http://exhibits.library.stonybrook.edu/mfp/files/original/22ce0e2ce2b39aba2aae8d5d1394cc60.pdf 2c9db7ac17279fda4146fb703f39bab1 PDF Text Text ' """ "r ' " WWO WW WW3. IN Max Rink, -*-' '"I’W v“ ”kw "FWHWOMV'.’ v.3. "m qr min...“ .7... W 14.1). mthofPoydmiatry of School Missouri Meir» , of MRI-nit}; Psychiatry, at the Nissan Institute of 63139. Macaw}. St. Innis, Annual Street, and Vii—072w, bin—927, m—zns, usms in part, by gums Missouri. of Formation :3 Iii-11380; ltd the Psychiatri 5WD W. VII: 7—25—65 Ram ��Wm, lQNQe) . The activity md emitement (Tracer and oembmepiml fluid does have measurable cholinestemse activity, however, principally of the ”true” or maholyl hydrolyzing type (Madmen and Rothenberg, 19%). In the absence of free acetyldroline and mder the cmditims described, electmenoephalogrm fail to (e) Show almorulity. mummy: Meta of Crmiooembml Trauma: Free mtylcholim was found in the cembmepiml fluid within a few minutes after experismntel head trauma in cats and persisted for varying periods up to #8 m9 (Bernstein, 19%). The quantity of free mtyldmline varied between 2.7 and 9.0 gamma percent, and the was related to the degree of induced trauma. wt electmemeptulogmm demstmted patterned Carma-rent charges. The records were first filled with high voltage fest activity, interpreted as evidence of an intense neuronal discharge, com to he succeeded by a short period of flattening of all recorded electrical activity. These phases were then followed by prolonged periods of high amplitude sharp waves in the delta . freqmncies. The behavioral changes related both to the degree of trauma wt of mtylcholine, md the of measured free acetyleholim. With higher Bernstein reported greater degrees of abnormality and greater charges in omecioumess. poet-tnunetic seizures were levels EEG Spmtmeoue also related to the ammt of free mtylcholine warring in the spinal fluid. �Bernstein applied amtylcholine to exposed cat cerebral cortex. men the concentration of acetyldroline was or less, high wlitude shup the electromoephalogrm. waves When of 1 gm percent low frequency appeared in the concentration was increased tOngmepemnt, theelectmencephalogmflattmdina fashim parallel to the post—tramtic records. Investigatims in neurological patients by Tower and HcEadrem (1909a) damnatmted free acetylclwline in the cerebmepinal fluid only in patients with recent head recem grind-mu seizures or after electmvulaive Free acetyldxolhe varied from 0.2 to 100 gm tram, therapy. percent. In assaying spinal fluid dnlineetemae activity, they noted a sharp rise in the nonspecific dmlimsterase fraction (bmwyldwlineaplitting) sad a drop in the specific dwlinesteraee fraction (mdmlyl-eplitting) in patients with head trauma and following convulsive therapy. The cerebmapinal fluid did not exhibit such inversion, although it contained free acetylcholine, after spontmeous seizures. They cmcluded that the level of free aoetylcholine varied directly with the degree of cerebral dmage and that reversal of the cholimvterase W was a m sensitive indicator of cerebral (image. Electroencephalogrm, taken at varying intervals following EEG of between the degree relation indicated a tram, also abnormality and the appeamce of free acetylcholine in the cerehmefiinal fluid. �. r -; o-Tn- "W wu-rm- V“ 7 ~ MNIWWF‘. «wwwnmw' . ”3-.— :Nr‘ ‘mw— l‘.«nmw~.—WMM v-y »".\—- (max .9 w— , r‘ "murmur 1 Wm" q‘ 4;. These observations were recently oonfimd by Kovaoh, wounded increased aoetjldxoline in o: 1.1;. rat brain after traumatic shock, and an inhibifin of this activity by the ministration of atropine to the muscle preparation. Tim the «want 05 {no aootgtchoune may ammo in tho who Aptaol staid {cunning WWW mum and the. mount 05 (no acugwwune, the dean.“ and typo cg mmmcapmogwuc «bloom/aim and «Maya in clinical bohavion appeal: cu Wound phenomena. (b) Antioholinegflo m and tram: oleotmgr'aphic, The bohavioml and neurologio signs of head trauma were blocked by the parenteral achinistmtion of 0.5~1.0 m/kg atropine (Bomtein, 19%), as were similar clinical changes: oomrring after the intmciutornal addition of acetylcrnlino. Ward (1950) applied these observations to tho treatmm: of closed head injuries. In 20 pttiants with varying dogmas of tram, he amtiniotomd atropine subcutanowsly in doses of O .1 mg/kg, noting clinical in soon and a reversal of the oleotmgraphic effects in others. Similar alterations in the poat-trmnnatic electroimprovement encephalogram were reported by Jenkner and Igdmer (1955) in a rtudy of diethaxino; amthor antidxolinergic drug. A single introvomm dose in forty patients maultod in normalizing the ' abnormal electroencephalogram in six othom. in twentyi-tm and marked ingrovemt .mr—‘xv �T-W‘vw 'h'mivu‘ -.-. ~.w—w.y‘~ WVMMW'Wn-uvw‘w—W 1."'"q'( v -— m7 "In“? - "mmwufiwuwmw‘vu “m""vw -WW’-xm -~ wr: TW'f..‘-|‘.Yr 1m Sinilar oboewatiam have been reported with mthylbezuctyzine md in minal exporimnts of post-trumutic shock and man 03mm}. Odom: (mm, affect of atropine Thu 1&5). assessed in the convulsive therapy was process by Ulott and Johnson (1957). With the administration of mnpordaydvmtngmwoeksthepatimts moeivnd oleotxoshodc therapy, the of slow wave activity atropinewto mt oigxificmtly lass than in a omtrol grow who had not monivod tho atropine adhinistmtion. (In a later study these was authors failed to replicate this study, suggesting that dosage factors or popllatim ohms-m multo [Johnson 93; &, may haw contributed to diffemnt 1960]). Similar affects mm obacmd with experimental antioholixnrgio was diothaxim, banaotyiim, the pipaddylbenzilates (Pink, 1958, 1960). The intruvonms injection of and JB-329 (Ditm), lid WIN-2299 JB-318. JB~336 111de ES damchrmizatim in psychiatric subjects. Those EEG ohmgos were associated with bahaviml alerting, anxiety, tram, illusions, and hallucina— tions. In patients the than had recently received eloctmomvulsive a reductim in slow wave activity md a manual of euphoria, denial md oonmsim. Atropine in low thumpy, dam, was was associated with tadnvoardia, mass E88 desyndumization acoarpmiod and Maxim. by At higher dosages, hypcnyndum slow wows, followad by lower voltage , poorly omitted delta activity with super-imposed beta activity wm associated with progressive confusion and disorientation. ”I..- —w m hwy”.-- �.erw—spmfllwtvnvamnw." w— r..«wwruun-x...—..,«».w..i. in combat Both Wguphtc mm"._., w-uvw-m .7..-7._~.-—v-—wwww..— um ~— ._.‘...,W wan rvw—Hw. ;W.——»—.- w—u w "r - , -— wwv—ku.“ and induced convulsions, the. ehahgu my be modified by the. WWMOR antichottuugte MA, Auggutbig that tamed manta 96 acetytehaane on. chawvigtc unpuvttg 4'4 undated with the. high vauaga Alon) wave activity. 05 Wed (0) Brain Similar EEG mfllcholim and mtfahnlimggzc ahmgaa and similar blocking by my mticblinergic drugs has been obserwd following the direct application of amtyldmoline to the central nervous cystem. The achinistmtim of a cholimtemse inhibitor Df'P (di-isagpmpyl fluoroplvsphate) elicited high unplitudn rapid frequency EEG patterns similar to of poststatus epileptiws, as wall as changes similar to M stma (Madam £314, 19‘69, Samson gt 9;” 1950, mid Hindi-m 333b, 1950, and Weasel 93.31;, 19%). These EEG traumatic effects were blodmd by small. dose: of parenteral atropine and in amtylcholim after awpolmim. The mat tetmthyl pyrophosphate (TEPP) was masumd and related to the toxic misfostatims and cmwlsims induced (Sim and inm Pepcu, 1952; Stone, 1957). Chatfield and W (1M2) prepared exposed miml cortex with pmstiminn and cvdcud oluhmnoephalogmphic spike activity. Thu spiking, or prior mismtim of atmpim blocked this if present, thc «mutuality could be eliminated by atropine. In contrast to that: findings, Bmmor and Merritt (19%) applied tepical acetylduolim in concentrations of 2~1/ 2 to to the exposed cortex of cats, and noted no effect on the 10% w- «flu-xwa—VVlwu- ��“mun-ny- rw-WV‘VKwnZw'w—w "1W:wmwvtwwav 1W”'_<1>vwnv.<_wum,vwwv ]- ‘_ VFW, .. .- w n - ~-....Vr.fl.--“ “W,- ..‘,_.,‘......_,.,.‘ -.v—--Y‘. ,-. -3- Elliot gt. 5}; (1950) md Crosslmd lid Herridc (195“). 61mm and Popou (1962) fomd the increm in aoetyldnlm following various dapmssants to bc proportional to the degree of depmssim of the central nervous system and the mduction in motor md Buck (196:4), turnover, studying 13min activity. My W lavas and sedation omeludod that some ”dating agents are associated with devoted brain aoetylomline, but that no dawns mlatimxshipo existed. In part, this may be mlated acetyld'xolina to the earlier obsorvatims of Wu: Elliott (1951) that acetylcholine synthesis unsound in mt brain slices, is accelerated by low dosages of mootic drugs, but inhibited by and him dosages. Pme autylcholim patimts with epilepsy was mported in the spinal fluid in (Cone, Tower and Wm, 19%; Tower an (7‘3 epileptic patients, Mom, domtmted free aoetylcholine in qumtities of 0.02 to 5.0 percent with an average of 1.0 gm percent. Acetylcholine and 191mb). 0f 56 gm lawla Hem related to the fmquonofi of seizures, the extent of electmmplulogmphio abnomality, and to the time since the lam: soizum, but bore no relation to mdication, type of epilepsy or lawl of cholinesteme activity. Elliott at al. also noted that :1: fm acetyldmoline was dennnstmble in the spinal fluid in cmoentmtims up to 3 gm permnt after mmzoln convulsions. 7 .w .. "urn“... �.7.~w.. V. - V ,, “my",w 1...,"— 4~.vn,w—._._.m~,m raw-w": '— 0.. ”75v.. .— _‘ . ‘wwm‘ ,van... ..__.,.Wry.~.~ m-Zwm-V'I—r‘wn W.W ”-mw-w.w.mwr~m - n—r.~~—. >¢r:'l.irmv --"‘v-w-V‘MVSWVP -9Tower and McEachem (19'4933) viewed mm the increased acetylcholine of the seizure, and not causal. Studying the hypothesis that the acmlatim of acetylcholixm induced seizures, Tom (1953) masumd the level of acetyldxoline in brain tissue after mtmnolc convulsions. She noted a rise in the as a aoetyloholim content of bmin, before a soizum and a fall during the convulsion. Below certain levela of acetylcholine, cotwulsiona failed to occmr. that the fall in tissue aoctyldaolim during a convulsion was due to inhibition She suggested of aoatylcholim synthesis by increased concentmtims of metabolites such as mimn ions. Gianna!) and Pepeu also measured chmges in cantml nervous system acetylcholine follwing various stinmlanta. moholyl and 3, S—dimthylbutylcthylobarbiturate Chly was after them a significant chmgc in the amtylmolim level. may noted a decmase in association with induced convulsions. With other drug: which they classified as stimlmts iprmiazid 1: (LSD, hydroxytmyptophan and iprmiaxid a ipmniazid, DOPA) tum war: no changes in acetylcholine level. may omcluded that despite intense excitatim produced an by these coupomds, them in acetylomline levels unless trace mm by convulsims. (The differences in obscrvatims no changes Wand between these MomdemcgggléandTmranndEaduem muted to the differences in mthoda of biochemical monuments, for the latter measured chmges in spinal fluid my be mflocting the free acetyloholim. while Gimmn and Pepeu «way—.- —-—.\. �T- - w;—----w~~~.~ .7 um . r - xu ‘ r v,m__.mwa,mflmuwwr~pw m~'mvv'v—rflr vav-u—w. ---—w ~ ,~ .fifir'A—HIwmmrrw‘(Wr-1Inr’mwmr"W'mv-w’ total acetyloholim reflecting band and free fame and Elliott, 1951]). of amtyloholim. The“ mom augguz that Apart/tango“ an. induced su'zwtu by moanpmécd in intercom 6n: mag/Maine an m abound 6m La bound {own which my be inflected in the (Laid. Cmbm activity and Auzwtu enhance magma” «lawman, awaiting wine Levels 05 Mots/Moan, Mule “up and muthuia my augment acetytchoune paoduotéan inc/away about mm. measured the [mm We W ’ (:3) Central Nervous sttem Cholinostemes: Tower and Worn (19%) also measured spinal fluid molinesterase activity. The typos of cholimatemnos are nomally found in the spinal fluid: mimestemoe-I (“tm,“ "opecifio," or macholyl—hydrolyzing), whim haaaa high specificity for aoetyldaoline; and cholinestemse—II ("psexido," "non-Specific," or banzoyloholine~hydrolyzing) . momds Both hydrolyze aoetyloholim but have different rates of hydrolysis for monolyl and benzoyldzoline . 'mis differential rate permits qualitative distinctions. By reporting the cholinestemsc activity as a ratio of the activity with a moholyl substrate and with a benzoyldioline substrate compared to a substrate of acetylcholim; two mtios are found: crolinestemse-L/aoetyldlolim and clnlimntemoolllaoetyldiolim. In such mtios normal oembmspinal fluid contains astemsea in the ratio of 33:17 for molimstome—I to dialinestcme‘ll . _ In patimts with head trauma, Twer and Mcanhom reported an inversion of tho cholinestemsea with an increase in the VHF-"147 �».———w ~. r... >qu . 'v—vv—W n» “W...“ mm xwwu-w_~ WY— . “-7 mrmm wnwW—u—mr- w...” maum—w—w—y w «W . unv'r“! "31A“ man-.wvvmw "w” w~:- -11.. dtolimtum—II fraction of the spinal fluid and a decrease in cholinesteme-I activity. Tho extent of the dualinssterass reversal was related to the severity of trauma and to the dogma of the electrocnccphalogmphic abnormality. In patients with elevated spinal fluid acetylchclins after $1)th seizures, however, no change in the ckmlimstomscs or total armlinestemse activty woof was found. in cholinestcms activity may be undamtood in relatim to ohmgcs in cell neutron: permsability. C'holixnsteme—I is fmmd in highest cmmntratim in the The charge cmtral mmus system whilc d'xolinsstemse-II pmdaninatss in othcr tissues, especially blood serum. With an incmm in acetylcmnnc levels in cerebral intcmellular fluids, vasodilatim md incmased cellular permeability may be predicted, with a dsgme of tmsudaticn of vascular fluids into the intemsllular spaces varying with the extent and duration of the vasodilatim and their (W g, 31:. 19%). Spiegsl, Spiegel-Adolf, oo-woflcem (19“1, 19M, 19““, 19148, 1953) demonstrated and: pemeability changes and inmassd conductivity of the titauos associated with the appearance of various ions (as pctassim and phosphate) in the Spinal fluid following electrically induced convulsims . Such nm~clcctrolytes as nucleic-acid splitting cellular psmability enzymes may also increased. in Changes thus provide the basis for the high concentrations of metylchclim and the increased concentmtims of duclinesteme-II in induced seizures or head trmma (Tcww V 4nd HcEcchem 19n9c). . persistence of acetylcmlim in spinal fluid after head dmlimstencsc dcspdte and trauma «fur seizma The imam . vmr Var" .muw ��rw ~—.r< —-._..'—v-w__ ‘- ,m Am w—w— WW 7- v nan—1"“ w—u-n w v mm mug; '- wmn—uw—v W v mm -- ,mmmm‘u—n w a"... mm -13- «mum m mm 5M nuvocu Mama 0‘ mbmu nmuimy «a WWW at «may. (a) Aceflldaolino, EEG 13mmmd‘wmy and Induced Oonvulsims: Alteration in the blood—brain permeability barrier by the cmtinuing action of acatylcholine may be a biochemical substrate for the postwlectmshoa hypemynchrmy of the electroencephalogram Sud: a possibility is evident in the damnation of an inmm in the mmtmtim of cocaine in brain tissues thme days after a series of 12 induced cmwlsims (Aird We g: .1332., 1956). The in emcentmtim of this large molecule, ordinarily absent in brain tissue, was associated with the appearance of syndimny delta bursts) in the electroencephalogm. We hove oonfimd the many hyper— pmvious reports that convulsive therapy induces electrogmphio hypersynchrmy (Pink and Karin, g 53;, 1961) . Despite a constant applicatim of treatments them is a great Variability in the time of appeanmce, 1956:, Pink the duration and the extent of the electrcgraphic slow wave activity as well as the sensitivity to modificatim by alerting, hyperventilation and barbiturates in pcytidaflxic populations. The early appearancn of dagroo hypersynchrony and high persistence thmugzout a prerequisite to mamnt cause has its been described as improvement following electmshodc (Roth, 1951; Roth, §£_g£;, 1957; Pink and Kahn, 1958). the differences in the dogma of induced It is EEG possible that hypersyndurmy mlated to differences in central clmlimrgic activity. The failure of certain patients to develop hypersynchrony may be associated with the absmce of fame aoetyldroline being related may be to him). changes in cumbml function and thus producing .a » “V.lvf"——Iw vu.- "a'v �WW. _. 7: .my- "“ .~..v.,W ”" . , . “V WW 7*MW--—- ‘-u :u wr—u ‘V-U-lw‘-um- WWWW‘,”._¢.~K—.wvflfl m”. ~"m--'~w , e ~ * .7 _,.,. , v ,7, , (lawn), in their study at” cmniocambml tmmna, included observations of six psychiatric patients undergoing cmvulsive trumpy. Studying the patients aftar 3~7 tmatmnts they reported free spinal fluid acetyldmline in two patients; and an increase in cholimstemse-II and a decrease in dwlinestemsesl with a reversal of the ratio of dialinestemses in five of the six patients. hm those obscrvatims they concluded that the spinal fluid changes in induced convulsions were more like those of amniocembml trump. than those of spmtmeous epilepsy. described the one patient in the series failed to show either fme mtylcmline or a dmlixnsterase ratio reversal in the. spinal fluid as: "It is interesting that this patient was the only one of the six to shrew no response to treatment." They If olectrogmphie hypersynchmny who is a mflectim of increased fme mtyldxolim, subjects who maintain hypersynchmny and those in whom it disappears rapidly may be exhibiting diffemnaes in the kinetics of the dwlinestamsawoatyldmoline hydrolysis systcns . Persistent hypemyndumy may result from a decreased rate of hyd‘olysis of wetylcholine , associated with low mntmtims of either- cholinestarase-I or cholinestemse—II . (Conversely, in patients with short-lived hypemymdurony, dmlimstnmse-I md -II in tissue md spinal fluid may be unusually high) . Fm thug chuwacéoM we would conclude demon; m mediated M an Mme in in W, mm enhancing 2th: MW“ that induczd {we acetyichouue Mg Momma. naming mutual 06 The and Lava as fine 1:; . ru- » m. “mmvw-w' - , v- �"w aw-"m, wrrwnw“—5— mmrwmwm._ . mallow 426 Wad m wm—w—w w. "mm-v m-u—v—v— nw—wuw- gwmy"w_mw u- m. -55.. by muted induud autumn. EEG hwynchlwny a one. Reflection 05 abtmed {even 05 Managua and muted 05 01h“ momtym. It 11A pubabtz that that chaugu in movide the mam mngw mm“ pwibtwt 4mm: Mochwécafi 50mm 56!: {nomad the bohemian“ changes mm“ . (f) malimstezm md the Classification of Psychoses: mesa studies have application to tho problem of autonomic reactivity and tho classificatim of the psychoses . Manstein, 91:. 31;. (19%, 1951, 1952) have demtmted a relationship betwaon the blood pmaaum maponse to injected mthacmoline (Macholyl) and the clinioal response of spydtiatric patients to convulsive therapy. is a potent cholimrgic agent which induces vasodilation, tamycardia, mating; and increased peristalsis . 11:53 rapidly Phflmacholinc hydmlyled by ermlimstemse-I and slowly by duelinesterase-II . mo blood pronouns of subjects falls after injected macholyl and returns to the baseline within five to whose blood pressure 20 Grow VI and VII have a 9 and a am recovery and Group VII mactom 1133;” 1952). patients in 20 89% to nfinutes. Patients 5 those whose blood Wine, Group II—III rate, respectively, while and 97% minutes have recovery mtes as reactors Group VI (Wotan GmupItoIII mactommybelohkeduponas whom while Grows v1 I, II, or III reactors; ormm minutes to motors. Group I and 35% than returns to the baseline within how classified as Gmup pronoun takes more the injected mdwlyl is rapidly hydrolyzed; ‘and VII have a slow hydrolysis rate. It is probable, themfom, that the blood and tissue oholimstemse activity levels of Grows I-III is high; while that of Groups - unr �.- n. .— . VI .wr-. .,m-w.w-,,. ..- - VII in low. A mwkwmr “or a mum: mviow, similar analysis systom levels of "'"ww—fii-m may in mud: r—nmfim.mn-‘mrmrp.’ "nu—mu“wl'r-_'In. m Rose, 1962.] mgarding central nervous dwlimammo-I in the dcvelqmnt of EEG hypmyndnmy and spinal fluid levels of acetyldxoline, providing the built for a hypofluais mgarding contra}. nervous cyst-m periptnral mt Inactivity to induocd convulsions and to momma agate. Arm �. ”V7“ :vn-r— www- 7.". New“- mu..~ “Av ‘:~vv-'me~'v xwmm~m.__en.sw—_. mm _.m immv—rmc "cw. .ww-‘rwwm-u-fi—Wrw—_ml -17- see significant in the convulsive therapy ptccess. The published data indicates thlt induced convulsions ame.associated with an inczease in intercollulsr scetylcholinc to levels greater than can be destroyed by cholinsstensse—I activity. Vascdilstion and increased cellular permeability are fblloued by increased amounts cf cholineetersse—II electrolytes in inter» and other enzymes and cellular fluids. These changes are hypersynchwcny which reflected in the increased electrical is recorded as EEG slow wave activity in scalp electrodes, and which can be modified by a wide variety of enticholinerzic drugs. In these reasrds, induced convulsions are more similar to cerebral trance, than to spontaneous seizures. The changes in the onrebmel biochemical milieu alter cellular activities sufficiently to be associated with altered behavior of subjects. Failure to induce high and persistent concentrations of ecotylcholine and Illiuwe to induce concomitant fbilume to produce behavioral electrolyte changes results in a ‘ change. Diffierences in the rate of development of cerebral changes reflect differences in the dependence of subjects on cholinergic mechanisms or in their sensitivity to changes in acetylcholine 1mm. mm differences provide the basic for the classification of the mentally The the mode ill by Funkenstein and by Pink and Kahn (1961). observations provide a rational biochemical basis for of action of induced convulsions in altering the �m" 'A "VI-v Ww—vv—n—u—m—«rrm mum-mam mm with tho mm «truer mmmmwrmawm -13.. of pomtie subjactn. 