http://exhibits.library.stonybrook.edu/mfp/files/original/9528d68ea90232ebce57ade28fbef74f.pdf 93461c25c5f8ae971bd4c1aadc2a1278 PDF Text Text I; I Mnémc . ' Recent studies changes in the 7&4 ’demonstrated that a necessary change in behaviort was the development of early mg sistent signs of altered cerebral function of slomgga ”a was a “f7 in these laboratories re-evaluating the role of cerebral mechanism of electroshock pie-requisite for ?. [ours Wt (Fm/IL indeay and per- which electroencep/alographic and/(ah , r:f.:'6) any. mes may of this observation remained unclear until the recent reports of Ulett describing the ability of premedication with high doses of atropine to pre- We wt}; (WMI‘Collowing 5 vent the appearance of the EEG suggestion of this report, we delta abnormality a . nth the investigated the roles of acetylcholine and cholinesterase in electroshock therapy. The data amply demonstrates a close relationship between the degree? and persistence of the ele ctroencephalographt‘cr abnomality and the appearance of measurable quantities of free acetylcholine in the m ‘ mm“ as“ as well {:5mm of. to ﬁcholyl-cholinesterase, The I q ”'2 ('7’de } Loewi u W? normal ratios of” cholinesterase WW of the ‘ p $.00» . 1 f .— p. role of acetylcholine in the transmission of nervous impulses has been a subject Edi} W x 072/) Q). for study since the first description of The arguments as «If theWeﬁ‘ects 4 (ﬁes r’ to whether actylcholine is the main or only �agent in the transmission of the nervous impulse are not of primary concern It is sufficient to here. of nervous tissue; that note that acetylcholine it excitation process; that exists in a it is bound form and a normal constituent is librated during the a is rapidly hydrﬁlyzed through the specific action S of cholinesterase; and as rapidly reconstituted by the choline-acetyléueg fluid iﬁ: Richter Crossland - 1916). Furthemore, normal cerebrospinal I‘M? Mariam ”‘?¢‘94) 4.94mi m‘t‘uﬁv contains no free acetylcholine deSpite the rapid breakdown of system ( & a, bound acetylcholine during periods of activity and excitement. The cerebra- spinal fluid normally has a definite level of cholinesterase activity, which is principally of the "true" or mecholyl hydrolyzing type{ IVMﬂM/“V 4“} "Romsuetkg. any). .111 the absence of free acetylcholineﬁand under the ”normal" conditions described! ﬁe electroencephalograms fail to (a) Effect of Cranlocerebral Trauma: variables was lationship of described by show any . The consistent abnormality. earliest changes in these 0 glmstein (l9h6) in a classical study of the re- changes, degree of experimental head trauma, and levels of cad/w»?!grew oft! cats free acetylcholine in the 09!. stu subjected to varying degrees EEG 0 a of head trauma, B/mstein first showed that free acetylcholine appeared in {Yaszwm the CSF ‘ céE. within a few minutes; and persisted for varying periods up to M hours. There was a positive relation between the degree of 17am and the quantity �-3gamma 9 per cent. cu- electroencephalograms demonstrated patterned changes. Initially, the of free acet’lcholtne which w Eg-rwﬁﬁal varied-khan 2.7 and 9.0 Ocn Com-raw records were filled with high voltage .fast activity, 516 int'preted as an intense neuronal discharge; only to be followed by a short period of flattening of all #01 recorded electrical activity. These periods were "followed by prolonged periods of high amplitude sharp waves in the delta frequencies. Mt 0 Ulth thes/e'zlectroencephalographic changes, Bﬁrnstein fur- ther noted that behavioral manifestations w{ he werencorrelated with degree of the of as as free level well acetylcholine traumal/ ”in; highest levels of acetyleholine; he noted the greatest degree of abnormality as well as the greater severity ””77? M u/ the of WW t'anges a the appearance ofAseizures. _ W, diva EEG alteration in consciousness, 7393!. rnnumnrm further substantiate these observations, B/grnstein applied acetylE Y 105553 choline to the cat cerebral cortex. When the concentration of acetylTo and choline was 1 gamma per cent or less, he observed high amplitude \sharp waves of low frequency in the electroencephalogram. creased to .7lmaém WAC/c! the concentration was in- he ~Wana Mada per-cent, the electroencephalogram we. fad-w 2 gamma 74: When Tower and McEachern (1919 a) flattened,‘ m repeated thﬁe studies in human cases: w �cere‘rospinal in the fluid only in patients following head trauma, recent grandmal seizures and electroshock therapy. to 100 gamma In cent. addition, per terase activity of the. ific cholinesterase spinal fluid. (benzoylcholine Specific cholinesterase ( mecholyl The free acetylcholine varied from 0.2 Tower and Mc Eachem assayed the choles- They noted a sharp - splitting)fraction rise in the nonspecand a drop in the - splitting) fraction in the patients head trauma and those following electroshock therapy. No with such inversion was demonstrated in the fluids containing free acetylcholine following spontaneous seizures. These authors also conclude that the level of free acety- lcholine varies directly with the degree of cerebral damage; adding, however, that the degree of reversal of the cholinesterase fraction is an even sensitive indicatbr of cerebral more damage. In most of these subjects electroencepéhlograms were taken at varying intervals following trauma. Here, too, as in Bernstein's experimental study, there Was a direct correlation of the extent of EEG abnormality and the appearance of free acetylcholine in the cerebrospinal Thus, we may conclude that craniocerebral fluid. trauma results in the appear» �-5. in the spinal fluid; and that a ance of increased amounts of acetylcholine direct {KN rJ relation “between the amount of acetylcholine, the degree and type of electroencep‘llographic abnomality and clinical behavior. (b) Effect of Atropine on post-tramuatic EEG and Behavior: In his studies, Bernstein, administering 0.5 0 atropine, demonstrated a reversal or a blféking of the EEG - 1.0 mg/kg. effects of trauma, depending on the relation of the dose to the trauma. Atropine also modified W the behavioral and neurologic signs of trauma. In the experimental condition of [Mrﬁﬁc/UEPNM acetylcholine, which induced EEG and clinical ﬂanges similar +1.14 to head trauma, Bornstein also demonstrated the blocking and reversing effect of atropine. Ward ( 1950) applied these ideas to the treatment of human cases of closed head injury. In 20 patients with varying degree‘ of trauma, he admin- istered atropine subcutaneously in doses of 0.1 mg/kg.. In selected cases he noted dramatic clinical improvement which action. He \ .traum.we. also noted, alographic effects of IA) lg. m M ATTRI Ben-5;} to he atropine selected instances, reversal of the electroenceph. In the study of another anti- �To“) f \DIW I cholinergé' drug, "DIPARCOL" ‘6' (diethazine), Jelkner and Lechner( 1955) re- port significant alterations in the post-traumatic electroencepbdogramio A single intravenous dose in no instances of abnormal electroencephalogram re- sulted in nomalizing in More 22 instances and marked improvement in six others, recently, Ulett and Johnson (1956) demonstrated the of peripheral atropine IL’ .0 to block the same effect occurrence of slow wave activity follow- ing electroshock therapy. This study suggests the possibility that the same biochemical condition underlies the electroencephalographic abnormalities in head trauma and One in electroshock. report stands out in contrast to these findings. the§5 In ex- periments Brenner and Merritt (19h2), applying topical acetylcholine in con- centrations of to 232‘ intravenous atropine to the exposed cortex of cats, noted no effect of 10% ng/kg) on the electroencepahalographic changes. It is important to note however, that the concentrations of acetylcholine in these experiments was significantly higher than the topical applications “a, 0.: ML andnmtra-steruc (0.2 Merritt, however, make - 10 gamma) (1-34 g7ama%) injections of Bomstein (19h6). Brenner aha-4.1L note of electroencephalographic effects similar to ace- 0 tycholine from mecholyl (acetylbetamethylcholine) and d’iryl (carbamylcholine) , ‘ each in concentrations much lower than the acetylcholine concentrations. �-7. They ascribed the increased effectiveness of these cholinergic drugs to their lack of sensitivity to cerebral cholinesterases. A - variety of experiments utilizing DFP (di-isopropyl fluorophosphate) a compound with irreversible anti-cholinesterase effects - demonstrate‘ the developnent of high amplitude rapid frequency waves similar to status epileptic“;s as well as lesser degrees of abnormality noted in post-tramnatic states _ wich et a1, 1950; Frefdman _e_t_ a}, 1929; and Hampson gt a}, 1950.) A! .. (Hit In these studies, too, the electroencepahalographic effects were blocked by small doses of atropine. In another laboratory study, Qhatfield and posed animal cortex with activity. The Me PR0 ST! Dempsey (l9h2) prepared ex- NW and evoked electroencephalographic Spike admestratgﬁof prior atropine blocked this spiking, or if present, the alnormality could be eliminated by atropine. Thus, from a clude variety of experimental and clinical studies, that electroencephalographic activity as a result of trauma, To PM; AL ‘5“ we may con- induced by acetylcholine, either application or interference with normal cerebral metabolism, can be blocked or eliminated by atropine. �-8(c) Role of CembraSpinal Fluid Acetylcholine in Seizures Acetylcholine is normally present in nervous tissue in a bound, in- active form. During periods of activity, the free acetylcholine is liberated at the cell ”I; The membrane, where it is rapidly deactivated by cholinesterasmﬁ- level of central nervous system a acetylcholine is this ant of the processes of synthesis, liberation and breakdown. It the result- may be post- ulated, there/jars, that the level will rise during sleep and fall during act- ivity. this hypothesis is tge That (1949) and Elliott, , was demonstrated by Swank and Henderson (1950) liquid air quick-freezing methods, Etc.“ ter ANIM in “8.1 experments. was 300% higher than ' micrograxmna the post seizure level. tissue levels is transoi'ent, however, as the 7 in rat brain is high (1 gr: . and Crossland demonstrated anesthesia and sleep level of acetylcholine (measured as brain tissue) Richter and Grassland ’R’tSW ”thesis The By using that the per mg ' difference in rate for acetylcholine J Elliott 33 a; confirmed thez'e (I950) gaxmna/gm/minute). observations. In addition, they noted that after metrﬂzole convulsions Jﬁi FK’EE acetylcholine was always demonstrable in the spinal fluid in concentrations up to 3 gamma per cent. In spinal fluid studies in Tower and Me man, Cone, Tower and Me Eachern (19h8) and Eachern (19h9 B) also demonstrated significant quantities of free �.9acetylcholine in patients with epilepsy. 0f 56 epileptic patients, meaSurable demonstrated/free acetylcholine in quantities of 0.92 to 5.0 with an average of 1.0 gamma per cent. gamma “¢¢ ‘7.) ()7 per cent, acetylcholine level was directly The related to the frequency of seizuresf/ the extent of electroencephalographic abnormality, and the relation of time of / n01 ., M sampling l 14¢, tonlast seiZure. It bore I relation to medication, type of epilepsy or level of cholinesterase act- ivity. As to whether the acetylcholine appeared in the spinal fluid is a by- product of the a M V“ ' s I o n / conclusion; or whether C the increase in acetylocholine was a is problematical. a, increased cause of the seizure, lieve that the Tower and [{cetylcholine liberation itself but related Me Eachem (19h9 B) be- is not due to the seizure to the basic process causing the seizure. I In a study of thfhypothesis that the accmuulation of acetylcholine is basic to the seizure process, Torda (1953), induced convulsions in animals by met zole. She determined the level of acetylcholine in brain fore and during convulsions. She W tissue be1' ' . noted that convulsions are preceded by a rise in the acetylcholine content of tissue; that the content gradually $118 during the convulsion; and that * 5423..) occur. Furthermore, she postulated convulsions u WAS 8. certain levels, convulsions failed to can?» send 3 factor} which in physostigmine probably acetylcholine, but in electroshock seizures was not. �Shendllu concluded was due that the fall in tissue acetylcholine during a convulsion to inhibition of acetylcholine synthesis by increased concentration?