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The convulsive patterns provoked by indoklon, metrazol and electroshock: Some depth electrographic observations in human patients
T H E C O N V U L S I V E P A T T E R N S P R O V O K E D BY I N D O K L O N , M E T R A Z O L A N D E L E C T R O S H O C K : SOME D E P T H E L E C T R O G R A P H I C O B S E R V A T I O N S IN H U M A N P A T I E N T S I GIAN EMILIO CHATRIAN,M.DY and MAGNUS C. PETERSEN, M.D. Rochester State Hospital, Rochester. Minn.
(Received for publication: October 27, 1959) W i t h the exception of the work of W a d a (1948), Lennox et al. (1951), Delgado et al. (1953), Groethuysen et al. (1957), and Delgado and Hamlin (1958), knowledge of the eleetrographic patterns associated with generalized seizures in h u m a n patients is derived mainly from records obtained from the surface of the scalp or of the brain. The present work deals with the convulsive patterns recorded directly from the depths of the h u m a n brain by means of implanted multielectrode leads. The convulsions were produced by inhalation of Indoklon, ~ by intravenous injection of pentylenetetrazol (Metrazol) and by electric shock. The convulsive properties of Indoklon in laboratory animals and in man have been described recently by K r a n t z et al. (1957 a and b, ]958) and Esquibel et al. (195S), who proposed its use in psychiatric treatment as an alternative for electroconvnlsive therapy. MATERIAL AND METHODS The present study involved 5 patients ranging in age from 30 to 51 years. Three of them had schizophrenic reactions of the catatonic type and 2 had schizophrenic reactions of the chronic undifferentiated type. h i these patients, several multielectrode leads were im0|anted into the brain through frontal burr holes that were used later for frontal lobotomy. The leads were left in place d u r i n g a period of 24 to 72 days. The technique was
that described by Dodge et al. (1953). ttowever, in the last two patients, a new type of intracerebral lead was used that is inserted into the brain externally to the needle introducer (Chatrian el al., 1959 a and b). The convulsive patterns provoked hy inhalation of approximately 1 to 4 ml. of hexafluorodiethyl ether (Indoklon) were studied on 2 patients (7 seizures). The drug was administered by means of a modified Stephenson mask firmly applied on the patient's fm,e. The drug was dispersed over absorbent gauze contained in a plastic reservoir with air inlets fastened into the one-way inlet valve of the mask. Thus, the patient inhaled a mixture of vapor and air. The expired vapor was forced through another one-way valve into a carbon absorbent ( K r a n t z el al., 1958; Esquibel et al., 1958). I n three of the patients, convulsions were obtained by rapid intravenous injection of 10 to 15 ml. of a 10 per cent solution of Metrazol (7 seizures). In all 5 patients, convulsions were produced also by electric shock (7 seizures). F o r this purpose, a Medcraft apparatus, model B-24, was nsed, which provided control of voltage and the duration of the stimulus. The stimulus consisted of sinusoidal pulses having a rate of 60 per see., an initial "glissando ris~," phase of approximately 0.75 see., and a plah~au of 0.3 to 0.5 see. The stimulatin~ electrodes, about 5 era. in diameter, were plaeod hitemporally. The interclectrode resistam,(. (measured with a common DC meter) was generally about 1500 ohms. A voltage of 12(1 to 140 V. was used. I n all patients, the eonvnlsive seizures were produced as a part of shock treatment. The patients did not re~,eiw. any premedieation. Ileeordin~:s of the depth electrographic patterns were taken before, during and after
1 This study was partially supported by research grants to the Rochester State Hospit,~l from the Minnesota Department of Public Welfare. 2 Present address: EEG :Laboratory, University of Washington School of 3~edicine, University Hospital, Seattle, Washington. 3 Trade name of the Ohio Chemical and Surgica] Equipment Co. for hexafluorodiethyl ether. This has been acquired by the Smith Kline and French )~abor~ltories, Philadelphia, Penn. [ 715 ]
716
GIAN EMILIO CHATRIAN and MAGNUS C. PETERSEN
administration of Indoklon and Metrazol. D u r i n g electroshock, the E E G a p p a r a t u s (a Grass ]6-channel assembly) was switched off, being turned on again after cessation of the stinmlating current. The delay between the end of the stimulus and the resumption of the recording occupied 3 to 6 see. Before each (.onvulsive procedure began, the sensitivity was reduced to prevent amplifier blocking and changing the gains at any time during the seizure discharge.
sharp waves (fig. 1, section A~). The slow waves generally involved all the cerebral areas but did not show constant phase relationships in the various electrodes. Some more rhythmic slow waves also were seen developing from a limited area or from a single electrode. The spikes and sharp waves usually appeared r a n d o n d y and asynchronously from various areas of the depths of the brain. Short bursts of high-voltage, bilaterally synchronous, nmltiple spike discharges
GENERALIZED SEIZURE INHALATION
PROVOKED BY
OF 4
rnl. OF
HEXAFLUOROOIETHYL ETHER (INDOKLON)
~ , ~
C,|, I I !