'nnu mm view mwopmsiologie—adapflm (Fink, 1957, 1962). an mistmt wavy expressed �_.,. m...“ ... .4. .. .fi-a v “3-..."- w..——_ww «av—m... ”VWFI-WquwLH-‘M‘AW‘K' w-v'lw . . "m." Inn—www-Iw‘m v. "uvw -wu v rays-y‘— :—.- me‘n—I'“m 32mm Aird, R. B... Strait, L. A., Pact, J. 91., muncff, H. K. and Witch, 8. C. Neurophysiologic effects of electrically indwed convulsims. M’ch. Newt. rum. scum, 1956, 75: 371-373. Pram and actim cf acatylchclinch experimntal Bomstuin, NJ). trauma. 1. Nuanpkyuatu 19166, 9: sue-355. min Horritt, H. B. Effect of certain choline dcrivatim clactrionl activity of the cortex. Auk. “want. (6%.). on Runner, C. and mm. Human, A. S. V. and NacIntosh, P. C. The physiOIOgical significant of acctylcholim. In K. A. C. Elliot, I. H. Page and J. H. Qustcl C. C. Thoma, Springficld, 111., 1955: 37I4~375. (Editors), uwmmuw. mtfield, on Dewy, cortical potentials. Mu. Cam, W. “Viv P. O. and Tm, in epil’psy. V., Worn, Jo‘oquo. 1&3, 73: D. B. Grassland, J. 1950, 162: “SQ—MW. E. w. Effects of prostimine md acetylcholine J. Pkg/«20L, 19142, 135: 633~6u0. and D. I. Acotylchcline and mammal 59.639 effect of anaesthesia on the matylchclim commit of the brain. J. Phydob, 195%, 125: 56~66. Dale, R. H. Th action of certain «tau and ether: of choline. and their relation to maxim, J. Plummet. Exp. Thu., 1913, 6: 1'47. Elliott, R. A. (3., Swank, R. L. and Henchman, N. Effects of mflmtics and cmvuhmts on acctylcholixn content of brain. W. J. Phgual... Pink, H. A and Merrick, A. Tm unified meaty of the cctim of psychodynmic therapies. Pink, H. Effect of anticholimrgic agent, diethazine, cn EEG and behavior: Iimificm for theory of convulsiva therapy. Mch. Newt. (cued, 1958, 80: 380-4587. was “ch. Fink, H. Effect of mticholinomic on pcat—cmvulsiw electromccplaogm md behavior of psychiatric patients. can. Humming 1%0, 12 (2): 359—369. Emeh. ’ Pink, view. m. of action of cmvulaivu therapy: the mm'ophysiolosic-adaptivc J. Nwaoplgcuazu 3: 231-233. M. Pbdo Pink, H. and Kahn, R. L. thtintive studies of slow wave activity following cloctmstnck. Bactuzuccph. can. "wuphyuotn 1956, 8: 158. Pink, 14., mm, R. I... Karp, 2., Pollack, M., Gm, H. A., Alan, B. and Lafkcwita, H. J. Inhalantuinducad convulsions. ma. Gen. mama, 1961, In 259-356. mm, A. PL, Bales, P. D., Willis, md Himwich, H. 8. Experimental pmdwtim of electrical major convulsive patterns. Amen. J. PhyuloL, 1&9, 1H6: 117—1218. Mkenstuin, D. H., Gmmblatt, H. and A. new Mutt. 0.3., 801mm, H. C. Autmmdc chins“ ramming electric shock Mutant. mm 19%, 108: #094122. J. New. �.- “ 'E'mr u-men... Mountain, wumW,mu“... 1~w‘mww.w“~-mmmern“—"~—IJ...- mm, amnesia H., paralleling peyoholofio 1951, 11”: 1‘18. D. qvp- —..,. WW me‘w ”Va-WV“..— mwmmwmvmuww W3 mantally ill pafllnts. 1. How. m. 01.6., H. and Solomon, H. C. Autonoiuio Menuhin, D. it, emenbhtt, M. and 301m, H. C. Autammio nervous system out of prognostic simfioanoe in mlation to alactmskndc treatment. P‘ymm. Mo, 1952. 1“: 3“?“3620 Gianna, N. J. and Pepeu, G. Drug-induced charm in bmin aoetylcholim. W. J. Fitment” 1962, 1% W233. A. and Hiwich, H. E. Effects of Mam, J., 33313, C. P., Manley, di-iaopmpyl flmmptmplmto (DEF) on alectmanoephalogm and cholinastarase activity. ,Eumamcph. can. “Mphysutu 1950, 2: Mil—ha. Basis, C. F... C. F. Hampson, J. L. Balsa, P. D. and Effect of trimthadima (Tridima) and other drugs on Madam, oonwlaions caused by di-isqwmpyl flmmplmphata (OFF). Ame-A. J. mum. Himioh, H. 23., A. H. 1950, 106: 816-820. Jonkner, P. 1.. no ladmer, H. The effect of Dipamol on the olectmmoopmlogrm in tho normal subject and in time with canme tmuna. EWmuph. can. ”meto' 1955, 73 303’3050 6., Ulett, G. A., Johnson, H., Sflth, K. and Sines, J. 0. Eleotmomwlsive thrapy (with and without atmpim); affect on Johnsm, I... analyzed ahctmanoophalogmm. chemically 2: 32u-336. 1960, Melt. Gan. Paychiot” alum, M. and Knaub, V. Quantitative estimatim of the Kabat, E. A., albmin and gamma globulin in actual and paflmlogic oembmspinal fluid by nomads. MM. 1. Mad" 193:8, *3 (5): 653-662. Wm Kovada, A. G. 3., meo, A. and Halmagyi, M. hm Hamid"Wit Aoetyldiolina‘omtmt of the brain in traumatic smdc. Aotc Phyaiozaglca (HungJ, 13: fiber Lou-vi, 0. Meir. £. 4. gas. 14. our Hemmnwfikmg. 1921, 189: 239-»2u2. Haymrt, E. W. and Buck, E. 6. Effects of C.N.S. Dapmsmts on Brain Aoatyloholim. 19M, 6: 191. Wtagut, Heisman, H. and Elliott, K. A. C. Effects on omvulsmt and narcotic drug on aootyldxolim aynflnus. 1. PM. I Expat. Thump" 19513103: 35. mam. Wm, specificity of We in mm D. and Studies on cholimtama: on tissue. 1. Biol. (than, 191:5, 158: 653—666. M. A. Ridxtor, 1). mad Crossland, J. Variation in acetyloholim’oontmt of the brain with physiological stata. J. Phyatolu 19%, 159: 2h7-255. W. Rosa, J. '1'. 'me We; Menuhin hat in the ~ A mview of the literature. Add mdor barhitmte anaesthesia produced by twain-mt mad their simificmoa for the theory of M clam-awake actim. Enougmuph. can. Managua" 1951, 3: 261480. Roth, )4. EEG �Both, 15., Kay, D. W. K., Show, J. end (keen, J. Prognosis and pentothel induced electmnmplulogmphic changes in electm—omvuleive treatment. summaph. can. Nemphy‘iol” 1951, 9: 225-237. Spiegel, E. A. and Spiegel-Adolf, H. Permebility chmgee in the brain induced by tamed and insulin cannflaions. J. Nuv. Max. 91.5., 19‘31, 93: 750—3755. Spiegel, E. A. and Spiegel~AwlL H. mysiooodieuionl effects of electrimlly inclined cmvulsime (mmbmepinal fluid studies). Tum. Mu. mm. 1455., 19%, '70: 130-132. Spieaal, E. A. and Spinal-Adolf, H. Physiological and phyuicodwmicel mechanism in electroshock treatment. Conan. Newt” 1953, 13: 38-53. Spieael, E. A., Spinal-Adolf, H. and Hem'y, G. mysiooodxdical changes in the brain electrically induced convulsive discharges. marina Tm. m. Newt. Au" 19M, 68: 17h. Spinal-Adolf, M., Wilcox. P. H. and Spiegal, E. in electrmhodc treatment of psydxoees. Mae 19.48, 10“: 697-406. Stem, We Tom, H. E. 1. Pk”. The mole Me, A. Cerebmspiml fluid m. J. mama, of acetyldwbline in brain mtebolism and fmctim 1957, 36: 222'255. Effect of omwlsion inducing agents in the amtylcholine content of the brain. J. Phyeutn 1953, 173: 179—183. (2. m. Effects of single injection of corticotmpin (ACTH) on We, ion and emtyldxolim ambmt of bmin. Ana. 1. Miguel” mnim 1953, 173: 1764.78. C. Wm, and patterns wetyldmline in the oemhmspinal fluich 0011th a. Aoetylclmline ma neumml activity. I. flower, D. B. and of patients with maimmbml mm. CW. 1. Quench, Tatar, Wehem, 27 lQuQa, (Seat. E): 105-119. D. B. and dnlimstemes in hm 1949b, 27 (Seat. 13): mutant and characterization of mmbmspiml fluids. Canad. J. Rum, D. 'Ihe 132-1'45. Acetyleholine and neuronal activity. Worn, II . Acetylmolim and dwlima‘hmsa activity in the Tuner, D. B. and D. fluids of patient: with epilepsy. szm'. J. (Sm. E): 120‘1310 Ulett, G. A. and mbmspiml RPAWA’?, 27 1mm, datum, M. W. Effect of atropine and soopolanfine upon eleetmenceplulogmphic charges induced by electm-oonvulsive therapy. Euwameph. can. Namaphguot" 1957, I: 2174224. Ward. A. A. Atropine in the treatment of closed head injury. J. Newsag” 1950, '7: 398-402. Ueeeoe, H. C., Green, R. Wm, of atropm md aoopolauim on the 3., B. P... and Kmp, S. central effects of DFP. Wt. The J. influence �DEPARTMENTAL CORRESPONDENCE DATE Julx 29z I965 SUBJECT Cholinergic Mechanisms in Convulsive Therapy To.“ Max Fink FROM George A, Ulettz MODo A most interesting paper, well put together and documented and with which I MoDo DEP'T DEP'T am in the main in agreemento There is one minor typographical error on page l2. GAUzlz �CFDLINBMC W315 WV!) IN Max W Fink, PM). mmmpmmotpmmnmmsmmmma Paydaiatzy, (immunity of Iii-semi. Sdml of Medicine SHOO Arsenal Street, St. Innis, Missouri. 63139. , Aided, in part, by usms grants ”44.921, 114-2715, ail-mus, md Iii-11380; ad the Psydiiatric March Fomdntion of Missouri. �VI: 7-17-65 WCWHWIVEW Despite mm application and study, the nod: of action offlnccnwhivethmpmmnminsufimic. Matudy mmmdtomumphysiological( paydwlogical( social ). clinical ( ), ( and aspects, elucidating me pmaent nam— ) phyaiological-«laptiw ). View of the process ). ( 'lha amply dnvalcpmnt and persimmon of signs of altered cerebral fmctiun mm mpomd to be requisite to (Pink md Kahn, 1956), with mess in behavior 0100*:ch slow wave activity as the mat significant index of altered brain function. Thu this Mien slow um that pmddcatim with ampina inhibited ‘Jormcn, 1957) and the report activity (Ulett and that antidxolimrgic a mm nursed these clinical ahatmgmphic alarms (Fink, 1958) 311mm that .me biodmnical basis for the convulsive therapy process the clnlimraic m as wall may be in of the central nervous system. This raviaw discusses the available data agarding acatylcholim fl �and the dwlimstemes in the convulsive therapy process. Acetylcmline has been extermively studied m an active agent in the transmission of dowdptiom of Dale mm impulses since the It is (191A) and Loewi (1921). first a comtitmmt of mmm tissue, existing in a bound form which is liberated during the excitation process. It is rapidly hydmlyud thrwgh the specific action of duclinestarase and in rapidly momstituted by the ohcline~aoety1ase system (Rid'ater and Crosslmd, 19W) . In noml cembmspinal fluid, free acotylchclim is not present despite the mpid bound and breakdown of acetylomline during periom of activity and excitement (Tower Wm, 19u9a). The cambmspinal fluid does have measurable dwlinesteme activity, havever, principally of the "two" or mdwlyl hytvlyzing type (Madam and mm, 19%). In the absence of free aoetyldxomle and mdar the conditions described, electroencephalom fail to show abnormality. �(a) Grahame flats of sootylcholim was found Crmiooembml Tram: Prue in the osmbrospinal fluid within a few minim after sxpsrimtsl Mad trauma in cats md persisted for varying periods up to “8 hours (Bomstein, 19%). The quantity of flu the amtyldmlim varied W1: was (:th between 2.7 and 9.0 gm pennant, and related to the degree of induced mum. shotmsnoephalogmms amazes. me mooxds were demtmted pattmd first filled with activity, immuted as svidsnoo of high voltage fast an intense neuronal distant-3e. soon to be sumedsd by a short period of flattening of all recorded electrical activity. These phases wen then followed by pmlongod periods of high mlitude sharp waves- in ttwdcltafmqusnciss. 'msbehaviomlohmgsswsmmlatsdboflitothsdsgmsof mmmd to tho want of mmd fme amtyld‘nline. Vth highcr lovels of amtyldlolim, Bomstsin reported greater dogmas of EEG Why and water changes in consciousness. �31>th wt post-traumatic seizures ware also related to the of fme acetyldwlim appearing in the Spinal fluid. Bomstein applied amtylctnline to exposod cat cambml cortex. When the concentration of amtyldxolim percent or lass, higx amplitude slurp waves appomd in the electxmmaphalom. When was W6 t0 2 gm percent. was 1 gm of low frequency the concentration 01.0meth the 1000160 fashion the patetzmnatic flatumed in a parallal to Parallel investigatima in neurological patients by and Wm (mm dumtmtad free Tower acetylcholine in the cerebmspiml fluid only in patients with meant head tmuna, meant wand-ml seizures or after alectmcmvulsiye therapy. M0 amtychlim varied fluid spinal assaying from 0.2 to 0310111103001”: 100 gm peasant. In activity, they noted a sharp rise in the nonspecific dwlinesteme fraction (Mmoylcholim-splitting) and a dmp in the specific cholinesteme fzmtian (mohaiyl—eplitting) in patients with had tmma and sanguine convulsiva therapy. The cambmspinal fluid did not �exhibit such invemion, although after it contained free acetyldxolim, spontaneous seizums . They concluded fr“ mtyldzoline varied directly with the damage and that the level of degree of cerebral that reversal of the dualimeteraae fmetims was a mm sensitive indicator of cerebral dmgc. Electmencephalogrmna, taken at arming intervals fellowing minim between the dagme of tram, also indicated a EEG-Wt); md the appoamm of free amtylcmline in the cerebmspiml fluid. mm Wkwwm Tim «the, 4;me We! mm 0‘ due magma-u. may tame in the (cumming {m autgtchouu, abnombbty, and WW «the. Mg“ W“ W. «tam and the want chalk.“ and type 0‘ 4'.» 05 demomuphalogmpuc dialed mm); «ppm «6 �Antietam} (b) bahavioml and mutual m and trauma: mmlogio signs of mum The m electrogmphic, blocked by tbs awninistmtion of 0.5-1.0 Wkg ntmpim (Bernstein. I 1986). as was similar inmcistml clinical change” mowing after the additim of aestylchcline. Ward (1950) applied injtmida. those oboemtima to tbs tmatmnt of closed head In 20 of patients with varying dean-e3 trauma, ha administamd mopim WW1); immt in some and in doses of 0.1 m/kg, noting clinidal a mml effects in others. In a study of diethnxine. Jonkner and the W at the W forty patients with anticholimgic drug, altemtiaw in (1955) mportad post-mmtic aloctmcmophnlnm. dose in electroencephalographic W A sinfle intmvamus electroencepmlogrmm resulted in normalizing in twanty-tm and marked inpromnt in six otham. Similar observations have been Imported by Denisamco (1965) using mthyl‘bamctyzim and poat-atrmmtic mmtin in animal that and 03li em. ewinmta of �Truss obssmtims were assasssd in the convulsive therapy process by Ulstt and Jornsm (1957). These workers administersd dosages of atropine w to the patients waived that the mt: mm slsctmsm of slow wave per day during the weeks therapy. They downstmtsd activity prodmsd in those patisnts ms significantly less than tbs control group who had not received the atropine ministration. (In a 141th study these authors fdlsd to mplicats this study, suggssting that dosage factors or population changes have contributed to different msults [Jormsm These observations provided the basis g}. 31., 1960]). for studies with othsr imam anticholinsrgic mounds (Fink. 1958, 1960). hummus JB—336 arid Wins. the pipsridylbsnxilntss JB-329 (131mm). and WIN-.2299 induced dssmhrmiutim in psychiatric subjscts. These Hum The injection of smrimntally active anticmlinsrgic camels as disthssim. JB-ala, may EEG EEG changes associated with barnvioml darting, anxiety, tramm, illusions and hallucinatima. In patients also had mently - �mind elootmoonvcnsivs the achsinistmtion of throw, these Imomds was associated with a mduotion in slow awn, mm wave and 'eonnnion. activity and reversal of Aunpim was also examined in low doses, and in these administmtims, EEG dosynctumizstion ms obsomd nervousness sod tension. At highnr dosages, hypersynchrmous slow waves, followod by lower activity with menisci by tachycardia. mimosa wings. poorly organized delta bots activity melamine: by pmmssivo confusion and disorientation. Both in oleotrogmphic annual tum and indwed convulsions, the 0W8 may be mdified by the commont (hogs, administratioh of mticholinargio thus suggcoting that immaud smarts of aootylohlim or inorusod oholimrgic receptivity is sssoointod with the high voltage slow wave activity. (a) min and iomlino anticholimm gm m: SimilanEGorangesandtublookingthmmnobumd following the dinct application of mm systm. sootyloholixu to the mm]. �The aministmtim of a omlineeteme inhibitor- DP? (di-isopmpyl fluoroxmospheta) elicited high amplitude rapid frequency We 19mm, EEG patterns similar to status epileptious, as well as similm to those of post—hmtio states (Freeman 33 11., Hanson Egg, effects were blod<ed 1959; and Himioh by small doses 339;, 1950). These EEG of parenteral atropine. 'me great increase in aoetylcmoline after tetmtthyl pyrophosphete was (TBPP) manned and related to the toxic misfestetims and omvulaims induced (mm and u: thfield and Dempsey 1952; Stone, 1957;) (19%) prepared exposed animal cortex with pmstigmim md evoked electroencephalographic spike activity. The prior mistmtion of atropine blocked thio spiking, the almomality oould be eliminated present, by or if atropine. In contrast to those finding, Emma!" and Merritt (19%) applied topical aoetyldxolim in concentrutima of 2-412 to to the exposed cortex of cats, and noted no effect on 10% the electroencephalographic changes after intmwnous atropine (1 mg/kg.) 'lhe concentrations of acetyldtoline in these experiments, �10 however, were higher than the and the gm topical applications (l-‘t intrusistemal (0.2-10 gm percent) percent) injections of Bernstein (19%).. Burner and Merritt also made note of elem- encephalogmphic effects similar to acetylcholine from motion/1 (emtylhetmthylcmline) much lower than the and cloud (oerbanyldlolinflin mtyloholim concentrations. They cmoentmtims ascribed the increased effectivems of these diolinergic drugs to their lack of sensitivity to cerebral almlimstemses. These data are conflicting and further study is museum to qualify this issue . (c) Oembxnsgiml fluid Amtxlcholine and Seizures: of aoetyldiolim metabolism indicates that it is One View fomd in nervous tissues in an inactive band fem. hiring periods of activity, amtylcholim is liberated at the cell dsectivated rapidly by mm, dwlinestemse. The where wt it is of bum asetyldmolim is the resultmt of the continuous processes of synthesis, liberation and bredcdmm. It has been postulated that the level rises during sleep and falls during activity. (Richter and Cmssland, 19%; Elliott, Swank and Hendersm, 1950; Giaruun �Pepeu. 1962). By using liquid air quick freezing methods. Richter and Grassland measured the level of acetylcholine (micro- gem per brain tissue) during anaesthesia and sleep to be mg. 300‘ higher than post-“12m levels. The difference in tissue levels is tnansient. however, as the resynthesis rate for acetylcmline in net brain in high (1950) confirmed m1. the” owemtiom, also Pepeu (1962) fomd an increase 3 noting that after gm per cent. Gimmn md in wetylcholine named by a central nervous mum depressants to be roughly reduction in and no mm activity. acetyloholim we reported in the spinal fluid in patients withepllepey (Cone, and PbEeahem. 19149 1)). 0f 55 'Ibwer and mascara, 19%; epileptic patients. demetmted free acetylcholim in quantities of 5.0 M proportiml to the degree of depression of the central nervous system m :3in convulaims free wetylcholine me demustmble in the spinal fluid in concentrations w to 1;! gm/gm/minute). Elliot (7 with 1.0 of an cent average per gem gamma Tower an (77%) 0.02 to per cent. �12 Acetylchclim levels were related to the frequency of seizures, flnextentofelectnnncemelogmphicmmlity,mdtothe the since the lat seizum, but bore no relation to medication, type of epilepsy or level of clnlinestense eotivity. Tower and Mafia-hem (1904912) vimd the increased acetyldwlim a by‘prodmt of the seiem, Studying the hypothesis that the and not camel . emetim of ecstylchcline indmed minutes, 'l‘orde (1953) measured the level of ecstylclwline in brain tissue netmmle convulsims. .‘ She noted a rise in the ,_ V V ecetylcholine content of brain, before a seizure and a the cmvuleion. Below fall (bring certain levels of ecstylcholine, convulsims failed to comm. Stu suggested that the fall in tissue acetylmolim during a oonvulsim was due to imibition of ecstylcholine synthesis by increased concentrations of metabolites such as mnium ions. Wmmmmumdohmgesmmmmm system acetyldmolim following various stimulmts . Only after �13 unholy]. and 3, S-dimthylbutylcthyl-barbitmte significant chmge in the acetylcholim level. damn. was They noted a in associatim with induced convulsions. drugs which firearm as stimlants Md mmmdumainmtyldmlim + other With 133mm, (LSD, hymoxytmyptaphm and iEprmiazid level. there a + DOPA) them WWW daspito inflame excitation produced by these commie. them wan no dung» in mtylcholim level unless than were accompanied by convulsions. (The differences in observations botmmmuwerkmmdmggglmdmmrmdflcfiadmm my be in diffemnaas the to related mummnts, for thc latter methods of biochemical wand changes in spinal fluid w 61m and Pepeu mflecting the fun acctyldxolim,‘while 12; bound and reflecting acetyldwlim mumdntatal true form of aoetyldzoline.) Thu: Atuau wages: that on: Wed by an sputum Lame. in an. induced 1mm law 5n: awtytchaunc �”mm—“hr“ V» 3- ‘ v w» . m w 1-: “r. 0... ~ W "n , nr-r-w, ..