- Sec” of metabolitesnas ammonium ions. While considerable argﬁihent waxes about the significance of acety- lécholine in the mechanism of seizures, it is apparent that free acetylcholine appears in the Spinal fluid following seizures; that activity and seizures enhanceﬁiacetylcholine; dfstruction/lowering tissue levels of acetylcholine; while sleep and anesthesia Aﬁgment acetylcholine production increasing tissue levels. �W!"— " WM—w-"ﬁ ' TNT <- Mm; E Aest‘ I. / I w- . , » urr u ' , M 0' - ,,._ -m—~ I 4,4 " 6Z7 v - ,1 5 M 1,;“414, m. -w—.‘ —V<.._—. .Avv»/— up ~~r .-———:v mm” M: . ~ . w.,-- ”v7 /’ W“, .. -v. .. . . . wﬂnm .,,_.V,r, _.._ .<‘._,._r_.__.=_,,m,_qw ' -. ‘ EE < ,. ’ I I: l -7' ['4imzzm4m-‘ean-,g-gﬁc ‘ ~ — ‘ , / -~—...:.;_.-f.._ Mg; ((244.4'4/pv A , , ,.. / /' l . ’ / 3 ‘ j Z e" . ��-« ”tum-35$: 434.. \2 as: {525% mthhw ‘3‘ M . {3%. «3%. Ma g. 7 \i‘xw _. , n ﬁwkﬁkxﬁhﬁ \.m§\. 5n Q“ W; ‘53 h}. 41“; 7 53.3% _ x w x ”‘1; (“VM , «$ka ��the level of free acetylcholine and should follow a decay rate equal to the EEG WWI-£6 rate of in desthtion. Since previous studies demonstrated that Ron hypersynchuy was a necessary pre-requisite to clinical response to electroshock therapy, it may be stated that the absence of free acetyl- choline precludes changes in cerebral function and thus precludes a ical response to electroshock. Certain assumptions 61M (1/ .WQS in \mﬁxam em . may be made regarding M‘ W£%,ML 4W; Cholinesterase I is found in clin- WM“; all 4 {a ;ﬁb€,¢.¢£ £0»£u64* ' ' highest concentration in the central W, W nervous system; while cholinesterase II is predominant inAblood serum. With the increase W! M/mx.dv£[7 in acetylcholine levels, in the intercellular fluids M Wftoaow M 6i mm ‘5‘”; vs odilation and increased cellular permeability degree of transudation of vascular fluids may be I: into the dependent on the extent and duration of the / predicted, with a intercellular spaces tasodilation, (Kabat gt 3;.) 19118); ration changesggﬁztlt high ncentrations of 15?; , enzymet, th 4/ rate of hydrolysis idndecreased, ' achnﬁnson and Rothenberg, �@ Tit/4M ﬁgﬂﬂﬁ W05! M. r ' ”1“." I (m0 4» w- ar A » W M L’ M.%u 7 . WW1 ’53), do W MW; - ’ . - W I44"! %_ /o¢ /ZM"‘ �2% Mwaﬂ.‘ éﬁ 7M/Cc 42 d a >/~7‘$[ 6a 56) iwwwh‘ 4M 444W ' 'wZ/zé 9“. ﬂ A—ﬁr7:9%__~_ ��__ _%j%i%% __M __~__ Meg/Eran!» , , M W/ 8&9- afﬂt ‘9 _4€§./_""f. ' 1% ﬁﬂwjg; W M; ___-#__ ��F:+r§¥¥33~%¢;*‘ '77 , "“37 ' \. *Q W~~ -~’ vM—w7ﬂx-«7A 77.7.«7-«7 . .ﬁW-M 1'} f MW~ §' \»M ‘ \ ﬂ r \- j "39% \~§\-&3~ .uxawk , 7 - 7 «.77; 7 777 , 77.7—7— ...-< w... 7- W - 7 7 7 7 77 77.3, 777 a Q7 M353; --:-..___7—a.7..7 ' 77.7.7 1377-3 ~&\ 71;;7.}7c§?§37\7:s7 sw C\ hﬂa§»3~§~3~ 77-.. 7.7.77 ‘ 7- 7., 7 x 77 5g .v‘wz\ if»; ~ \ f ��I: she/ﬂ ammunummmmmmmmemw at our.Mating um 'mmsmmmmaozmmmmmmumu Meat 11: than Inherited“ ﬂu 1-01. mmpn—mquuiuformmhmurnammtot mhwpmtsim ddﬁndocobulmuondmam Wcummawmmm(mmmv$6h topmtmawotthamdalhtmutw(mttmdm 1956). rationing the Inseam at this report, In investigated the , of acetylcholm Ind cholinoatome in diam-tutu n clone of w’ My. «f ﬁfe? ":9- ‘ therapy. as. data amply the dean. and persistm of the ham 1".th 010W 113109 mm 75:, role: “humility math- I'm acetﬂdwlim in :ppm of measurable quat- the cerebmpinal fluid as wall as an in- moralenrucetvlchdjnohthotmumornemmpnmm Mamamrormsmmtmtmumotmwxm affects by Dale M1 (1911s) Ind/(1921). ' rho W: n to another «1th 4 ' �“wwwmmmtu‘mdmammmm of M 0mm hon. It in affluent to who that mtyldmnm 1| nmmlmtitmtofmmmmy mtnmmmabmtmaaa is liberated as. an mum normal cut-Ironing]. 1.913%) than“ th- or activity and that m ﬂuid contains an hm saga-mt. no true of bdund 1?. iallnpidly mtylchoum (faster and McEachorn new periods The comma-121ml dummy; nomliy has ﬂuid lenl of Munster-nae activity, Men is principally of the mM W was; a: Manning and .- mam mmtitutod mun (mm-a 6mm - 19M). Funk-awn, «citation W through by during thy W (W n “two" deﬁnitm- and Rothanborg: 1935). hmmdfmmtylchonmmdwwrthc'mml"condium (a) fact. :10 mmbrd Tm: th- mliast chug» in than Wmaomumwaommmwmuauummdm vngaumpdEmm,mdoxpommhudtm,mdm otrmumymwminthoembmpamnm. human-numbMtedtonqingdogmluthomtrm,homu1nnruahamdthattm �v r A—w— WWW—«WW. W-_-m_w..__quw$ mtmmmwnmcsruuunarummmmm per-1m for varying poriodl up to Mm. that m a. pain» mum ‘mmmmammmmwnttnomwmma mamaandsammmh human; mum, W was rm activity{ inmlytohtoﬁmdbyawm tbs records won filled with high voltam urpntodalunmﬁeuo neuranldiachatgoy period of mtumd We. {humus of :11 room-dud Glacial-191 activity. Thou period: ~mwwwmm—n -M." mthntoﬂmndbypnlowmothighwnwbshammmh fw. summogmmc . tbs delta. than With that behavioral as wen u . i changel, - Barnum 11mm:- new Nautical! an duo 00th with dogma of tum, with the 15931 of tree mtylclmline. with highest levels a: mmmmwmmuudagmotmmnmwumuum the in alteratim in seventy gm‘bar ma the 1'0 Wmu.» o: apontanam farms:- ahounotothnupoud mam, change! Wanna: animus. those chain-mum, in m. Bantam applied acetyl- «teen-balsam. Unauthomntntimot amylmmlgmporom.arm,hooblemdhighmpntudu �Mmsdloufnqumyintheauctmmoplhlom. manommutation an increased to 2 gun pen-cont, the ﬂattened; in a tnhiun pal-Inn}. to the Tatar,“ kaW mammpmlogm pout-twat“ a) repeated mm. § rum. mm mum-um otnxwingtmofwmandoﬂm»wm¢nsordem. 13112 mmmmmmmrmmmmmnmwm mummmwzm,mmiummmm therapy. murmmtyloholimuxﬁsdhuOJwMgmmrmt. In muQMrmm-aemmdmmmmmiuwatmm ﬂuid. Mm:MmmmmpMcmmmM(m wmmntm) - (tn-chem fondling dug: in the lpociric chainsaw emitting) fraction in the pntiantl with head trams mm W. tho fluids outlining mean faction m a lo s'ugh hint-310nm and We Wadi: rm antyloholim tanning mutations mum. more also conclude ﬂat the Laval a: nu agctymm uric. Wummmotumbmmgm,mr. than: Mmdnﬁmldmmnmmmtnmummmw sitiw indiutor of mm m. �Inn-tatuaumjomwmrmunmnmh— iamla tanning. m. Hun, too, an in Bernstein's W cm, Mmammwmumamumtdmmwwum adenwmmmaﬁWMd. mmmmmludnmtmmnmmnmunthaw ”ammuarmmmmmmnudgmum adfmtrahﬁondmhomﬂnmtofmwlm,ﬂum mmdwogmowwmmhémmﬁ Banners gm Am 9&th of (12) In u.- on BEG and mms, Barnum, maturing 0.5 - 1.0 lag/kg. um, mumudamdor&umdmm¢hm¢tmb Mam'unumorunmmmm; Atmpimdsomdm tho Word and usablogic aim of tum. In tho maximum eon-.- .wmgm mmmwmm,mmaumnwmm dmm of mmcistam induced Km and clinical m: rmrsing arrest. or «3mm. m<m>mmmmmmmathmm¢ WWW. mmpumummmotmhmintend atropin- aubomunly in data «(0.1 W0. In about! an! �.__.. _“_«, _._.__,,....<.,.___,. W7. w _. mmwmmummmmmmnmwam actim. ”waww", .. __._ 7 bmmnmmma,mrmafﬂualectw 'exmpmpmpmo effaahl .w M” wwwmmwv—WWWWWV.W_ 0239113301110 «um. hmsmammu- am, Inn-mm (mm). mwmuﬁﬂ mmamwmmwmmnm.” AWWMHMMWOIWW mmmmmmammwwmmomn: IMW,Mtandemm(1956)Wthume£fm -A——.~-T.v _ ofpoﬁpheglatnﬁminﬂocﬂngthemmotdmmwacﬁuw following unattached: the sm Wen]. mm. 00:811th mm saw mggom tbs Minty any mm. the mmmmmmum WWW mu- MWMdsmmnmmnmmgﬂndi-nga. Inmates- 3m: W mmmm in Wmmdzimloﬂwtmmedmnaotmu,wbudmdfm parjnants and Hewitt (1913); topical .ofinWatnﬂmﬂM/kﬂmthooloatmmmm xtumrwmmmhmr, thatthecmnmumofmamwm mmmnmamswmwmmmmmmappuuuéu (Mm$)mmmmmm(o.2emm)mmatnom �thin (W). 3m: and ”.11“. of hm“, mar, WW]:- ognplun affects 81:11” to noetycholino (WW), chonu) and duty]. than th- mmm mmm. 1mm at that. cholinorgic drugs mums. IA - n van-Low ma at expert-ants nah in commutation! Inch lover my mum ﬂu 1mm attach thou-lack.“ to um with incur-11:10 2m mmm (awwmﬂ- DFP muutytomhnl (div-1W}. Imam“) cumin-stoma. strum - mum- thadaubmtnthighmpnmdonmdfuqmymvelmumm mnpueusuuuumm dugmoxabmmutymmnmt-W mm 919;. (Es-non. museum, too, 1950; mag, 192m and Ema-ca mmmmmnphicoftoctImnWby Inn dot» at am. In W as. 1950). mama-y mm, tantrum and 3-way (191:!) pm mud dwtmmphdomplﬁc m1 mmuw. ﬁnpriarWtimotnmpimelm, expand cox-u: with procugdno md ovum, mmmntyoomuonmmmbyatm. m.rmanneworupommae1mmam.mmm and. tint datum-MW activity induced by mtyldzoune, um �tuna, uI combs-alum unbeblocbdoralmmmbyatmm. topical tpplmuen or interference with mum. of am run. may. mummpnmtmnemuamuam, mmmotacuuty.mrmmmunhenuumw maxi-,1Ihonit1lnpiﬂym1nudbycholmmnu. thunder Wmmauwlm ilyﬁnnﬂaruulhntd’ﬁbpmm at manna, ulnar-1510:: and mmmuuuu - this mm is true um It N ha mm, Wm. dudngnlupmdhﬂdnﬂngmiﬂw. nut m Maud by aches:- and 02-083de (1919) NW§.mmﬂdeM'(19SO)mmupemu. 11mm: on quash-trauma methods, Riches: and cm wining dam-mad um (many-dam mwmmmxamwm prn.mmm)ulwmmmmtmm an wmmmmnmymnummm rats. for Micheline 1n nth-11:1 18 high (1 gulp/mu). Elliott ggmmjmmunu'obsemum. 111mm, thqmtndthat snot-mm mmmrmmwmmmmmn �_...—_——___w wv—wwrvnvr—ﬁwwv—wvw th‘smmnmmmtmﬂmuptoJEtmmm Intpdmlﬂuidotﬂiuinnn,“m,Tmrundﬂon(19hﬂ)md mwhmmm alumnae-ad mimt managed rmmmmupumuumomm. 0t56wihpthpt1mﬂ.hh (1919 B) (Wmmmnmmmwmnm'mmuuudoawa mmoem,umqmndeJMWM. magnetism:- mmmnmpdmmmotmymmot WWw,wmnuumor‘motmm¢ “Whitman“. Itbonmnhﬂmtomdicgﬁm,typadepﬂsply armaehammnuacuuv. hummumtymwmmmamuam mammumrmmmmamwmma _munofthaac1mn,1apobmm rmrlhdmmm (19193)» mmmwmmnumumtmuwm iwmmnudhthohsdcmumth-mum. ht’ahwdmlwmmmdmdmw lib-intact): «13m process, rm (1953).1ndnoodoauvu1d.min mwmtruoh. Sheatoxudmdtholmlofmtyldxolim 13an - �”memcm. mmmtommmmm,addbytmommmmmmmmtdusmj anthem” Mfmsdumgwmmgwdmtmmmmh,m Wmn,mmudtmtm, .MhWWumpmmyaummm,bﬂh mmmmtmrmnmm WWWM. maimhiladtoopw. Wmammmmmummumotmtymmm that: by increased mam-cums ﬂ ”tam“. such a min in. M13 mm nrgunent mm the significance of newb- ‘Wmﬂnmcmdms, niaappumtﬂmttmmwh mwmmmmdrmmm; thitmvityuﬂ mummammamum, «mm; mm sloop mug-mm, M W mammal-19701.net tum @tyldzonm product“ mm with than muse: 80m omimumdchmgummmm,2mrmdncm(mwhw (a) , Walnut! ”1:413:de «shun-ammo activity. «Wmaammmrmmmmmm Twin.- Minster». �"w ——_<__~___..——ww—m_mw—.wrw “—vwr , wwwv I (”ta-m“, .. ”apedtic',: for Mahlﬂgdw mid: he a ma: Spain-o{r 21w for WW; and «shaman-a II ('psendo", ﬁes-Specific,“ a!" WW Warsaw-MW). m have 6133mm ram «Wrormmawmmmoum. differential a..—vnv—_——-_ nu cholimteme activity an mm he» 083 Bach/Ann and mm 1133a, This qualitative dintlnctim. W Rpm-ting the 138111158 substratu’to mtylchonnc, but a ratio of the activity mtylcholm mum-nu, an Wm (mu Wm - me). autumnal m the zonal as: consist: a; mm necholyl and haul- m nuns are found: In mch ntiol non-1 of 33:17 for lack/10h to sub/Ash. manor “pawn" amt-Suez- with a mi]. ‘ non-speciﬁc eaten“ emporium. In patients with hand .‘IZ chainsaw” activity. tram, I'm and kitchen report a sweat may, manu- mum. the county of mammmm eorrdnﬁm between ﬂu extent at tho th- dagm of Wu. tuna and usert. that. there in a definit- mend both with �r,_._W__,__.___._... Inpuumvith mmmmammuvmru: unatotopmmuiznm,hmr,mm1nthonuodobd139mm or total audits-Item activity“: round. Imrandlhmm (191:? g), in than study érudounbnl at tram, n- W‘mmmtmmtmmmw. 3m» &pm WW, zuwnzmmmnmmmgmmmmmw ﬁmw decram c‘Wmﬂthnmerulofth Wotan“, amr 3-? am Mupomd rm mtylchanm m..1? ratio at abolition-M7411 ﬁve pt tho :1: patient.“ Fro-than ohm» nmmwmmtmmtmwmmmmm nor: 1113 than. of crunooerehnl um than that: found in opium. kmtmmpmmmmmmmmmwum Momtmwaweamna ratio reversal,- fb-ymwﬂn ummmmtmnpcmntmaaamlymotmmumwm to want." W �mrmmyaahmmmu. Alia, fmmcwdmrmﬂ pungent m ot’l'mrmdgcﬁcehcémb), mtthctcguths fwdtoMspimlncid WWW thalamus tomcat-ant, penuts us to considor the yummy basic to the anaemia of the um:- that such hm 9:.th pmceu. Ghana‘s: .g. . ocmlusians Certain further deauctiom and agaafalectric m mmmgmmma mum. The pmscuce intcmnnhr ﬂuids Mean alcctmcn Maximum; The pen-- mduccaachangeinccn— ﬂax-activitywith‘anmmu when acetylcholina induce; to gradual pastime. tom: “trim ofﬁo mtylchaum inﬁll WW, nﬂwted in tb nudomeofhwanmmncmtelymﬂm �»;y- mmarmmwmmmwwrmamnuoqmmw an at new destruction. 