,
¢
Fig. l
(Case 2). Electrographic pattern of seizure produced by Indoklon. Section A, (prodromal phase) started 5 sec. after the beginning of inhalation of 4 ml. of Indoklon. Twitching of the mouth and two strong myoclonie jerks of the upper limbs were observed during this phase. Section A~ (tonic phase) is continuous with A, There was an interval of 30 see. between section A~ and B (clonic phase). Section C, which started 70 sec. after the previous section, corresponded to the end of the clonic phase and the beginning of postict'~l eonl~l.
RESULTS
Conwdsive Patte'rns.
The eleetrographie patterns recorded from the depths of the human brain d u r i n g these induced convulsions varied in the prodromal, tonic and (.Ionic phases of the fit. The prodromal phase was characterized by discharges of irregular, high-voltage (as much as 1 mV.), delta waves (1.5 to 3 c/see.) mixed with spikes and
appeared sporadically on this irregular background. The clinical concomitants of this phase of the discharge were blepharospasm, twitching of the mouth, and one or more strong myoclonic jerks producing abrupt flexion of the u p p e r limbs and of 4en of the lower limbs, head and trunk. These myoelonie jerks generally were bilateral, although sometimes they were asymmetric. Because of the
DEPTH
ELECTROGRAPH¥
AND CONVULSIVE
lack of cooperation of our psychotic patients, it was not possible to test conclusively the state of consciousness during this phase of the discharge. Following the appearance of slow waves and spikes during the prodromal phase of the fit, the recording suddenly decreased greatly in voltage (fig. 1, section A:). At this time, a low-voltage, fast discharge was often (tis(~ernible that. developed after a few seconds into a rhythmic discharge of higher voltage
717
PATTERNS
area, while in other areas a similar discharge is only at the onset or the recording is still a p p a r e n t l y flat. In some regions of the depths of the brain, the slow waves and spikes of the prodromal phase passed ahnost directly into the rhythmic discharge of the tonic phase without a p p a r e n t intermediate flattening of the recording. Not only the development but also the voltage, forln and frequency of the discharge varied to some extent from one area to another.
GENERALIZED SEIZURE PROVOKED BY INJECTION
OF
15 ml.
OF
PENTYLENETETRAZOL (METRAZOL)
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7Fig. 2 ( C a s e 2 ) . E l e c t r o g r a p h i e p a t t e r n of s e i z u r e p r o d u c e d b y M e t r a z o l . S e c t i o n A~ s t a r t e d t; see. a f t e r i n j e c t i o n of 15 ml. of M e t r a z o l . S e c t i o n A.. i s c o n t i n u o u s w i t h At. T h e r e w a s a n i n t e r v a l of 30 see. b e t w e e n s e c t i o n s A+ a n d B, a n d a n i n t e r v a l o f 40 see. b e t w e e n B a n d C. T h e r e w e r e no s i g n i f i c a n t q u a l i t a t i v e d i f f e r e n c e s b e t w e e n t h e c l i n i c a l c o n c o m i t a n t s of t h i s nnd the previoas seizure (fig. 1).
(up to 2 inV.) and of lower frequency (about 10 c/see, in fig. 1), which gradually slowed down (to about 8 c/see, in figure 1). This electrographic p a t t e r n corresponds to the generalized tonic spasm usually described as the " t o n i c " phase of the seizure. It should be pointed out that the a p p a r e n t flattening aud the subsequent rhythmic discharge do not occur simultaneously in all cerebral areas. A high-voltage, rhythmic dis(.harge already may be well developed in one
Following this, the rhythmic discharge gradually became discontinuous, breaking down into bursts of multiple spike discharges separated by intervals of quiescence or by a slow swing (fig. 1, section B). The intorvals between the r e c u r r e n t bursts generally increased in duration until tile discharge ended and isoelectricity ensued (fig. 1, section C). Clinically, this pattern corresponded to the " c h m i ( , " phase of the fit, and each burst <)f nmltiple spikes was associated with a
718
GIAN E M I L I O CHATRIAN and MAGNUS C. P E T E R S E N
movement. The passage f r o m the r h y t h m i c to the r e c u r r e n t discharge was gradual, as was clinically the passage f r o m the rigidity of the tonic stage to the r h y t h m i c jerks of the clonic phase. D u r i n g the early p a r t of the elonic phase, the discharges generally occurred synchronously in all areas explored, while (luring the last p a r t of the seizure the dis-
GENERALIZED
SEIZURE
BY
i
induced seizures (fig. 2) a p p e a r e d to be practically indistinguishable front each other. While no information is available as to the depth eleetrographic p a t t e r n d u r i n g the prodrmnal phase and the first 2 to 6 see. of the tonic phase of electrically induced seizures, the rest of the convulsive discharge provoked by electric shock was fairly similar to that
PROVOKED
ELECTRO-SHOCK
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Fig. 3 (C'~se 2). Electrographie pattern of seizure produced by eleetrosboek. Section A (tonic phase) started approximately 5 see. after the end of the stimulating eurrcnt. Tlms, the
pattern should be compared with tlmt of the last part of section A: in figures 1 and 2. Between sections A and B (elonie phqse), the interval was 5 see.; between B and C (end of elonie plmse and beginning of coma), the interval was 7 see. ,.harges often showed some degree of independence in the various areas (fig. 2 and 3, seetion C). The convulsive p a t t e r n s induced by a given eonvulsant were repeated almost identically f r o m one seizure to another in the same patient. Also, the electrographic patferns recorded f r o m the depths of the brain in the same patient during seizures produced by Indoklon (fig. 1) and d u r i n g Metrazol-
provoked in the same patient by Metrazol or Indoklon (fig. 3). The general p a t t e r n of the seizure diseharge recorded f r o m different patients a f t e r administration of the same or of different eonvulsants was essentially the same (fig. 1-5). However, some individual variations were noted concerning the frequency, voltage, f o r m and duration of the discharge.