-.p:..u<flv.»rrw-¢.M “av—w. . .,. 4. ....“.,_. w... ,, 'zs-sznr-W"“air‘quvww'fi'qmti'd‘u. w. » ,‘rv —.».‘ wm‘ , w - 1n abound 4m in bound (on which my wind. (Laid. Cmbm nativity Micheline dalmatian, manna. Lemming mum 15qu in #1: enhauu tame (cum 9‘ Me blew and Mama auguwut mallow: madam“ 42mm aunt (d) Comm]. Nervous Wm and be mm . Sgt” ('holinostemes: (19%) also uncured spinal Tower and fluid cholimsturase activity. No types of dnlimstemes are normally found in the spinal fluid: dwolimstemad ”true," "Specific," or Molyl-hydmlyzing) . whim has a high specificity for acetylcholim; and dxolimtemacu-II ("pseudo," or bonmyld'uolim-hydmlyzing) . "mpacificfl Both oompomds hydrolyze acetylcholim but have diffmnt rates of hydrolysis for mcholyl and bonzoyloholine . 'mis differmtial mta permits qualitative diatimtiom. By reporting the cholinostemse activity as a ratio of the activity with a mocholyl substrate and with a homoyldmoline substrate compared to a substrate of acetyldmlim, two ratios are fomd: dzolimsteme-I/wetyldzoline . --- v r v , -- ‘ ~- a"; . ��rmw, 16 vasodilation and increased with a degree of cellular permeability may be pmdicted. amudetion of vascular fluids into the inter. the of duration md with extent the varying cellular spaces g: vaaodilxtutim (Rabat mad their comma pomability such 51;, 19%) . Spiegel, Spiegel-Arblf, (19%, 19W, 19%, 19%, 1953) chm demtmted and increased oonchwtivity of the ions (as various of with the associated appearance tissues potassium and phosphate) in the spinal fluid following electrically indwed convulsions . Such non-electrolytes , as nucleic-edit: splitting mama , also increased. Ganges in cellular permeability @6011th may thus provide the basis for the high of aoetyldzoline and the increased concentratiom of aholimstemse-II in induced animus or head and We!“ The head 1989c.) . persistence of acetyldxolim in spinal fluid after tram activity tram (Taver- and may be after seizm'es despite increased cholinesteme related to the sensitivity of the acetyldxoline- dxolimsteme-I system to meantmim relationships (Nadmm W. , ~1— ~- A” .—,.- �17 and Wu, 1935; Tower and Wm, muse; Burger: and McIntosh, 1955) . At "physiologic" comantmticrns, hydrolysis of mtylcmlim is rapid (3-4 lunar com—um, MW) but at higher and the activity falls off quickly . In contrast, the dialinastemaun acutylchclim relatimship is map-cite and the rats of hydrolysis incimma with increased: ammunition. 0m view of these mktimhips suggests that while the usual concentrations of mtyldmolim a cell dostmyod by the specific activity of few Wounds, my «and the seizum are dnlimstomeJ in a m excessive concentration following excitation the mate of hydrolysis by coir-m Mahala mnbms may be itself cholimstcmeJ. m reached and a seizure inclined, with adding to the mum: of free amtylcholim. The immune! acctylcholine diffuses rapidly, affecting vascular and annular pumability and imam; the mntmticns of various iom and dmlinentemmn in the of molimateme-II , though of low 031". The activity efficiency and depending on ��in brain tissue, associated with the appearmoo of hyper- (delta bursts) in tho electroencephalogram. syndmrony We was have oonflmd the many pmvim reports that convulsive thumps: induces elootmgmphio hypomyndarony (Pink and Kahn, m 1956; 93. 93;, 1981) . mutants than is mom. slow by m Despite a constmt application of a great variability in the the W103! and the exam of the alcotmgmphio mitivity activity as well as the alerting. hypeantilatim synchrony and in psychiatric dew hyper- its persistence thmmlmt a treatmt has boon described as pmmquiaite to It is to mdifioatim and barbitumtes populations . 'lhe early appearance of high Week tins of (Roth, 1951; Both 93.2%, mm 19531;th possible that the £15.fome in EEG-hypemynduw my be of central oholimrgio following and @,1956) . induood the dogma of muted to differences in the activity ”Wm . patients to develop hypomyndmmy pnoluding a clinical me name me failure of certain may thus be associated to Wood convulsions. Tower �.. 7.7. wrunvx—u— 20 and Will“ (lauea), in flair study of mommbml tram, included obaawations of six paydziatrio patients mdergoing convulsive therapy. Studying the patimts aftor 3.7 momenta aootyldaoline in two patients; may mpootod free spinal fluid and an imam in (momma—II mumstomod with and a demase in a reversal of tho mti-o of mono-stoma: in five of the six patients. hm those observations they minded that the spinal fluid dmges in induced convulsions mmmliketmmofcmimmbmltrmmanflmoof spontaneous epilepsy. Boarding the one pttient in the series failed to who show either true wotyldmlim or a duolimoocmse ratio reversal in the spinal fluid, they wrote: patimt was Mt." "It is interesting that this the only one of the six to show no rospouso If electmgmphio hypemyndxrmy is of inommd {me acetylcholim , subjects whammy and those in whom it who to a reflection maintain hyperh disappears rapidly may be exhibiting diffemnoes in the kinetics of the d1011nestemse~ wm. w,- Nx‘vrpl .1 �-\ “ --~w an» .7 r'v-vww-‘ 1". -.r Ti'prp"-fl-=Au‘n “-6.“..- ~-‘ ‘31 . W W . , “‘7.dvzw‘". V... mu. metw'w—mwmlv‘lu":.e.vrlvn—“Atm-‘mWW w-xm “m.- Y‘a""' 21 acutylctwlim hydrolysis system. 'Fhmistant hypemyndumy result dsmd {mm a may rate of hydrolysis of acetylemline, associated with low mnemtmtions of either molimatemsea-I with shortin patients '(Oonwmly, dlolimutcmc-II . or lived hypemynduw, dxommteme—I md -II in tissue and spinal fluid PM: be mmually him) . may that: anomalous was 0&0:va «wanted “W‘m, «shaming the We. an: WWW a EEG 51prwa 1.5 a; Lgtu at WWW paovtde We in We mwmum.‘ wumtuuu. Mad one WW W pubable that saw! an that induced Wag embmcpweabuétym and It a on would coucmde aw by The Level. 05 upcmd Mad .5qu . mama of pmabuéty Mud Law 05 exhale. flzuc changes in 05 «anaemia. mm deem- m mama: 4mm (an m pmumx chugu foaming induced 0.0qu . w ..—-.w-w~.-w... �K. i [ ‘ v. ,7 W .. f m .l . V, ». V, ,,,,_V -. .o “:2 ....V flu, ”w...“ - w-wfll’m'." ”no”. .7 ..n “w... amp-“mm- "...v'vmm. ._, f.v-w—«-—v~—— v0?" m—v‘ wkumu. , 3‘“ .7 a run ,. . -- 22 (6) Gaolimtemes Thus studies may and the Classifimtim of Paw: also have applicatim to the problem of ‘ automic Inactivity mum and the clansificatim of the psychoses . and athora ( a «Miami-nip between ) true blood haw ”castrated pmssum response to injected madmlyl an! the clinical mponae of psychiatric patients to ammlsiw whim filmy. lel is a potent cholimrgio agent mm, mama vasodilation, tadxyoardia, peristalsis. It is rapidly hydrolysed by and W6 diolinesteme-el and :11me by dzolimstemse-II . Tbs blood pronoun of subjects fall: after injected mohalyl within five to more than 20 md mtums to the basolina minutes. Patients whose blood E l I i plum returns to the baseline within classified as Group panama takes 20 Group VI and VII 5 minutes have boon I. II, or III mentors; those whose blood armors minutes to mtum to baseline, as rumors. Group I md Grow; IIoIII motors �23 have a 9 and a 35% recovery rota, respectively, while Group and Group VII reactors 9:92;, 1952). Group patients in whom 89% and 97% recovery rates I to III reactors may be VI (Menorah looked upon as the injected morolyl is rapidly hydrolyzed; while Groups VI and VII have a slow hydrolysis rate. We may predict, therefore, that the blood cholinestamsa activity levels of Groups I-III would be high; while the activity of Groups VI A - VII would be low. similar analysis may be made mgarding central nervous uysten levels of cholineatemmel in the development of Em hypersynolumy and spinal fluid levels of acetyloholim, providing a basis for a oongment hypothesis mgarding central nervous system reactivity to induced convulsions dmolimngio agents. and to peripheral �. ..— .—\..‘ .. .—Vw-~'. 7...... "any.” “.7 lmr.r"vv,~ .. ...~ y.. . _,_,‘ , ~~,.. m. .WWV mm. rm. ~ v-y ‘ WV W H .wa-flq 2'4 CONCLUSION : Central oholinergic Insomniac: appear nah- W in!» in the convulsive therapy process. ‘ significant The published data [that induced convulsions are indicate associated with an increase: in interoelluler acetyloholme to levels greater thm can be destroyed activity.“ Veeodiletim and increased are followed by increased other enzymes and by cholinestemse-I cellular permeability wants of cholinesterese—II and electrolytes in intercellulsr fluids. These chmges are reflected in the increased hypereynchrmy which can be modified by is electrical recorded in scalp electrodes, and which mticrnlimrgc drugs as atropine, benactyzine, and diethazine. The changes in the cerebral biochemical milieu alter cellular activities sufficiently to be associated with altered behavior of subjects. Failure to induce high and persistent cmcentrttions of acetylcholim and failure to induce concomitant electrolyte changes results in a failure to produce behavioral change. 4'u-L...» 1.x. —~- -- 7 �2S Diffcmnoos in the mates of development of reflect diffemnoea in mbml that ‘0me of subjects on ohangas cholinergic ruthenium or in their sensitivity to changos in aoetyloholixm levels. Then diffemoes provide the basis for the classifica‘ tion of the mntally “most: the mode ill by Pmkonstein and by Fink and Kahn (1961). observations pmvidu a rational biodnmical basis for of action of induced mnvulsicns in altering the buhavior of psychotic subjects. These views are consistent with the mom general neurophysiologio—adaptive theory expressed earlier (Fink , 1957) . �REFERENCES M, R. Bo, Stmit’ L. A0, PM, do We, “muff, Mo K. ma Bowditch, S . C. Nemphysiologic effects of electrically induced ccnvuleicm. Melt. Peyehiet. 1956, 75: 371-378. ”Wt. (cum, Bomstein, M.D. Presence and action of acetylcholine in experimental brain trauma. 1. Nwophyeutn 19%, 9: 3%«366. Bummer, C. md Merritt, H. H. Effect of certain choline derivatives on electrical activity of the cortex. Mch. Munoz. Psychmt. (cum, 19fl2, H8: 382~395. Wu, of ecctylcholine. A. s. V. and Macintosh, 1-“. C. In K. A. C. Elliot, The I. physiological sigiificancc J. H. Springfield, Ill... H. Page and Queetel 1955: 37u-375. (Editors), Numchmmg. C. C Thomas, Omtfield, P. 0. and Way, E. W. Effects of proatigmine md acetylchcline on cortical potentials. Mu. J. P11544201... 1m, 135: 633~6H0. Cone, W. V., Toner, activity in Wm, D. Acetylcholine and neuronal and epilcpey. J.A.M.A., 19%, 73: 59-63. D. B. Dale, H. H. The action of certain esters and others of choline, and their relation to marine. J. thueol. Exp. Thu... lSlu, 6:1»7. Elliott, R. A. C., Snark, R. L. and Hmdemcn, N. Effects of mathetics end ccnvulsmts on acetyldmline content of brain. W. J. "15161.0(" 1950. 162: ass-hm. PM. M. A unified theory of the action of paydzodynmic therapies. J. Hill‘idl H06p., 1957, 6: 197-206. Pink, M. Effect of mtichclinergic agent, diethezine , on behavior: simflcance for theory of convulsive therapy. Adah. Mental. Paychiat. {Ch£c.). 1958, 80: 380‘387. EEG and Fink, H. Effect of mticholinergic compom$ on poet—convulsive olectmencephelogxm and berminr of psychiatric patients. Eummuph. cu... Nauphyuot" 1960, 12 (2): 359-369. Pink, H. and Kuhn, R. L. Qumtitati-ve studies of slow wave activity following electroshock. Eucmemph. can. ”canophyaiat” 1956, 8:158. Fisk, M... Kahn, R. 1..., Ken), 2., Pollack, H., Green, M. A.. Alan, and Iefhowits, H. J. Inhalmtoinduc-d convulsions. Mch. Gen. 1961, “:259-266. mm, ' m, Bales, P. p., Willis, A. md Hinwich, H. B. Experimtel production of electrical major convulsive patterns . W. A. J. ”twin-L" 1%9. 1%: 117.12“- B. hymn ��an'V-WI' -3Spicgol, E. A. and Spinal—Adolf, M. Physicochemical effects of electrically inclined convulsims (cambmspinal fluid studias) . Tm. MM. Newt. AAA” 19%, 70: 130-132. Spicgel, E. A. and Spinal-Adolf, H. Physiological and mysicochomical Marxism in tmatmnt. Conga. NewwL, 1953, 13: 38-63. 013::th Spiegol, E. A., Wm Spicgclmlf, changes in the brain H. and Benny, G. Physiococl'xcmical electrically induced convulsive discharges. Tum. ML. Haunt. MA... 19%, 68: 17a. Spinal—Adolf, 14., Wilcox, P. H. and Spiegel, E. A. Cembmspinal fluid menses in electroshock treatmnt of paydzoces. Mu. J. mm” Stone, H. E. The role of acatyldmolim in brain metabolism and “mm. Tom, m. J. M0 M9, Effect of convulsim content of the brain. Man. J. C. 1957, 36: 222“255c inning agents much, on the acetylcholim 1953, 173: 179.183. Tonia, C. Effects of single injection of corticotmpin (ACIH) on manium ion and acetylcholine (intent of bmin. MM. 1 . Myuol" 1953, 173: 176-178. Acctylcmline and murmal activity. I. Warm, Gnumtomso pattcrm and acutyldwlim in the cembmpinal fluids Tower, D. B. and D. of pationts with armiommbml trauma. 27 (seat. E): 105“].190 I cm. 1. Rucauh, 19u9a, cmtent and dmmcteriatim of cambmspiml fluids. Canad. J. Rumch, Tow-r. D. B. and McEachcm, D. The hm 27 (Sect. E): 132-1u5. dwiimatcmes in Rush, w Tower, D. B. and HcEaclnm, D. Amtylcholino and neurmal activity. II . Acetylcholim and cholinestcme activity in the cembmspinal fluids of patients with cpilnpay. Can“. J. Image, 27 (Seat. E): 120~131. Mum. “We Ulott, upon Rum, Effect of atropine md scopolminc changes indumd by electm—conwlsive G. A. and Johnson, H. w. can. MthyAioL., therapy. Ward, A. A. 1957, 9: 217-22u. Atropine in the treatment of closed head injuzy, J. Nwww., 1950, 7: 3984402. �cmLINElEIC WIfliS, AND BEHAVIOR CONWLSIVE TIERAPY Max hm tha Pink, M.D. Wt m1 of Psychiatry at the Miami. Institute of Psychiatry, University of Hisawm'. School of Hedicim, suoo Stmet, St. Louis, Missouri. 63139. Aided, in part, by USHiS grunts $1.009”, I‘m-2715, ”ii-07239, and Mil-11380; and thc Psychiatric Recent-h Poundaticn of Missmri. 'mismportispartofflnstudypmmminhmctimand Behavior" undertaken New York. Hillside at Hospital in �n -.v-..ww.nmipv~.. NJ, mi V: CHOLINERGIC MECHANISMS, CONVULSIVE THERAPY, AND BEHAVIOR Studies of induced convulsions have m that the early develommt and persistence of aims of altered colonel function are prerequisite to chmgee in behavior (Pink and Kenn, 1956). Electmemptmlogmphic slow new activity was found to be a significant index of altered bmin ftmction, and the dmnonetm- ticn that premdiceticn with atropine inhibited this slow activity (Ulett and Johnem, 195$) suggested a wave relation to cholimmio melamine. In the following review the mle of acetylcl'olixn and the axolineetemeee in convulsive therapy is diamond. Aoetylcholine he: been extensively studied as an active agent in the transmission of nervous iwulses since the descriptions of Dale (1911;) and loud. (1921). It is first a constituent of nervous tissue, existing in a bomd form mich is liberated during the excitation process. It is rapidly hydrolyzed through the specific ectim o rapidly reconstituted by gelimetemee and is the cholimfleoetyleee system (Richter s V 6~28~65 , �Croeslmd, 1909). In normal cerebroepinal fluid {me eoetylcholim is not present despite the rapid breekdom of bound ecetylcholine during periods of activity and excitement (Tour and HoEecMm, lease). The cerebrospinal fluid does have neasmble ctnlineetemee activity, beaver, principally of the "true" or mctwlyl hydrolyzing type (New and ibthenberg, m5). In the absence of free acetylcholine and under the conditions described, electroencephalogram fail to show abnormality. (e) Effect of firmiocerebral was Item: Free eoetylclnline fomd in the cembroepinal fluid within a few minutes after- experimntal heed periods up to '58 tram in cats and persisted for varying hours (Bernstein, 19“). The quantity of free ecetylcholim varied between 2.7 and 9.0 game percent, and the mount me related to the degree of induced Concurrent electmmoephelogrm The records were first filled he followed by e demetreted patterned changes. with high voltage fest interpreted as evidence of an intense to tram. nemel activity, discharge, only short period of flattening of all recorded �alactriaal activity. periods of high 'Iha These phases were than followed by prolonged mlituda sharp wam in the delta fmqmncies. behaviml chmgea wan nlatad both to the dame of amt of masmd trams and higher haul: of acatylcholine, of amornality and EEG to tha addition, spmtmaous to flu matar With Bernstein uportad snatcr degrees (mange: poet-Me aunt of free fm aoatylcholim. in consciomnass. In aaixums «am also ralatad amtyldlolina app-axing in tha spinal fluid. Bomatain also applied acatyld'zolim to exposed oat cambml cortex. ”Mt When 01‘ tho omeantmtion of mtg/lanolin. 1808. fraqmncy in the was inmasad to ht EX: vaporized high amplitude sharp waves electmphalogm. “man ’7 2 was 1 gm pamt, wam by Towar- and HoEaeham of law the oonoantratim the alactmonoaphalogrm flattened in a fashion parallel to the Pamllal studies ' post-Mic ram. can'iad out in mlogioal patients (19%”. Pm: acatylcholina was fomd in 7 1 {wéli 14?”! [6cm �«1—. . ;_.... 7,. rm. . ‘ 4‘1"“.7 .. run-- «m w, raw-"aw ~~.w.:-v-w—.--lam—www—nv-rwww - the cambmopinal fluid only in patients withmoent Mad wv .r'. r tram mount pond-m1 seizures or aftor convulsive trunpy. Free ...;—--°-"“' " aootyldioline varied from 0.2 to 100 gm __ ~ peroent. _,,./ Tour ~ v. m3...» Mom also assayed spinal fluid oholimtome activity, rating a sharp rise in the nonspecific cholinestemse fmctim (benzoylclwlimqmitting) and a drop in the specific oholinestemse the oeubmopiml fluid did not exhibit such invasion, although it “dined fm mtyloholim. of They concluded fm mtylcl'nlim varied directly with the damage huge. taken at varying intervals following Kantian batman the dome of {m EEG was a mo Electmmoephuomm, tram, also indicated a abnormlity and the appeazmoa aootylcholine in the umbmspinal fluid. Thu, flu spinal dogma of oombml andhat reversal of the dwlinesteme fraction sensitive indicator of cerebral of that the level want as 549.: Micheline. my {mug in the (Mdéaltmiugmuocmbwmmmdmmuntaé Wt / W“ _4___._.._..-' follavdng oonvulaivo mommy. Pollovim spontaneous soizums 01W, 4a.: \ and fraction (mohalyl-splitting) in patients with had 12mm and , �.5and the degue acotylchoune, (no Wenuphdogmfiic «type 06 abnambbty, and changu in clinical bellow»! my be {Wad phenom. (b) antioholm Am1m, o behavioral and neurologic aims of pamtenl m mm and The EEG were blocked by the Mimic»: of 0.5.1.0 lag/kg atropine (Bomtein, as were similar clinical charges counting addition of mtyloholim . to the tram: W1: Ward (1950) after the intmistenul applied these observations of closed head injuries. In varying dogmas of tame, he 20 patients ’with ministered atropine subcutmly indousof0.lnglkg,notingclinioelimrovmntinsommda Md reversal of the eloctxmoephalogmphic effects in others, In a study 09m, mower ufitmolinergio Inchner (1955) reported altemticns in the moephalogm. W A p‘tvtremtio electro- single intravenous dose in forty patients with aleotmpmlom resulted in normalizing in twenty- ), �F i H4 ~37». .V v . “WW. awn" V l -.—.p..r \':v';"'r~~ gw~-_.....—m .— ...r 1"" “v: n n‘ , , , m. ,- two and marked , . , .- ,,_ _ , , __.,,_3._.7,,_,._ “,1”, ‘4‘._,V , an- a www-ruymumrm-e ,, ., .F ‘7...arm'Hfl ,_ ya,V. a“W. .. fiauawfll.‘ .w-qflw’ uvwwwrvw-1': -r~)\w‘nw . . . I 5.1119th in six others. In subjects following convulsive therapy the (feet of atropine inblockingtheappeamceofelwwaveectbdtywaemported (mm 139 :Iohnsm, and 1956). (In a later study these authors failed replicate this study, suggesting that dosage factors or population changes [Johmcn gel“, “niece may have mntributed to different results 1980]). observations provided the basis for studies with other loom mticmolimrgic canpcunth (Pink, 1968, 1960). The intravenous injection of experimentally potent antidwolimrgic momds as dietlmine. bemctyzine, the piperidylbenzilates JB-Bls, and .— JB—329 (Ditm), Wution. VIN-2299 and pmcyclidine induced The EEG chmgea were alerting, anxiety, trauma. illusions and JB—336 EEG associated with behavioral hallucinaticna in peyduietric subjects . In patients with recent induced conwlsims these «awards resulted in a reduction in 31m useciated with a reversal of euphoria, denial wave and activity cmfmion. .3 “‘11 i a 5161,! . fig?“ �“Rpm, .,,,,..( ,“_.,. ,.. , N" .37.. 7”,. v Atropine was also Md, . ”a“, N mined in y:~.uf..~r\v.“r - o—r- .. n «v low doses, maniac] by todnyouwdia, “any "n www-mur - voltage, poor-1y organized delta activity with activity was Mum.” ._..-t m... who .er ixflu’Joitor, I)?!” elicited high anplitude rapid 935;, post-tmmtic states 1950; andHiwidx 5.3;. m as (mm 1950). These 3: 2.1.2. m; offoats won block-d by small doses of parenteral atropine . Qutficld Tho - “law‘vpm-x- superimed beta patterns similar to atatm epileptious, as charges similar to those of with .