31m. pm” IMO? Mutated tint lmonnnnmmmnmausaxnmumuypnhunmxuwintnhumnxmqmmnijhmbmahock thonpy, it my be stated that the absence a! {mo acetylchcnne pm- cludu chmgu 1n eczema]. {motion and thus pracludu n clinical aspen-e to electroshock. ‘hﬁhhnummmummsnybomwbrqpnnmgdumpainaﬂluuwmmepmb usability at! explaining the increald 1n Ghanaian-Ame activiw. I is round in highaat cannuntrttian in the central narvoun estemse Quintet-rue aystaum while n is pram in other games, especially blood serum. choline- With the increase in mtylchoum levels in the inter-cellular ﬂuid: as a result. of stimulation and convulsion, “sodium and increased cellular pemeability may bawm¢mum,muhacbgmouttnmmmmmaaatwumnurﬂmuh1Mmibuhﬂmm celluhr spaces dependent on the extent and duration of the ﬂuctuation, (but �r_"__. m,_m into tbs spin-1 fluid; and that thus the electrolytes increased, than siwmsnt increase in changes . mm in permsbmty of calls may ﬂms such u nusledc‘soid Splitting was s amps“. pmids the basis for the sppomncs of high concentrations of scstylchouns and for increase concentrations of Cholinutsrus II, (Tatar sad With the increase HcEschom 19h? in cholinss’oerssa activity, should not the free sooty. lchouns be rapidly destroysd? ﬂuid after trams a). To what melanin cam it's persistence and seizure be «embed? An explanation is available in the for this discrepancy observations 0: Hush-am and Rothsabsrg (191:5). continue! by Tower and Ks ﬁschsm (191396) and Burgaa and the Intosh (1955), tylchouas - shonnsstersse I system “humanips. At ”physiologic” extremely rapid (3-4.1 1vity in spinal is cmcsntrations, mdrolysis microseconds) but falls of! very ﬂuidly extremely sensitive to (Haldane at higher and lower of, ill-t the sea- montrstion acetylchonne is consentmtims, set.- tbs Cholinesusrass II cum). In contrast, acetylchonns uhtionship 1s non-specific, and the rats at hy€re1ysis incmsss with concentrsum. 0011 mums, insstarase this I, in the 11:53 acetyai‘shonm functional with nouns]. st. 1m_ls o: soatylsholins is dsstmysd by the specific. oMsr 0! milliseconds. Where wvity of chol- the excitaﬂea is such as to - �1nd. to an of “casein mm by concentration of sootyloholino in nervous tissue, the rots momma. ‘aooodoo. choline mounts, the ssisuro threshold dissociation in sootyloholino - unt vaaouur ad As is ruched the oonoontntion o: oootyiand c soisuro occurs. 1h. _ cholinostorsse I motionﬂzip vaults in s per- sistonoe of acetylcholine. rho «ism-o, In. acotylchouns. ‘ itself, perhaps adds to the Ian]. at inc'mmd mtylaholino airing.” rapidly. with result- 1'1» permeability connineffects and the appearance of increased names») mmoimnuooohomonom II. Itumoouvuyorwo onlym, though of lot sfﬂciomy, roduoos tho sootyicholins ~«mum of cholinostonso and 69th on concentration aworim, 1on1, InAhours to kinetics that - to levels for the plvsiologic I. Altontionintlnbloodbnin pewbmty humorbyths cantimingsutim omo observed in pout-electroshock oioctmooophnogrm. 1: evident in the mount apart no Aird 33 g (1956) Such s possibility- «annotating a significant increase in tho concentration or odd-inc in bmin tissuo 3-day: utter s ashes of 12 elects-om. an on. shows #olooulo, ordinarily obsent in brain tho clung. tism, in omcantntion of this mg. to b. con-eluted with the spposmoo �, w— _, N‘erm—. #179 WW ducal unu, however, the 1:: mt subjects. the ma 1tuntoa 311 com awumum of trout- «‘WW AM» 7 ms extent; miuuw to «- Despite a Maﬁa: nry may in the of high dogs-ea hypersymhmy, m: by Alerting, mule the duratiamdﬁ' hypnrvmtmum populating. me and wly appearance m persist-mo Wont the tmtamt cont-u, has been described In a neceﬁnry pu-requinita for imprwmmt following shook( nuke: Kuhn. 1956). Batman certain patients to dovdop 137”“an aholine Ind Manama: Assuming my be um mechanism Perhaps and gloom- of.macs-mug the failure them staring of acetyl- nﬁud. is. that a gnnd m1 leisure indicative of the developmnt of tissue 1min or free acetylchonm in mass at the I; hub- at. at hydrolysis by Mae-unl- that the electroencephalographic Wrenchrany in a reflection of tbs persistence of this almond. concentration of acatylcholineg than tho diffemnco in paint: who maintain hypermchrm and those in when it rapidly (tumour-O Ida] disappem, 15 a nﬂactim of the theta.“ of the wonmatemmcetyldmum hydrolysi- Byataa. Persistent. Mommy "cults non decreased "to of �rw‘“. a“ + V ‘. , “m---“vmw hydrolysis of acetylcholim. .Ismbmmmmmdm'oomct, dWrmorbothof the following postulates m opantin an patient: with persist-mt hyper”:— chm. 1) Western” spread batman the the tiam. opt“ ammunition, so that than in a great Imam.- substrate concentration and those present in with high gootylchaline) Ind/[Y 2) Gunmetal-nu m I~1a in 108 1113.1”, lo that the cmntntian kenotion a: this mm opemtim, thong) at a slow decay rate. Conversely, in patients with short ed lampemymhm, cholineatomaelandnintismandspimlﬂuidm Anthem, at” the appunnce of high oomentratiom of acetylcholine stuns!» the production or tissue cholinestemse I in the central Frau tho lucid studies of ”am-noun (195$), a stated in depnasive psych” induced mtylchonne my pncnorbid m1. (1 nervous system. dim rahtionahip batman cm— Mutton of tum cholinestcmse‘ I and level . /) luv-750.. of nervous nativity can be mmpnuul depression) , than the choc:4 . g.» alumni“ I to production a maul. Waters” amt. m �g; hmmmmmwmmumummm _atummuv1ty. Wuﬂaweiwtnmwmmmd WWNWPGW. Itilmww mmmxmmbymmmxx. rhpbhodpmmnotnb mrmcmwmohdmmumbéomuam matm.g.g.nntommzomm. hummus-Wm” mmumuimmsmwmmmducmx,n,mmm Mgmwmmsmuﬁamwmm tomato: Wumumdmmum. mmxnﬁmmaﬁw mtnuuummmmmamnumw;sssmnm �4t). awn-mwmm. the l «tutor cautnlnorvm ”Input Immuoimumm” 1, human tn: of our): and sustained ma levels of :cotylnhouno m Khan, the Wencﬂlhareaaidhrpndicumnm data Wmnohm and 910nm spinal ﬂuid mum to a slow 1nd of chainsaw” activiw. at peripheral “mat-.1431 w chained: neat: 1| thn hypotheti- roaming central nervous syntax nictivity to “rte elect—reducer. �thmmphmdem, 1) mammmamnmmmnud. It'snhuato 3) Whmdduudbwhmcuaoﬂurmmﬂmﬁxm ﬁn" memm—Wrww. «swim 1nd... W tht ‘3) a) shamans activity and patterns ethical norm all at up blame mm a m” a) ‘) 1’) at. of W at M “1 frequency at emu-mu (patina-1) mung; Momummy. mm 1 .7 �NEW» J? I i . , \J Danae ReleefAeetylchenne / bu]. ' E ”Km m Mm at i E Wvulsulﬂ 45% (”<— thenpyﬁdmtnted thet/ Gen-change in behevie 6 wee the development or slowing up he"? as f Wheat oheervetion W - we. index (Finkw and ﬁlm, mined unclear until the «out report! J’ the than; at Mention with high deeee of atropine s f1. E «‘1 E {E ""1? ijmtmg Week WWM”) ﬁcdw- View. describing "‘" hum-tomemﬁemmenw E)W” “M" “ W131- '7: the role of care- Wrelrequeite , ?:- Conan/.hve in the melanin o: WW0 E F amazes - 7'3""‘ early and persistent eight of altered cerebral Mention 2 E 15:7 umrmwwww22". 'W‘m~" "M" m-dbe’prevent the appeennce of the EEG delta abnormality (meet um John-on, name“) 1d; 1956). Following the mggomm at this report, we role/ Convu' | £09 of eeetylchame and cholineetereee in therepy. The data up]:- m E W ”‘35“: e m clue relationship ehetreeneephalogrephic S‘ounvxﬁ ities of free eeetylchonne 1n Wane ~> between the degree and persistence of the led the appeuenee of measurable quant- the eerebreepinel fluid as wall as an inn. vereim of the annual ratios of bensoycholmemlinemme to monomehenmetereee . W he role. of ecetylehenne 1n the bum tea! study since the Loud tnnuﬁdan first eﬂeﬁe—by m1. (1911:) and/(1921). the 3 description of We. W of nervous impel-ea he: as to whether gmmm "’ �lawmanaalyﬁgentmthomaiuionofmuwmmmmmt cf pm", man: here. It in mnmnt a normal constituent of nervous is liberated m it mm in n baund torn and tiuuo; that during the excitation process; that through the specific notion of that mtyldzonm 1: Minute” 11'. in rapidly hydrolysed aid as rapidly raconttitutod by tho Wtyhu‘ Bysm (Righter h mainland - new]. «3&0;me ﬂuid 191m) damn W W contain- no 1910).. in» mtylcholim (Tower and 1493116th mo rapid breakdown o: bound acetylcholine during periods of activiﬁy and excitement. cerebroapiml fluid manually has The chain-stance activity, principauy ”ohm hydrolysing typo (Warm and of the ducribed, eloobmemelﬁdlogma Effect. :3 crab fail to 'tm‘ or w condition- Wm Show Tram: W Bothenborg. 1915). In tbs shame of fmo «Mammalia- and under the (3.) Fummm, any conailtant abnormality. 506-) ﬁﬁMU Jeotad to varying degree: of had tram, Bomtainﬂﬁut abated that (I 4 In. �‘1'. acetylchmne uppeu'ed in the 08? within a _ few aw” minutee etterhtnme and Wm up“: Wﬂoeitiwhnktm persisted for verying periods up to he hams. hw_¢,_e./ ”MK“ at tame/:1 ﬁe quantity of tree W... W”-~Nu '{L versed heaven 2.? and 9.0 pm per cent, Mi 'Wgne 7__ ‘ , “MM . Wu} Mm amount-m. electroencepﬂlogrm 1111:1113, the Vracorde were mud filled with all patterned changes. high voltage recorded electrical fut Witty. 1n:1 short mm in immune. my!» mum F. - activity. mane periods then Inﬂated by prolonged perloﬁe a! high amplitude sharp the delta “V, z.- terpreted as an intense neuron-J. discharge; only to he followed by m “I. were 0.190 correlated with degree of tame, WW mtylcmhemthegmteetdegneotmmmntylmthe M seventy-M WM. as well all with the level of tree mtylcholine. with highest levels W MA. 5(- in containment-change- in greatef and '20 J gamma“-/' ‘ period of ﬂattening of Iﬁ‘J‘ eponteneoue of. name, poet~tremt1c eeimree/ 0/1/24. Wow furtmr substantiate these abstention, Bemetein applied ecet choline to the apoeed cat oerehrel cortex. acetylcholine use 1 gm When the concentration of per cent or lose, he observed high mutude �W“ sharp ms at low frequency castration m immune! to mum . m (£2, patimto therapy. gm pan-09111.; Eu mount "(19349 a.) :1me mpeutud was found Wham the can. the electmcaphalogm in a fashion pummel to the poototnmtic Tower and @ 2 in the electroencepmom. ”com. by}; WI W ”arm. thou studios in in up «rebroapiml ﬂuid only 13' '7 adtmm,moentgmm«1uuure3}nd’m that :m neotylchguna varied IMOA to .100 gm per ant. In ”1 addition. Inner and Mencken-n assayed the cholkutenu activity at the spinal “Maternal M (W ﬂatwf/ m. W W fluid. They noted a sharp rise in the mamaiﬂc oholinesterase (berm. Molina-splitting) .WW” with”. taunting thanpy._ Ho such inversion m dmmstrated 1n the fluids containing tree acatylohonm following Spontaneous seizures. than: authors oL ‘ do. concludcﬁt the m1 of tree acetyloholm varies directly with the degree of cerebral W P. .._ ‘ 3% dam; Mr, rover-:1 of tho ohalinenterue slum inﬂate:- nt con-bra dunno. adding, tau a, that the traction/tram non m �W -5- want-)Ww an m at (g m of those i P 5 tervala tanning MA mm, direct cox-“hum of the _of Em Mommy m appearance of true uoo‘ylgaolmo in the nnbmspzlml Tf (-l [I m. I' that. eminent-b211, traum- WM ﬂ” W/ m I 1" m?! mes-d a in- the ﬂuid. . min-11mm- ofﬂaoctyldmnno in tho Imus]. ﬂuid; and, that the” bemoan mum the dim: degree pthmtylcholiﬁ, aim wt at and type ()3) {“49— . ‘ varying 1 . lA~ mammognphic nbnomlity/ an!" clinical War. am Am g. mtg-swan at EEG and Behaiorz ﬁw‘x mu Mud- W u“ /w mama-d {munching at mam attests/Mb— . W j—h‘ “1.31m °£ 3th. 6‘“ W ”ﬁshnet-n1 a and neurolcgic {.1336 of W *h tum. trams. 4;; W ”1.574; Mn“ 2 “:86 awn/9 Men of 'mtncistorml acetylchoune, which induaod Em and clinical . W effect of utmpdm. closed head In 20 clung” 11:11:: to had Ward (1950) tum, Bgmatoin applied axons 1331117. 1m: 06 31.10414. _ Water! ibis—W to the trentmt of 0... human pttienuuith varying agree of iatarad atropine subcutaneously in dam o: 0.1 when In cues 9f m, , be achin- M can! �r WWWmmmm—W’mmww E aux. mmmmmmlmm'mmm rmml at tho electro- ,_ .W. . A E. enceprmlognphclc effects . W ~vm1Wv—wr E m. cholinergic drug, a! alterations in the report 31mm Inﬁm study of author anuJaguar and Loom (1955) 915::th We Ammumtmnmmhommammmmm E E «(At a_ 833”“me r A-..“ ‘ m . __V W tu: 9.11.4447 M W mudmmmnmgmzzmmmmmdwmmcmm of atropino in blocking the following the 010% and Johnna (1956) WW w W and I in m Wm of that wave activiw therapy. this study suggest; an biodmictl in head mm.- Mutated the smith“ ﬂat uﬁdeﬂ; th- chctmnoepkﬂommic \ I \\ E I ‘ _ manpoz'tstandaoutinconmsttothuennmngarlnﬁwhm_ ' \ pennants Brenner and Merritt. (19M), applying topical aoéﬁyldzoline 1n concentratiomctﬁtomitoWWcomdmu,Wmdfm i or intmenma atropin- (1 E E It is important to not. the r ‘ 1r E nag/lag) on hmr, oloctraomphnlom that the concentrations of “Mabel!” in thésa expemnta ma signiﬂmﬂy higher than the topim¥ upplioationl . r E . L E «hang». (1-1; game. S) and than intncistamn1(o.2 . - 10 N , Born.of gum)1njecti%a 1 .:/\_ .\ �mm Banner and (19115). ognphic affect: 01101130) and than tbs imu hunt, annu- to doryl hunter, m not. of 0100th :cetyuholina from mecholyl (nootylhetmthylo (Micheline), not: in mneontrations 193$).de concentration. mh 1m:- Thq ascribed the manned effect- at those abolinergic drug: to their lack of maitivity to cerebral mums. mm high «11 u n epileptic”, mm In (W, ﬂan at 913;, am. In author 1950; degrees a! abnomlity noted in mhtmmtie boom 339,, 1919; and Emma 23$.19So). m1 if present, ﬂu», mentor} The tho in: warn W by ‘ study, Ghntﬂald and aorta with prosuwm 39m activity. or 1075531; studios, too, the olectmneoﬂnlognphie effects .1111 date! exposed W «puma. npid fnquencykw similar, to status Dempsey (19152) and «oh-d pnpmd eloctmemoptnlomma prior aduiniatntim of ntropinn blocked this spiking, Ibnomlity could be 15leth by atropine. a variety of upexdmntul and clinical elude that eloctroenuphnlogmphic nativity induced by studiu, u- my con- uctyldmuno, nth»! �w .