DEPTH E LECTROGRAPHY AND CONVULSIVE PATTERNS TABLE
I
Duration of Generalized Seizures Provoked b,v Various Convulsants Duration, seconds
Case
Convulsant
Total seizure proper
Prodomal Tonic phase phase
Clonic phase
5 8 5 9 {i
16 17 '2'2 18 2l 2O
38 16 19 2'2 22 2O
54 33 4t 40 43 4O
5
I
Indokltm
2
Indoklon Metrazol
9 8
21 22
94 60
115 82
:~ Metrazol
14 10 11
12 12 15
25 25 42
37 37 57
6
4
11 12
25 28 23 21
36 41) 39 3l
1 {i
?,7 24 37
54 36 53
4
5 3
Metrnzol
4
16
Elect roshoek
--
10
Eh~etrosho(,k
--
17 12
Eleet rosho(.k
--
14
26
40
"2 Elect rosho(.k
....
18
37
5;5
1 Electroshock
-
19
21
40
The accompanying table summarizes the d a t a c o n c e r n i n g the d u r a t i o n of t h e p r o d r o real, t o n i c a n d elonie p h a s e s of eaeh s e i z u r e a n d 1he t o t a l d u r a t i o n of t h e s e i z u r e p r o p e r (toni(. a n d elonie p h a s e s ) r e c o r d e d in t h e p r e s e n t s t u d y . A c c o r d i n g to t h i s table, t h e t o t a l d u r a t i o n of the s e i z u r e a p p e a r s to be influenced by individual differences rather than b y the n a t u r e a n d t h e m o d e of a d m i n i s t r a t i o n of the e o n v u l s a n t . I'ostconrulsicc Patterns. Following the l a s t b u r s t of spikes, t h e r e c o r d i n g b e c a m e f l a t or of e x t r e m e l y low v o l t a g e (fig. 1, 2 a n d 3, section C ; fig. 4 a n d 5, section D ) . T h i s a p p a r e n t f l a t t e n i n g was o f t e n s i m u l t a n e o u s i n all electrodes. H o w e v e r , t h e d i s c h a r g e f r o m one a r e a o c c a s i o n a l l y o u t l a s t e d t h a t f r o m the o t h e r r e g i o n s b y s e v e r a l seeonds (as m u c h as 13 se,. in one M e t r a z o l - i n d u e e d s e i z u r e in case 2). W h i l e t h e r e c o r d i n g s w e r e a p p a r e n t l y
719
flat, the patients were unconscious, cyanotic and flaccid, and showed an extensor plantar r e s p o n s e . One or m o r e b i l a t e r a l l y s y n c h r o nous, m u l t i p l e s p i k e d i s c h a r g e s sometiines al)p e a r e d on t h e f l a t p o s t i e t a l r e c o r d i n g ; these discharges usually were associated with a strong bilateral myoelonic jerk. A f t e r 10 to 90 see., h i g h - v o l t a g e ( u p to 450 ~V. ), i r r e g u l a r , d e l t a w a v e s (1 to 3 e/see. ) appeared in the recording. This disturbance i n v o l v e d all t h e e l e c t r o d e s b u t was niore p r o n o u n c e d in the m o s t a n t e r i o r r e g i o n s of t h e d e p t h s of the b r a i n . No c o n s t a n t phase r e l a t i o n s h i p s were d e m o n s t r a b l e f o r these slow w a v e s in the v a r i o u s r e c o r d e d a r e a s (fig. 6 a n d 7, section E ) . The d e l t a w a v e s g r a d u a l l y became m i x e d w i t h a n d t h e n w e r e r e p l a e e d b y m o r e r h y t h m i e t h e t a w a v e s (5 to 7 e/se,..) t h a t in t u r n g r a d u a l l y w e r e r e p l a c e d b y ~he p r e i e t a l r h y t h m s . These c h a n g e s were m)t s i m u l t a n e o u s in all c e r e b r a l a r e a s b m p r o ceeded f r o m t h e m o r e p o s t e r i o r to the m o r e a n t e r i o r p o r t i o n s . Thus, d e l t a or t h e t a waves or both o f t e n w e r e still p r e s e n t in the d e p t h s of t h e f r o n t a l lobe while t h e p r e e o n v u l s i v e p a t t e r n s a l r e a d y h a d r e a p p e a r e d in the most p o s t e r i o r e l e c t r o d e (fig. 6 a n d 7. sections I:. G a n d H ) . W h e n t h e p r e i e t a l r h y t h m s became d o m i n a n t , signs of consciousm~ss r e a p p e a r e d , a l t h o u g h sonletimes the p a t i e n t s were still confused. COMMENT