-- slow waves . followed by lower mumatarau (di—isopmpyl flmmphooptute) Hanson .,.,, associated with pmgnssive confusion and disorientation. mo administmtimoof a 191:9; , nervousness and tension. At hyporsynolm £1qu ...,,.,..;. dosynohmnizatim was BEG higher dosages, BBC V and Dupscy (19“!) pmpamd exposed animal cortex prostim and evoked eleotmenoaphalogmphic spike prior aministmtion of otmpinc Hacked this spiking, or present, the abnormality could be olimiratcd In contrast to those findings, Mr activity. by and if atmpim. Darrin (19%), applied topical aoetylobolino in concentrations of 2~ll2 to to the exposed cortex of oats, and notedno effect on the 10% «- �ehatrmnaphlomxic The damages after intravenous atropine (1 mg/kg) . concantmtims of acetylcholim in those encperimants, however, were higher than the and thc topical gpplioatims (1-4 intraeistemal (0.2-10 gm gm pement) percent) injections of Bomstoin (19%) . Bmmmr and Merritt, also made note of electro- enceplnlognphic affects similar to aoetyldxolim from nacholyl (mtylbetmt‘m‘lmoline) much and doryl (carbmldlolim) in concentrations lower than the amtyldtolim concentrations . may ascribed the increased effectiveness of these dnlimrgic drugs to their lack of sensitivity to cambml dzolincsterases . 11qu nativity Mamie The“. W and war. 0‘ man, mama induced by autgzehaune 46 can be. backed out mafia, mama“, of mtyloholim antebellum indicates that an oak“ as Wed a imctiw bound by anti.- etc. (a) Cambrmghnl Fluid Anglcholine and tissue in that!» topical application, M lintuéowm. with chum-Amt activity 49M studio» tuggeat that it is 34513112.: Ono View fomdv in nervous fem. Wing periods of activity, mtyldxolinc is liberated at the cell membrane, where it is �.v. .mTr,--m.,—,w..‘_-w.. ”“51“,”, wwryw , . "a". 7.,“ -\‘-yuv;-vv—n—-,17'zr'~.m"--r mm.-- .fl‘vv—‘r- - MW‘VW'v'bn-‘Imwx‘y ,. ..,,..‘v-_.v..—-u.-~, ,- -10.. rapidly deactivated by molmesteme. acetylcholim is the remnant of oontinm lihemtion and brim. rises dining sleep was amputee! and mmt The and It processes of synthsis, has been postulated that the level falls during activity. This hypothesis in miml experiments Elliott, Sunk of bomd by Richter and Crosslmd (19%) and Hmdemm (1950). By using liquid air quickffnezing methods, Richter and Grassland observed the level of aoetyldmolim during metathesis and sleep (unsound as W per levels. mg. The basin tissue) to be 300$ micro— higher thm post-seizure difference in tissue levels is tmsiont. however, as the msynthssis nuts for aoetyldaoline in net brain is high (7 gum/Walnuts). Elliott 939;, (1950) confirmed these observetims. After utmsole convulsions they also noted that free aoetyldaolim in concentrations m always demnstmble in the spinal fluid up to 3 gm per cent. In spine]. fluid studies in mm, Cme, Tower and (19%) and Tower and HcEsctnm (19am) reported Wm simificant �quantities of free eoetyldwline in patients with epilepsy. or 56 epileptic patients, an (77%) in quantities of 0.02 to 5.0 gm per cent. The gm mmted free acetyldxolixu per cent with at average of 1.0 eeetyldroline level was related to the frequency of seizures, the extent of electroenceplulogephic ehmlity,endtothetiusinoethelutseizm. Itboreno relation to mdioetian, type of epilepsy or level of dmlimstemse activity. Mather tr: ecetylcholine appearing in the spinal fluid is e by~prudmt of the oonvuleim or Mather the increase in acetyl- cholim is e eeuee of the seizure is pmblemeticel. HeEeehem (19%») suggested Tower and that increased acetyleholine liberation ismtdutotheseizureitselfbuttothepmoese causingthe eeimre. In e study of the hypatrueis that the mmlation of mtyldtolim is causal for seizures. in urinals by mmzole m (1953) induced convulsion and determined the level of acetylcholine in brain tissue before and during convulsions. cmwleime are preceded by She noted that a rise in the acetylcholine content of �M- iv“... “.0". ,_ v Hr. “7 a.“ rm . . ~.— ,VT .m", ...,. ‘mr—v-,~7..‘..v.».. . , ..,_ 1mm- ’77.. ., w.‘ .5, 1. .w, 'TVV'WHP-‘ ‘(n'ry Humannnruu .. . ww'" v-vm ‘r‘ ~ , 1-v.‘.r—~-.- r---v um”... mam-awn” -12- tissuc, abut the content fills during the convulsion, below and that curtain Invals of acetylcholinn,‘eonvulsions failed to occur. She sugspstod that the fall in tissun aeotyldholine during a canvulsion was due to inhibition of acutylcholine oonc¥ntration incroaéed synthnsia by the of mutaholitns/ such as ammonium ions. Seizunzb nan aceompanizd by an lacke¢4¢ {act aettytchclluc libeaatld {Ann (:3 in inteacnllutan bound £03m, Amucmybeumuedinmwud (Md; and’liit this Mammal nativity and Atizultb cnhanct acatyteholluc debthuction, lawtning 125£u¢ (cvelt as aettytchalilc; ukilc Attcp W and ancsthetla acaywwm wanton Alumnus tune. mm . (d) Cuntral Nervous SystaEKCholinestcnanas: Oanoamitant with their~obaervarions of changpa in aestylcholine, waor and HhEaahorn (19kg) neasunod Tho spinal fluid cholinnstcraso activity. types of cholinnatexuscs are normally found in the spinal ,, -~a 1 Wm "F-Ir «rm-“r Tau—w �fluid: cholimter-ase-I which has a high Wm," ”specific,” or mdnlyl-hydrolyzing) , specificity for acetyldzolme; and cholinesteme-II ”punch," "um-specific," or bemoyldiolim—hydmlyzing). Bath mama-uh hydrolyze wetylclnlim but have different rates of » hymolysil form‘mdiolyl and hmmyldxolim . This differential rate permits qualitative distimticns . By reporting the cholinestemse activity In a ratio of the activity with a maholyl substrate with two on Walnut» substrate mated and to substrate of wetylcholim, ratios are found: dwlimstemso~1Iacetylcrwlim and oralinesteme-II/metyldaolim (with WM'IOO) . In Inch ratios noml cambmepinel fluid contains estemes in the ratio 33:17 of for dwlimtemee-I to eholimtemedl . In patients with head tram Tower md Wan reported an inversion of the cholimstemee, with an increase in the dxolimstemeI fraction of the spinal fluid and a decrease in cholinesteme-IL. (ctivity. me extent of the duelinestemee reversal was related ��u. wc- 15": w“: w—qggywww—mqw 'vwflvw‘r' w'w. ;~m«w usedatcd with the plum“) . we “c- ,‘ rm-“ ,n, mvmr "W_.,“-..‘w .fl. appear-am: of variws isms (as potassium and in the spinal fluid follwing electrically comm. than was electrolytes u cellular an. ._- ~———~> also a significant increase in such nan- music-acid splitting mama . Minty may aluminum-41 in md madam ‘13:. with the and the induced mixtures or hand km may be in cholimstem activity should of true mtyldxoline. be associated The persistence L a“? M man md after commas: relationships 1945; Tamar and Wm, mummtiom, microseconds) but Men (Nadmnsm and ”MA n5 and laser matmfims, contmt, the dzolimstemo-II— 5e 5 5744 (K biz k 4% 4: Mute-h, hydrolysis of mtyleholim at higher the activity falls off quidtly. In 19169; . é'dééflloéj“(.1 related to the sensitivity of me mtylahomu-v 1955) . At ”physiologic" (3—43 (Tamr- 54’2“” [w mid damnation Murmurs, is rapid than muse). dmlimstcmsed system to and in incmmd concentrations of mtyldaolim in spinal fluid after hand mum‘s Oranges thus provide the basis for th- high cone-stations of matyldxolim of inctuoed �. “N-r —~ n. 7., VFW..-” W _ a. .. vw—w-‘w— 7..- .—-..~,-— :7 tm'w“‘n‘.mm"\ "Va-"er-rwswrwnh‘ Inwr'n'ra'" ., "mu-wmu» m y'WWW—m. w~~vw-'VI"-’wr11‘xn—n‘ ~ .x v . .. ”rip-“73“‘miwl‘wuw1vv'1‘y; NV”; —,—-.-r~.. .nr w "WWW,— «.v “ «mu—v..."- ‘ . .15acctybholino rulaticnship is non-specific and the rate of hydrolysis inexact-a with cone-ntratian. Mi 1‘“ ; Aum£-‘£o’%}4i 4;; ‘T f? dnatrcyud by tho spocific activity of cholinnsteraseol in faw lasso-.aondn, an excessive concentration fallowing excitation may canned tho by cholinesterase-I. The L¢¢1¢4 A¢M4 ‘ acixurn thrushold nay be reached and a noifnnu indueen, with thc stizumi f i rats of hydrolysis Thu itself adding to the amount of free acetyldholine. innrnanod acutylcholins diffnoos rapidly, affecting vascular i and cnllulnr poxlnability and increasing the concentrations of various ions and cholinnstnrusc~11 in CSP. The activity of dholinnstoraao-II, though of law efficiency and depending th- mmmm kinetics, Mass on the mtylcholim in the tissuns in hours to days to lavels for tho physiologic action of cholinnatonuae.1. 422;“ 42351“ �‘vr , wwvw—M. . ‘ «ruuuv <t—V'1vwv “—w—ww wwwmwrwwnw. raw—em: un.mnv:.-.Wm "WW—.1» yrmlmx-N ltd-www'fia'wmw'guw‘I‘v ~ 1.. —_ '~V"(—m'v M.Wr>‘\'m‘ .17- Choumtmu «ppm in nu mind We! as a acumen 05 their. 41mm: in Lu ceu. The mm: gammy ma m swam 6;;th (e) 5mm», muting 5m mentioned by changes 1,2:qu Midtown. momma; m pout of the eybmetéc mechanum awn-(muting the 604 Ante/Lem Me 05 «mama»: at was mainland: mu‘uy WW9. Mainline EEG! and Induced Ccmvulsiam: . Almmtion in the blood~brain pemability barrier by the cmtiming team of amtyldaolim may be the biodwmical substrate for the post-ehetmshod: hypcmyndmmy of the alectxmnmphalogrmn. Such a possibility is avid-at in the report by Aird «mutating an increase W 23; 3141955) in‘the concentration of cocaine in brain . tissues thme days after a series of 12 induced omvulsiom. His data Show the change in mnemtmtion of this large animals, ominarily abaerrgu: inbrain tissue to be mociated with the appeamnoa of hypnrsyndzmy (delta bursts) in the electm~ W. , �. inn-ha -'!SA‘-’-"—'r-.“ viva... ..».-~=v—-nn , wan-.wp» ‘ wn “-1....er fl.” .7,» :w .r x» In studies of induced convuleime, many flaw-u. we WW“ -; ‘v w "M”,Vrmm “ w... -wA.we--wfim~mvav" . _ ‘1 dump-.— have confirmed the pmvioue reports that convulsive therapy induces electmgraphic hypersyndxmny (Fifi: and Kahn, 1956) . Despite a constant applica- tion of mutants, the time of appeamsoe, the dlmatim and the extent of the electromphic slow sensitivity to modificatim by wave activity as well as its alerting, hypemntilatim barbiturates vary greatly in paydxiatrk: populations . appear-awe of high degree hypereyndumy and Too and early its persistence through- out the txeatmnt name has been described as prerequisite to iapmvemnt following electmehodc (Fink md Kahn, 1956). The failm of certain patients to develop hypemyndmmny may be related to differences in the activity of central aeetylcholine and dwlineetemeee. with the absence of free acetyld'xolim beingmlatedtoninimalehangesincembmlfmctimmdflnm precluding a clinical response to induced convuleime. Tower and HeEaehem (mum, in their study of Madembml trmma, included observations of six peydmiatric patients mdergoing mleive therapy. Studying the patients after 3—7 treatments "- mpg-w“... �.ww pwzwrn . 7 .19... thay reported free two 41lede patients; and an 1mm activity in the spinal fluid in in duelimstemae-II md a dome in dummtomee-I with a mammal of the ratio of dwolixnstemes in five of thn six patients. ms that the spinal fluid like those of From mica-tubal these observations they concluded in induced convulsions m Ragar'dim the mo patient were mom than those found in epilepsy. in the series who failed to show cithcr me mtylaholim or a cholimstomc ratio reversal in the spinal fluid, thcy wmte: "It is interesting that this paticnt an the only can of the six to show no msponse It a pawn that induce! mama» £6 mmuu i/ t:”PM/1AA fly ff-WLL AW by 1.6 3 0‘ JA mm, sums. Law 96 me EEG Fm «commune hypwyueMony mama“ and 1.6 mm on: mm ascenumcngm. uuuueehuguzazmouummm- AMM‘W was that plowidc flu. biochemical. 60.be (on the pmaaut V WW) mamnt." mm mm pmabuuy m Mug the. mam a; mumamu. W W Wilma mm “#19” ( in Wt to bchaviom changes {allowing inland canmuiau. w;- �(f) Choline-tomes moss studies may and th- Classification of chosos: also have spplicatim to the problem of catatonic reactivity and the clmificntim of the psychoses . Mkonstoinsndotlwrs( )havsdsmxstmtedamlatiom ug ship botwun tin blood possum response to injectedflm) (dd‘é’flfl and the clinical mpomo of psychiatric patients to convulsive W. lbchclyl is a potent molimrgic agont which induces vasofimion, tachycardia, mating, It is and harassed peristalsis. mpidly hydrolyud by mournstoms-I and slowly by clmlinutcmc-II . M, injoctod m m blood pmssum of subjects falls aftor udulyl and 2‘th to the five to m bssclinc than 20 minutes. Patients Mobloodpmsmmtxmtothbaulimwiflfinsmutos are classificd as Groups blood possum takos 2O I, II, or III auctions; arm aszprIdeIImctims. imprcvomnt mactors a minutes to mum to baseline, mexoupIrssctorshawa9% rats with conwlsivs therapy, 35% those whose and the Group II—III memory mtc. In contrast, the Group VI �_.__.. ”(ya-v —— . h\'~rvhl."ll'F reactoreheveasstm'themupvnasfl recoveryme (human-1n 35;. Patients in an patiente in 1952). “main Groups I to III may be looked upon whm the injected maholyl is rapidly hydrolyzed; VI and VII patients heve the a slow hydrolysis rate. 41121311. 65‘ Weny predict, themfoze, that an blood ahalimateme activity levels of I-III would be high; while the activity of WV” y ’ ,-. u... V,._V.......,m--.-n—nw ’0 fly” 6/” W W hypersynchxuny and spinal In studies of EEG fluid levels of acetylcholim. ahengee {uncaring induced omvuleicne subjects were identified in when e few seixme resulted in e greet of elm wave activity; mile other subjects exhibited mat few changes to my and to frequent seizures (Pink and Kuhn, 1956). If electmgrephic hyper-gum in e reflection of incremd (Conversely, in patients with short-lived hypereyndxrmy, dwiineetense-I be unusually and high). -II in tissue Thue and spinal fluid these epeauletime provide may �-22a basis fcr a congruent hypothesis regarding central nervous system reactivity to clactroshock, and to peripheral éholinergic CONCLUSION: Ccntral dholincrzic nadhanismsqmpoar to be a significant flycflu«’g factor in the convulsive therapy process. ”Inc published data {unrinriznlmymnandhto indialté;that induced convulsions are associated with an incruasa in intarcallular acetylcholinn tn 4L¢¢4Eygd4£5414¢¢¢délAbifl— lnvels greater than can be dustxoyed by choiéanoturuneéE— nativity. Vascdilatian follouod and and innnuasud callular'permnabilitylin«a4wc. 71L‘5@fi¢.4;«xu> g aibcgérfiyxapglugu‘542;;wmatvi byflincrnascd amounts of~ehoiinnaflcuuao~¥l~ other'enzymas clactrolytas in inturunllular fluids. ��n, w~. «v— ‘w—rr‘Y .r uy-nmvv—mwum-mn "vv'. rwzm—r w—uw-v-mw-wztwvm... a ~II'-v-'<w-:'W.\1v;w'rku'svmv‘mv'nvflwv wwww CEDLIWC WV}: mm. MD mum Max w;— .n»;_...v W... "on." ,vurw»; M Pink, H.D. W at th- Pflnmi Initiate of -Pmthanapmntof Psychiatry, admity of Miami School of Midas, 5800 Annual St. Louis, Missouri. 63139. attest, W, W mm. Wmismofthnwm"hinhnatimm York. Hillside Hospital in Ethnic!” at mm in part, 2:57 aunts iii-00927, iii-2715, W72“, md $11380; and the Paydaiatric- Renard! Fantastic: 0! New - - w—n mu, mung—.w an �CHOLINEMIC W, AND V: CONVUISIVE BHWIIOR 11W, StudiuofinMdmwldmhnwmmmufly dwalopnntmdpmittmofsiguofutomdmwmmm mpnmquiaitetoahmguinbahavinr (Maximum, 1956). Wesleyanwmivitymfommm: aimificmtinduxoflltondbxuinfmctim,andflndemmticn that Mention activity (015th album-sic and Jdmm, W. mtylcmum and with atropine inhihimd tho 196’) this slow wave muted a minim to In the following review the dwlimmruas in mole of Waive finnpy is discussed. Mutyldnlimmwcmivelystudiedummive amtintrnmmuimofmmusimluusimsmflm It is a dcnmiptions of Dale (191k) and Load. (1921). mtitxmrtofmtium,uistinginaboundfommida illibnmtcdmmwiutimmm. )J and is action of culimmme specific hydrolyud m Itiarupidly W rapidly matitutcd by the cholimmtylau cystem (Richter 8 sum-55 �wan-r”... Grassland, 19%). In actual autumnal fluid has mtylclnlim Emmanpitemupidmmofmmmm (Town-mm, Magmaoaofactivitymdcmitmt 19%;). The activity. ”Mimi mm, fluid does but Infinmoffm 19%). matylahonm md undnr the conditions than cholimatcraso principally of tho “tan” or medulla wdmlyzing typemmsmwibfimbcrg. fail to gamble Whoa, cleatrunmpimhgrm Witty. (a) Effcct of m Mint}: W hm: hm acetylctnlim mun-951151 fluidwififinafwninuua after demmmtsmdpmiuedforvmina periods 2.» m as hours (Win, 1”). The qumtity of fun gm mtmmumdmthdumeofimmtrm. mtylcholim vanhd between 2.? did 9.0 The W accord. chcmewaphalogzu um first filled with percent. and th- mutated patterned W. high voltage fast activity, intorpmtad as alderman of an intern. mm). diam, only tobfoflmdbyadmtpexiodofflmingofmmcomod fluv - v > .. �-- .vwru V.—.Ym'> electrical activity. Thou phuu wen then followed - 'u-uwuflxm n. ww- by pmlmgod mamamummmmmmmmms. mwmsmnmwmthtothedameof mmmmmtafmmdhumtyldnflm. highs:- levuln of mtyldnlim. Romania 911‘th "Modulator dew ofmcmntymdmmrctmpsinmcimu. In addiflm, apcntmn post-We aim wan also muted totbmmtoffmmtylebomnapparingintmspiml fluid. Wain also :13le acntyldxolim to expound out 03:11me W. Mthommmimofmtyldmlimmlgm pamtorhu,hnpwtodhighm11tudoshupwmoflm fmmncyinthocloctmmmplulogfim. mmmnoentmtim mimmdtoZmpcmt,flnchctm-naplulogm Whafuhionpqflhlmflnpon—tmicm. Parallel studios m wr carried out in analogical patients byrmmunsmnumw. Pmautyldnnmmfmxdin - r-w» ' 'c . ' -' ' �- the Main]. mount grand-ml mtyldwlim 7...» 7w wn>wwv 'v'vcv’ ku- w. VII-"I'M‘WW fluifl mly in patients withncmt head 1""!t-W'J" \‘vv- "ram-V" tram 301nm or afar convulsive trnmpy. Fun vadedmefitolOOgmpcmt. Tomrmd Wm also assayed spinal fluid cholimstcme activity, noting a map rise in the mpocific cholimtcme factim (WW-cpnttim) and a drop in the specific mailman” fmtim (metnlyl-splitting) in paticnts with had mm and following minim W. Followhu sputum calm the cornucopia-l fluid did not exhibit such it comma {no mtyldmlixn. inwaim, Thay cmcluded 11W that the lavel of {no mtylcmnm varied d1mct1y with the dame of comm}. Manama: mnnlofflnedlolimctem fmflmmam with» indicator of Gambia]. m. madam, talcmatvuyingintorvalsfonowingmm, mimic-med: mhtionbctmcntkmdcmeoffimmntymdtheappem of In: mtylcholim Thu. due in the annbmspinal fluid. want 0‘ We autylchounc my (me. in the ‘mmgoummwwmmmmmog ' 'v "F “'4‘“ �, 'V'lvw—‘U‘ w‘ war.- —',~3 nan—- u ,w--y_.n..-. u. ‘ ., .- ww,———w~.wm_w—w-q ‘1‘ wwm “- v-~.-W . a..“.~,~.-u . q. . WW -..' .m “Fwy-Fumwyv,‘ “15;.” .w, , .7 “mm .-.» 7w.v--m»w~uu-——. .3... 51m. “Wotan, abunuty, MW. (2)) «the «glue and type mmmmgupuc a; mmummmmamumw m, WWMO m and m: The EEG aim ofmmnmmodadhyflu behaviomlmdmmlogic (Bnmstein, pun-nun). examination of 0.5-1.0 ug/kg atropine mmmmcunimmmmmmmmum addition of mmmu. Ward (1950) applied mmmdmmmm. We m, Wand of varying ho m'obumum In20patiantswith ntmpim 3W1)? hduudOJq/kynothmdhfimliqmtinmmda mutual of the 013:!ch effects in om. In a smdw.mufiamwm¢Jmm Loam (1955) meoph-‘logrn. m1 W am A single 5.an WW in the pit-atrmmatic ghetto— dose in forty patients with resulted in normalizing in twenty- ), was” w, �two and marked Wm: In subjects in 35.): mm. £011ng conwlsive therapy the affect of atropine inbloddmmappemotslmwmufidtymmmd (um and Jdmsm, 1956). (In a Later smdy these mfim failed maplicmfixiastudy,suggastinsmatdouge facumuw popnlldmdwgauyhmmtdhumdtodiffemntmulta [Jemima $5, 1960]). Moumatimpmvidedtmmformwithm hum “idioms: Wad: (Pink, 1958, 1960). me hummus injection of Wm, and Wm “WW. durum, may, We mamas mum-yum. thn piperldylbmzilnm JB-318, (Dim), JB—329 pan-m: mticholinergic VIN-2299 and an JB-336 3% 1mm mendim MMWmm ammflfiabduvioml truism, illusion whim. and mlminttims in In patients with mount induaad mnvulsium Mqultodinamduefiminslwm activity Wuiflzamdofmplmia,dmidmdommsim. ��-. _«.w...-.——~.m. w, .u . . r” v flaw-v v "'wA“"‘f'N‘" . wrv-r-P electmncepiulogmphic The concentrations of were higher than Win W arbor _.. w-av. rwa-mvnw—wvm- v-.-~ TWZ'Awyvq-u'n‘Vtvmw‘T“ "Ann—w- 1::th th- topiml appliantims (1-4 (19%). atmpim (1 Myldlolim in these oxpeflmts, imiatnml and the , (—7.“ ~;—v—u~.~~.—.u—pv.—.—~nn:,+-ra.-w—u w... (0.2-3.0 gm pennant) gm '-‘a nag/kg) . however, parent) injectim of Exam md thud“, also made note of chat-.m- axmptulngmphic effects similar to amtyldwlim firm mcholyl mtmtiom (WWW) (mtylhetmflxxlmonne) ascribed mmh Mrthm tho amtyldnomn M Wm. in and duty). Wimqffmimwmwmmcmmm lack of mitivity to rumba]. duality-sums . ThuewmmmmmsuggutmuumWWWWWbyMWu/tmua man 9‘ aqua, tam Won, imam on. with WW¢Mmbebum¢ueummdbgma~ WWHMAn-gmnmmdmw «new (c) a mm, mm. etc. Onoviw «mlmuWMwa-smnnfomdiamm Winnimatiwbmfom. Wyfinchofactivity, WWhnmmdatthno-ummm.m1tia r umnnmv~wv yr.- -~ �“Hwy-v .7 m. » ._v .W”...w.— —...‘..r,.u...,...._...,-, Hm..."- va,unlum‘w‘hi‘wv'mvmwv;'QX.‘""“ W ~n-- v “w a”... ‘ ,7 ,v W---w mw_.-r—... Wt “‘1': run”... -- - ww» v" ‘7. "‘ ww.-,-_p.w.~.wmw. midlyduwtimdbydwlknmo. mamtofbomd mm is the resultant of continuum 1122mm lad mm. promotes of synthuis, It has bun pastuhtad that the rdmduuingslmmfnummuctivity. level Thishypaflmil mwmmwwmrmmammum) mm,mmmm(1asm. Byusing liquidair qumumm.mmmmmmmmm ofamtyldwlimdndngmflmiamdalup<mamdumim www.mmm)mhaocthigturthmpoum hurls. nudiffminmmmlaiatmsimt,hmm, uthnmthaismforamtyldacliminmbminism (7 gums/gallium). Elliott 539;, (1950) mnfimd than obsorvntima. Affirm}. mum-ism Malacnated that {no mtyldxolim am always «washable in the spinal fluid mmwmagmparmnt. Insphulfluidstufiuinm,flam,lbwnrmdmm (use) md fear and Wm (19m) “perm dwicam: ��m.ufiumtfansmgfiumnmdm,mdm balmeevuin lawn of mm, convulsions failed to om. Stunumudfintfinfanintium Winona: Wamwhimmdummiflmofmtfldmnm m‘md mm byst- anemia“. We! sud: mtabolim, Bummwwnmeumm mmmmwwwmmwm Wmuumam¢mm MW mmm;mmmuuyzmuummmn,zmmg rmumumzmum W MW WW madam» (d) §xg~ an MAMMWthuLa W (new: tutu. Lena. Cmocnitam: wimflnirohamtiam ofchmm inuntyldaolim, Wm (1939) Tutor-mt! name! spinal fluid dolimtcrm activity. Mtymofdnumemmmmnyfminfimspiml �» ‘am-V ”II-"Iv ."V'a. ~,.1- . u -;— V’V~-¥'U'~‘v‘<~u Tam—xv... mw—uL-ww-"wv Wanna-I fluid: mich .V m ("pocudofi W as nu-mq-wnwh-..