—-——\W- W.. 'WM as e result at Btu-Lug tram, topical application or interference with nee-all period! of aetiviﬁy, 3% free acetylcholhe in liberated W, mm, when it in rapidly Mum by 01103111081283”. {mu—ML WAammchmne 115M101: at ma We, hm. that the than the Th9 10701 mint, of remnant of the processes It may be postulated. therefore, m1 mm rise during aleep and run mmiﬂw. this methane is true and is at the cell That we: denountrehd by Richter and Cree-land (19h?) Swank and Render-eon (1950) in animal uporlmntn. m using liquid air quick-freezing methods, Edema: and Greenland denomtrated that. mm the anesthesia and sleep 1M1 at wetylehonne (manned ea per a. brain tissue) was 300% difference in ﬂame level: rate for acetyleholme in 21g f” (1950) Maw, “ _ Vﬂ ' *~-~r-—.._ (ﬁtter mtmole camﬂei brain is however, an the meynﬂxeeia high (7 W‘“ observation» The game/alum“). Elliott W‘mey H“ , 0,94» A noted that ”W «J'N'n‘ﬁ' a free mtylohnline was always demmatrabh WW”, x. is tme’imt, at 6611th these higher than the poet eeiaure level. in - �-7 w» mmmwmm_—-— '“ " ' - : qumm unmadﬂﬁdmmcmquptoBmwmt. m, In ’lpin-J. ﬂuid audio. in fear and Kahuna!!! (191:9 B) Illa Geno, Tan:- and He Enohem (191:8) and mmm woman!) in patients with opuspay. free (77%) mud lignuieant quantum: at Of 56 OpilOPtic W mammal.- rm miyloholine directly ranted to the momma to the last minute. W ‘in quantities of 0.02 to 5.0 at cultures, the extent It hon no mention to mansion, cm emulsion, orwhetharthe «nun, that. the 3pm ﬂuidisabyb mummammoamumd-s is prom-untied. Tm: and When: hem-ad mtylchoum liberation in not itself m‘mntod to the mic is buie to the scum process due mung ﬂu ”inure.” process, Torch (1953)/ induced» animals by metruole. She dctomined mm; type of epilepsy mm.“ line ot‘ I “ﬂammumymmmauzymm or the mo-ammm af-f;m abnormality, ml the mung»: of or lavai of choljnaatemne activiw. product of the M; J gum per cent, with In may at 1.0 gum per cent. 16791 ﬂuent“, tin level 01' (191:9- B) to up be. “ism § mm Won: 1:: mammalian in bran �Mam berm nadduring W Wm. mm¢me convulsions rise in mintymmum Mutant of tissue; that tho by a my» mum Mfﬂndudngﬂwcmnlﬁm3umﬂutbomcemm15,m whim failed to occur, )hrﬁzem/de a - \\\_~_,_.H_. than” K.’ as during u convulsion We»; H111» duo V‘; to inhibition at aoetylchenno mama; martial. argument” about. the MWWM’ZMMM choline the W Mum mﬁummum Inch 3: ram-m; ' mtylchaum; while sleep and W . mtautivity tum 1m].- nf and - 15min. WW magma: mem- mum 0.th mtylchoum produnﬁan abut-ration: of change: in mtylchonm, armor and of of W»! Gmtlnt War/wed...“ 03m. Mun 1m. W Mb... in clam ﬂuid Jan-L, dostmcum, lowering mowing J.» —_‘_..~... . ,‘_‘ manned concentration- at by tum, /" prob-Lb acatylohouna, but in m msm"ﬁot¢&nmumtthofmmmmw in mm poetuhud /,:v’ . ‘ whim: z” with When: (1916),..— min-1 fluid cholinemmu activity. are normally fwd 1n the spinal fluid: than Two W Minuteman-I �\ } 0m”, - ~apec1nc',§ or ity for wetylcholine; and hm mxéming)mm Bath W W Wyn for Mom and differential rite pend” qualitative distinction... cholirmstame activity a, memo. has a high cholimtarwo 'II (.“psaﬁdo', 'nm—apecitio,' or Mam-manning). dittemnt. rates a! madam—1 1 .éetymxoam, but Mandamus. By Thin ‘ ”porting the M ratio of the activity ”errand and prf W(mﬂ1M/Aah Wk”: bent. oylcholiué swam—ates to an aoetylcholim substrate, m_ meio- are round: WMw-‘C/WLW M osr contains antenna in an _ Thus, normal 68! consists ntio - /1,u?l’zjdua.2 mo)‘ In such 0133:17 for n“ non-specific ester-nae component. In institute with hand tram, Tour and Warn report ‘5 dwinzfTr W the dog-reset mmtyg ﬁzz-J2 65.x; tram and‘tho “Av-o: ”” mu it" ,g 3 nAsimﬂmt correlation batman the extent of the chalkenamc reversal “in with ' 1 WW a)”; M minly of imposing" octane“ with a . no I , the oWncomalogmphin 33 3 Jr”? �In patients with 130de mu ﬂuid hétylcholm activity a I result of Ipcntenoouc seizures, hammer, no change in the ratio of chol- inestemea or total cholineeternae activity an Wm Manx:- Tower and a their study of creaioocrehral (19w 3), in ‘:A six portede psychiatric phtienta mapping in: * ﬁle rm. W); W patients utter 3.7 troatmntc, theymported {1; m M decrease cholimntame, a “I. tram, re- therapy. ﬁtm- rm ioetylohonne act- a: cholinectemco with a revered of the 5 W We: W ratio of chcnneetoru? in five of the six patiente. Fro: tho/e oblont “time more (V they concludejthnt the apinﬂ. ﬂuid Wax: are- “Du—4 ' in lib those of cmniooemhrel tum than then found in opucpcy. haul-ding the one patient in the series who {tiled to show either 1“ﬁeyW“ tat "It {mnwetylcholim or a cholincaterace ntio reversal, 0 u mum-ting that this patient was the only om o: the six to chow no recponce to treatment .' �Ducunm m , but than variant obnomtiom, In my comma that therapy induces spinal ﬂuid changes mm otrmrandwchem (191:9 rum to maps»). ﬂuid b), ﬂu W 111m cerebral tram amt. that onlytho gamma, railed ta show a response to peanuts us to consider the pwnibmty that such biochemical “t, basic to the machinist o: the W at alas-uric current through brain ular activity with an .inemaae to inﬂuee a grand mal'acisun. in m. Thu tmtnant, We m process. cnmlusiom certain further deduction: and ‘ago than than. an mamas poasibla. the pun-- manna: a change in cell- mtylnhnuno to level: uranium. presence at! free :1lech in tho �enema—II in Mt in other tam, W blood anew man. With a. 1mm in acetylcholino levels in the inter-canning fluids an a result of . mum amm'umnmdtmundmmmmmmmm annular ms dupendantm ma ottoman duration or themuon, (mm. ngm)vltmwpmwmwmbmmsmmmmw 81:6.me in mm mom (19M. "s2. W» M. '53). Thu I!!! convulsion, 3111:9301 and modihﬁna and nomad annular pemahility my �throws mumm;mmtmbmehmmud, luxuriant mmmmmmumw-m splitting m. 4 mummramtydmmmmmﬁomtormtw _ wwmumamwmmwtermmmtma ﬂmmm ’n. (rmr w mm 1916 B). mammmincholmMmae activity. mummfmmwb 1mm replay be ﬂuid nth-r m doatroyud? and re whet We. ”ism I» «edited? :1: can . . it’- pal-datum in in amplmtim for this (1180mm ammuntheobumtmormmmmm.mm" tyrower and He Enchun (1919c) and Bax-gen me monoun- At ”physiologic“ mantmtione, m «2% (m rapid (3-15 dam) mtnﬂm. mm: but at. higher and fans acetylnhoum nation-hip 1: with (195$). thet the 33.6w sensitive - chonmteme-I cyst. is mtienehipe. 1v1ty he Intonh cm). Wu, mg. with hem-1 ne- to concentrationor. acetymhenne 1s Mr concentmtiona, set- In contrast. the [hasten-e411 and the mm rd: of hydrants 11mm levels of acetylohnnna et eettutyoreheaamteytheepune «name-nu, theseemohenne inseam-I, 1n the order or nimucom. . more 3% annotation W - �loaf» In main menu-luau or mwlaxolm in mm tissue, at hydrolysis Mascara-2‘1: by ehouneumtn, my As tha rah an mutation at acetyl- thaimnthrydzouu mammalian”. occurs. In. dissociation inpootylcboum - Ghanaian-a I whammy results in a par-- mm,1tu1f,par}upalddstothtlmlof unﬁt-#61:. with munnu mom-ea untmoeofaoetylchonne. nu ﬁtym. mm gym: pemmuw grim .W 1mm muesnmnummmmnmumﬂ.'1t1umauuwottua ant. vascular and 0mm, aid the or mummcm,mmmmnmmmmmt, ypuulbi uduoeathnm‘ylcholmm, action at ' mmudm,umrermmo1agu muons-I mm,muhasentumm,ubccomnmummw �all?» . ! I W dwwm{mubm)nmmmmm hmumnamwaotmmmmmmuu Wuhnecmﬂmdmmpnvmmmmtmmm due” mu, )2pr m, extent) its in lost abducts. Ila-pelt. n m up at uppunnoa mum: m vuy greatly in of mg: dogma WW. nut.- daumua: m 2171 to modiﬁcation by ﬂex-ting, ituntosa- has bean W applicatiu: of b mmmﬁan and hub-- w psyuhntzic popﬁhtion. me and 1t! any appearance courts, trait“: Want yum the 63mm u n uncanny pn-mquuiu for Mt following 01.0m— m( ampmumwmm'z Pcmmiomudwm. M&Km,1956). ButmtutbcmhmiumucﬂnngtheMnno! dialing and Mentor-Ion m be nut-d. Assuming that a grand Ill is. seizure indicative of the MW of tism le'nlloffmo mmmnm-«mnudwwwmm-I/ ’md ehctmphdognmc hyperqnchmil a reflection at u: um. the per-31m of thin abnoml commutation a! Micheline; than the difference upmummnmmmmmmmman W(Mhouni Wm, 13 a nﬂactian of tho mm m W «we. d tho dammsuwtymm Persimt types-3mm units m- M nt- of �.vp—v—vW—yw—qw—nw « W ‘13mzmmmmmmm.dummorwd WWW. of ! ﬁn {ma-mg postulates are opontiiu k £3 menu with pom-tons E chm; l E W . Westerns-i 18 in low cWﬁﬁ;u tint 12W in a great 1) . spread tho hm tho amigo]. mum- aubatmh Mutation and at Wanna-II 131m. no that tho concentration 135mm. of chum on oporatiw, [and hi. W1: a lion docq nu. Camel-loin in patients with short hypersy'mhm, Whoomrnae-I and-II in tissue mm and spinal a. ”7 fluid am we produotion of tissua cholimsteaé-a-ao-I 1n the oentml nervous syntax. W mm WW ame-I my“ aim-rm tho lucid studio! o: (1955’), mutation of Mam? cholimateroao-J ﬂ ‘ 35 4‘— high. \Purmemon, the appeal-once or nigh concentration of acetyldxouno am in I new with high mummy 2) and those pmsent and a direct mum}: between on» level of aetiuty can deMa’o be ‘ do... 91»th 1M Manon» my stunts chainsaw-1 pmduotion to o m zoom. stated 1:: Massive psycho-3 (fungus-.1 60pm). than tho Wu! mu. Eﬁofji 1 �‘ .53.- In moth-r cutout, those studies of outcome reactivity. “Eadie: _ In have opplioation imp-W by to the woman Watch an! other: havo damn-tram a mhtiomhip between the blood pressure reopen-o of patients to inject“! mohohl and ahock. Namely]. Ward“, is ﬂair mama). naponaivity to alcoho- a potent oholinugio agent which induces sweating; and vuadﬂation, momod peristalsis. It is rapidly cholimutoma-I and slowly by cholinostam-ﬂ. Tho W 15'de w pressure of sub- mu an: arm- mused menoml and Muml to the baguun. 1n n variablo length of tin, 3.3. the to natal-unto ' 20.119112“. more than Patients whoa- blood pressure “mummswmmomieduaroupl, II, QMIII no notions; those whose blood pressure “has 20 or more 11mm to rotum to o MWImotonhwooﬁm WM M”! mt ntouitthdthonupII-vmructomaﬁimute. hmmmmnmtonmoMmmmwpﬂIn9ﬁmmxy buoﬂmueroupvlmdmmcum. , g" Wilt-v rats. (momma at, 1952.) ' hmmmzummuummupumumm-mmA Wmédmlylio a lion npiﬂyhydmlyudy than the W81. nu. V. may Gmumm potiontahan m» predict. Hanson, that tho tholinoutenu ‘ uuuwmnmdwxammuldbohighyuhuoﬂmmuvﬁy \va x �a. dwnamwum. Homnhnrcaamrpnmnm mmurwmmmmdemM4,mumuu mammmmwmmmnmmmm mammmmﬁarhmammmmmum mmaudpwmmwmmmumpmu mwnmmuammmmuwumm. �Wmmamnﬁanummotmm-oraammmm W emmwmuummamyummtmwmm l quire #11: veriﬂmtim. 1mm For this purpose mutionahipo ho WM Wash-at 1) it in anaemia. ' murmumaammmmmnm. typo, OllQWﬂogrlI patterns. m and magnum at suggest-d that an mam. 1‘4an A1», the “mum 2)Rohumdmchmty1choumuvohtothomnicalmd patina“. 3) mung» 1:: indie” or mama brain nmcuon othorthnn mama: such mtylrhmao 10701:. h) mums; of cholinoatenae actimy and patterns or blood spinal ﬂuid to: 41)le b) We!“ a) ram otdwoloznant of 3m , d) amber and frequency of tmtnentl a) antennae (perimnl) mativity f) 60mm]. meti‘rityo 14 .& 7’ 5. Wm n... WWWM? éIJMW~ 4* , um and �111: 7-3-6A (I: on rue ROLE or AcsrrtCHOLrue ' ' 'vh .d) AND CHOLINESTERASE 'IN'OONVULSIVE THERAPY -« IStudies evaluating the role of cerebral changes in the mechanism of cenvulsive therapy have demonstrsted that the develogpent of early and persistent signs of altered cerebral. function are prerequisite to changes in behavior (Pink and » t A ~A. . at ': n . ' .c. ‘ I: ‘c .' V A s ', <:-~t ‘ Kahn,‘l956), In these studies, electroencephalographic slowing was the nest significant.index This ohzrvation remained un-v clear until the reports of Ulett describing the effects of pre- medication with high doses of appearance in the atropine preventing of the EEG delta abnonnslity (Ulett and Johnson, 1956). Following reniewed the suggestion of the we report. role dt acetylthis cholinestersse in-‘convulsiva' therapy. ‘he data suggests a close relationship between the degree and persis of the electroencephalographic slowing end the appea ence of and choline measurable quantities of free acetylchnline in theygnrebrnspinal / influid as well as an inVersian of the aerial ratios of benenycholine. . 