I t a p p e a r s f r o m o u r r e c o r d s t h a t th~ irr e g u l a r slow w a v e s a n d s p i k e s t h a t charm.t e r i z e the p r o d r o m a l p h a s e of seizures in(lu(.~,d b y M e t r a z o l or I n d o k l o n r e p r e s e n t a well-individualized pattern that constantly precedes the onset of t h e f i t p r o p e r . T h i s s u g g e s t s t h a l s y n c h r o n o u s d i s c h a r g e of s m a l l n e u r o n a l g r o u p s is p r o v o k e d b y t h e d r u g b e f o r e t h e w i d e s p r e a d s y n e h r o n i e i t y of the t o n i c p h a s e is p r o d u c e d . I t is r e g r e t t a b l e t h a t , d e s p i t e t h e e a r l y d e s c r i p t i o n s of Cook a n d W a l t e r (19381. S t r a u s s et al. (1938, 1939, 1940) t / u b i n a n d W a l l (1939), D a v i s a n d S u l z b a e h ( 1940 ), a n d G o o d w i n et al. (1940), l i t t l e a t t e n t i o n often is p a i d to t h i s p a t t e r n in d e s c r i b i n g the E E G c o r r e l a t e s of t h e c o n v u l s i v e seizure. The s t r i k i n g s i m i l a r i t y f o u n d b e t w e e n the p r o d r o m a l d i s c h a r g e s of s e i z u r e s i n d u c e d b y I n d o k l o n a n d b y M e t r a z o l , as well as the sire-
720
GIAN EMILIO CHATRIAN and MAGNUS C. PETERSEN
i l a r i t y b e t w e e n the c o n v u l s i v e p a t t e r n s p r o p e r p r o v o k e d b y t h e i n h a l a t i o n of I n d o k l o n . b y the i n t r a v e n o u s i n j e c t i o n of M e t r a z o l a n d b y electroshock, m a y i n d i c a t e t h a t these a g e n t s act on the h u m a n b r a i n t h r o u g h a c o m m o n o p e r a t i n g m e c h a n i s m . W h e t h e r t h i s e f f e c t is p r i m a r i l y c o r t i c a l or s u b e o r t i e a l or c o r t i c a l a n d s u b c o r t i e a l a t the same t i m e is still u n certain. In a s t u d y on h u m a n s u b j e c t s , W a d a (1948) f o u n d e v i d e n c e s u g g e s t i v e of a p r i -
t i c i p a t i o n of the s u b e o r t i c a l s t r u c t u r e s i n t h e seizure p r o p e r a p p e a r s to be s e c o n d a r y to e v e n t s in t h e c e r e b r a l (tortes. R e l a t e d to this p r o b l e m a r c the i n v e s t i g a t i o n s of I l u n t e r a n d I n g v a r (1955), who f o n n d t h a t the v i s n a l c o r t e x p l a y s a l e a d i n g role in the d e v e l o p n i e n t of M e t r a z o l - i n d u c e d " i r r a d i a t i o n " of v i s u a l i m p u l s e s a n d the p r o d u c t i o n of seizures. ()u the basis of s t u d i e s on the e o n v u l s a n t a c t i v i t y in isolated p r e p a r a t i o n s of c e r e b r a l cortex, l ' r e s t o n (1!}55) suggeste
R
GENERALIZED SEIZURE PROVOKED BY
I'111~ i ~.