“ .,.,fl_. .. Um," sfiociflcity for him "rm-amiflc,” ow two .,. ,... .. n. ..~-. - . ..- ’r .,.,_H. .\..v7,..,,..~—V.TM ,wv, .,.,.< V . a a ‘ , , v.“ .w: _v_ ”specific," or manlyl—hydmlyzing) , Micheline; and “museum-II WWHMWIM) . Both for udzolyl and bemoylduolim. This diffomtial me panda qualitatiw dintimtims . with 3 ”a.“ hydmlyu amtylcmmn but have diffmnt arm: of mm activity ,. By I: a ratio of the activity with MW!» ratios an found: sub-mu mind mpovting the dwlimstumsc a maholyl substrate and to mm of amtylcholim, mumm—I/amtyldxolim and Wm-II/mtylcmnm (with Adi/@8100). In much nudes 'mlm‘bmupimlfluidmuimuminttumioofflzu for Grantham-J to aluminum-II . mpnfimwimmmmmflcfiadmmdm invasion of th- daolimumu, with an We in the cholimammac-II fmtim of tho spiral fluid and a dam in circumstance-I. iathity. m mam: of the WW maul was related �we: --r"vr— mr ww- ~r-r—vrm...‘ v .—-1«w‘ms¢—ae.—r ”"7.“ mgr-nus, r, mm, a." 'W nve- “w, -~. w n r...“ mwv “van" e w.— ‘1‘“ m‘r‘nvwvflfi‘l'v—vV-v ”Wuwx—m‘me - vuvax wmmrityofmmmdmmawoffiuem- WWOWW. Inpatim with eleveudspimlfluid acetyldxolim other WW,Wr,mminmmioof dulimetemesortommlimtem wdvitymfomd. ‘meimmindxsmnetemeactivitymbemdentood mnmmmmmnmpemmmty. mW-Ihfmmhimmtmfiminfin mud nervous system while duelineweme-II pram inwartiam,upooianyb1mdsem. Hiflamimas fin atyldnnne m1: in intemelluler mum fluia stimledm, communion: or hm, modiletim oellulmpemeabilitymybepmdiotod, Wfim and We! withedewof of wonder flunk into the inter-0011M spaces vuyingwdmthemmddm'etimofthevasodimion g g, 19:0). Spiml pun-Ability following W 1953). may cheer-val no Spinal-Molt in mm (Rabat m mm reports (19%, 19%. 19W, 19%. memo mndactivity of the tissm , ~~y-..‘.--~_~~.m-mm-v, �av“ y."— ww_"v-w.w . w «mum...»- a. 4 W cm van—n: . Wwmwum u wI-ww—t'h wmw—wmew-mw ..-,m.— w --u-- mumps—m mum-PV- Hw'ms a: w :w-n r- "rm usociatadwithflaappemofvuiwsm (apotmiummd W) in the spiral fluid follwing chemically inducad mm. Mmdmasimifimthmminsmhm- electrolytes as madam-acid splitting cums. Chang-s in alluhrWilitywthmpmviwfiabasisformhm demmmmmmmm ofdnumumeIinirmmdmoermmflw MWIMQGJ. mmmmmwuwmammm with the mid «instruction of hue mtyldxolim. me punctuation rammummspimnudmwmmm aims any be minted to the dxolixastuaso-J syntax m and Wm, 19%; mitivity of the mtyldzolinc- Widen mummy (um Tm adficfiadam, 19%; Burger: and martian, is rapid (3-H mama) but at high» and lunar 1955) . At ”physiologic” helm-h, hyckolyais of amtyldxonm the activity falls off quidcly. In contrast, the mm, chainsaw-II- �«.18.. “mum nhtimMpismn—spocificmdfiumof mmmwifizmmim. mmammmsummmmm WWWOfac-tyldmmnnmnmm We hy the spadfin activity of him, an massiv- WW4 mfim in few billowing excitation mmmmdmmlmwmum-I. The uhmuthruhuldmhomadndnflamimindxmd,with mmimuwngmflnmtoffnomtyldnfim. n» and W murmur: durum 'mpidly, cellular pambflity and humming tho vmmmdwlimm-Ilmw. alum-II, W affecting vaswlar mmtim of 'nnactivityof of lowcfficisxwy mt! chpcnding m flammflgmkhnua.mmm1mmm dominhammdlyatohwhforfinphysiohgmmfim of <21»me . �“.1. -. _. n "w' .~. -»~ uv- r—r-wu. szfl‘”R—vu'w.vw w-W-wt mm- W-w—mwwswwmwwrrwmxmm’mv-mwmmun-m zmwm-Wm “W A. A. V. AW mmmuWuM¢mmuaumm _\_A_._V_-__‘__.__~V.A,__ ‘-_,__,A__________ 05mmc&W.W, Wad “WWWW m put“ ma Wm“ waning smut-Maya by The {named the waywam. Wade. madam-u ammmoguagmumauumw WW ‘MMWMAmMWW. (a) mymm. HE‘S MWintbblmd—bnin mm permeability and Induced 000mm: bmiwbytheconfimm actimofmtymnmmybafilebiodmimmtmfwfin chphuogm. _m.mmwuommmmmbymgggy(ms} pout-electroshod: hypemymsm of 13m Wmmmmmumormmmm tummaysamrambfnmdmmm. mmmmmmimufthismmhm, ordinarilyabsmtinbnintissmtobemociamdwimm W orhyponyndm (delta bursts) in W. the electro- at: . �- Inmoffimmhm,whmcmfimdfln mpmimnpmflthflmwhiwwmchcmmuc Imp-W (Maxim, 1956). myimamtmt applica- www.mmaw,mmmm Wtdflunhmmdcslmmaadvityuwnuim sensitivity to mdiflwtim by muting. tamer-ventilation whim‘ vary my in manta: Wow. The and only memwmmmiupu‘ismmghmumthmmasMupmmmium W 1‘0le «loam-rm (Fink mm, 1955). m «land in diam {dimofamainptdmtodnvolaphymymhmxymybo Nahum. 1n th- activity of annual mtyldxonm withfinmoffmemtyldmlim mmmmeWMmmm mamammmemnmmmm. W (19‘8“), inmiz‘ttudyofcz‘iimbml Tmrmd trauma. imlududobumtimofdxpsyctflatricpafim underpins mad“ W. Ming the patimts afar 3~7 mam-ms u I'vv: WW7 ~,-- a'fir‘f �mwmmtymummutymmspmunudm mmmsmdmimmmmm-Hmdams in “11:33th with a mammal of the ratio of WW3 infiveofflnuixpatm. mmmWaflamflnyomclmed wmspimlfluiddminhumdmhimsmm mmwmmnbmmmmrmmcmy. wmmpatimtinmududnfdhdmm dmmmldnnmwacholimummmmalin thespimlfluid,fiuymz“1tisinmtingfiutflfia WmmmlymnoffluaixtoflIwmmpm-emtm." Itammwzmwmuuuzm¢m mamgm,mmmm mmmWoammu. 1%...qu umbyupuudAumu. EEGhyme/uom umo‘mmwumgzmmmmmwxy at Mumwuqm. Radian muammmmmWMWWWWM‘MMMAM 6:!wa Mu 60W Mad «WM. ��-21- WanamaeflmtthmaSflmmrym 1952). 93a]. (Wain Patimtsinhmuinmltonlmybclmdupm when the in is injected rapidly hydmlyxed; putientl mdmlyl u uhiln fin Groups VI and VII pctimts but a slow hydrolysis rate. V. my pndiat, theni‘on, that tha bleed dulimatem activity huhofWI-lemfldbohiflu mihflnaotivityof WAdlihrunlysiouyboudumaxdingmtnlm VI - VII walla be 1m. mmmhofdwmmm-Iinfiummtofm Wynclumy and spinal fluid hwls of amtyldnlim. Instadiosoffififldumgu followingixducudmnvulsim subject-wan idlntifiodinmmafwsoimmultedin a mat mat of now an. activity; while othox- subjacts mind mammmymmMu-Muim (Pinkmdm, 1956). IfWWionntbctimofmd Inbjommuintainhypcnynm in: mm, inwmitdiupp-m them did mpidlynybccadfibitingdiffgmnccs in th- kimtim of the dwiimntm-mtylmolim hydrolysis mm. Panhtcnthypcnyndmyuymultfmamd Mcofhydmlysinotmtyldwlim. mociatcdwithlow I mutation of cithcr choline-tumult or mummy-II . (W13, in ahefirutcm-I In many paints and «II high). with m—livod hypnmyndmmny. in tissue and spinal fluid any Thus thou mutations provide �. ..‘-.,—r >17 ,...v v“ » , may .1 ~w ~ v....<~u-.~,nz‘y«.r.-~, w‘wrr' ,. ~_»w—-w-y- ash-:1" ~ want »-.1N" vmn www-z-‘w BMW-“‘1‘;- n ~wm~wvv qu-w-m-w- wrumrwS—V-‘a W-xmp‘rvww .22... amumamhmnmmmmm reactivity to W syntax: em, and to poripmm dwlimrgic WON: mmmmmmawmt _1’minfin mmiwfimupypmu. 1119me whimdmiflmomtimdmmmm Wummmmmmnmmmw MhWMmbodntmyodbydmlimmI nativity. Vuodilatimaflimuodmllulupmbflityis follmdbyimuodmxtsof diam-II, strut-am and electrolytes in int-”114mm fluids. - "r' :1 Wyn-mu wr “unawa- "I“ �mwmminmmdumm mmmnmamswom.mwmm Mmeidufiuminbiodmicalnfliwwhidz alters cerebral «11.qu activities sufficient to Alter the 1m behavior of subjects. Failure to mountmim electrolyte dim. of acetylebalimi lid W, high md pmismm: {aim to 1m tht results in a failun to produce behavioral ”mummuofdowlmntofmw reflect differences in th- 63ch of subjects «1 dour-remit: admin”, or in their sensitivity to changes in acetylemlinc lawn. tim of M tho diffcmm finally in W by Mountain These observations provide a the mode the Win for the classificaand by Pink and Kuhn (1960). rational biochemical basis for of action of induced convulsions in altering the behavior of psychotic subjects. These views are consistent with the more general neurophysiologic—adaptive theory expressed earlier (Fink, 1957). �IFn->"'v'—-'—vnu—w— w—r—v-r—u ”fit—W‘- ".9. ‘- -. u » V . WWII-.11“: CI-DUINEIBIC . , nv— rm mw- WIN, WWOR Wmvw—qmvmmpwmw'm x.xm~.;w~ww-ww mum—w". CONWLSIVB AND 13%”, Stalin of cerebral changes accounted with (Pink and Kain, 1956). convulsive trump}! In these studies, electroencephalographic slowing was the most siyzificant index of altered brain function. The dematmticn that premedicetim with prevented the appearmce of slow 1956) suggested a wave high doses of atropine activity (Ulett relatim to ctnlimrgic mefiiims. and Johnson, The role of acetylcholine and the dmlineatemaes in convulsive therapy is mlified in the following review which summizes the published am. The role of acetylcmline in the tmsmissicn of nervous imulsea has been studied extensively since the first descriptions of Dale (1914) and Loewi (1921). Acetylcholine is a normal which form bamd is in a tissue existing of neurons cmstituent �.,, ~21- ' - "~va ":murmmrnur-v— «m . Ernie-'4 ‘ ,. v “War W'r’W-erd - 4wr‘; Wr' .w-nv 1'5“”uH-I'J. .1m- ,.w;uwv‘.m,w.‘. liberated mixing the excitation process. It is “m ...Y.,_.,. F“. -v-v—.fl, ,. . t .. 7 m" ,..,nvrv.w._,,m_1w V,.w.,‘.,.,.,,v rapidly hydrolyzed thrmgh the specific action of eholinestemee and as rapidly reconstituted by the momfiiaeetylase system (Richter 19“ 9) . No a Croeslmd, free ac}tylctoline has been reported in normal mmbnospinal fwd despite flu rapid bmakdom of bound acetyl— eholine during perioa of activity and excitement (Tower and McEechem, 19u9e). The oembmpinal fluid normally has measurable cholinesterese activity, however, principally of the "true" or mcholyl hydmlyzing type (Neelmensm and Rothenberg, 19115). In the absence of free acetylcholine and under the conditions described, electroenceprnlogxms fail te show any consistent ehxornality. (a) Effect of Cranioeerebml Them: Free acetyleholine was found in the cambroepinel fluid within a few minutes after experimental head trauma in cats and persisted for varying periods up to #8 hours (Bomstein 19%). The quantity of free aeetylcholine varied between 2.7 and 9.0 gamma related to degree of induced percent, md the ammt was tram. N" ._., , . V.‘ ,.. . �F‘s—“fl 4 w .iv-IJ'n-urr'wlv'i- \I'-w-v|n"r" ».v 21‘.- .IN w— rh- W Th! records were u. . - ~~w~mvww. a?“ : aux-rum W...“ m“- - ‘vv‘ w—a—E.ww~r_~w um... g‘vi- wn-rv-w mun» r: 1- K—‘Irw' «a...» ,. w... w” ‘quw u,- 1,- \w electroencephalogms demonstrated pattern-d changes. first filled with high an voltage fast activity, intense neuronal discharge, only to all short period of flattening of electrical activity. mesa recorded phases were men followed by prolonged periods of high amplitude sharp waves in the delta frequencies. The to the behavioral wt mrfizlated 13%:ng of clmges trauma and of seasoned free eoetylcholine. With higher levels of eontyloholine, Bernstein reported greater degrees of abnormality and greater charges in cmscicusmss. spmtanecus . -3- interpreted as evidence of be followed by a -~ post-tmmtic seizms were also EEG In additim. related to the want of free acetylcholine appearing in the spinal fluid. Bernstein $31- applied aoetylcholine to exposed cat cerebral cortex. men the concentration of acetyloholixm was or less, he observed high mlitude sharp the electroencephalogram. When waves 1 gm percent of low frequency in the concentration was increased to �-- <vw'x' >1:- 2 '.‘W',WWV\Wmm/'FP a». an gm . W v- .n ‘n'uv 7 ~m—w-w..». v m... .vvc'wTV-t or v'.‘.wwuwxnn_r'~u—l’v»wy wrv-suw‘ mw~wwn~w~mnpmmm .- »— -nnmmw—rr-muwawu nvre --u w percent, the electmenoephalogm flattened in a fashion parallel to the post-tramtic meant. 11.1% stndies wemWin neurological patients by Tour and Hohdmm (19am). Free aoatyloholine the oumbmspinal fluid only in mam, The 1.: patients was found in with recent head mount grand-ml seizures or after omvulsive therapy. free acetyloholinc varied from 0.2 to Tower and HoEachem of the spinal fluid. 100 gm percent. also assayed the molimsterase activity They noted a sharp rise in the nonspecific cholinesterase fraction (benzoyloholine-splitting) and a drop in the specific cholinesteme fmtim both in patients with head .trmma convulsive therapy. amd 'me oembroSpinal (moholyl—splitting) in those following fluid following spontaneous seizures containing free aoetylcholine did not exhibit such inversion. 3-2:. and-II: concluded that the level of free aoetylcholino varies directly with the dogma of cerebral damage - �that the reversal of the cholinestemse fraction sensitive indicator of cerebral (image. and was a more Electroencephalogrem, taken at varying intervals following mum in most of these subjects, indicated a degree of EEG relation between the abnormality and the appearance of free acetylcholine in the cerebrospinal fluid. ‘hecstmfiu Watt. an to. mom 0‘ (no. aaetzfldwdne m1 incuae in #:24me {Md 4011ng Macadam tum and me a «wad: lactation my mwowa, duomug, (b) «in. degm and dumgo Effect of anathema“ fie and type as in Am mount 05 fine demamcmuagmic dialed bdrawloa. on fib-traunatic EEG and Behavior: Bernstein aministered 0.5-1.0 lag/kg atropine parentually after head tram and denmstmted bloating of the EEG, behavioral and homologies signs of clinical tram. changes occurring Similar EEG and after the experimental addition of intruciaternal aoetylcholine were also blocked by atropine. �w. --r.-~r-v—~--ww- w-Im-vmm 'mm' "-W‘mmv'm" Ward (1980) 'memnmw applied tmse observations to the hum cases of closed dogmas of tram, head injury. In tremnt of patients with varying 20 he aaninistamd atropine subcutmzsly in doses immt in of 0.1 rug/kg. In saw‘oam he noted clinical and others a reversal of the eloctromoephalogmphic effects of the tmma. In a study of .1er and War diethfif’ mother mtidmlimrgic drug, (1955) reported sigmificmt alterations in the post-tmmtic elactmmoephalogm. dose in 1&0 patients with in normalizing in The same slow wave 22 A single 1:1th ahmal electroencephalogram subjects land marked «act of atropine in inmt msul’cad in six others. blocking the appearance of activity wm reported in subjects follwing convulsive therapy (Ulett and Johnson, 1956).. (In a later study thé‘authors failed to mplicate this study, suggesting that dosage factors or population mass” may have omtributed to the different results [Jdmm 559;, 19603). M... �8: These obeervatiom provided the basis for a series of studies with other Imam mtidlolinemic ooepomde (Pink, 1958, 1960). The intuvenom injection of experimental patent antidmolinergic «mantis es diethezim. (Dim). Maine, the pipeddylbemiletes, Jana, J8336, and pmoyclidine were shown to induce EEG illusions deeynotmiutim and behavioral alerting, mxiety. J8329 WIN 2299 end md helluoinetiom in nm—ehotmehodc subjects; and e reduction in allow new ectivity associated with e mvemal of the Wm; euphoria, dmiel ma omfmion in these with prior meant induced omvflsiom. In these studies, atropine was also emineddn low doses, EEG desynohrmizetion was observed, eoooepmied by considerable peripheral tachycardia, mmaenese and tension. At higher dosages, oonfmion and disorientation min! hypemyndzmm slow a mduction waves and of-hmmiutiea their replacement by lower voltage. poorly organized delta activity with superimposed beta activity. . �~. . a" ~~_,—vn~m«~p.-~W» A q ”We," W. _ ,_. 1..“ ., ,. w." .-—...n-r.. t ,, . u ,t. .( m...w-,V -—..~— _\|=V-\w:w.~a ~FVJH-fi'u—p‘muwt »‘wb‘wfl- 7.;r._‘,.,v,wr _fiuv;a_n.‘--,,.p‘m .w-wunw... \ .,.—_,.....~ variety of experiments with a potent duolinesteme inhibitor, D}? (di—isopmpyl frequency EEG fluorophosphate) denmstmted high amplitude rapid patterns similar to status epilepticus, as well as lesser degrees of abnormality similar to that noted in post-tnunatic states (Munich 333;, 1950). 1950; Pmdman 3331., 19:49; md Hampson 93.51,. These electroencephalographic doses of effects were blocked pumteml atropine. Chetfield md Dempsey by small (19%) prepared exposed mimal cortex with pmtigmine and evoked electroencephalo- graphic spike activity. 'lha prior blocked this spiking, or ministration of atropine if present, the abnomality could be eliminated by atropine. In contmt to these findings, Brenner md Merritt (19%), applied topical aoatylcholine in cmcmtmtiom of 2-1/2 to to the exposed cortex of cats, and noted no 10% effect after intravenous atropine (1 rig/kg) on the electmmcephelogmphic changes. The montratims of acetylcholine in these experinmts , hmever, was significmtly higher than the topical applicatims (1-4 game percent) new v” rm— ‘7“ .wv-u- �and the intmcisteml (0.2-10 gamma percent) injections of Bernstein (191.6). Bmmer and hmzitt, also made note of electroencephalogmphio effects similar to soatylduoline from macholyl (aoetylbetmthuldsolinefmd Meryl (wbaxyldloline) in oonosntmtims moh lower thm the aoetylcholine cmomtmtims. inmd They ascribed the effectiveness of those oholinergic drug to their lack of sensitivity to oembml dualinsstemses. FM a waist; conduct: that and MAW“ Wencapdz Logaafitic activity Mu a a “nu mu! upwwtaz 06 as deans tome. Manama agent induced by acwjzdwu'm, appuc'mon'og Mam, topical be. backed can it was; a (Lt/topaz, we may on. Magma Wand by humans, as. (c) Carebmsginal Fluid Amylcholine md Seizures: Aostyld'xolino bomd form. is nomally present in mrvous tissues in an inactive wring periods of activity, free acetylcholine is �. ; .m, . .. ..., , m .. .flzwuwflurww—w 1.... y ..‘ , v ".4 .4 .. J, vV—I-N‘r W. . . ._... dwlimstorase. The v—- "’W\‘,a(')~\ro" >m»":qnaArv-n3l.!' 'r ~w.'vu.* '4.-:--wr~vr g~u~wr~a~~u~w> www.1-v-u mm it is libemted at the cell madame, by K." w- level of “mum rapidly deactivated bound aoetyloholine is thus the resultant of the prooosses of synthesis, liberation and It breakdom. may be rise during shop and pootulatod, therafom, that the level will fall during activity. lhis hypothesis was support“ in animal emunants and Elliott, by Richter md Cmasland (19%) Swank and Henderson (1950). By using liquid air quick-frosting mthods, Richter and Crosslmd observed the mtl'nsia and sleep gm per levels. mg. The level of aoatylcholim (masumd as brain tissua) to be 300$ higher than poet seizure difference in tissue levels is transient, however, as the “synthesis rate for aootyloholinc in (7 mimo— mulmlfinute). Elliott gt 5;, mt brain is high (1950) omfimnd these oheowatims. After- mtmzole oonwlsiom, they also noted that free mtylcholine was always fluid in concentrations up to 3 domtmble in the spinal gm per cent. v -.~~v~ , . .- �- .... nut, v-wwgg—w mauw-Vr‘ u-~0'iv-a—. n... mg. ._, -:Jpag-.'~vw1 4mv..l.‘N'-rv-~Vr‘-\ firm—um r“ nmww-r w WM- "— w—rw" .“ - -wmv~—-w--m.. -v.‘ F»; "-v-q .~ www-rwt:.v—.m.-v .10In spinal fluid studies in man, Cbne, waer and (lSMB) and waer and McEachern (laugh) reported McEanhern significant quantities of fro. acntyldholine in patients with epilepsy. 0f 56 apilnptic patients, an (77%) dnmnnstrated measurable acetylcholins in quantities of 0.02 to 5.0 «warns» of 1.0 gamma per cunt. The gamma free per cent with an acntylcholine level was directly related to the frequancy of seizures, the extent of olnctronnccphalogruphic abnonunlity, and the relation of the time of sampling to the last seizure. It home no relation to mndicatian, type of epilepsy or level of cholinesteruse activity. Whethcr>tho acutyldholino appearing in the spinal fluid is a byiproduet of the convulsion or whother the increase in acetyldholine is a Wu!!! cause is of the seizure prublamatical. (1939b) suggested Tower and that the increased wetyloholine liberation in not due to the seizura itself but is related to the procnss causing the seizuma. In a study of the hypothesis that �11 the acommlstim of acetylcholine is basic to the seizure process, Tonia (1953) induced convulsions in animals by mtmzolc and dotsmined the level of acatyloholine in brain tissue before and during comulsions. She noted that convulsions are pmcsded a rise in the acetyldmolim contsnt of tissue; Wily falls during the cmvulsion; levels, cmvulsims failed to occur. and an that the content that bolas curtain She suggested in tissue acotylctmline during a omwlsicn by was due that the fall to inhibition of aootyloholins synthesis by increase! concentrations of metabolites such as In. mim Likely ions. #:215de m mmwbg mm {m mam; ohm «:3;qu an wanted (m it inmate in bound tat t3 isms my be inflected in sum 5%; ands wanes «wanna: do 5m, and that cumbmt auction, taming and Leap nhuu an to in augment Minoan; tin no. touch as “mum“ pmduoaon imam ing “A as touch . �v......,.,.w.,. ., 7.“..- www. min-w: .~-.Twr-r.~a y: m nvmw-m ...v 'Nwwmu‘agnar' "n T“.1.,1~V;’§mm- ,M m..., . .u..." .“WWFV . m: or..‘m--.w-,.-W,‘_..< WW. m.fiwl... .V w‘~...oww»..wm-_v m_w,fi WWW-A“ .12. central nervous slaten Cholineetoraaeez Concomitant with their observations or change: in ooetyioholine, Tower (d) fluid oholinoateraae end noanhern (1949) mnaeured epinel activity. Two types or oholinoetorenoe ere normally found in the epinnl fluid: oholinoetereee—I ('true," "specific,” or neoholyl hydrolysing), whioh has e high specificity for aoetyloholine: til oholineetereee—II ('peeudo.””non~epeoitio,” or bensoylcholineohydrolyging). Both compounds hydrolyze eoetyioholine but have dirforont rate: of hydrolyeie for This meoholyi and tensoyoholine. qualitative dietinotione. activity as a By differential rate permit: reporting the oholinootoraee ratio of the nativity with meohdvl end with bonzoyioholine outstrnten compared to an noetyloholine lubetrete two ratios are round: oholineeteresoai/aoetyicholine and cholineoterooo-II/aootyioholine (with retfloa Initials! norMul 08F th/th: 100). In such contains eeteroeeo in the ratio of 53.17 for oholineatoreno-I to oholineotoroee-II. Thus. normal 08? consist: , ,»-.