'cholinesterase to lecholylcholinesterase. that: The role of acetylcholine in transmission of nervous the impulses has been studied since the first descriptions of Dale (1915) ..snd Loewi (1921). The srgunenta as to whether actylcholine' is the main or only agent in the trans-ﬁssion of the nervous, impulse are not of primary concern here. .It is sufficient that acetylcholine is a normal constituent of nervous tissue; that it exists in a bound torn and is liberated during the excitation is that process; it rapidly hydrolyzed through the specific'action~ - A ‘ " . A .1 F .v «an ‘ -< _- : .V. l antes-.3 var-I‘m.- ,, . “be”: wMYJ/I'" 44:: gauges-5mm �. .1 of cholineeteraae and as rapidly reconstituted by the choline- I ' acetylaee system (Richter &.Crossland, 1969). Furthermore, normal cerebrospinal fluid containe _ free acetylcholine despite the rapid breakdown of (Tower and HcEechern, l9b9a) bound no acetylcholine during periods of activity and excitement. 'The cerebrospinal fluid normally has measureeble cholin- esterase activity, principally of the "true" or mecholyl ’ hydrolyzin3 type (Nachmeneon and Rothenberg, 1965); ' In the absence of free acetylcholine and under the conditions described, electroencephalograme_fail to consistent show any ‘ I abnormality; .. ‘ i (a) Effect of gregiggerghggl . 3 Exagggz .1n n study of cats subjected to varying degrees of head trauma, Borenetein (1946) reported that free ecetyltholine appeared in the CSF within a few udnutes after experimental head trauma and persisted for varying houret acetylcholine quantity of periods up to £8 free _The varied between 2.7 and.9.0 gamma percent, and-the amount weeV poeitively related to degree of trauma...‘ Conconntant electroencephalo3raes demonatrated patterned chan3ee. Initially, the records were high , filled with n fast activity, interpreted as voltage intenee neuronal discharge; only to be followed by a short period of flattenin3 of ell recorded dectrical activity. These periods were then followed by prolonged periods of. hi3h amplitude sharp waves in the delta frequencies. The . behavioral chan3es were also correlated with degree of trauma, as well as with the level of tree acetylcholine, with ,higheet levels of-acetylcholine. Bernstein reported the greatest _‘-_... �_, ‘ 1 , _ ,. .3 w. a yawn-mun?” lift!“ .1»? . .. my vmr in?! 0...“, yr,“ y». my -1,“ 'V'W'FM' cream-ls“. . _ . .~ > I -3degree of m abhor-slit” the greatest. and thence; in consumes ' furthermre. spontaneous post-Ftrat-oticseisures livers also related to the of tree aco'tylcholino- appearing iii the apical fluid. 1 “t l..,‘_.‘.__.. l... V A t ‘ ’ further substation ,theae‘ohsarvations, Bonstsin applied .acetylcholine to the eiposed cat cerebral cortex.' "h. the concentration of sutylcholine use percent or less. he To , ‘ . . ' EI - . line ‘ observed high amlituda sharp waves of low froqmncy in tho electroencephalogram. When/the concentration ‘ves increased to 2 3—: perceot,’ the electroencephalogr- flattened in. afashion parallel l to the post-trematic records. ‘ . Tower and HcIIchem(l9lo9a)'-Iropa_ated neurological pstients. thssa studies in Irse acotylcholins ass 112 foond in the cerebrospinal fluid only in the patients with. rocoot hood trams, ~recent grand-ml seizures or convulsive therapy.- The free acetylcholine varied from 0.2 to lOO' 3‘s perceot. lnladdition, Tower end lichchern assayed the cholinesterasa activity of the spinal fluid; They noted ashsrp rite in the “nonspecific cholinesters'se ‘ fraction '(hensc'ﬁiholine-splittiog) and a drug in the specific choliioesterasefractiou (escholyl-splittioc); in the patients ‘ with head trams and those'follwiu in Mlsive thereby. no ~ - such inversion was ’d-oustrstod it: the fluids containing tree acetylcholins fondling spontuooos soisores; These authors concluded that the level of tree acetyleholino varies directly} the degree of cerebral dance; «nesting, haever. that with. the reversal of the oholinostersse' frantic: cos ‘a sore sensitive indicator ot-esrshral donate-V ,' I. ' _ ' ’ �7-1-2 intorvalo following varying at cm in loot of theoe anhjeeto. .‘lhe nthore reported a direct Electroencephalocrnooere trano - m and the appearnce of the of ahnorn'lity degree correlation oerobroopinal fluid. in the of free acetylcholine _ two Theoe ' increeoe the etudiea indicate. that crnioeerehral tron-a nay nomt of free acetylcholino in the opinal fluid; ’wt of froo that a direct relation eniota between tho acetylcholine, the degree and type of eioctroondphalouraphic and abnormality. and changeo in clinical behavior. ' Bornotein adainiot'ered O.5-l.0 tog/its atropine after hood traumawae tho induced anddennatrated blocking of mifeot no effecto. Following the experitrana.~ induced intreciotornal which ecotyldlouno. addition of jof and neurologi'c eigno behavioral nntal 2 clinical change. oililar to head trouno.'lornatoinohoerved 1 blocking effect or atropino. zoo and , Vardf1950) applied theoe idoaa to tho treatnont caeeo. .. of hulah ' of closed head injury. .In 20 patiento with varying degree of trau'oa.‘ he adminioterod atropine outmoly dooea of in 0.1 tog/kg. In one eaoao'henot'ed'clini'éel ignorant. and in tho of electroencephalographic of the 1 othero, revoroal effocto am: ntioholinargic of 'otndy a another dm. tragna. In Lechnar (1955) reported oinificant altoretiona in the poet- and » tranatic electroencephalogrn. inota‘nceo ' in 22 of A. oingle iatrovonooo dooe in abnornal electroenoeph'aloorno reoulted in inatoncea and unto-a iaprovooont 1. eix othoro. ‘ 1.0 nor-dieing ! o , �. 3 Iv. . . p 5 u ' .. ' ‘ , . V“ U - 'F ‘ ‘ ' r ‘‘ Ulctt and Johnson (1956) donoootntd tho I... ’oﬂoct'ot Antroptno 1n blocung tho oppnronco of no: 111601” couwlo1n. oct1v1ty vi. than". an' mood: tho study oouuto tho that 0.- Motbdcal .chauo. oloctMuphoch on... 13 hood ; m... cod 1: ,.- i . “owl-1o...1:: oootrut t6 thou 11.11:. In an: out undo noon 0. mod-onto Broom: .d Hordtt _(1m).__m1y1og top1c‘11'ocoty1f161111.11 ,' - 1 ’ thou. of tom! 1o concoctrouooo o1-2-1l2 «to; noted no offoct of clocttooocoohologuohu that tho mtntw. no “unfunny atom an... 11: to tho otrop1. of oootylohou. 1o than tho tinted lad-or tho .rooot) ,m :5 ~ ' I m2. W at onoophalogtophic otfocto won Modal by . ‘_- A #ﬁ.1w-_ ‘ moot“. . -V . in ﬁ...___‘..-% 1.,mr-4gmv4._.ﬂ 41V W to 6.1;.an about:- ‘Wq 1950) 11.. 1950).. Inothou 3 . 1 «duty of 1.011qu nth choumtoruo' 1nh1b1tor on (614.9:ny (Imam-photo) Mutton 1113b qutodo 1‘.“ (Money pot... “-11“ to out. 1n opuoptmoo. u -11 u 1.3.: «lop-o. of no.6 .' 1969; and v _ tho potont post-truth: . _' . ototuﬂlltnttcmuot 11., - on tho h w ‘ motion. to. thutlod o1 logo1t1v1ty A . _ . tut1oom1hoyucﬂbold01Wdfott1Mﬂthou- at"... ‘ 1"...“ § (mutants). I _. '34; (oatylutuothylcho1bl a“ by: -chol'yl 111 commutati.oh 1.» ti.” on. .otylobu. concou“ch ennui-31c. drugs to w...h- hM-—mbvwmmr wWe... am (OJ-IQ ‘ A quuuuu'u (1-1 3-1 oloctroooooohologrqluc oflocto 011111: to 4 ﬁlls) to ooto. '- ‘ (1 1-..... earth: Mt tho. Wu 1; atria-tuna 'o’z Wain (1946). mm: .11 smut. potent) at] ow w. m new”. at .1... too, tho “cotto- 0.11 dam of otrop1oo. �- 6.In another_laboretpry study, Chetfleld and Dempsey (1942) 'ptepered exposed animal cortex with proatlgnlne and evoked electroedcephalographic spike actlvlty. The prier.edu1nlstratlon of V . _ ‘ 'atroplne blqcked’thls spiking, er if present, the abnormality could be elimlnated-by ettopineuv Thus. from a _ variety of experimental end cllnlcnl studles; __ we A may conclude that.eletttoencephaldgtaphic aetlvlty_1nduced by ‘ acetylchallne. either as a result of trauma, topical applleation qr [ntefitxcnce with cerebral metabolism, can be blocked gr ellmﬁnated 5y atrnpxne (a) ‘Role of Cerebtnaplnal Fluid W...‘ " Acetyicholtne normally appears to be present-1n nervbus tissue in bound. inactive farm. 'chollne 15 activated thus the During periods of liberated at the cell by Ac cholinesterese. activity, free acetyl- membrane, where The it is rapidly de- level of-bqund acetylchcllne ls resultant of the processes of sinthesis. liberation breekdpunw It may be and postulated, therefore, that-the level wlll rise during sleep and fall daring ectlvity. ‘That this hypothesis '15 true was demonstrated by thhtet and Crosslend (19a9) and Elllatt. Swank-and Henderson (1950) in anlmal experiments. By using ltquld-alr‘qule-freezlug methods. Rlcﬁter_and‘Croaslapd demonstteted that the anesthesia and sleep level of acetylchollne {measuted as microgtemﬁe per mg: brain tiesue) was JCCZ higher- poet thaﬁ the seizure level“ ‘The d1£fetence_1n tissee levels is trapslent. however. as the tesyntheels rete for acetylchollhe 1p rat brain is high (7 gimme/gm/mlnute). lﬁlllett‘et a1. (19$0l; a �- 7 _ AIter metrezole convulsions, confirmed these observations [they also noted that free acetyl~ was choline ttatione always demonstrable in the spinal fluid in concen. up to 3 V . l genus per cent.> ln spinsl.£luid studies in and and Tower (1948) Cone, Tower and Menschern men, Mcéechern.(l949h)-slso denonstrsted significsnt of free eoetylcholine in pstients with quantititCe 56 enileptic patients. 49 epilepsyl"0f (77X)'demonstrsted’messursble free acetyl— chuline in Quantities of 0;02'to 5;O genus oer cent. with an average per.cent. lhe acetylcholine level was directly reletedl extent eelzures; of electraencephslogrephic the to the frequency of ebnormslity..snd the telation.of the time of coupling to the last of.l.0 gamma seizure. It hare no relation'to indication, type of epilepsy or“ .Ievel of cholinestetese sctivity.ll ' . , Whether the acetylcholine appesttng in the ~ '. A 3 g. spinal fluid is a by-broduct of the convulsion, or whether the incress} in acetyl- I]choline is'n cause of the seisure, is problematitel. McEachern (l949b) Tower and believe that the increased scetylcholine libetstion' ls not due to the seizure itself but related to the basic procees' causing the seizure; In a s“dy of the hypothesih that the accumulation of scetylcholine is basic to the seizure process, Terds'(1§53) induced Canvaeions'in animals by nettezoles She_determined the level of scetylcholine in brsin tissue before and during convulsions. .She noted that convulsions ere preceded by s " rise in the scetylcholine content of tissue; that the coucanc‘grueuaiiy fells'durins the convulsion; and that below certain levels, convulsions failed to ‘occur.v She suggesteﬂ that the fell in tissue scetylcholine during convulsion use due to inhibition of see.tyleholine synthesis by concentrstious of metabolites such so smunnium ions. increased a ' �While ebout erguneut the role of acetylthere.ls considerable choline in the mechanism of seizures. it is probable the: free acetylcholine ie increased during seizure. and appears in the cerebral spinal fluid; that activity and eeizures enhance acetylcholine destruction; lowering tissue level. of acetylcholine;‘ WW while sleep and enestheeie.eugmeot acetylcholine production, . increasing tissoe levels. 7 l. . rd) Concomitant with their observations of changes in acetycﬁbline. Toqer and Mczechern (1949) oeaeured spinal fluid cholineetereee activity. ‘rwb types of cholinii lesteresea are normally found in too ebinel fluid: .cholioeeteraee-I ("c-me". "specific" or-necholy'l hydrolyzinﬁ), which has a high: ' nod specificity far eeetylcholioe; cholineeterdIo-II ("peeudo"." epecific". or beozoylcholine-hydrolyzine). -Both coupounds hydrolyze' - ‘ ecetylchollne, but have different rates of hydrolyeie ftr mecholyl "and beoZOylcholine. -Thioldifferehtiel rate permit! duelitetive' distinctionse of the .By repertins the cholioeetereoe ectivityJee e ratio. activity with uncholyl and benroylcholine substrates to on retidio ere found: cholinesterene-l/ choline-tereue-II[acetylchbline.(with Ash/Ash - 100). acetylcholioe substrate, acetylcholine and ln-such ratios normal CS? two contain: eatereeee in the ratio of 33:17 ‘ior choliuentereee-I to cholioeetereee-II. Thus; noruel CS? consistedllllllli with of "epe¢i£ic” utterance a euell non~apecific eetereoe component. mainly ' i In patients udth heed tron-I. Toner end Holechern reportm m inverting of the eniupte of dbollniptirg‘le with d lignIIiCInt meg. mime unionist-nan meme decreaue in choline-cerebe-I ectivity.