mm Ghana's Ind h. mm: is West in all 6100mm imam. during drag mumum, and persists far one Concurrent with electroencephalogram changes, uillon}. and language patterns at the pm-dnjoatioa language in 313% m putter”, Nauru: awn uppured. ciascxfibed. With the to three as the ho- mum the para-injection behavioral and �as w: fitness obaorntions confirm the report of Jeanne: and Manner of tho affects af diethaaim altars moot-d: subjects. in’*uonm1" we also note that diam II‘ with mammal: induced delta activity in a fuhion dearth“ similar ta atropine and ocopolnmine, l5 ty- Ulett. Memo". Shea patterns are similar to the affect of these anti-showman conpaw-ads in records 1'0le head tram. In the» subjects, intmvma ammo caused immediate changes bath in the we and in behavior. It is appsrmt, Wafers, and that. it; its: duration of activity is most mum). for the @0an mm. mutual: aim audits by mmus obumra at new man attracts of head firm point to an inflate of muralagie dyst‘motion, the :2» mwlohonm 1n the the madly affects the centre). nervous when, basis fer the owned EEG alteration; and the 1m). at spinal fluid. the effmt at ttmpine both an mm a» continuum tin-tho: support to flu chm: of relationship batman the dome an mm» m wbjoets with heaé mm mm Wim Em putt-rams. of mmm. In those studies of Wain. and u the patterns and has nutylcholmo chatmahook, the intimate relationship 13¢qu EEG bonnie: �.7. m trauma... m fluid m mama. beam On We the bases note the parallel to we observations» in head of, these observatim, as wall as studies at spinal chanmmmu lavela, would magi-st that [the (Tower and mwem, Mammal substrate in similar to that. of head tram. Fink and W22), of the electmshack promos: Electroshock my be Ionized upon as a continua-d mothod of inducing cerebral dysfwc’oian for its bazaviaml “Tact. Purim pmidas 13m atudiaa have (1th that. alteration in cerebral mm: pbyuiologic basis for the behavioral changes in electmahock (Fink and Kahn, 1957). Such altamtion in embm mum pmidol m milieu for a change in the eat-mum's adaptation to his environment. aspects a? behavior, in pemaptim, mum lama, mood, recall, memory, m affect, the basis for the therapist's ovalmtim ate. Margo mange, and of immanent. studies of fiiathudm amplify this neumplvnolegia mm“ The hypothesis of electroshock by suggesting the type of Minute mat. Marlins both the Wuhan biennium and the beluvioral chm. �m: Dicbhaam, a patent mfiwohcainergic unwound, 1:1th was upemmntnny intuwnmsly in wyuhiatric subjects in various sages at commlaive thanpy. mectmmcephalogma minimum theme in voltggs, a. and observatmm or éeaynchronixatim of fmquencioa, hyperventilation Manson in mean}: mmmt print dnlta activity. accords with delta activity sham! ammu- changes with mama‘s-anus of delta burst activity. Gmmt pat-amass with the ahetrogmfixic effects, behavioral and language indicative of a reversal of the electroshock affoct. were charred. It is maelndod that: (a) Disthuine is a patent anti—cholimrgia amount! that readily enters the antral not—mus system upon intmmm ministration. (b) The Modalities}. butts ras- Fm changes in electroshock is to this of head trams; and (s) therapy The may biocheniml lie in buis of the mode of action or m cmflsive the acetylchounoocholmatemu system. ��(glum‘firzr Wfl «/¢V7/‘ “W“W WMWW— #MZ ; _WMQ!4¢W MM ‘ é; 7% WM/ 64331” .461 ha— @ffi/If/y EEQaQ/JW gag/M1114. fl 64x7 ���14.3.,“ , / -4I/ . .. M... �é“; sessé c W fig? ngz/ & W‘Za- MWX m ’55 2 “a! gégil Mara. 461/ 4. .4“) ¢ MM: Wu W Jeni #M“ K/m 1» 14:44::____ ��/Z¢, Afiffigg L££A4AIZI~ mWMmQ ("43 2% 2 . @a M 3" ���/ / 'v-—-9:' wpw'.” v -' MIG/’4 4trsmg+¢zi9 - ._ ~‘ ~ . " . Dr ������10/ M‘ £77. ~———-—-—-————-——__ / 1 w W? WW M tr M WM mu 5 m; Mar fir WM ltra in x1“! EEQ. 32 ' #2 Cf; .- .20 _ Wa MAX—«l 4.4.!” . #34“... 4'“ ‘7 AIM xcreq cwé‘.’ :4. ('3) M44. Min-A- ��“0011/ /;4a+ a” ._—————-9 ,4¢,,‘“‘“':_:=, l/aw M #u/t. 410/ fi’é‘fu’” S“ v MM ��[f7 x, W/ r{ /¢C// A"! wax / (31) I) 2 %%l -———-> MIL. ”cw / ) ��flew- �O EST —_WU. ”WXW IK. Bag 11“» “~ f ‘ 4W Iy .NQ W .CW ‘e’ Iaéas/uue' ‘ MM? c) jivfeaflfiufip 041.. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Files: Acetylcholine and Cholinesterase, 1956-1966 (folder title 1/4). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-003-0-001 Date A point or period of time associated with an event in the lifecycle of the resource 1956-1966 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Research