/'
INHALATION OF 1.5 ml. OF HEXAFLUORODIETHYL ETHER (INDOKLON)
2
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D
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II I
Fig. 4 (Case 1). Electrographic pattern of seizure produced by hidoklon. Section A was ol)tained before inhalation of Indoklon. Section B 1 (prodromal phase) started 6 see. after beginning of inhalation of 1.5 nil. of Indoklon. Tonic spasm, twitching of the mouth and one strong myoclonic jerk were observed during this phase of the seizure. Between B, :uld B, (tonic phase), the interval was 4 see.; between B2 and C (clonic phase), it was 21 see.; between C ,qnd D (end of clonic and beginning of comatose phase), it w~s 29 sec. m a r i l y c o r t i c a l a c t i o n of M e t r a z o l . H o w e v e r , a c c o r d i n g to this a u t h o r , a g e n e r a l i z e d convulsion d e v e l o p s o n l y w h e n a s t r o n g s u b c o r t i c a l
1 ) r i m a r i l y a c o r t i c a l c o n v u l s a n t or is e q u a l l y e f f e c t i v e at c o r t i c a l a n d s u b c o r t i e a l levels. A s to h l d o k l o n , its p r i m a r y site of a c t i o n w o u l d a p p e a r to be s u b e o r t i e a l ( e e n t r e n e e p h a l i e ) a c c o r d i n g to K r a n t z et aI. (1957 a a n d b ) , b u t this h y p o t h e s i s h a s not been s u l ) s t a n t i a t e d b y d i r e c t s u b c o r t i c a l r e c o r d i n g s . E q u a l l y deb a t e d is the p r o b l e m of the p r i m a r y site of
DEPTH ELECTROGRAPH¥
721
AND CONVULSIVE PATTERNS
action of electric shock on the h u m a n brain. A m o n g others, Bickford and Rome (1949) upheld the concept of a subcortieal origin of the seizure discharge, while Lennox et al. (1951), using cortical and v e n t r i c u l a r electrodes in monkeys and h u m a n subjects, found evidenee suggestive of initiation of the discharge in the eortcx. F u r t h e r investigation
some instances, duration of the tonic and ohmic discharges indicate that the eonwflsive p a t t e r n is f a r more complex t h a n it a p p e a r s in recordings obtained f r o m the surface of the scalp. Regardless of how it is initiated and controlled, the discharge a p p e a r s to develop with some degree of independence in the various cerebral areas and is fairly consistent
GENERALIZED SEIZURE PROVOKED BY ELECTRO-SHOCK
?~++++* + ~; ,+ t+
,+
+~ +t
+~
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B
D
'+;+: 9
't'
l l O O , lI v i II¢ I
+~.....'+-
J.P III
Iloo O v I iiii¢ i
Pig. 5 (Case 1). E l e c t r o g r a p h i c p a t t e r n of seizure produced by electroshock. Section A was obt'fined before electroshock. Section B (tonic p h a s e ) s t a r t e d 4 sec. a f t e r end of s t i m u l a t i n g c u r r e n t . T h u s , this t r a c i n g should be c o m p a r e d w i t h the last p a r t of section B~ in f i g u r e 4. B e t w e e n B a n d C (clonic p h a s e ) , the i n t e r v a l was 13 see.; between C and I) (end of clonic p h a s e of seizure a n d b e g i n n i n g of postiet.d c o m a ) , it w',s 24 sec.
by means of simultaneous cortical and subcortical recordings f r o m stereotactieally implanted electrodes a p p e a r s to be needed before the question of the p r i m a r y site of action of these convulsant agents can be satisfactorily answered. The regional differences as to time of onset, voltage, f o r m and frequency and, in
in each area in successive seizures. This agrees with previous findings of Delgado and H a m l i n (1958). As to the postconvulsive patterns, the predominance and longer persistence in the most anterior regions of the brain of the slow distnrbanee that follows electrically indueed convulsions have been attributed by some authors
722
GIAN :EMILIO C H A T R I A N and MAGNUS C. P E T E R S E N
(Boshes et al. 1943) to the fact that the stimulating electrodes arc located close to these areas. In accordance with this, Delgado et al. (1953) found suggestive evidence that during electroshock the current alters the activity of the various parts of the frontal lobe in proportion to the proximity to the plane of application of the stimulating electrodes. However, the following findings are in disagree-
(Blaurock et al., 1950); (3) the studies of Smitt and Wegener (1944), Lorimer et al. (1949) and Hayes (1950), which are in disagreement with previous results of Alexander and LSwenbach (1944), provide convincing evidence of wide diffusion of the current through all portions of the brain. These findings suggest that the frontal predominance of the disturbanue following an electroshock-
ELECTROGRAPHIC PATTERNS FOLLOWING GENERALIZED SEIZURE PROVOKED BY INHALATION OF INDOKLON
~"-.'.-'
+~:,'-'w@<-;v>,'+i'/v
~--A.V'-','- ',aA-.~.~?z~1,-.v~
4 '~
-
J
j J\l \ fl.< ~+./\l~,z~ :, i>v. . . . . . . . ..]%.A,r',,~
G
H
~~'-%~.A~d~,~ldq , , ~ . ~ . ~ e ~ . 2 " ~
~
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•),1/
III
,
,
.