- betweenthe current or the cltolihbotereee of mm fluid and e They eleogreQOrted a Mﬂel correlation with the severity �of cm... W the of electroencepheloirmhic and with the degree I II I abnormality; '- . ,I" In patients with increeeed result of spanteneoue eeieurne. of. 1 e 395-1221: r" , eoihel'tluid ,ecetylchoiine howewet. no cerebral ad Tower tum, ee e thmge'ingthe ratio. cholineste'raseslor total" cholineetereee ectivity‘ w _ wee found. nonethern (194090. in their etudy of crazie- reported obeervetione in eix peythietrit petiente undergoing convulsive there", \Studyiegthe patients otter 3-? treatments; they. reported tree ecetylcholtne activity in the Iepinel fluid in two petiente; end en increeee in cholineetereee-II and e decreeee' in aoli‘neeteree'e-I with e revel-eel of the retio of cholineetereeee in five 6! the eie petiente. In: the,” Nobeervetione, they - like thoee of ctmiooen‘hrel tron-e epilepe'y. petient in the Veeriee who foiled to ehow. free eoetyltholine or e cholineetereee retio either Mani-in _ Regarding the one the eoihel fluid. they Petient wee wtou:_"1t.ieinteteetlnsthet thie no" one-of. theeie tee-me. to only. to a... the tree'tneut". .. . I 1 ' I DISCU§§ION . Fran theee verioue met-yetioneQwe hey contlode thet canvuleive therepy iodueee epiunl fluid like cerebrel sore ehmgee emtw thn than of maintained. we chpredtet trans” , epilehey. If the perhllel ie‘ ot the degree ehhtitn new electroencephalogrmhic ebnouelity, the acetylcholine, end e— , thaaee the thetfluid epinel in cootlmd induced céwuleione were sure thihkthoee found in . “arena of free revered of cholineetereee ectivity retioe �-.10 _ the splnal field and the nunber and frequency of lnduced cone vtlslons., Also, item the observntlans of Tower end McEachern 1n (1949b), the cemment thst ohly the patient who failed to shew. -§pinal fluid changes-talled'to show a response to treatment, ptrmits us tu consider the possibility that such biochemical bas1c therapy of the the chmges are to ccnvulelve medical“ process. cpnClualonsiare pnsslhls'. ad The hasssge of electric current: through breln sw‘stencesilnduces in change sctlvlcy with an increase 121 free a deductions Certain further mm“ . acetyl-. choline to levela'suffictenti‘to1nduce a grand nsl seizure. The . presence of ' ' free acetylchollne 1n the intercellulsr fluids electrical hyperaynchronyr‘renscted lathe .386 as delta? slwlng-r The degree of hyperaynchrow sc'mrate-ly reflect} the, decay acetylchollne of should fonds! free a ad rate equal level S1nce studiesthe purines of deatrhctlon. acetylchollne rate to demonstrated. that EEG hypersﬁchtony use: a, necessary ﬁrvrequlsite induces. ' . ' ' to the cllnlcsl respome 1n central‘slvsthﬁapy. it my be stated .mu'mm chances that the dunes of free aestylchollne in cerebral fulcrum ad thus prilud'es s clinical rem the 1ndueed convulsions. tn Certain eat-muons nay be ends regardles changes In cell embrace permeability as emlal’nlng the incresse in theme-:- .estetasd activity; Chollnesterase-l ls feud m htgheat concen- ' tratlran . 15 ~- 1n the centre} nervms system; predominant in other tlesues. especihlly the increase in eoetylchollne ‘ anus chounfcsmrsse-II Innis blid serum With 1h the 1ntercel§lulsr cerebral fluids as a result of stlmletlon and cmwlslhn, vasodilation and increased cellular permshillty be Pradicted’;’ my ' D E .MLr-JM: 4‘ . ‘ . M. -. . t a ‘- . �~11} thﬁ inch:vasculdglfluids'tnto with a degree of ggancudatian of dnrittan of thg'. and ch. on dlpcndcnt spaces nxtcnt cellulnr vnddtlptlio-n _do occur numétous wag (um 0:11., 19m, anpiy.dcnonstrstcd ‘Ihnt ouch ”manna chm ' SﬁlejiIFAdolf 8910331 1n and by répofti (1961; '62, 'bb,"£§;.'53)é - . . denunstrat§d They cdnductivity cbhvulsldnn e1.c:r1c.11y_iuaucgd tacguased.che that Idikqgo pot-saint as ﬁargous of ions. 1n n cf the clouue; resultud thh lldid§ el§ctgolyths the while phbiphatQ, that and ipingl into and nan-cltcirolytés nngsnittcant 1n .tncraalcd. incrpaso 1h Gunﬁght prﬁibiliﬁy nucleic-acid abutting 'enzyus. of £011; may'thtu prﬁvida thé basil for-thudappoarahco of high ‘w-u 'contgntrati§u§ of a¢§tylch611ns and for lqcrcnand cancantgattons' of cholineaterasefll (Tower 1nd1HcBIéhern.19b9c)." _ . within. 1n;glil%;1n‘ch011héytct‘ne‘acglgitz; free act-tylﬁtoiiné _rnp1d1y> b0 dutioyoih? T.“ wit ohoﬁﬂd not tﬂe $phdnsn can ind uéttbed? agitate-ht. sbtml' fluid. arm: ugh; m panache-e. in. 1‘ qbuertitiann. EB. thin‘diactcpcdcf nvnillbla in An éxplanattqn.for ' Sy :kuurgxl (19.005). Nachuntoh of Mun-ad and__loth¢nber3 . McEdchcm (1969c) .ind poison and HuprtoIh (1955),.{thaf the acetylcholinc-cholthél'brabe-I'uyatﬁu is vary aanptttvi~co:¢on¢aq4 itdtibn relpttonshlpq; At "physiqlogic" éoncentrdtlons, hydtolysis , - and, buc'd: 1i higher of ncntylcholigi tdpid‘(3—6’nucranecoudn) qu1c¥1§itiL}dqno off cutv,). activity £111: lower cqngcptrgtionl. rtiatiénﬁhip to chbltneutaraac-Il-acutylchollno In conraac. the rafd with egocenttaiian. hydrolyita-tncfgases of the and non-specific. i . 'um. nor-.1 um. {mama mu- n: «manna. a cell ' Qéttvity' chi geocylchbltnn ipqctftc by thidgntioﬁjd npnbr-neny tho f ;_1 ‘jt �.i. V-“ wry...” m.“ r'rr'l r . v: _, r“'\7ﬁ"x.:r'7m¢rm., _ ’0"; 3 Of cholineaterase4l ithhe order of niliiseconds. . _Where - . . 'l excitation 3 A a , lead% to an'excesaive‘concentration of acetylcholine in nervous tissua the :nté othydtnlysia I by cholinesterase-I is F 4A A 'A’Q": exec-eded. thu con:enrration of acetylcholine mounts, the seizure threshold is reached and a seirure cccurs. The dissociation in ncetyichoiine- A3 m}! 1 “+4—ow cholinestern5u—Z zclationahip chnlinn The neiznrej liree acetylcholineul itself, The results in a perniatcnce of acetyl— pernapa adds to the level of “gt“..i. increased acetylcholine diffuses rapidly,» with resultant vascular-and cellular_permeability effects and the iPPEﬁvahcé cf inzréaaed ions in CéF; ﬁnd also etficiencf, increased cholin- r LAM; astsrawemii. 4 Aﬂnmnmm. It 15 the activity of this enzyme}.th0ugh'cf lqw- 3 and dependent on concentration kinetics that rdduceﬁ’ the acetylcholine leval;yaperiod I . j ' , of houra to days. tb levels - .__\._-xw-:‘.mz...' for the p‘Eaiologic action of cholinesterase-I 1“ Alteratian in the blood brain permeability barrier by the f ~continuing action of acety-lchoiin e may be the biochemical aub'5trntc {or the hvpcrsynchrony so often obServed in past~electro~ «nu—“\me'mut maﬁw—«A .hnck-electraencephalogramst Such a possibility is evident in the' I 'i ' ' report by.Aird et all (1956) demondtrating a significant increasn in the concentration of cocaine in brain tissue 3 days after a' 'seriea'of 12 induced convulsions. ‘ g of concentration tiisued to he His data about the change in i, . 1M . ' - ' In ..—.u..‘,~«.r.n.v.— 9-1.4.L — .1. “F... thi a large molecule, ordinarily absent in brain torrelatcd with the appearance of bypersynchrony ’ I (delta.bursta) in the elecnroencapnalogran. In our studiea of thc appearanca cf clactroencepnalographic he, have confirmed tire many changes with acmvulaimi .previous reports tnat convulsive thctapy induces hyparsynchrony in most subjectst Despite a constant application of treatments, ‘ a �«.13-‘ electro- however. the time-of'appeatancé. duration and extent of the graphic slow ' 1' A . 'ventiiation it; its sensitivity barbiturates - all QAV$f and populations. and - The to wodification by aierting,'hypervary greatly in psychiatric appearance degree of hypersynchrony, high early beeﬁ has the course; tieatmeﬁt persistencv throughoﬁt described as a necessagy prerequisite for improvement following Electroshock(Pink and Kahﬁ..1956). But what is thé~mec§anism" "undcrlying the failure of certain patients_to deielcb hyperaynahrony?_ Perhaps-thgse studies of aceryléhollne and cholinEstﬁraﬁes may be rélated. ‘Assumiug that a grand mal seizure is indicative of the at‘ttssue levels 9f free acetylchnline In eicess of "' ﬁhu fate of ﬁydzoiysis by cholinesterase~I;-and_thét the electroencephalographiC.hypatéyuchrony.13 a reflection of the'peraiatenCe, development ' of this.abncrmél concentration of acetylcholihe; than the differencé 1h pugzehts who maintain.hyperaynchrony"ind those lh'vhom it ‘rnpidly (fgv hears) disappears. is a reflection 0f the kinetics of the ch01tngsterase-acegylnhollne h§dtofysis systeﬁg Persistént.. hypersynchrbnj Insult; from dccteiqéd rate of hydrdlyeﬁs of ’cboline.v ¢ ‘arahstn-nﬂ acttyl- ,. _If the hypothclla~prevtouely'deducgd are cattact; nithér-ane» ‘ . . V ' . , f u-ww-xa..yrmwméw.w}v-JH‘ or both bf the felLowlng postﬁlateg‘are operative in patients with 99 tslsteﬁnt hypersy nebr‘ony: (1) is a ‘ . Chaitaeﬁteraseél is in low great.spread betweén the apt! thosé preéent '_and 1n cancentratton, an that théte' trace concentration the ttésue with high acctyicﬁolxne;vandlor' '(2) Chalinesregage-Ii is a1 enzym¢~aub low, so that the concentration Ltwetzks cf chis‘system are opcratxve, though at a slow decay .. .13...- ...,.__..J rate“ �‘ _ fonversoiy. :u patientc with short-lived hyper:yuchruny. Cholin- cetetaee-I and -II in tissue and spinal fiuid may be unusually - Furthermore, the‘appeatﬁnce at high concentrations of acetyl-~ Ichcline stimulates the production of tissue chclinesterdse-i in the(antral nerVDus.system.- From the lucid studies of Nechmanaon (1955). a direct relatzonship bétwéen concentration of“tiesue cholin-- estethee~1 and level of nervous activity can be deduced. It 109' ievels of cholinestereaeél can be dull- demonstrated in depressive 'psythoseé (? menonaueal deptession), then the electrcshock_induced _acetylcholine may stimulate cholineetetaee-I production to a mare normal. pre~morbid leverm , cantext, these studies 1n_enqrher problem of autonomic reactivity. may have application to the. ‘Rncent qtndies by Funkenltein and others have demonstrated a relationship between the blood presents of patients .respbhsefto injected mecholyl and their event-n1 reopensiyity to ' :i' ” ' - 'Hecholyl which a induces“ cholinetgic potent is agent electsaShack. ' “ ~2i: tachycatdia, ic?‘ perietaISist sweating. incteaeed and vagadilation. chnlin~e hy hydraitzed cholinestetaseél and slowly by ls rapidly estetaee—II. 5;.. atter injected fails vatinb'le length of time, blood pressure of subjects return. to the baseline in a five to more than 20ninutee. Patients rthalyi i The and presiﬁre'l whose blood 5 the minutes are classified as Group I. baseline in to returns those whose blood pressure takes 20 or more '21! ':an reactions; minutes II to return to‘a baselineg‘es Group The Gtoup 1 reactors have a 92 improvement ' VI and VII reactions. 'IlllI-I-I - rate with canvuisive {1- - H; i ~ therapy. and the Group II, II-III reectorl : 352 rueovery rate In a i contrast, the Gto up VI reactors have a 892 and the Group US;da~9§1~agent-uzeaauuzyq:ate.£runktntto&n-otqe3~y¥$953-- I ; 1 �“ VII a 97! recovery as patients in 2W4"??-:'£€i§:?fjw*ja 15 _ Groupu_ I to may llI may be looked ubon the injedted mecholyl is hydrolyzed; rapidly while the Group V! and VII patients have We a slow hydrolysis rate. predict, therefore, that the blood cholinestereee ectivlty.-' levels of Grouce l-III would be high; while the activity of Groups Vl-Vll would be low we recall here a similar prediction cholinthe date central for of nervous levels item Iy regarding esterese~l, in which the develovuent df early and sustained EEG hypersyhchrony and elevated epinel fluid levels of acetylchdline related to low level of cholineeterase activity. _Thus, the date of peripherelystlmulatiou by cholinergic agents is A ,was congruent to the hypothesiq regerding central nervous‘system‘reP activity to electrcahock. cammsmus: This survey of the literature of the roles of acetylchollne of cholinesterase in convulsive therapy hue led to a number speculetione which require yeriflcetlan. 'For this purboee, it and 3 is ‘ suggested that en-investigetion of the following relationships, 'be undertaken. (1) Level of free_ecetylchollne iu the epiqal fluid. 1‘3. type; cbnvulalye frequeucy. to number and therapy relation Also. the essociated electroencephalogram'patterns; Reletidn of such ecctylcholine levels to the clinicel (2) behavior of patients. (3) than z‘ 3;“:Ww’gwwm‘us rate (Funkenetein $5321" 1952); ;Patients in Funkeaetein whom .24; EEG in indicec of altered brein function other with such ecetylcholine levels. Changes ’ , .7 ., _ �{4); Reiéttoh chalineate'fﬁe gétivify of blpbd scrim andpspinu fluid to: (I) ﬁattémﬁ of and ‘ age, , (b) alméta (c) rate bf deveiwopt'zent of‘ EEG (d). numbg: ,md fréqqencyof . f ‘ treamhts . (e) ,aﬁtbn'omc (heriphgnli reactivity -(.f)',cerébu1 reacthﬂty‘ ‘ ‘ , 3 . gpexfsonauty Run: ofatroptne“. physos‘tiglnlne'admini‘attatian on (’8‘) (5) hypersyhchrony ‘qliﬁical behavtdr. , _- ‘ ~‘ E36,“, j 4 �III: 7-3-6A ‘r (1:, ﬂab-(i) ‘ ON THE ROLE OF ACETYLCHOLINE AND CHOLINESTERASE IN CONVULSIVE THERAPY Studies evaluating the role of cerebral changes in the mechanism of convulsive therapy have demonstrated that the development of early and tunct persistent signs of altered cerebral are prerequisite to changes in behavior (Pink and on Kain, 1956) - was the most In these studies, electroencephalographic slowing s significant index. This obhrvation remained un- clear until the reports of Ulett describing the effects of pre~ meo11ation with high doses of atropine in preventing the appearance of the EEC delta abnormalitv (Ulect and Johnson, 1956). ’Followlng the suggestion of this report. - we Eg 5: reniewed the role of acetyl— choline and cholinesterase in convulsive therapy” {é to data The lg; ve x close relationship between the degree and persistence? of the electroencephalographic slowing and the appearance of Suggests a T: .