- .- �_.w.W—-« “mu-wow. arr-u- fimwmmm "WW?“ me-‘Ww‘wmvjrimwmmrm )5 s: mainly of "specific" estomes with a small mn~specific ostemse want. In patients with head tram Tower and McEnchem report and inversim of the dualinestsmos with a simificant increase in tbs daolhnsts'mse-II fraction of the spinal fluid dualimstems-I activity. They and a «mass in also observed a relation batman the extant of the momentous” manual with the severity of trans and with the dogma of the olcctmmceprmlompie In patients with 5.an spinal fluid acetyldzoline as a result of spmtmom saizms. howswr. of cholincstsmss or total Why. no change in the ratio duelinsstss-ase activity was found. Certain usunptions my be mad. mgmding changes in cell mm psmability as explaining the humans in duelinsstcmse contamination in found in highest is Gaolinsstcmse-I activity. the antral mm systm mile molinestemse-II in atlas:- tissues, especially blood sewn. pmdminates With an increase in �,7. ,.~.n_..._..‘..,.q—. 7. v . ...,~ “NW... . «g..- Wv-slv'n-nrrh w-rw-muwwwmmmwwvaWmn-mmmmmv‘wvwrvhmv w -w~'r v- acutyloholim levels in interoellular cerebral fluids following stimulation, convulsions or trauma, vaaodilatim md increased cellular pomability may be pmdiotad, with a degree of transudatim of vascular fluids into the inter cellular Spaces dependant on the extent and duration of tha vmodilation (Kabat 33:. 9;, 19%). Spiegal and SpiogebAdolf dummtmted such pamability ohmgas in nmorma "ports 1953). Thay reported inmmd (19141. 19%, 198%, 19148, oomhzctivity of the tissues associated with tho appearance of various ions as potassium and phosphate in the spinal fluid following convulsions. more was also a significant as nucleic-acid nm-clactmlytes cellular pamability mtmims electrically inmoed may imam in such splitting mzyms. Chases in thus provide the basis for the high of acetyldxolino and the managed omoantmtions of dwlinostorasaJIflTmr and Hoanhem muse) . '5 �— m‘ w «'7'- M-mrwrvva-mmmw.mw m The increase in ammnstcme activity should be associated with the rapid «stamina of free mtylcholim. Its persistence in spinal fluid afar tram ad 931m related to the sensitivity may be mtmim of the amtyldwlim—dmflmstm-I system to ships 5mm (mam md Rathmbarg, and lowar Midtown Mauritius, ad mo mnemtmtims, tha nativity falls off quickly. In contact, of hydrolysis mm minimip «sciatica mm who in few isdestroyedbythe udlliuomds. where bmoentmtim of mtyldwlim in tiasun. tbs mm of hydrolysis by dwlixnstome-I is W. com. m WWW—I to an is nut—specific with concentration. Thus, the mlhwnbfmtyldxonmatmnmbm specific activity of Wm, 19kg; is mpid (3-3 mimeoonds) but at higher th- dnlimanmc—II-m‘tylcholino the m and At "physiologc" and HacIntoah, 1955). hydrolysis of 19445; mktim~ mmmMMMmybemadndmdaseizm me disaoaiatim in ship nouns in a pemiatm amtylmoummfineamml relationof mldwline. The seizure may �16 itself in add wt to the of free acetyloholine. 'lhe increased mtylctnlim diffuses rapidly, affecting vascular and cellular permeability and increasing the cmocntmticns of various ions and dmolincstemse—II (SF. activity of cholinsstemsc—II, though of The on the concentration runs to days to efficiency and dependant kinetics, reduces the acetylcholine in the tissues in in! levels mm” 1c»: for the physiologic action of cholinescemse-I. #:1st am Manuela manta 5M, «may 5m «ppm in {Add dowsmaa someway in. «was {on mm 05 ma past a a gestation dzangm “mad Mwouflne. Mme. madman; om «toned by (named in 06 «he :1ij (fl 05 in cut 'hc mechanism mun-um at sou moms nausea; system sanctioning. (c) Agglchclinc a EEG WNW and Induced Convulsicns: Altamtion in the blood brain permeability barrier by the continuing action of acotyloholine may be the biochemical substrate for the post- olectmsbock hypemynchrmy of the electroencephalogram. Such a possibility is oviduct in the upon an increase days by Aird 93 9_1_, 1956, W denmstmting in the cmocntmtion of cocaine in brain tissues three afar a series of 12 induood convulsions. His data shows the change in �-17concentration of this large molecule, ordinarily absent in brein tissue to be seeocieted with the eppearence of hypereynchrony (delts'burets) in the electroencephalogren. In studies of induced convulsions. we have confirmed the neny previous reports that convulsive therapy induces electrcgrephic hypersynchrony (Pink and a constant Kuhn, 1956). Despite time the or however, or treetncnts. epplicetion slow the and of extent electrosrsphic duration eppearence. wave activity; its sensitivity to modification by alerting, hyperventilation and barbiturates psychiatric populations. degree hypersynchrcny. end The - s11 vary greatly in early appearsnce of high its persistence throughout the treatment course, hes been described as prerequisite to improvement following electroshock (Pink and Kuhn, 1956). The failure of certain patients to develcp hypersynchrony may be relatedto differences in activity of central seetylehcline and cholineeteraees. may reflect The degree of hypereynchrcny the level of tree ecetylchcline and should follow s decay rate eqael to the rate of ccetylcholine destruction. �vuzvnc—v-w: —. Since previous studies demonstrated thnt ens prerequisite to the it may be EEG hypersynchrony clinical response in convulsive therapy, suggested that the absence of free soetylcholine suggests minimal changes in cerebral function and thus precludes s clinicsl response to induced convulsions.Touer snd their study of creniocerebrsl trauma, hoEedhern (1949s), in included observstions of six psychistric pstients undergoing convulsive therspy. Studying the pstients after 3.7 trestu meats. they reported free soetylcholine activity in the spinal fluid in ten pstients; and en increase in cholinestersse-II and a decrease in cholinestersse~l with a reversal of the ratio or cholinestersses in five of the six patients. From these observations they concluded that the spinsl fluid changes in induced convulsions were more like those of creniooerebral trsume than those found Regsrding the one show in. ilepsyu pstient in the series who thiled to either free ocetylcholine or e cholinesterese ratio reverssl in the spinal fluid, they wrote: that this patient was the only one "It is interesting of the six to show no _.,. �7‘ response to treatment." It is I probably that induced convulsions increase free acetylcholine and enhancing cerebral perniability altering fluids. in intereellular the appearance of cholinesterases. Free acetylcholine by JMAco repeated seizures. EEG hypersynchrony is one is maintained reflection of altered of other electrolytes. and altered permiebility of acetylcholine levels It is these changes in intercellulor electrolytes that provide behavioral changes the for substrate biochemical persistent the following induced convulsions. L/ (f) Cholineatersaes and the Classification of Pezchoses: These studies may also have autonomic reactivity and the Funkenstein and others ( application to the problem of classification of the psychoses. ) have demonstrated a relationship between the blood pressure response of patients -“.:')l\w - w—w - Fry-w M7.“ �rm, w.» v—v-v- ya—_ -7. -. v'*a‘ 1——.r an ad“): , v-u n.7,. y ~. 7' V .. - r—*yx:'\r‘~'7—‘ —..vwr rhw- revues—WWI: a-m-x) v aw. 'IIMIN'.WP1L _,.. wr—Mrn 'w .n-u- u ...- nun-mun—u-wwwsrx— I‘d 'fllr-nr-F-qlf r".:'m~ — - —» ~ to injected meoholyl and their clinical response to convulsive therapy. which induce! Neoholyl is e potent oholinergie agent Vlsodiletion, tachycardia, sweating, and It is inoreesed peristelsis. rapidly hydrolysed by cholinesterese-I and slowly by eholinestsrese-II. blood pressure or subjects tells etter injected The meeholyl end returns to the baseline in a variable length of time, 2‘2;, five to pressure returns to the hgaeline in as Groups Pstients more than an minutes. I. II, or III reactions: 5 whose blood minutes ere olessitied those whose blood pressure takes so or more minutes to return to baseline, as Group and VIII reactions. The Group I reactors here s 9% improvement reactors s rate with convulsive therepy, and the 35% recovery rate. In contrast, the reactors heve s 89% (Punkenstein 35 3;, 1952). petients In whom IInIII Group VI and the Group VII 3 9'71 recovery Patients in Funkenstein Groups I to III upon as Group VI may be rate looked the injected meeholyl 1s rqpidly ~ �. . ”(Inni- rwlv‘v -. v -hr ~r. ‘r Wflm‘r;vz.z ~~w~ ‘ vmvrmm-mwvnvmwurr . . . . -.n- . ~v-cv rwwmvrrw-r ’Hm . , . warm-n'ku-w—w-vwvu-r‘mwm ’W'I-W‘WW . , ., . ‘23.. Groups VII v1 and the while hydrolyzed; slow hydrolysis rste. we may patients have a. the therefore. that predict, would 1.1!! Groups of blood oholinestersse nativity levels be high; while the setivity of Groups A VI-u-VII would be low. central odds nervous be rsgsrding similsr analysis msy devsIOpeent of the in system levels or oholinsstersse~l EEG of soetyloholine. levels and fluid spinal hypersyndhrony In studies of EEG changes following indueed eonvulsions resolted in seizures subjects were identified in whom a few a great amount or slow save activity; while other subjects (Pink seizures and to frequent exhibited few changes to many and Kuhn. 1956). If electrogrsphio hypersynehrony is s that probable is refleetion of inoressed tree soetyloholine, it subjeets who rapidly (the usintain hypersynehrony end those in whom it differences be exhibiting hours) disappears nsy hydrolysis oholinestsrsseoseetyloholine the of in the kinetics systems. Persistent hypersynehreny may be seen to result from associated of soetyloholins. s decreased rate of hydrolysis with low or oholinestersse-I either oonomntrstions of z - w mv as ‘— e �nw—w—uurw—u-A ~ «wv-u . "Hp; v-r w: w-ws-u—mxw —» al’im'rw‘imfll'wnnmmfi.rww-‘wmm' cholinesterasemII. Conversely, in patients with hyperaynchrony. cholinestoruaoul and fluid may be a basin fbr :yutom 1110111 : unusually high). wwwvvnwa >vv'wwa-uww «VII-MWI—w-W short~IIth .1: in tissue and spinal Thus these speculations providn congruent hypothesis rognrdlng central norvnua ruaativity to electroshock, and parephoral ahelinergio 09‘. �‘‘ r— v» -v «'1: -w:. . ~v~wr 1.». —.vn.~n—u nvw .w is w,“ . V m .,._v you-um: v...“ .uw m...” w. i. (“Hwy . , . V . v—wr\wl~;r‘-V‘va"vwg . 7-..,emu.,_,._c w‘,_pwmi,,”.w.'w.ww rtr‘ ., 1”,.“ M y OOHGLUSIONI be to e neehsnisns appear Gentrel eholinergie The convulsive the therspy process. dignifiesnt teeter in induced that to indioste be date interpreted any published Leonvulsione ere ssseeisted with en increase in intereelluler be by destroyed than esn to levels greeter seetyleholine eholinestersseal activity. Vhsodilstion and increased oellulsr pernisbility is relieved by increased amounts of eholineetsreeeoII, other and electrolytes in inter- celluler fluids. It is these changes that ere reflected in the increased electrical hypersynehreny which is recorded in scalp electrodes, and which esn be modified by sntieholinergie drugs. as stropine, beneotysine, dietheeine, proeyelidine, etc. It in these changes. else. thst provide the change in biochemical milieu which to slter alters cellular ectivities euffl.eient the behsvior of subjects. Fhilure to induce high and failure of aoetyicholine, concentrations and persistent ( . . 'W—vnww �- —-——--p~rm- ,v-vln’ .-. ‘w-m-w --v< w u-wv «m ”uru-ewmmw‘ vat—rm,“ W'WV -. - . wwwm mmnmnuw—wm "wrrm,w— "-1. Wm, chengpe, concomitant results in a failure to induce electrolyte to produce behavioral change. Difference: in the rate 0! development of cerebral chengee may on reflect differences in subjects in their reliance cholinergic mechaniene, or in their sensitivity to changes in acetylcholine levele. These differences provide the basic fer the claeeificcticn cf the menilly by my: and Kuhn (1960). 111 by Funkenetein and �.4 w . .._u~mv — \w"wxww ~ wlxmw-mwmmwwrlmmrrw IV: 6-6-65 CI‘DIINEmIC WISE, CWVULSIVE AND BBMVIOR W, Studies of cerebral changes associated with convulsive therapy have indicated that the development of early and persistent signs of altered coronal fmctim are prerequisite to oranges in behavior (Pink and Kern, 1956). In these studies, electroencephalographic slowing was the most sigmificent index of altered brain function. Th demonstratim that premedication with high doses of atropine and Johnson, (Ulett slow of mve the activity prevented appearance 1956) suggested a relation to cholinergio nechnisms. The role of eoetylcholine and flu cholinestemses in convulsive therapy is amplified in the following review which smrizes the published data. The mle of acetylcholine in the tmsmis sion of nervous impulses has been studies extensively since the of Dale (19136) and Loewi (1921). Acetylcholine constituent of nervous tissue existing in a first descriptions is bound .21 normal fans which is �. -~»-.- cwlwx—Wm.m~mn mmmvwvx 'w'w-m‘ w'dnuev—Wn —-'-v.":'-v-yvl~<-wmv -‘-w'-W"’mnrm"u'm’mmp '«ai-lu'vwv'w»; umpnw-so w-wm'n It is liberated driving the excitatim process. W the specific action of ctnlimstemse and as rapidly recmstituted 19:59). mpidly hydrolyzed by the dwlimacetylase system (Richter 8 Welland, free ac etylcmline has been reported in normal No cemhmspinal fluid despite the rapid breakdom of bound acetyl— choline during pariah of activity and excitement (Tower and HcEechem, muse). The cembmspinel fluid normlly has resemble chclinesteme activity, homver, principally of the "true" or mechclyl hydrolyzing type (Nectmensm and Rcthmberg, 19u5). In the absence of free acetyldxoline and under the cmditims described, electroencephalogram fail to shm: any mietent abmmelity. (1:) was fmmd Effect of Wiccambml Mm: Pme acetyldioline in the cerebrmpirml fluid within a experimtel heed tram varied between 2.7 and 9.0 dew after in cats and persisted for varying periods (Bernstein 19%). an hours to m related to few minutes gamma The qumtity of free acetylchclim percent, and the amount was of induced trmrne. -n way-a ---1-m'— «mu-w v;- �v ‘ .v-vuwv—‘uwuwaI—r'm mm ‘lh'une‘ “an”, . - 1W um van-mar ammw— mmmx($—‘Wv~ ~-;Www Ww-v' .wma a..- ‘nv‘w I'u Commitmt electmemephalogme Th records were first filhd with mmted patterned dwxges. high voltage fast activity, interpreted as evidmoe of m intense manual disclmze, mly to befollmdbyasrwrtperiodofflettmingofallmcomed electrical activity. 'Ihese planes were then followed by pmlmged periods of high amplitude sharp waves in the delta frequencies. The to the beheviml enemas were mutant of measured fme related to degree of acetylcmlim. tram and With higmer greater of acetylcholine, Bernstein reported degrees of abnormality and greater- changes in moiwmss. levels EEG In addition, spmtaneous poct~tmunatic seizures were also related to the mt of free eontylcholine appearing in the spinal fluid. aoetylcholine Bunstein later applied to expomd out cerebral cortex. mm the cmmtmtim of acetyldaoline was 1 gm pement orless, Mowemdhimmlitude sharpwavesoflwfmquencyin the electmenoephalm. When the concentration was inmd to w... wal‘r-vunu .,.. u ��min-u .41. - v... and :— » -1~—— “Va-x v,m..,».«n—n ww'Al'wr‘w'nx‘xa'r .. ”-p- vwrn 'iwrylvv.-ws“ «firm-mu». tr'r'r—I‘lumm$1~I'm’w-VWW-Iv‘rn'wwu .~ that the reversal of the dwlinestemse fractim sensitive indicator of cerebral BMW tram Jag-Anny... ”a.“ r‘np‘woyppfl" v—y- x w— v—w-1,msw»: v. was a more damage. were takan at varying intervals following in most of these subjects. me authors reported the relation homunmoffimahmmntymdtheappeammoffrm mtyldwlim in the w‘bmspinal fluid. Thu: AW my We and that a «the mount 05 (m acdytcholxiuc 5mm summing Weenebmdtflawm batman the mount 05 mayuuz Won W Memory, main wind In the Micheline, (1)) M indicate m dcgm and changes Effect of and typc 05 in AM mm on unfinisnmd 0.5-1.0 awomuphatogmmc bchawéoa. at-«mmtic nag/kg (an. atropine EEG and Behavior: pmtually after mmummdmmmmdbmmofmeme. behaviomland anatomic aims of tmuna. Atropine also blocked the clinical changes similar to head mum EEG md seen following the experi— mtal additim of intracisterml aoetyldnline. n-w �.r .nwm-nuw v m, 1‘ x—~.wwrv-—um—mw“n-«WW«-Waqm v Ward (1950) . mm dawn c." m xwwuv— m ‘- um ,r—m—xw applied thase observations to the treatment of hmm cases of closed head injury. In of a: patients with varying be administered atropine subcutaneously in doses tram, of 0.1 mg/kg. In 20 some cam he noted clinical immanent and in others a reversal of the electmphalogruphic effects of the tram. In a study of dietlmint. another antidmolimrgic dmg, Janknor and “dancer (1958) reported significant alterations in the post~trmmntic olectmenoephalogzm. dose in #0 slow single intravenom patients with ahmml electroencephalogram resulted in normalizing in The A 22 subjects and marked immvemnt in six others. sum elect of atropine in blocking the appearance of um activity convulsive following in subjects reported was 1956); (In a therapy (Ulett md Johnson, later study then authors failed to mplioate this study, suggesting that or population changes may have [Johnson 93.51., 1960]). dosage factors cmtributed to the different results .u-wmwm �"rm—W .7, . .\.—.~ v‘ u. w wr— w' w --=»—-.--«-v- 'w' nu.- "I 1- nun.“ mm-‘Ivm’lwuu‘twr "uvmq-WIWVWW. “HM-:rv‘lwr." 1— x—A 'i‘w'wwuvuwrwwn uvvmw": «rung-w unmoun- . aw awn:v-v—nnJ—m variety of experimta with a potent dzolinestomo inhibitor, A DI? (di—iaopmpyl flmmophosphatc) fmqumcy EEG mutated hiya mpflttxde rapid éimilar pat-hams to status epilepticus. as well as dam status (Md: 5331.. of abnormality similar to that noted in pmt—trmtic looser m 1950). doses of mad 1950; W fig, 19139; aid Won 95%, eleotmonoeptulomphic effects were blocked by small pmteral atropine. Chatflald md miml com»: with proatignine Way (19142) pmpamd and evoked electmmoamalo- graphic spike activity. The prior uninistmtion of atmpim blodmd this spiking, 'cuminatod by wif mat, the abnomlity could be mine. what to these findings, Banner md Harri.“ (19152), applied topical mimome in Momma of 2-1/2 to In 10% to tho awed cortex of cats, and noted no effect after intravmous WClm/kg)mflne1¢otmumphalommicdmges. 'Iho mtmtims of acetyldnlim in those experimts , mm, was significantly higher than the topical application: (1—1; gm meant) m "nm‘lV‘I-"WPX' mm» �.9— intmifiuml and the Bormtdn (19%). (0.2—1.0 W gm percent) injections of and Pbrz'itt, also made mate of elmwuhgrmic effects similar to aoetydxolim from ucholyl 1n (mummyldwline) commenting: dam. '33); m and dozyl (carbmayldloline) later than the acutyldnlim concentrau ”W th- inmmd offeetivomss of these momma. drum to their mitivity to animal lack of durum. FmavWa‘WandWaMu my I mama that Waupiwgwm «may mm by «wane, uau we. on a a mutt 0‘ mm. Magnum: with chaunutume blocked M (:3) We): Waxed bg We. Role mm away applied.- can be ‘ of Oanbmsgg fluid @951me in Saizums: Amtyldzolim is normally present in mrvous tissm in an inactive bound fem. Daring periods of activity, free amtyld'aoline is ��. N...- ~mv nun-7‘ «mamwmw-nrwu-W-ww-m—mmw Yum—U" v2»: 'lwwvv Wx-uwww- vv'r‘wr-I w-ww ‘t‘I—L :\ mean-v1- avast-Lo— nary-row: .10... Inspimlfluidstudiesinm, (19%) and Tower md Warn Cone. TmrmndEadnm (mush) reported significant qumtitios of fun mtyldwlim in patients with epilepsy. 0f 56 cpilaptic patients, an (77%) demastmted flammable free Michelin in quantities of 0.02 mm of 1.0 gm to 5.0 gm per cent with m per cunt. The acetylcholine 11.3ch. was dinctlymlaudmflmfmqmcyofaeizm, theemntof 0W0 dun-normality, and the minim oflthe It‘bom lagt seizure. tha to angling tingof no mmim to of Ila-dictum. type epilepsy or lewd of dwlimtemse activity. WW a W 61011110 Michelin: appearinginfin of the awn. is a (mm of the Madam arlwhetha-r the aim fluid is spinal W is pmblmtical. (mush) suggested that the in acety1~ Tower md' inmd acetyldwline mlat§d liberation is not due to the seizum itself but is to the process casing the seizum. In a study of the hypothesis that v w. �' “W "m’ W“"‘W*P"W‘ TW""-'“'M'rmz‘m-ww' : ~<I w'l-w' uzm-w-wwnw-rmr wrmnsa-mmrw “my; —nwu—n-»mrw—u-—r w-w w n—w- wan-m .mmw- n- -_w.—..