~
,
~
~
=~'v-~
I,~:
Fig. 6 (Case 1). Postconvulsive electrographie pattern of seizure produced by Indoklon. Section E began 1 rain. after the end of the convulsive discharge; the patient was lying motionless and breathing stertorously. Section F began 4 rain. after the end of the convulsive discharge; the patient was agitated, unresponsive and mumbling, and was scratching his face and body. Section G started 8 rain. after the seizure; the patient was still agitated and confused but was beginning to answer when called by name. Section H started 23 rain. after the end of the seizure; the patient was lying quietly, giving appropriate answers to simple questions.
ment with this hypothesis: (1) tile topographic distribution of the disturbance following seizures induced by Mctrazol or Indoklon is practically identical to that following eiectroshoek; (2) unilateral shock is followed by slow changes that are not significantly different from those provoked by bilateral electroshock (Bergman et at., 1953) or that have focal characteristics which are unrelated to the position of the electrodes
induced seizure, as well as after a convulsion produced by Indoklon or Metrazol, is probably related to the structural and functional organization of the brain rather than to any local elective action of the convulsant. Thus. the disturbance itself may be interpreted as a nonspeeifie response of the brain to the physiologic stress of the convulsion regardless of how it was produced. It is significant that similar changes can be observed as a result of
723
D E P T H ELECTROGRAPHY AND CONVULSIVE P A T T E R N S
a variety of physiologic stresses on the brain, including anoxia, acapnia and hypoglycemia (Roth et al., 1954). SUMMARY
The convulsive patterns provoked by the inhalation of hexafluorodiethyl ether (Indoklon), the intravenous injection of pentylenetetrazol (Metrazol), and the administration of electroshock have been recorded by means of nmltielectrode leads implanted into the brains
dromal phase, and both these agents plus electroshock during the seizure proper act on the human brain through a common operating mechanism; (2) regardless of how it is initiated and controlled, the convulsive discharge develops with some degree of independence in the various parts of the brain, and (3) the predominance and longer persistence in the frontal areas of the slow disturbance following electrically induced seizures are related to the structural and functional organization
ELECTROGRAPHIC PATTERNS FOLLOWING GENERALIZED SEIZURE PROVOKED BY ELECTRO-SHOCK
7
~
E
G
v
~
i I|¢.
Fig. 7 ((~mse 1). Postconvulsive electrographie pattern of seizure produced by electroshock. Sections E, F, G and H started 1, 4, 8 and 23 min. after the end of the convulsive discharge, as in figure 6. The S'mle clinical signs were present.
of five psychotic patients (unmedicated) preceding frontal lobotomy. The patterns observed in these tracings, which were free from muscular contamination, during the prodromal, tonic and clonie phases of the seizure and the postictal period have been described and correlated with the accompanying clinical phenomena. Evidence has been found suggesting that: (1) lndoklon and lV[etrazol during the pro-
of the brain rather than to a local action of the convulsant. Rg;SUM~: Les patterns convulsifs provoqu~s par l'inhalation d'ether hexafluorodiethyl (Indoklon), l'injection intra-veineuse de penthylenetetrazol (M4trazol) et l'administration (l'~lectrochocs ont ~t~ enregistrgs au moyen (l'~lectrodes multiples implan%es dans le cerveau
724
G I A N E M I L I O C H A T R I A N a n d M A G N U S C. P E T E R S E N
de cinq malades psyehotiques (sans m6dieation) a v a n t lobotomie frontale. Les p a t t e r n s observ6s dans ees trac6s qui sent indemnes de tout art6fact musculaire, d u r a n t les phases prodromique, tonique et elonique des krises, et d u r a n t la p6riode postcritique ont 6t6 d6erits et mis en relation avee Its ph6nombnes eliniques qui los aceompagnent. Les observations suggbrent (1) que l ' I n d o k l o n et le M6trazol, d u r a n t la phase de prodrome, et ees deux agents plus !'61eetrothee d n r a n t la crise elle-m~me, agissent sur le cerveau humain p a r un m6eanisme comnmn, (2) clue la d6charge conwflsive se d6veloppe avec un certain degr6 d'ind6pendanee dans les diff6rentes r6gions du eerveau qu'elle que soit la fat:on dent elle a d6but6 ou dent est contrS16e, et (3) que la pr6dominance et la persistanee plus league darts les r6gions frontales des p e r t u r b a t i o n s lentes apparaissant ?~ la suite des crises induites p a r 61eetroehoc sent en relation avee une organisation structurale et fonetionnelle du cervcau plutSt qu'avec une action locale du conwflsivant. ZUSAMMENFASSUNG