¥ measurable quantities of free acetylcholine in the cerebrospinal {g fluid E; as well as an inversion of the normal ratios of benzoycholine- cholinesterase to mncholylcholinestersse. I h:§ . . Ihe role of acetylcholine in the transudssion of nervous impulses has been studied since the (1914) and Loevi (1921). first descriptions The arguments as d of Dale to whether actylcholine is the main or only agent in the transmission of the nervous impulse are not of primary concern here. .It is sufficient that acetylcholine is a normal constituent of nervous tissue; thst exists in a bound form and is liberated during the excitation process; that it is rapidly it hydrolyzed through the specific action g) �oi cholinesterase and as rapidly reconstituted by the choline— acetylase system (Richter normal cerebrospinal a Crossland, 1949). Furthermore, fluid contains (Tower and McEachern, 1949a) no free acetylcholine despite the rapid breakdown of bound The acetylcholine during periods of activity and excitement, cerebrcspinal fluid normally has measureable cholin- esterase activity, principally of the "true" or mecholyl hydrolyzing type (Nachmanson and Rothenberg, 1945); In the absence of free acetylcholine and the conditions under described, electroencephalograms fail to show any consistent . abnormality. Effect of Craniocerebral Trauma: .In a study of cats subjected to varying degrees of head trauma, Borenatein (1946) (al reported that free acetlehcline appeared in the CSF within a few minutes after experimental head trauma and persisted for varying periods up to 48 hours. The quantity of free acetylcholine varied between 2.7 and.9.0 gamma and the amount wasl percent, positively related to degree of trauma. Concommtant changes. electroencephalograms demonstrated patterned Initially, the records were filled with high voltage fast activity, interpreted as an intense neuronal discharge; only to be followed by a short period of flattening of all recordedeaectrical activity. These periods were then followed delta frequencies. behavioral changes were also correlated with degree of‘ trauma, as well as with the level of free acetylcholine. with highest levels of acetylcholine, Bornstein reported the greatest The m �consciousness in change the greatest degree of EEG abnormality, also seizures uere and furthermore, spontaneous post-traunatic the in appearing related to the amount of free acatylcholine spinal fluid. applied' Bernstein observations. these To further substantiate when the cortex. cerebral exposed cat scetylcholine to the he gamma 1 less. or acetylcholine percent was concentration of waves of low frequency in the electrosharp observed high amplitude encephalogram. When the concentration'vas increased to 2 gamma parallel fashion in-a flattened percent, the electroencephalogram to the post-traumatic records. A 112 in studies these Tower and McEachern(l969a) repeated the found in was Free acetylcholine patients. pneurological head trauma, with recent the in patients only cerebrospinal fluid The free acetyltherapy. convulsive ‘recent grand--nal seizures or from 0.2 to varied choline lGO gamma percent. In addition, Tower spinal the of and HcEachern assayed the cholinesterase activity cholinesterase the nonspecific in rise fluid; They noted a sharp fraction (benzcyhholine-splitting) and a drop in the specific the in patients (mecholyl-splitting), fraction cholinesterase therapy. No those convulsive following with head trauma and in free containing the in demonstrated fluids such inversion was acetylcholine follouing spontaneous seizures. These authors directly acetylcholine varies concluded that the level of free that however, damage; cerebral of with the degree suggesting, sensitive more a was fraction cholinesterase of the the reversal indicator of cerebral damage._ -' �- 4-following intervals varying taken at were Electroencephalograma direct a reported The authors most of these subjects. trauma in of the of degree correlation EEG abnormality and the appearance cerebrospinal fluid. the in of free acetylcholine trauma craniocerebral indicate that These two studies may fluid; spinal in acatylcholine the of free amount the increase free of the between amount and that a direct relation exists electroencephalographic of type and acetylcholine, the degree behavior. and changes in clinical abnormality, (b) Effect of Atropine on Bernstein administered 0.5-1.0 pggt-grggggtig mg/kg EEG 5&4 thgviog; atropine after head trauma- EEG effects, manifest of the blocking demonstrated and induced was the experiFollowing of trauma. behavioral and neurologic signs mental addition of intracisternal induced which acetylcholine, trauma,“Bornstein' head to similar EEG and clinical changes observed a blocking effect of atropine. human of treatment the Wardflgﬁo) applied these ideas to degree with varying 20 In patients head injury. closed of cases of doses in subcutaneously of trauma, he administered atropine and in improvement, clinical noted he some cases In mg/kg. 0.1 the of effects electroencephalographic the of others, a reversal Jenkner anticholinergic drug, trauma. In a study of another the in putreported.simificantl'alterations (1955) Lechner and 40 in dose intravenous traumatic electroencephalogram. Asingle normalizing‘ in instances of abnormal electroencephalograms resulted others. in 22 instances and marked improvement in six _ �- 5 - atropine effectwof Ulett and Johnson (1956) demonstrated the sane conVulsive‘v illoﬁing slow wave of activity the in blocking appearance biochemical‘nechanisnl same the therapy. This_stndy suggests that ’ . V ' under£:5the electroencephalographic changes in head cranes and in . *-',._—s Mov ~...,_..-—~ in contrast to these findings}: In their i _. M. . experiments Brenner and.Herritt (1962), applying topical scetyle in concentrations of 2-1/2 to choline 102 ‘ to the exposed cortex of cats, noted no effect of intravenous atropine (l nglkg) on the electroencephalographic changes. lt_is iaportant to note, however, that the concentrations of acetylcholine in these experiments than significantly the topical applicetions (1-4. was higher 3“. I percent) and the intracistsrnal (0.2-10 galls percent) injections Bornsteind(1946). Brenner and Merritt. houever5'slks_note of of electroencephalographic effects similar to acetycholine free mecholyl (acstylbetanethylcholine) and doryl (carbanylcholine), each in concentrations Inch lover than the acetylcholine concen- effectiveness of these incteessd the ascribed trstions. lack drugs cholincerebral of to sensitivity to cholinergic their They ‘ estereses. A I variety of experiments with the potent cholinestarsse' inhibitor DFP . .31. induced convulsions. due report stands out a.m- fluorophosphate) demonstrated high (di-isopropyl amplitude rapid frequency 885 patterns similar to status epilepticus, as well as lesser degrees of abnormality noted in post-traumatic stete!!(ainnich, et el., 1950) Freedman et a1., electrohempson the 1949; and et al.. 1950). In these studies, too, encephalogrephic effects were blocked by snail doses of atropine. -——.‘ Cs- �In rustle? labcratbry study. Chétfield and Dempsey (1942) evoked and anxmai prestigmlne :ortcx expasud ytch prepared r9103hdlU.YJDF1C Spiﬂe autlwtzy. electro- prior.admznzs:ration of The 'uzrcane biotk\d this 5:1 1:5. a: if present, the abnormality v?u.d be viim‘:1th by atrepir~ 7C 1 trtn 'hu.. a variety of experimental clznlcal scudzcs, and 'har eie-ttnuvcethIographic acti;1cr ._:ti;:hrr;:¢. irhc: -T;t'!‘!". ‘th as 3 wﬁ tnd¢¢¢d bv reswlt of trauma. topical appl;astict or :rrvzral m;:a‘clzﬁn, can be blscked ur elzmztated ltz'tln|k‘ -. (r) ‘3}.: 'x '.;re:.cwg:n31 ~ a:e:yL.n;1;1¢ ﬁcrtully appnars :; “Jqu, ;v¢;ttae iczm. It trcaxd;un {L58 Ln 4 The level of spund acetyichclinc is v c: the pro: I! 3325 cf synLEcsig. liberation an; may be Lcscuiat is true :45 npmanstratpd 1W: -. nex.{;3;. pr-Sen: 1: vezvous 11554t a I u . therefore, that the level bill during «lead and fall duslng activity {111352. 9v'xn a“ ‘T ac:1;i:;, r:ce acatvicell membrane. where it is rapidl; de- Activated ty challnestarase. c::.:an; bv . Du::n3 pazxud$ of :hu;in# is liberated at the ;h;. the .,‘.‘.:l Au€£.luld.;‘£- "‘ r.u.J 2 by thhte: Pyzdur$;n (1950? and La That this hypothesis Crosaiand {19u9b and aagzyz uxanrimun;s Sy Richter and Grassland qu1ck-freézing methods. asxrg liquid air deﬁoﬂSLYdtzd that the anesthesia ard sleep level of acetylchoiin‘ .Lgustcd mi:ragra:13 per 25 :Fdn fn» Ln»? uvi;urc lcvc; Itdnxieﬁt .. ?. .5 (D N mg. The brain fiSbUd} was 3092 hich? difteteECe in tinauc levels 13 .5 the resynthesis rate for azetyluhclihe in m rat braxn is high (7 gammaigm/clnute). 'Elliott er a1. (1930} :. par-- �After metraeole convulsions, free noted that also XIhey acetylobservaticne, these “K ;3r?ic~‘i n ; chul;ne :ws always demunstzable in the spinal fluid in concen- tratians to up In spinal 3 gamma per cent. man, Cone, Tower and HtEechern fleid studies in ahd Thuer and McEathern (1949b) ‘1348) ti quantititls 86 also demonstrated significant free acetylcholine in patients with epilepsy‘ 'Of patiehts. epileptic Lhuiine in quanti'iea 49 (7723 demonstrated 0:02 tc of SP0 gamma naeeurable free acetyl- per cent. ith an average was related level directly acetylcholine pu:.cent. Ih: (L the frequeﬁcy cf seizures; the extent of electroencephalzgraphic t6 the last of relation of time the sampling and the abnormality, cf 2 O gamma It bore seizure. no relation ta medication. type of epilepsy or level at cholinestetase activity. Whether the ', a . a the in fluid is spinal appearing acetylcholihe ty—prcdcct of the canvulsion. or whether the increase in 9 - catae of the Seizure, is prshlenlticela acetyl- Tower and chachern (1949b) believ that the increased e;e:ylchcline liberation (T; itself but related is not due to the seizure caaeing the seizure. A“ In a to the basic preceee s“dy ef the hypOthesls that the accumulation acetyleheline is basic to the seizure process. Torda (1953? indured convdsxcrs in animals by metzazcle She determined the level of acetylcholine in brain tissee before and during convulsions.» convulsichs byla She noted that preceded are rise in the acetyicholine content of t:ssue; the: the content gradually falls during the convulsion; and that below certain levels, convulsions failed to occur. 