——,aw—. mw'hmmrmw m «w -11. the accumulation of acctylcholine is basic to the seizure process, and animals metrazole convulsions induced in (1953) by Tcrda dctcrnined the level of aoetyldmlinc in bmin tissue befom and during convulsions. She noted that convulsions are pmocoded by tissue; of content that the content in the acotylcholinc a rise gradually falls during the convulsion; and that below certain lcvols, convulsions foilod to occur. fall in tissue acctyldholinc She suggested that the during a convulsion was due to inhibition of acctylcholinc synthesis by increased concentrations of notabolitcs such as alumniumicns. Tho passagp of electric current through brain substances induces a change in callular activity with an increase in free aoatylcholinc to lnvcls sufficient to induce a grand mal soizumc. Tho prosenco of free aoctylcholinc in the interocllular fluids is associated with electrical hyperoynchrcny, reflected the EEG as dolta slowing. (d) Effcct of Electroahock on Acctxlcholinc and Cholin~ saturates: Tower and McEachern (lShQa), in their study of cnanioocrcbnnl trauma, includcd obscrvations of six psychiatrin �, .— “7 hin""'-"""""’n w—xwwr‘W'wv-Wsmuwvw ”‘1.meer!. ., . A a .m "Jaw-«v 7 wmr- mm- vmm:wwwq~mw‘m¢7~w 1"‘3-0! w ~12-- patients attu- 3-7 Linda-going mmrulsive therapy} Studying the patients mam-atmflay upwind fm Micheline activity an.incseaae .ad rxuia in.two in in th. Spinal patients; dwlimsteWII rawnrsal a: a damase in and mum-I with a the ratio of cholinesteruses in five of the six obsewatims time has paints. W they concluded that'the spinal new; convuisions were 11kg those tunic ahansps in induced mm a! than those found in epilepsy. Ragarding the ma patimt in‘the series who failed to show 01th» I’m mtylolnline or a dwlirastemao ratio reversal in this intsmsting the spinal fluid, thoy smote: "It is that pstimtmflamlyaaoftrasistosmwnompameto mamt." WM than. a show: in «1mm, cons/Lamb“ augment about flu. note 1,: 1.6 05 “chaste that 7W!- acaytchaune mwmgaammwmmuwsm <1“ch 4:.qu and Adm/Lu enhance. autyb Ls that «sorghum damnation, �“mu-w. v— vaw >W—Wrfiww.vwam—.m .‘w'wwrr Mr“!!! wrwwumm'm WV - W9 augment wmm 1WW"WYI3"W'FVI'W‘VW wwmmww-zw (”wan-vim -13- Lawn. tww 05 “Midtown whiz: “up and auuthau wetytchauu puduocéou inc/mum about. (was. (2) Central Nervous Sygtem Cholinesterases: Cbneumitant with their observatims of W (1939) muasumnd spinal in acetycholine, Towor md Hcfiadxem fluid cholinesterase activity. The types of'dholinostoruscs art normally found in the spinal fluid: momentum—I ("trm,” "specific," which has a <92" mdmolyl hydrolyzing) . big: specificity for amtylcholim; and duolinestemseofl ("peeudo,” "um-specific,” or bonnoyldwlinc-hydmlyzing) . wands hydrolyze mtylmolim but have different Both rates of hydrolysis {bu-ulcholyl and banzaylcholine. This diffcrantial rate permits gamma distinctions. By ram-ting the cholimsternse activity as a ratio of the activity with macholyl bonaoyidaonm substrates two mama and with acetyldmbline an to- substrate ratios am fomd: momentum-Ilacetyldnlim md alwlimstcmeII/amtylmolim (with ratios normal CS? Ach/Aeh a 100) . omtains ostemses in the. ratio of cholimstcme—I to dmlincsteme-II. Thus, normal In such 33: 17 CS? for consist. �-.v rmvs 'mm l-F'W'WW wmmmm .mpr—w— rm . . may of "specific" caucuses with a small now-spedfic estemae coupon-mt. In pathmts with hand inmim of tho cm the fluid fraction of the spinal activity. dam the and 'mey also observed a of tha dwlhmstomse with ad mm Wm report and daclizmtomes with a simifioant increase in the “Wm-II Wanna-I mm Tower and of the W a decrease in relation batman with the severity of cummpmlogmpic mun. In patients with increased spinal fluid amtyldxolim as a multofspmm of Wm warm seizmu.‘hdnvor. or total dwlinestcmo activity in the made was found. metimmybomflomgamflngdmgeainmn mm activity. tha pemability as explaining the WWW-I m1 mm: syatcm is fomd 1n imam Wt in dulimstemse mnomtmtim in mile dwlixmtemesfl pmdmimtes in 0th:- tissuaa. especially blood scrum. With an increase in �,- xw- m-mmwm m anatylmolina lawla in intercollular cambml fluids following atimlatim, convulaima or tram, vasodilaticn md cellular pamability my be filmed pndictod, with a dogma of mmudafim of vascular fluid: into the inter gallular spams mtmmmtmdamimofmvmodimm(mt g; g, 19%). Spiagal and Spiegal~Adolf mutated such pamabmty W 1953). marred inmaaad omchctivity of the tissues Thay associated with W than in mm reports (19%; 19u2, 1m, 19%. appaarmca of various ions as potassim and in the spinal fluid following electrically indumd commie». Thom was also a simificmt-imm in such nm-aloctrolytaa as manic-acid splitting anzymas. (images in of circumstance-11 (Tower and Wm lSth). _ �wwlv mun-am.- V‘r‘ww.\\.sm uwrvvu‘x' ..- me—wwmvmvwn .q-zwuwm pawn-w ., cannwmuw v-Mr-ru-m‘ovr WWWWW «um—a. -.--< www.mm -15.. The increase in dwlinsstsms activity should be associated Its persistence with the rapid dostmctim of free asstyldxolins. ' in spinal fluid after trauma and seizure of the amtyldxolins—dxolixnstsmsvl may be system related to the sensitivity to concentration relation- ships (Nsdmsnsm and Bothsnbsrg, 19%; Tower and 3mm and MscIntosh. 1955). At “physiologic" Wm, 19%; oonosntmtims, hydrolysis of aostyloholins is rapid (3-H mimosaoonds) but at higher and mosntmtims, the activity falls off quickly. In lomr W, the cl'nolimstsms-II-sestylohomm relationship is naiospscific and the rats of hydrolysis increases with concentration. usual levels of sootyldxolim stosll sambmms is specific activity of cimlinsstemss-I in Thus, the destroyed by the few milliseconds. Wm omosntmtion of soatyldioline in emsssivs excitation leads to an mm tissue, the mm of hydrolysis sxosedsd. com. The ssizm threshold may by cholinsstemss—I is be roamed and a seizure me dissociation in mstylduolinwdxolinestemseul relation- ship results in s psrsistsnos of aostyldaolfine. The seizure may �mm “a." "W.— .mflmpw txm mm Wm-mmwmm—mwm m "m . amtyldiolixn diffunes rapidly, affecting vascular md cellular pamability and and Wins catamaran-II W of in the concentrations of various ions CSP. The nativity of dwlinostamse—II, cfficimw md depuuhnt low on the oonomtmtim kinetics, mmmldnwninmetissmsinhwmtodaystolewls for the physiologic action of dwlinostemse-I. (I) mo md Classificatim of mmm, gmmm . mamas: Altemtion in the blood brain pemability barrier by the continuing actim of mtyldmolim may be the biomenfical sub- strata for the post-3W hypemyndumy of the electro- mmpmom. Such mag, 1956 is possibility o mom in the report by Wmtingm 5.11m intha concentration of‘ miminbmintissmsmmdaysafteraserieaofuinduoed Gambian. this His dun 1m mlccmln, aim the change in momtmion of mutually absent in brain tissue to be ��mm. WV wwwm'wmmww’rr‘v m (memwmw“'m'ww .19- my be mama“ in the. mum nub/mug ad the. dwuuuthu— hypmymmuy Awwu. my mama Whom 1’th be. ofi acetyl— dummzd hyd/wtyau to as a mt: {m mm an Law ma mammom wowed mun, u Cthénutcmc-II. Comma (Ly, in and Wmmv! WW, my be muddy 06, mm ~11 ewwc with 5h0u~uv¢d in Mac, to the Wainwmmk Mammy. WW and spinal (laid high) . stat-flea ’meae may also have application 3 chaunutmvr MM}: between the blood problem of )have pmsum mponse of patients to initiated médblyl and their (minim). response to I convulsive mm tram. which is cholinorgic a potent hamlyl amt vaodilatim. tachycardia, mating, axomestemeq hydrolyzed by is It midly astemo—II. "me blood and hemmed peristalsis. and slowly by moun- pmssm of subjects’fans after injgcted manlylmdmtmmtofinbmeuminavariablplmgfimoffim, �-m. “...u. “v ,,.. ‘mw you ,,, d . ”are". ‘V‘ -- m, mus-www- I vm‘ five to W rm www.- w. m 1 ”3.... v- .-r'l w - way-vr—v- .m-MWWWW. “gnaw-why , Patients more than 20 minutos. Mums to the baseline in 5 an minutes ,,.mu(._“‘,_,m,“ . whose blood classified as present. Groups I, II,’ arm mmmmbaaoline, amHdeIImactions. MW]: or III mactima; fines mean blood rams hm a 9i Wt the aroup II~III reactors a 35% rate pmsm takes minutes 20 and convulsiva'thompy. with. unwary rate. In umtmst, the MHmmmmmaast'mddnGmupsvnath-wverymu (main 5; g, 1952). Patimtsinmflcmaminmltolnmaybelmdm as patimts in whiu the We may the injactgd mdaolyl is rapidly hydrolyzed; Group Hand VII predict, hvels of W when: Won, W H~Vii a slaw hydrolysis rate. that tha blood Esolimstemo activity -I~III would be him; whim the activity of ma be low. regarding the data for eatcmenl, in patina hm We recall hem a similarpmdictim mntmlm which the domiopumt syntax: levels of cholin— of early and sustaimd EEG lypamynclumy and elevated spinal fluid levels of aoetyldlolirm was minted to a low level of dwiineaterase activity. mus, w-n —. wu- �,-.n I ‘ -21- the data of paripiuml stimulation by dwlimrgic agents is wt to the hypothesis regarding mutual “activity to electroshodc. mm system m1? m'.mrrw-uww gum �CIDLINBMIC PECHANISIS IN WV}: m m M, NJ). From PM the Departunt of at the Missouri Institute of Paydziatry. Lhimity of ransom School of Medicine, 5WD Arsenal Stunt, St. Louis, Missouri 63139. Aided, in part, by usms grunts 1914-927, 11-1—2715, mmzus, and Iii-11380; and the Psychiatric Renard: Fomdation of Missouri . �VI: 7-17-65 GIOLINERGIC MICHANISI‘B IN CONVULSIVE W Despite extensive application and study, the mode of the oonwlaive therapy process “mains enigmatic. has been devoted to neurophysiological social ) aspects , ( Much study l, ( ), clinical psychologice1( . of action ), ( elucidating the present neuro- ). physiologioal-edeptive View of the process ( 'me wly development and persistence of signs of {motions were reported to be (Pink and m, activity es the The this and muisite to changes altered cerebral in behavior 1956), with electroencephalogramic slow wave most significant index of altered brain function. demtmtion that pmdicetim with atropine inhibited slow wave activity (Ulett and Johnson, 1957) and the report that mtidaolinergic «wounds reversed these clinical as well as electrogrephic menses (Fink, 1958) suggests that the biochemical basis for the mvulaive therapy process may be in the cholinergic mdmmisms of the central nervous system. This review discusses the available data mending acetyldxoline and �and the dualineetemsw in the convulsive therapy process . Acetylcmlim has been extensively studied w an active agent in the transmissim of nervous impulses since the deecziptiom of Dale (191») and Ioewi (1921). It is first a constituent of nervous tissue, existing in a bound form which is liberated during the excitation pmoess . It is rapidly hydrolyzed through the specific action of molimaterase and is rapidly reconstituted by the choline-acetylase system (Ricmer and Crosslend, 19%). In normal cerebmspinal fluid, free acetylcholine is not present despite the rapid breakdown of bcmd acetylmolim during periow of activity and excitement (Tower and Hailed-tern, wheel). The cerebmepinel dwiimnteme activity, however, medxclyl hylmlyzing type fluid does have maurnble principally of the "true" or (Madman md Rothenberg, 19%) . In the absence of free acetyldmline and under the conditions described, electmenceplumgm fail to show elmozmlity. �(a) Cholinemc Aspects of (kmiooembml Trams: Free eontylcholine was found in the oerebmspinsl fluid within a few minutes after experimental head tmuma in cats and persisted for varying periods up to “8 hours (Bernstein, 191:6). The quantity of gm free acetyldloline varied between 2.7 and 9.0 the wt was Wt related to the degree of induced electroencephalogram menses. The records were percent, and tram. demtmted pet-rm first filled with high voltage fast activity, interpreted as evidence of an intense neuronal disdurge, soon to short period of flattening of all recorded he succeeded by e electrical activity. These phases were then followed by prolonged periods of high saplitude sharp waves in the delta frequencies . Ihe behavioral changes were related both to the degree of tum and to the want of measured free aoetyldwline. 9th higher- levels of aoetylcholine. Bernstein imported greater- degrees of EEG abnormality and greater damages in consciousness . �Spmtanccm post-traumatic seizures mm also related to the mmt of free acetylcholine appearing in the spinal fluid. Bernstein applied ccatylcholine to exposed cat cerebral cortex. M the cmccntmtim of acutyldrolinc WM 1 gm low frequency of waves unplitudc sharp high percent or loss, appeared in the electroencephalogram. men the cmcantmticn was Wed to 2 gm percent, the electroencephalogram: flattened in a fashim parallel to the pcatétmumatic records. Pmllel investigations in neurological patients by and Madam (191ml) Tower dammtmted free acctyldrcline in the ccmbmspiml fluid only in patients with meant head trauma, recent grmdoml seizures or after clactmconvulsivc therapy. Free acetylchclim varied from assaying spinal fluid 0 .2 to 100 gm percent. In drclimstemc activity, they noted a sharp rise in the nonopecific cholincsterasc fraction (benzoylcholimnsplitting) and a drop in the specific cholinestemse fraction (maholyl-splitting) in patients with head trauma and fill-owing convulsive therapy. The cerebrcspinal fluid did not �exhibit such inversion, althougz lit command free acetyldxolim. after Spontaneous seams . that the lavel of They comluded two watylcholim varied directly with the dame of cerebral damage and that reversal of the dzolimsteme fructims a more sensitive indicator of mmbral dmaga. taken at varying intervals following mlntim batman the W EEG 935;, Ehcflmmaphalom, also indicated a abnormality and the of fme mtg/10mm in [Add 1 Kovach Thu dogma of mm. was fine cerebmspifial fluid. 1957] mmummmuummcam maumuuam WWWMdflwmo‘ (an Widow, the ham and. type. 0‘ WWch abmmutg, mmuummuuaappmu Mandated pm. �Fwy-.. W, .,- V l .7..— (wt‘ mm- M 1-... WWW“ 'mw .. :‘w ,v- a. , , m1. vv vv-uw-u-,o-vw-w.w.w ‘V'I-V-t.mNrIV-WI AntiohoMc (b) wry-urn "I“ wv-mvww—w-wuam—run-mnw—uu—wxw m and tram: ”myr—w—vm—wwwq wrivlwmwwr-wflw v: ,«w- me electmmphic, beluvioml md nemlogic Sign of trauma were blocked by the mutual ministration of 0. 5~1.0 ag/kg atropine (Bomatein, 19%). as were similar olinmel oranges occurring after the inmatemel additim of acetylcmline. Word (1950) applied these observations to the Moment of closed head injuries. In 20 patients with varying degrees of amine tram, ministered subcutaneously in done: of 0.1 ng/kg, mating clinical improvamt in some and a reversal of the electmenoepmlogmphic effeots in others. In a study of dictum, mm mticmlinergic drug, Jenkner and warmer (1955) mpwted electmmphalogxm. the postnmtmtic done he in forty patimts with A altemtims in single intmvemua em}. electroenceprulogrmne resulted in normalizing in twenty—m and muted imminent in six others. Similar observations have been reported by Denisenko (1965) using methylbmectyzim and ‘ meantin in poet-trumatic flock and cerebral edem. animal experimts of ‘ . u—v. . .mmrrmm �- .v -'4In v'nvwr»vr Anew—Wt nv -V “war w rr v. I1wurwuu‘wv gm" w'twv‘z' 'or‘ Ila-3 », ~.,r-.mwm-w-—~ v.“ ,1,“ .‘ .v-y m twinw-vp "Ivy" .m.‘ war. .r my rnm ~; . "mam—q .74- ..w w. .... , Thee duet-mums wen eeueeed in the omwleive therapy process by Ulett and Jornem (1957). Then workers eduiniotemd doeegeaofatmpineupto the patients received that the was mt: mper'daydm‘ingthemeke «mm of slow wave therapy. They Wed activity produced in these patients significantly has then the omtrol m who had not mind the atropine ministration. (In a. later study these eutm failed to replicate this etuiy, suggesting that douse factors or populatim changes have Wed may to different results [Jomem 3:311; 1960]). These observations provided the basis otlur 1cm mtieMlinergic W for studies with (Fink. 1958, 1960). The intmmue injection of emerimentally active antiomlimrgid comma es diethedm, benectyzine. the piperidylbenziletes JB-318, JB-336 and JB—329 (Dim). and wan-2299 induced deemmmiution in psychiatric eubjects. These were associated with bernvioml flirting, anxiety. EEG EEG clmges tram, illusions and hallminetima. In patients um had recently �,__.,,__,,.. . V... 7)... W- w -— ....,... . .V-r—w, .wx-7'Uwiwt ~s| '1‘ u u a...” ,.. w‘mmjwlm‘vwnmu‘m . "0...an ”mi—W- .thwuww. ‘ m.,.m-.-.,,, M_ "H". H," ., ,.. .w-.m.1, , a“, r .neqy..-mw—-; - .r» vr'." received eleotmoonwnoive therapy. the eduinietmtim of theseoomomdemeeaooietedwithemdmtioninslowmve activity and meme]. of euphoria, denial Atropine was also EEG emined in desmlumiutim WI m and tension. and confusion. low doses. and obeemd in these administratims, mind At higher superimposed beta tachycardia, We, hyper-8mm slow waves, followed by lower voltage, poorly activity with by activity mined delta “mind by progressive confueim and disorimtatim. Both in oenbral mm and indumd omvulsime, the ehotmfimphio clauses my be modified by the comm-rent administmtim of micmmemic drugs, thus Weed mt: of aoetyloholine or- mating that incmeeed cholimrgic receptivity is eeeooieted with the high voltage slou’ wave activity. (o) 13min mmnm and m! mmm : SimilarEBGohmgeemdthblookingthmfheshenobmmd following the direct application: of aoetyloholim to the centre). mam. - .rml... ww—wu-uuwy w— “WY—r! �'lho anninismticn of a chainsaw. inhibitor DP? (di-isopmpyl fluomphocptute) elicited high maplitudo rapid frequency W EEG patterns similar to status cpilcptiws, as well as similar to those of post~tzmmtic states amen 23%, 19%, 1950; and ma: gag, (W We 1950). effocts'wom blodcad by small doses of pmntaral atropine. mat was 91; 5}; EEG The inmaso in acetyldaoline after tetmrdxyl pymphosphate named indumd and routed to the toxic mmisfostatims (Wand 3m, PM: 1952; ('11???) and convulsims 1957;) Chatfiold and Dummy (19h?) pmpamd exposed animal cortex with Tho pmtimim and ma chmmlomic spike activity. prior administmtim of atmpino blodcod this spiking, or pment, the mutuality could he oliminatcd by if atropine. In contrast to those findings, Bram” and Merritt (19%) applied topics-.1 acctyloholim in to the expound cortex mania-ts of 2~1l2 to 10$ of cats. md mted no effect on the electroencephalographic changes after intravenous atmpim (1 Wits.) 'me concanmtims of acatyldnlim in fixes: cxperimanta, �10 harem, wan higher than the topical applications and the inmoistomal (0.2-4.0 Bernstein (19%). Exam» and gm (1-14 gamma percent) pennant) injections of hwitt also made note of electro- m unholy]. onooplulogmphio effects similar to Midtown (nostylhotmfiayloholine) and doryl (Wlmlinofin mantmtims moh lowor than the acutyloholim oonoonmtiom. 'Ihoy ascribed tho imaged effoctivomos of look of sensitivity duolingio those drugs to thoir to oembml olnlimstemes. Thou data one conflicting and furthr study is masonry to qualify this issue . Gummyiml Fluid mglmlinc (o) of aoetyloholim mtabolism and inflates that it is Selma: found in One View mm tissuns in an inactivo band form, wring periods of activity, mtyloholim is liberated at the call midly mum, Mum it is deactiva‘ood by dzolimstomso. 'Iho mount of bomd mtyloboline is the resultant of tho oontinumas pmoosses of synthesis, liberation and broakcbm. It the level has been postulated that rim timing sleep and falls during activity. and Czomland, 19%; Elliott, (Richter Sam): and Hmdorson, 1950; Gianna: �,7... ,r‘ w .w..,» "gun-w WW, _ w w" Rpm. 1962). .1,‘ A. 4w- By ....- a. m brain mg. higher than 3005 tissue levels is mw. 1...,” wr'w".‘— wan mama basin .v—w tho love]. of during :- "w m:a..»=-v~<wmu «we» u-m—v .fr'um-g v.~'mrw-"n—u'w .r‘xm is high mtylcmlim (micro- munch and sleep to b- mm, mini-It. \‘w‘ , air quick freezing Minds. post-ulna! levels. (7 Thu diffm in as the msyntlnais mm for gm/m/ndnuta). Elliot $3; omfimd these observations. also toting that after nan-uncle aonwlaims spinal "Wu-1 tim) wotylcmm in rat (1950) , using liquid Richter and Cmoclmd per ‘v-‘w‘m fm acetylcmlim m «flammable fluidinmncmtmtimamtoagampermm. Pepeu (1962) fomd an qt central mm 11mm in mtylclnlim Wan depressants to in the mm caused by a group be roughly proportional totindamoofdepmasimoftheemmlmmusmummm‘ mdmtim in Prue mm activity. mtylcrolim m 'fluid in mportad in‘tha spinal patients with epilepsy (Cone, Tum“ md and mum. mmud 5.0 m 19149 b). or 56 fm amtylcmlim percent with McEncMm, 19%; epileptic patients, an (77%) in quantities of 0.02 to an average of 1.0 TM:- mm cont. �v— v w. «...v..v,v .-A—W. ,_.1,._,...V,. -v-.»-m—wv —-.~ ammm‘ «wwwm 'y'vvx'v u—wu.uw,n-w.-w.