Die K r a m p f e n t l a d u n g e n , welehe durch die Inhalation yon H e x a f l u o r o d i e t h y l - A e t h e r ([ndoklon), die intravenSse I n j e k t i o n yon Pentylen-Tetrazol (Metrazol), und die Anwendung yon Elektroschoek h e r v o r g e r u f e n wer(ten, wurden mit implantierten Multielektroden im Gehirn von fiinf psyehotisehen Patienten, welche keine Drogen erhielten, v e t frontaler Lobotomie registriert. Die Bilder dieser Kurven, welche frei yon Muskelartefakt(,n waren, wurden fiir Prodromal-, tonische m~d klonisehe K r a m p f p h a sen sowie fiir (tie postkonwdsive Phase besehrieben nnd in Beziehung gesetzt mit den ldinischen Begleiterseheinungen. Es wnrde Anhalt dafiir gefunden, dass (1) hMoklon und Metrazol wiihrend der Prodromalphase, nnd beide Drogen plus Elektroschoek w:~i.hrend des Anfalles selbst auf das mensehliehe Gehirn durch einen gemeinsamen Meehanisnms operieren, (2) mmbhiingig yon der Art wie der K r a m p f erzeugt und k o n t r o f liert wird, die E n t l a d u n g e n mit einem gewissen Grad von I:nabh~in~:iodkeit in den versehiedenen H i r n t e i l e n sieh entwiekeln, und
(3) das Vorwiegen und die liingere D a u e r der langsamen Wellen naeh E l e k t r o k r a m p f im Stirnhirn mehr der strukturellen und fmlktionellen Organisation des Gehirn zuzuschreiben sind als einer 5rtlichen W i r k u n g des k r a m p f e r z e u g e n d e n Mittels. Tire a u t h o r s e x p r e s s `appreciation to Dr. Charles E. t i e n r y , H a r t f o r d I n s t i t u t e of L i v i n g , H a r t f o r d , Conn., for his valuable s u g g e s t i o n s a n d to Mr. Ctetus S. Pollack, Miss M a r y A. B u s h e y a n d Miss N a n c y T,. Moehnke, R o c h e s t e r S t a t e H o s p i t a l , for their as s i s t a n c e a n d interest. REFERENCES ALEXANDER, I~. ,qlld ],O~,VENBACH, It'. ExDerimentM s t u d i e s on electro-shock t r e a t m e n t : T h e i n t r a cerebr`al v a s c u l a r reaction as ,an imlie,ator of t h e p,ath of tire c u r r e n t and t h e t h r e s h o l d of early c h a n g e s w i t h i n the l>rain tissue. J. :Vm¢ropath. Exper. 5rcurol., 1944, 3: 139-171. BERGMAN, "P. S., ]MPASTATO, ]), I. ,and BERG, S. E l e c t r o e n e e p h a l o g r a p h l c f i n d i n g s in p s y c h i a t r i c p a t i e n t s t r e a t e d with unilqteral electrically in duced seizures. E E G Clin. 5"r~ropby.~'iol., 1953. 5 : 463-464. ~ICKFORD, a . G. and ROI~IE, IT. P. Tire (,lectroenceld,a l o g r a m recorded d u r i n g seizures pro~lucecl t)v electroshock. E E G Clin. Nr~trophy.~iol., 1949, 7: 3~9. I:ILAUROCK, M. ]~., L'ORIMER, ]~. ~]-., ~QEGAL, M. M. `all(| GTm+s, F. A. Focal electroencetlhalographic c h a n g e s in u n i l a t e r a l electric convuNi,m ther'tl)y. A r c h . . ¥ c ~ r o L Psyehiat., Chicago, 1950, a4: 22t)2oil. ]7JOSHES, L. D., DARROW, C. W., SOLOMON', A. P. and ~DATItl~IAN, ,1-. H-. Eleetroencephalogr'll)l,ic s t u d y of the local e f f e c t s of electric shock: A ore l i m i n a r y rellort. Arch. ~rr~l~'ol. P.e?l('hiat., Chlcage, 1943, 50 : 108-11(~. CtIATRIANr, O. ]~1., DODGE, H. W., .JR., PETERGENr, M. (L and B1CKPORD, R. G. A multie]ectrode lead for i n t r a c e r e b r a l recordinffs. E E G (!lira .¥curophysiol., 19~9a, 11 : 165-169. (~I[ATRIAN, G. E.. I)OLLACK, C. S. qlld PETERSRN, ~1['. ('. A 1)rocedure for t)reparing a mnltielectrode ]e:ld for intrflceret)ral recordings. EEG Clin. .Y~'urophysiol., 1959b, I l : 35~-361. CooK, L. (L `and WALTEI¢, W. {r. T h e el,~(.tro-enceplmlou'rmn ill convulsions induced tly c`ardi`azol. J. Xe~rol. Nr~ros,r.q. Psycldat., 1988, l: 180-1~6. ]3Avis. P. A. `and ~qULZBA(',H, W. Ch`anges in the eh,ctrocncei)halo~'r`am d u r i n g M e t r a z o l t h e r a p y . A r c h . . Y c ~ r o l . Ps.ychiat., Chicago, 1940, / 3 : 241355. DF~LC,al)O, d. M. R., ALEXAXDER, L. :rod II,X~ILIY, H. E f f e c t s of electroshock on the cortical and intr`acerebrM eleetroaetivlty of the b r a i n in schizophrenic t m t i e n t s . Con.fibula neurol.. 1953, 13: 287-294. DELGA1)O, .1. ~ . R. :tilt] tTAMIAN, ]1. Direct r e c o r d i n g of s p o n t a n e o u s `and evoked seizures in epileptics. E E G Clim Nm~rophy.*iol., 1958, lO: 443-486.