3 She ccnvulsioc suggesteﬂ that the was due fell in tissue acetylcholine during to inhibitien of acetylcholine synthesis by incrcdeed reagentratiacs of mezabclites such as ammonium ions. �While there is considerable orgumcnt about the role of the machanism of seizures. choline in it is acetyl- probable thot free atetyltholice is increased during seizures and appears in the spinal fluid; that cerebral activity and seizures enhance acetyl:hcline destruction. lowering tissue levels of_acetylcholine;while sleep and anesthesia augment acetylcholine production, V inLrGaSXSg (d) tissue levels. Svstoo Nervous Centrai Cholinestegase: Concomitant with their observations of changes in acetycholine, measured spinal fluid choliuesteraee activity. Tower and Hcﬁachern Two (l9é9) types of cholinii esterases are normally found in the spinal fluid: cholihesteraso-I i"true". "specific". or metholyl hydrolyzing), - which has a high specificity for acetylcholioe; and cholinesteraBe-II ("pseudo","nonspecific”, or beozoylaholine—hydrclyzine). Both compounds hydrolyze acetylchcline. but have different ratio of hydrolysis for mecholyl and beozoylcholite. distinctions of the .By This diffexehtial rate permits qualitative reporting the cholioesteraso activity as 5 ratio activaty with mecholyl acetyicholine substrate, two and benioyloholine rati$ are found: substtates to an cholinesterasevl/ acetylcholine and cholinesteraoe-II/acetylcholine (with Ash/Ash - 100). in such ratios manual CSF contains esterasea in tho ratio of 33:17 for cholinasterase-I to cholineateraee-Il. Thus, normal ‘ CSF consists- inly of "specific" eaterases with a small nonhSpeciiic esterane component. traoma, with head Toner and Kcﬁachotn report an patients inversion of the amounts of cholineoteraies with a significant In increoae in the cholinei‘trase-II fractiOn of spinal fluid and a decrease in cholineatorase-l activity. They also reported a correlation between [la extent of the cholinesterasc rcvérsal with the senority �the electroencephalographic of trauma and with the degree of ‘ abnormality. scetylcholine a as patients With spinal‘fluid increesed .In however, the ratio in change no sponteneous of seizures, result found. actitity was cf :holinesterases or total cholinestereee (e) Effect of ﬁle trnehock on at A Tower and McEachern’(l9493), esterases: it oline and Ch in- in their study of cranio- psychiatric trauma. in patients six reported observations cerebral Studying 3-7 after the patients convulsive therapy. undergoing the they.reported in activity free acetylcholine treatments, . ’spinsl fluid in increase in cholinsstersse-II patients; and a decreaee in cholinestarase-I vith a reversal of the rstio llron'thess Of the six patients. of cholinestersees in five and an two in changes fluid the concluded spinal that they observations, cdnvuleions trauma craniocerebral those like more were at induced than those found in * epilepsy. Regarding the one patient in the series who failed to show cholinestsraee in ratio reversal or s free scetylcholine either the spinal fluid, they wrote: "It is interesting that this response shun to no of to the six one the was only patient treataen.." . DISCUSSION From these various observations, vnlsive therapy induces spinal fluid we may conclude changes more that con- like cerebral is. 'trauma than those of spontaneous epilepsy. If the parhllel of. the degree maintained. we can predict a relation between of abnormality, the appearance free electroencephalographic qcetylcholi1e. 3nd ; ra"97331 of cholinestcrane activity ratios ' �‘“ the L-L Fpl'd: fizid and the number and frequency of induced-con; xtisisrs. Alsu. irsm the Observatians of raver (1959b), 1hr ccmnent that cnly the patient suing? ELUiJ ;hangua us in ptrmits :hnngcs are filled who and McEacharn failed to Show to show a response to treatment, cozsider the pcssibility that such biochemical basi: to the :cchanism of the achuleive therapy process. Certain further deductions and conclusions are possible. rhé brnin subrtances of induces through electric current passage change a in cellular activity with an increase in free acetylchclinc to levels sufficient‘to induce a grand mal seizure.i The preaence 3f free acetyltholinc_in the intercellhlnr fluids electrical hypersynchrony.ref1ecced in the induces , slaving The degree of hyperaynchroqracturately reflecth the level of free acetylcholine and should follow to the rate of acctylcholine destruction. demonstrated that 1c the as delta EEG a decay rate equal Since previous studies hypersynchtony was n_neccssary pre-requisitc EEG clinical responsc in coavulsive thcrapy, it may be stated that the absence of free acetylcholine suggests minimal changes in cerebral function and thus pracludes a clinical reapanse to the induced convulsions, bc made regarding changes in Certain assumption: may membrane cell permeability as explaining the increase in cholinf esterasd activity“ Cholinesterase-I is found'in highest concen- trarian in the :entral nerQOus system; while cholinﬂesteruse-li is predominant in other tissues, especially bloba sdrum. ~With the increase in acctylcholine levels in the intercellulur terebral ilwids as a ‘ xesult'of stimulation .-J.-;'..L ..i ;w::tjs;; and convnleibn,‘ :uliuau: gartelhllzty may be predicted, �.. 11.. interthe fluids into of vascular with a degree of transudstion of and the duration the on extent dependent cellular spaces vssodilstisn (Rabat et all. 1948). 'Ihst _do such permeability changes in and Spiegel-Adolf by Spiegal demonstrated amply occur was ; . demonstrated They '53). 'é8, '6h, '42, (lQél, numercus reports cenductivity the increased that electrically induced convulsions cf the tissue; resulted in a leakage of various ions, as potassium and phosphate, into the spinal fluid; md that while the electrolytes iignificsnt increase in non-electrolytes permeebility in Charges nucleic-acid splitting enzymes. i .creased. there was a Wes of cells may this provide the basis for the appearance of high :ﬁccentrations of acetylchdline and for increased concentrations - oi chalinesterase-Il wt ch~he (T owe: and Mczachern l9h9c) incevihy in cholinesterase activity, shculd not the free acetylcholine be rapidly destroyed? To what Mechanism can seizure be ascribed} its persistenze in spinal fluid after An explanaticn for this descrepancy is available id the ebsersetidns trauma and cf Nachmsnson and Rothenberg (l9é5), hy confirmed McEachetn (1949c) end Bergen and Macintosh lever and ' (l955),lthet the scary!:hcline-chclineglerssc-I system is very sensitive to concen- tration relaticnships. of acetylcholine At is rapid "physiologic" concentrations, hydrolysis (3~4 microseconds) but at higher and quichly_(hsldene off curve). lower concentrations, activity falls relationship is In conrast. the chdlinesterase-Il-acetylcholine nGt'EpCCllli, and the rate of hydrolysis increases with csncentration. Thus, with normal functional levels of scetylcholine membranes, the scetylcholine is destroyed by the at cell specific activity �where'exzxtJZLcn -:41 in the Urdu: of "111;3dC9ﬂdi '!;U&uLVc '1..‘q;. :rL:.:1"-"wf cchaevtratton of acatylcholisu in “Bfiohs is Hytirwﬁxw ‘; ‘b: ‘*::e:tr3:icn f :lr311rﬁ:ster.19a—I t.s ex;cc:J¢d_ Ev: {Htéskrld the seizure uf acatvlzholivc mount:, The :2 I tree acetylahoiine t"r‘1"; -~'.' *1 I: ~~II .r‘;c1nn;y. The “erhaps adds to the level of rapkdly,« diffuses ucstylcholtne increased a; the actlvtzi cf thia enzyae. Jun LCgﬁﬁduﬁt ad Lu CUCLUDCYaCXCn A ‘Lc acetylcholice level’ f): fke shwcx persistence of azwtyl- a the and pctmrubility effects vaatulax-ind cellular £53; cholxn~ Inzteased 413: and .v‘retued inn. 1n 1" t.~':t"’ '¢ ’.vnshiv rzeults in nex:;ra. itself. The Etna 'W' disscnlation in acet/isholtné~ a tﬁOugh c1 low klnolizs that lchls period of heurs to days. to p cholineatetaRP-I. of action /w;alcgic (lottrtcnvcphgiagraMs Suuh a posstblllty xs ev.5c:t in the' I Tcpﬂ$2 by Axrd e: 1n 1n-.e;ae a democdttating (1936) sxgniticact 1;. erin gdcszte in of cuvuent::;103 the ‘ 12 L9LC€RTT¢L10a itisund Cedutuw ’v‘ tiesue is data induced convulsionq. 3 da,; af e' shows the change in brain in absent tﬁis ordinarily nnlecule. large ct of wﬁtﬁ hypersynchrvnv the ;nTT91aLcJ Appearance ta be eleCtroancephaiogram‘ the in (deitu bursts} electroencephalographi: of of the appearance In 0d: stLdica nuwbuni' the many confirmed have we changes nuth hypersynchtony induces therapy convulsive previoug reparas that of treataents. application constant a Deepitc in maqt Suh‘c~(w ' #cmwnlsiozs, _ �FLHCLICof the Jnd 54r3:1cn extra: ILmv of Appearance, (it “VlﬁVﬁf, ‘rT'XXATXOH 315 *"ri‘::w“" . ‘ {v hyperaler21u1. c;d1‘i:1L1‘" tc senaazxvzty its Qaca graph;; 5ch I herb:tgrates all cgrly appearrnce TLQ vary greatly in géyzhiatric of?.igh degree hvpe: vnchrany. bwaa has tzcatmunt the ::.r:‘~‘ 1:* ::§ 33:1IHEE'CV (Lfvgghiji 31¢;Yihﬁﬂ as a nuccaaary E'sctrgﬁﬁ”( t-tr': 'quh:iwlrr 2H: and Kihn. 1956). Bu: what 1: ch; meghanism' imitate of caftain pﬂttents_zo deveiop n3persy1.Lrauy be and acccyléhriine may chottneqterases of <tgiiee - L%ewﬁ 9:;L4y3 greraqgtsira to: inprrvcmeu: folluwing \s-uﬂ.' .la "Z¢piwﬁx seizuze ls :ndznattnc o: thy *EA: 4 armnd m;. ; {13:uc KQIHL; 2f {tee a»:'{2.chv'LHv in ‘HH and ghnlznugcaraae-i; by ," -«;c *nd~a;;z‘s n. erlag'-.5;; hypetsyncnrcnv La 1 iKSQ$E a! that the alertrc— ref\r\::LLn cf the pvrstazunce the ditfctence then 3f acetylcholinu; c~rven‘:¢;2cn Phﬁ”':d1 ‘32: 9‘ u. :rﬂ-tr:: -in ra:a;¢1r ry;c:e,n :n:;r.v in- at in whom it Persistent .frizzc=2-r3we-QLPn;l;bol{we hydrolysln system. {La 3 Lh of ace:"Lhvnral of atu I decreased fr3a rate I h5“a7annchtnn", resulcs K . . V s-prrvlousiy deduced are correct, ezther one 'J 9" 0' LI V 1 rv- in .A 0‘ t r9 n ’ I‘ ‘1 ,— P" patients with (a as are operatlva pcstula: suing .cr'xst.uz hyﬁvrzy nebrbny: (" 1% :‘i attrast-I IS in law s: rte er: in LF: tisSue t2) h‘ Yh<‘ 2 Cb'litugrpzata—II is :oﬁc=n£r3££nu , «12L h1gh Kev, so %: that thc:e a;¢:ylchclzne; and/3r that the noncancraziou at though are 02e241122. g; 5. suqtyt 'h:..- 1 slaw decay rash o �I ‘, f)‘:W-‘rvrs. t“: " st: gfztzl Ira in» ‘.-* “2:- 1" 2 ~ 3 :: "ca proqz tlcn <th .L . Fran Chv a:v:yl- nzgh cgnawnLratiors or :"l':us:eraae—I stuchn suuid . attivit" cad be (;Q55!. . of Wacnmunsan ill-n If can be deduzcd“ 13w demorstracad in dapre:?£ve yzr~xe5 g‘ acnopausal depr¢sszct), then the electroshock induced ' $:L:V1-‘QIIUL 1¢v-:rimula:2 ;%;l;ne {grasp-I graduation to a more usn“ku: Eu ,4 -\ \ v 1‘! :g: - - cgﬁu"'crac#3 c r .t “.CE Ha4.3: xu“ « chhriy. 2 z: ‘“"gi;ia:: r, tzarv122d;3, an r31): l éﬁn y‘;rra L) txue to more than -;‘.c;- upnli:ation cm Rucent szudius by Funkeaatein and. rglarlcsshlp Fatwaer the blond p:e>3ure a "aren* L!(11FP:51~ ‘gegt whicb iﬂduces swancpag, and in;:¢n.cd peristalris. 20 minutes. 5 minutés are :lauSLfied as Gtaup 1. .1, 20 or were c ‘JYI .3. 'daczsrs have h.'..~¢‘ax:u.-, ax a 92 Improvemant C’W‘Tiht, the Group ‘,~.. , .._..- V1 sir-.1 GK'C‘J-P charapv, and the Group II—III reactors a 'IIIII-III I: Patients whcsa bleed preséﬁre 'na.r1:#e: zhcsa vF‘ue blaod presecrc zukej 92:13:: 2:. (ha :1: b43313: in.a varlnc;e {ength of time. t;ﬁh.ﬁ$ to [J3 baseline in xrd .L‘ :1J11e3_may hive untrrgvi: [EdQLIUity ‘Ezm 01 '\ Iiﬁ.~it. tigsc 4 if tiaaué ;nclltester85&—E in the ogzuac‘ ctaLentrat on 0‘ chxuu 'hcixn— aid snvgi cf rer"ccs 3t _ _‘ c..". x‘ _ "\c_r..e— ‘ ’P?‘ é ratu with Louvulsive 35% recovery rate reactor: have MW. -......»n.a.cac textzmw a 892 and the Group I‘*'Hal-*mHO‘vw-Iy9ﬁ-’ ' In ,- �ﬁll a: 31., 1952). :e:c"crﬂ rate (Funkensteln 9—“ -Pa7;ean in Fuzkensteln Grcups l to Ill may be looked 972 a ;: Ew;l;ui- :1 "him ET n 'J' m C‘. '1 de Ch: 1716 and VI; V1 upon tad weuhalyl is r2p;dly hYJrolyzed; patients have a-slow hydrolysis rate. predict, therefore, that the blood cholinesterase activity. levels of Grorps I~III w0uld be high; while the activity of Je may Grazps Vl-Vll would be low We recall here a siuular prediction rega:ding the ds:a fur central nervous system levels of cholin-A 11 which u‘rergse~l, the development of early and sustained EEC hyperaynchran) and elevated spinal fluid levels of acetylchclinc relatvd to was a law level of cholinestarase activity, 1. 43"¢ cf 9:11pﬁnral ‘u: V \ u \ . azngtuast 0y 8 cbslincrgic agcntz is the hypotheeib'regarding central nervous sysrvm re? :5 aztivitv :2 :zzm‘;atl>n Thus. a ., ”w“ “a ~c:r.shuix. a A,~‘ ,.-."..( 'c-~ :AJ'L H—-—.- as... ThLG survey of the litarature of the rJlos acetylzholin (f "V .o. :hclinestarase in ccnvﬁlslve therapy has led to a aﬁd speculations which require verification. For number of this purbose. ‘t L Rdgglilhd that an-investlgarion of the ftlivwing relationships :elztlon :c :3Evulslve therapy - type, ,0 J I v o 9 L." I in 14" number and fttquency. .ociated oleczrcencephalogram'partarns. h Relsclcn of such a;eryl:hollne levels to the clinical behavior oi patients. (2) (3) Llaé BE“ Changes in lndices of altered braih function other with Such acetylchcline levels �(L) 'Relaciou of :holinesherase accivity 1:03 serum and splnal and patterns of fluid to: (a) age (b) diagncsis (c) rate at development cf (d) number and frequency of EEG hypersynzhrocy t:eatmehts reactivity (e) autcacmlc (peripheral) reactiﬁity [csrebral (i) if») «g; _pe:sona11ty Rut at" :nLrIL Eshxvic: atropine. 'physcgstigmine adrainistmticn on ’ EC,“ � 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 2/4). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-003-0-002 Date A point or period of time associated with an event in the lifecycle of the resource 1956-1967 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