~:.wmw.1». mu '1 “a“. - .vwruw—Nv- l2 Maryldnlim levels wan related to the froqmncy of seizures, mmdcmmmhmiomlfly,mdtofim 1b zinc. the lat column, but bore no mlation to medication, type of cpilopsy or level of Tadcr and Wm ($0th (Hugh) Vimd tbs increased acetyldmclim a lay-product of the Stwying the hypothuis that the inducod aim. m activity. (1953) 301m, and not causal. mum We! of acotylcholine the level of acatyldiolim inbmintissucmotmaoh convulsion. Stumtcdarisoinflae acetyldaolim content of brain, baton a sebum and a fall during tho convulsion. Below curtain levels of acetyldmolino, convulsion hind-to comm. She smeared that the fall in tissue can due acetylcholim during a cmvulsim acetylcmlim synthesis sue): on by Wed to inhibition of concentrations of natabolites amnim 10m. Wendhpoualsommdclmgosincenmlmm systcn acetylcholim follauins “rims stinulmts . Only after �13 SMDutyhthyIMimte was there a mcholyl and 3, W significant dam in the acutylcholim level. they noted a in association with inmost! omvulsions. drugs which may qumtifiad as atiwlmts 1:me maninaoetyldwlim impmniazid 4» and no W mind + 1309A) comma, them in mtyleholim lava]. muss these by convulsions. (The than WWW duspite int-mo excitation produced by those mu imam. (LSD. mpmma level. other With were diffemnms in observations mmmmmggmrmrmdmm may be related mutants. to the differences in fm‘ methods th: Lunar unwind of biochemical changes in spinal fluid nflcatingttnfmeaoetylmolim,whilnsiamamandhpeu‘ manna tatal Myldwlim in tissue uncaring bound fm form Thu: an and of acetyldmlim.) AW W Auggut flux Apontaum by an u induced We 1mm in law (no. acotyzchouue �-, .4.‘ . rum- .1:.--—.-. -. ‘T r. .l ~,w ':.»"-rx\~\I--«-~-v~’ ‘mw"‘ m~.r...v.w—.m...~»-. . .«m-n vyr -. . 1-.“ , —;..- r...» ,.r;« “a v.—~ 1n tummy-1 La 5pc“: (mid. mmwe bound (on which my Wag dalmatian, “up and mduafion immune mane (d) Oantml Nervous activity. (19%) also ‘mo Austen/ted 6mm «cavity and Aazuu mm:., m Wm be. tum . Sgt” mama enhance Mae. Lama masthead in the W 06 acetytdtoum (holimstomaa: Tour and spinal fluid diolimstema typas of duolimstarms we normally fund in thc spinal fluid: dmlimstume-I ("tr-m," “specific," or Molyl—hydmlyzing) , which has a high specificity for acetyldiolim; and daonmstemo-II <"imudo," "mspadfic," com or benzeyldxolim-hydmlyzing) . Both mtyloholim but rates of hydrolysis for have diffamnt hydrolym diffcmtial rate Molyl and bomoyldmolim . This qualitatiw distinctions. reporting the duolimstemse By permits activity as a ratio of the activity with a maholyl substrate with a bemoyldxolim aubstmtc mud and to a substrate of mtyldmolim, ten mtios are found: dualfinatemeJ/mtyldmlim �-- ~ :4: 7r>m\‘-Vrmwu~<hvuwrr. n >--'rw. aw, ww H'VJ’IW'W‘VCu-‘rm'"‘l ~w:wa-w-._,.rm unr— w .vumma .w. "- urfi ,. .... 0-» ‘wV.M-a>vfi “Tr-aw -r-.-~,:-. 1m.” ~ m 15 and Mm-II/mtyldmlim. comm fluid :30an censuses for “must-men! to In such ratios mall in tho ratio of 33:17 dawn . Inpatimtswithhadtmm.mrmmmmmd mimmimofflndnflmtmwifi'minmeinm W41 Mum-I fraction of th- spinal fluid and a activity. ‘11:. W in what of tho cholimtomso Wmmuudmtmmtyofmmmdmm m at the In :13qu WW. mints with owned spinal fluid acetyldxolino m:mm,mvar,mm1nfinmioof dwlimtm or total mun-statue activity was fomd._ mmmannmmmymmmamm mumimmminanmpombiuty. WWW-Ii: antral mm system while Manama-II pmdminms 1’ththth in other tissue. specially blood scum. in mtyldmlim hula With an inmue in mnbml intcmauular fluids, up“ .7. 7" .- » -~ ..,_, , u �A , . ,_ =...V........ w...” ..l.._, nv'rvxw w." .7 "Myw-IlI-Irwwaur- ‘7 ""Fvwmm“ v raw-4‘7“-” ”Val n”,_~ -17 . "A «rum—u fl,” "mum—.1,“ NW... , 16 vasodilation and Wei with a degree of umudatim of vascular fluids into the inter» cellular permeability cellular spaces varying with the extent vaaodflataticn (Kabat and their Wm 35. _a_1_, 19%). and may be pmdicted, dmtion of the 81313301, Spiegel—Adolf, (1981. 19%, 19%, 1938, 1953) WWed sud: permeability changes md maimed mndmtivity of the tissue associated with the appearance of various ions (as potassium and prosphate) in the epiml fluid {alluring electrically induoud convulsions . Such nucleicaoid splitting cellular permeability WWW of aims, may nm-elactmlytes, as also ixmaaed. Changes thus pmvida the basis for the high acetylde and the inmased mntratims of cholimsteme-II in induced animus or head tmuma and Wm 'Ihe in ' (Tamar- 1939c) . persistm of mtyldwlim in spinal fluid after head trauma and after aims daspita increased dwlinastemse activity related to the sensitivity of the aoetyldiolin'e- may be dwlimstarmd system to Wmtim relationships (Nadmansm �,wn‘ww’ ,.. i . ..-.. _‘ “a... n”. “ ‘,,_ .3», .1. m, .Vq‘r‘. am-rw , ~,--‘V~rwtrm—Ww ..~.-—-~—..-w wr".v\-4I"\9-rr"x““w-myrvwrmmwn'v .(-,.‘v.,..._..-..‘_w,,,,rn.—.y~.—_-.r~,- 3“ .~.-. 17 and Withers, 19'65; Towcr and Wm, HacIntosh, 1955) . At ”physiologic” 1909c; Burger: and comtmticns, hydrolysis of acatylcholinc is rapid (34 micxmocondn) but at higher and lower concentratims, the activity what, falls off quickly. In the dmlincatnmo-II acctyldmolim mlatimship is ad fin mn-cpociic m 01’ hydrolysis cmccntmtioc. W witl': increased. anvimcffinscmlatimhipc suggestsflmtwhilem usual commtrwticns of acetyldmoline t cell m: are dcstmyud by tbs specific activity of cholimsteme-J. in a fut micro-cm, an emaive concentration following cxcitaticn may exceed the rate of hydrolysis by cholimstemso-I. seizure mmmm the uixum may be mmd and a seizure itself adding to the mm: The induced, with of free amtylcmline. 1110 increased acetylcholinc diffuses rapidly, affacting vascular and cellular minty and increasing the various ism and circumstance-II in the of dialimtcmc-II , mums CSF. The of activity thaugh of low efficiency and depending on �the mien kimtics, mamas tho watyldxolim in the tissuns in hours to days to levols for the physiologic actim of dwlimstame-I... Chaumtemu «ppm is flu. camamemmmm In The. am 5M cu a. gamma gum, mating 5m a“ when pmabuug “mined by imucd changu mm. Wed mm“ me put “the hmmtéc Wm “mucus the ants (n ma agate»: 05 Wu manually «mum. (a) Amgzleholine, Alumina in MW at cm EEG the. blood-brain Mum and Indumd Oomvulsiaw: pemnbility barrier winning action of mtyldwlim may be the by the biodmmioal substrate for tha poatwlectmahock hypemyndmy of the eloctmanmpinlom. 3% a possibility is evident in the Mommim of an immense in the concentration of cocaine in brain tissms thme a series of 12 induced convulsions (Aird army in concentration of this days after 5331., 1956). The 1m mlecmle, ordinarily absent �mnpr- rug—m.» r m «7 r.~L,-»---.--,V-...Ww.‘n - v v '.>T4wmw‘m .mw—z , ru71.,‘ mu mr‘m—D'J.lr>aw' yawn-vanquas,‘ ‘w. - p". yr. -., “wharf” . WV. ”us-apt..." 1.. .19- in brain tissue, was asaociatad with the appoarunoe of hyper» synchrony (delta bursts) We hIVD in the electroencephalogram. confirmed tbs many pruvious reports thut convulsive thaxapy induces olectnngnlphic hyporuynchrcny (Pink and Kahn. 1956; Pink 33.3;, 1961). Duspite a constant application of mmmmuammmty'mmtmo: appoarunnn, the duration and tho cxmnnx of the electrogruphic slow Haws by activity as wall as the sensitivity to modification alnrting, hyporvuntilatian and barbiturates in psychiatric (papulntians. Tho early appoarnnnn of high degxan hyper~ syndhmuny and its puraistnncn throughout a truatmant course has been dnscribod an pmuruqnisite M (Roth, 1951; Roth It is possible that EEG to £11., impruwument fiollcwing 1933; Pink md M111, 1956). the diffirnnces in tho degree of indncod hyporuynchrcnv may bc related to differances in the activity or auntrul cholinnrgic mechanisms. patients to davalop hyporsynahruny The may failure of certain thus be associatad precluding a clinical rlsponse to induced convulsions. Tbuer .. l . V , ”.17 v ,, n �w, ._‘_,._..._‘,|,,, r. Wm. ;.,,,,.__ m. ,. ~ "v.0... . (T W . r r, -_ "u . rw.par.-‘W-.~ .erz. .7.” , .1 . _ y . ., 4.1-. . -- n v-uvnwwwv-wm‘uv “wave-«W.www—ur-p—, w-n—w—w M-ru- "n" .,-v , . _ _ , ‘ v—av-um . . woun- 7 -w v-_. .- m 20 and Wm (19%.), in flair study of W231 tmm, hcludcd observafim of six psydtiatric patients mder'going omwlsive mampy. Studying the patients after 3-7 tiny upon“! {me spinal fluid and an inmm mutants Minimum in two patients; in mournstcmvn and a dam in .mvemal pith of the ratio of dxonmatorms a dwiimstame-I in five of the six patients. From mludad that the spinal fluid these obscwations flwy We: in ma commlsiom mmfimmoofmioambmltmfimmof sputum epilepsy. WWMpntientinflwmflaawhofanedtom oither {no acetylomnm or a dmlimsteme ratio reversal in ifitemsting that this the spinal fluid, tiny. wrote: "It is patimtwaaflnonlymafflnsixmshwmmsmoto Wt." ‘ at If alectmgraptdc hyporsyndmrmy increased free acetyldmolim, subjects who is a mflectim maintain hyper- syndmymdttmeinfimitdisappemmidlymybc waiting diffemnoas in the kinetim of the dmolimstemsw » , _ v—-— w . 7 v vamp-omen“ W . p ,. . V... , ‘ �22 “I (21011th 'mooo studios and the Classificatim of a : malochm applioatimtotmpmblanof atomic mootivity and the classification of the Mountain Po mm and ( ) mlatimhip boom the psychoses. how dumstmted blood possum response to injected ndxolyl and the clinical mpomo of psychiatric patients to convulsive fixaapy. Homolyl which W is a percent cholinorgio agent vaoodilation, taduyoudia, sweating, and peristalsis. It is rapidly hydrolyzed dxonmotorm-II . slowly by The blood falls after injoctod Immolyl within five to more than 9mm and takes Group 20 Group VI and VII oholimstemeel md pussum of subjects mtums to the baseline minutes. Patients whose blood {within baseline the returns to classified as prawn 20 by W 5 ndnutes have been I, II, or III reactors; those whose blood ormminums tomtumto baseline, reactors. M I and thp III—III as mam �.. pr 7: . -r WW..." . . .r. . n .. 7.. .- -. mm». . 1 unw- u . “val ~ « - ....._. v .. wiv'r—z-v .?-'a‘.v~'uV.—T{=n‘)("\filr- - ,r., "saw-- wry-WW...» N. mv—fi m—m ‘»-y-_I-sfi-vvvvx , 23 have a 9 and a 35% recovery and Grow VII mentors 91; gl__. 1952). patients in Group whom while Groups VI 89% rate, mspectivuly, while and 97‘ recovery I to III mactom the injected mornlyl Group VI rates (Funkeastein may he looked upon as is rapidly hydrolymd; md VII have a slow hydrolysis rate. We may pmdiot, thcmfore, that the blood dxolinesteme activity levels of Grow): I-III would Groups VI A uystcm - bu high; while the activity of VII would be low. similar analysis may be mad: regarding central nervous levels of dwlinectemse—I in the duvelownnt of EEG hypersynchrmy and spinal fluid levels of aoetylcholim, providing a basis for a omgment hypothesis regarding centml nervous syntax: reactivity to induced oonvulsims cholinergic agents. and to peripheral �- ~—-~vw=rr'u. . ~ . “,_ w-vvww (“vwxx mu, .- v*'ul""‘v‘“""w“1-c-»w‘mlh-rtr"'4<-Ia‘.—-vuz‘ --— (—1 m-wry_._ 7...," .V, 7 ,_, . ‘ my — . w". ,.c_..,.. .. u... w. Flaw—w. v3. ‘~.,..,,‘w,-." 2‘4 CONCUISION: Central cholinergic mechanism appear to be a significmt factor in the convulsive therapy process. may The published data interpreted to indicate that induced convulsion: are be associated with on increased- in intercellular acetylcholine to levels greater than can be destroyed activity. Vaeodilatim and increased by dmlimsterese—I cellular pemability are followed by increased ammte of clnlinestemee—II and other enzymes and electrolytes in intercellular fluids. These chmgea are hypemynclu'my which can be mdified by reflected in the increased electrical is recorded in scalp electrodes, and which mticholinergic drugs as atropine, benactyzine, and ydiefiuazine. The changes in the cerebral biochemical milieu alter cellular activities sufficiently to be associated with altered behavior of subjects. Failure to induce high and persistent cmoentrttions of aoetylcmline and failure to induce concomitmt electrolyte changes results in a failure to produce behavioml change. n: M ...1,.“‘..w. “,4 _. ...... ._ �25 Differences in the rates of development of mm reflect differences in their lependance of cubjects mechanism- changes on chom'cergic or in their sensitivity to chmges in acetylcholine levels. mean differences provide the basis for the classification of the mentally ill by kaenstein and by Pink md Kuhn These observations provide the mode a Miami (1961). Mechanical basis for of action of indmed nmvcflsims in altering the behavior of psychotic subjects. These views are consistent with the more earlier general neurophysiclcgic-«iaptive theory expressed (Rink, 1957) . �" -v~1r'-W4'VY—,‘V.'Z"V‘."-‘ w "- ---'~-' REFERENCES Aim, R. 8., Strait, I... 1‘... Pace, J. W., Hmnofi', M. K. md S . C. Nemphysiclogic effects of electrically loaned deitch, convulsions. Aach. ucuxoz. Izyahtat. (catc.). 1956, 75: 37l~378. Pmmoe and actim of coetyldwline in oxporinnntal Box-cumin, M.D. brain trauma. 1. Nounaphga£o£., 1986, 9: 3%9-366. Brannon, C. and Merritt, H. H. Effect of certain choline derivatives on electrical activity of the cortex. Moh. Newt. Pageant. (ChicJ. 19H2, M8: 382-395. W, of amtylcholim. S. A. (Editors), V. and Hoolntcsh, F. C. ‘lhc physiological Biglificmoe In I. K. A. C. Elliot, C. C limos, ummag. H. Page and J. H. Quutcl Springfield, 111., 1955: 378-375. Omtfiald, P. O. and Dagny, E. W. Effects of proatigmine and acetylcholim on cortical potentials. Mn. 3. Phyaialu 1982, 135: 633-630. Wm, D. Acetylchclino and murmal Corn, w. V.,-'l'cwcr, D. B. and activity in cpilcpsy. J.A.M.A., lane. 73: 59-63. Dab, H. H. thoiz- The action of certain caters md others of choline, and nlctim to maxim. J. Hamel. Elliott, Exp. The)!" 19114, 6:187. C., Swank, R. L. and Henderson, N. Effects of mostlutico and cmvulamts on acetylcholine content of brain. MM. 1. Phytiol... 1950, 162: 888-1371;. Pink, H. R. A. A mified theory of the cation of psychodynmic therapies. Pink, H. Effect of mticholimrgic agent, dietmzinc, on behavior: simificmcc for theory of convulsiw flxcmpy. Melt. Pogohiat. (Chic). 1858, 88: 380487. BBQ and mm. Effect of mtichclimrgic compomdc on pat-mullahs cloctmcnocphalom and bobcvior of pcydaiatric patimts. Eltethoenctph. Cliu. Neukophg6£a£., 1960, 12 (2): 359-369. Firm, M. Fink, H. and Kahn, R. L. Quantitative studies of slow wave activity following electroshodc. Electuuceph. can. Newman!” 1958, 8:158. Pink, 14., Kuhn, R. L., Karp, 3., Pallcck, M., Green, M. A., Alma, B. and Infkowits, H. J. haunt—induced convulsions. Molt. Gen. Paychiatn 1961, “:259-266. W, m. ' 8 A. 14., Bales, P. 1)., Willie, Hiwich, H. E. Exporimtcl production of electrical major omwlsivc patterns. 1. MM” 19kg, 1.35: 117’12“. A. and �'"WW.'I<-.~;—-- -, -‘—-'-a . .. r! _‘,',.."_'__m, ,- . ‘1).m. u ‘P. - ..~—.—.-a..nuu.~.~ . ‘~»~..ww*m‘m—. - v w W .-w-rvu.wm.m .w, ”mu “.3 w-w WW..."— xw-mv-vrv at K Ib‘mwv": “nun-ms?” u mmic mutt, of in mlation pmgnoatic system sigxifiomoa to test mm Maintain, D. H., 013011031106: truatmant. Payclwaom. “ad” 1952, lb: 3u7~362. .Giaman, N. J. wtyld‘tolim. H. and Solomon, R. C. ML, F., Md Pepau, G. W. 1. Drug—inclined changes in brain 1962, 19: 226-23“. A. and Hiwich, H. E. Macaulay, J., amen, Effects of diwinopmpyl flmmplmsm (DE?) on ahatmenoepbalognm and dwlimtama activity. methamph. can. ”Mphgunl., 1950, 2: “1-48. Basis, C. Wm, W,mm" H. 3.. Basia, C. In, J. I... Bales, P. D. and A. H. Effect of trimathadiono (Tridimo) and other drugs on mvulsims named by di~ioopmpyl fluorophosph'ata (DFP). 1950, 106: 816-820. mu. 1. Pfiwidl, Jamar-r. F. L. and bachnar, H. The effect of Dipamol on the ehatmwmphalogminmmmlaubjcctminfimewith Gambia]. 7: um. 303‘3050 Ehctaouuph. can. Namephgalatu 1955, Jansen, L. C., Ulatt, G. A.. Johnson, 24., Smith, K. 31:! Sims, J. 0. thanpy (with md wiflmt atmpim); affact on alantrmioany Julyzad electroencephalogram. Malt. Gan. WWW! mm" 1960, 2: 323—336. 61mm, M. and Knaub, V. Quantitative estimation offinalbminandgmglnbulininnomlmdpafimlogic cembmspinal fluid by imxmehamiml methods. Mu. J. Meet, Kabat, E. A... 1938, k (5): 653-862. Loud, 0. Fiber hwmrale {Ibertmgbarkait den Hennammiflnmg. Mali. 5. d. an. ”quiet" 1921, 189: 239~2u2. Wm, mm, spadficity mm in new on D. and Studies on dualinestame: tissue. J. Biol. (than, H. A. of 19%, 158: 653-666. Richter. D. and unwind. J. Vaziatim in acetyleholim content of the brain with physiological state. MM. 1 . Phyaiatu 19139, 189: 2157-455. W in the EEG mdar bubimmte Mmesia pmdwad by alactm-omvulsiva tumult and thair significance ECT of the action. Manuphguol.” can. Eumuuph. may to? 19 1, 3: 261-280. Roth, H. ‘ W mt. WW. Ruth. 14.. Kay, D. Pmtothal omwlsiva 1957, 9: 225-437. J. md amen, J. Prognosis and ahetmphalogmphic changes in electroW. K... Shae, can. Memphyauln Spiagel, E. A. and Spiagal-Adolf, H. Permability changes in the brain induced by mm). and insulin convulsions. J. New. Matt. v.3... 19M, 93: 750-755. �F ” rum" , ,7“... T9,“ wm.~n..wr.”“.,.,r,.w ..;._‘.,..,_,Vk,»,mqr,..r. 14."... _.-..,.4,. r...“ ‘. ”um-um..." :w-"CRIWJEFIMI-‘wf‘t . .,»;r-,W—;.—‘m'w"Ir-E'WAn-‘n-vu-I 1”“7(IAHV«——l ._ - n -.--~ 7»-v—-———~r-—-n~—w-v-—. -3Spicgol, E. A. and Spinal-Adolf, H. Physioochemiml effects of ohctrically 1mm oonvulsiam (oembxospinal fluid studies) . Tm. Mu. Haunt. AM” 19%, 70: 130-132. Spiogel, E. A. and Spinal-Molt, M. Physiological and physioochemioal mohanim in electroshock tmatmnt. Conga. Newt” 1953, 13: 38-63. Wm Spiegol, E. A., Spinal—Adolf, We dinning“. in the brain Tm. Mu. and Kenny, G. Haysiooodmfioal electrically indumd omvulsiw Nunez. AM" 19342, 68: M. m. Wt Spiegcl-Adolf. 21., Wilcox. P. H. and Spiegel, B. A. Oambmpinal fluid in elnctmehodc of psychoses. J. 19%, 10”: 697-706. chm W. 3ch” Stem, W. E. The min of acetyldxolim in bmin metabolism and fimction. Man. J. ”13‘. “£41., 1957, 36: 222-455. Torda. C. Effect of omwlaion flaming agents on the acetyldmlim content of the brain. J. Phyaiol., Amen. 1953, 173: 179—183. Tom, C. Effects of single injection of oortiootrvpin (ACE!) ion and acetyloholim content of brain. on I. “watch, 1953, 173: 175-178. mum W. and nauronal mtyldmline activity. I. Mr. Wm. Cholimterm patterns ma motyldwolim in the oambmspiml fluids of patients with Canad. J. Hum, 19mm, tram. 27 (Seat. E): 105-419. D. a. and Wm the omtmt md WMim of W323, in human cerebmcpinal fluids. Cam. 1. Tower, D. B. and cholimatcmes 191.9», 27 D. D. mm, (Seat. E): 132-435. Tower, D. B. and unis-clam, D. Mutyldxolima md mama]. activity. Motylcholine md daclimteme activity in the In”! osmbmspinal II. fluids of patients with epilepsy. Canal. J. 3.914%, 27 (Scat. E): 120-131. mm, Ulett, G. A. and Johnsm, H. w. Effect of atropine and soopolaminc upm chotmonoeptnhgmphic changes induced by electm—oonwlsive therapy. Eamomuph. can. Monophyunzn 1957, 9: 217—22u. Hard, A. A. Atropine in the tmatmnt of closed hand injury, J. Meano.ung., 1950,‘7: ass-noz. .V. .- - �(July 2, 1965) Jan. 3, 1958 EDIE 0!" ACTION OF TheCNS BIWCAL ms IN EHAVIOR indopendcntupmanmrofenzyne for systems proper mtabolism and functim, including cholimstemae- aoctylcholine, glucose-phosphatase, etc. The bahavior variety of is large, in either direction wt: that affect CNS fimcticn and, thereby, since processes in equilibriun by increasing may be shifted or damaging the available quantity of a metabolite. A. For drug action, thanfom, tho following are cmsideraticns in potency: ‘ (a)mescdrngaffectmmzymsyste1nina reliable my? it (1:) Can (c) What get to CNS to affect the system? defenses does organism process to block or limit drug's actim mac in CNS? metabolism the affect directly amt of a specific system, to that extmt is the CNS dependent upon the system? Is the dafoct thm induced sigiificmt for the metabolism B. of CNS Secondly, while an may mderlying behavior? Rut Menace can body call into play when system has, is affected to substitute other may system? the variatim in drug effects in behavior depend upon: (a) Beluvior at onset; and pmdispositim (personality) to response; (b) mug dosage - availability to has on m mzym system; CNS and the effect it �W'wv‘mw n—m—.n-u.r:~wvmr .v 4-:- \I.’—:r~"!lwwmi‘ mama v; M'er‘ui'v-V-‘P 1‘2'.~vr1v-'wv— (c) Depmdence of war "-3;*..)I(7'4<~<'I‘R,IWT~’:~.~HV~’V~W ~, - an.» :uru.r-owr:< , .. mm? a. mum cvw V:""\ 1 < =- 1 w - -—-v. again on specific enzyme ommimic defenses (Le. substitutim for affected system). (d) Whether effect was gradual (allowing for system -— defenses, and ,r'ia Le. , enema metabolic system) or acute (not allowing defense). Individual differemes in meme may be due, thus, to differences in: (a) Dosage, ratio 8 mute of mainiatmtim (b) dependence on the affected system (c) adaptive ability to biochemical changes. To these changes, EEG is a me approximation and indicator, reflecting the homeostatic balance in various the CNS. enzyme systems of ��21 mtylcholim hydrolysis system. Persistent malt from a damned rate of hydrolysis of aoetylomlme. associated with low mmantmtim of either or Grantham-11 . livcd W, hypemyndmany my (immunised (Oonvamly. in patients with shortcircumstance—I md «II in tissue and spinal fluid my be mustang! high). Fmthuc obawa‘ioumwouldcsuaudetmmduud MW ”mam m «wanted We. and in cmbut pmabuoty 5m. Wag MW mm (at. EEG «the hypwymmny Wow nu 06 wumwmu. Mad a WW and 426 in 6m with as on. attend by amazon 9‘ WM W behauiuat dung“ the blockade“ 50M um 06 muted Mud bum. pubabLgtMtuu the“. dungu Lgtu that The We! men 06 ethyl. 05 campus“. ammummamm- mm 60!: the. attuned wavubiana. mam � 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 3/4). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-003-0-003 Date A point or period of time associated with an event in the lifecycle of the resource 1956-1968 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