(Received for publication: October 27, 1959) W i t h the exception of the work of W a d a (1948), Lennox et al. (1951), Delgado et al. (1953), Groethuysen et al. (1957), and Delgado and Hamlin (1958), knowledge of the eleetrographic patterns associated with generalized seizures in h u m a n patients is derived mainly from records obtained from the surface of the scalp or of the brain. The present work deals with the convulsive patterns recorded directly from the depths of the h u m a n brain by means of implanted multielectrode leads. The convulsions were produced by inhalation of Indoklon, ~ by intravenous injection of pentylenetetrazol (Metrazol) and by electric shock. The convulsive properties of Indoklon in laboratory animals and in man have been described recently by K r a n t z et al. (1957 a and b, ]958) and Esquibel et al. (195S), who proposed its use in psychiatric treatment as an alternative for electroconvnlsive therapy. MATERIAL AND METHODS The present study involved 5 patients ranging in age from 30 to 51 years. Three of them had schizophrenic reactions of the catatonic type and 2 had schizophrenic reactions of the chronic undifferentiated type. h i these patients, several multielectrode leads were im0|anted into the brain through frontal burr holes that were used later for frontal lobotomy. The leads were left in place d u r i n g a period of 24 to 72 days. The technique was
that described by Dodge et al. (1953). ttowever, in the last two patients, a new type of intracerebral lead was used that is inserted into the brain externally to the needle introducer (Chatrian el al., 1959 a and b). The convulsive patterns provoked hy inhalation of approximately 1 to 4 ml. of hexafluorodiethyl ether (Indoklon) were studied on 2 patients (7 seizures). The drug was administered by means of a modified Stephenson mask firmly applied on the patient's fm,e. The drug was dispersed over absorbent gauze contained in a plastic reservoir with air inlets fastened into the one-way inlet valve of the mask. Thus, the patient inhaled a mixture of vapor and air. The expired vapor was forced through another one-way valve into a carbon absorbent ( K r a n t z el al., 1958; Esquibel et al., 1958). I n three of the patients, convulsions were obtained by rapid intravenous injection of 10 to 15 ml. of a 10 per cent solution of Metrazol (7 seizures). In all 5 patients, convulsions were produced also by electric shock (7 seizures). F o r this purpose, a Medcraft apparatus, model B-24, was nsed, which provided control of voltage and the duration of the stimulus. The stimulus consisted of sinusoidal pulses having a rate of 60 per see., an initial "glissando ris~," phase of approximately 0.75 see., and a plah~au of 0.3 to 0.5 see. The stimulatin~ electrodes, about 5 era. in diameter, were plaeod hitemporally. The interclectrode resistam,(. (measured with a common DC meter) was generally about 1500 ohms. A voltage of 12(1 to 140 V. was used. I n all patients, the eonvnlsive seizures were produced as a part of shock treatment. The patients did not re~,eiw. any premedieation. Ileeordin~:s of the depth electrographic patterns were taken before, during and after
1 This study was partially supported by research grants to the Rochester State Hospit,~l from the Minnesota Department of Public Welfare. 2 Present address: EEG :Laboratory, University of Washington School of 3~edicine, University Hospital, Seattle, Washington. 3 Trade name of the Ohio Chemical and Surgica] Equipment Co. for hexafluorodiethyl ether. This has been acquired by the Smith Kline and French )~abor~ltories, Philadelphia, Penn. [ 715 ]
716
GIAN EMILIO CHATRIAN and MAGNUS C. PETERSEN
administration of Indoklon and Metrazol. D u r i n g electroshock, the E E G a p p a r a t u s (a Grass ]6-channel assembly) was switched off, being turned on again after cessation of the stinmlating current. The delay between the end of the stimulus and the resumption of the recording occupied 3 to 6 see. Before each (.onvulsive procedure began, the sensitivity was reduced to prevent amplifier blocking and changing the gains at any time during the seizure discharge.
sharp waves (fig. 1, section A~). The slow waves generally involved all the cerebral areas but did not show constant phase relationships in the various electrodes. Some more rhythmic slow waves also were seen developing from a limited area or from a single electrode. The spikes and sharp waves usually appeared r a n d o n d y and asynchronously from various areas of the depths of the brain. Short bursts of high-voltage, bilaterally synchronous, nmltiple spike discharges
GENERALIZED SEIZURE INHALATION
PROVOKED BY
OF 4
rnl. OF
HEXAFLUOROOIETHYL ETHER (INDOKLON)
~ , ~
C,|, I I !
,
¢
Fig. l
(Case 2). Electrographic pattern of seizure produced by Indoklon. Section A, (prodromal phase) started 5 sec. after the beginning of inhalation of 4 ml. of Indoklon. Twitching of the mouth and two strong myoclonie jerks of the upper limbs were observed during this phase. Section A~ (tonic phase) is continuous with A, There was an interval of 30 see. between section A~ and B (clonic phase). Section C, which started 70 sec. after the previous section, corresponded to the end of the clonic phase and the beginning of postict'~l eonl~l.
RESULTS
Conwdsive Patte'rns.
The eleetrographie patterns recorded from the depths of the human brain d u r i n g these induced convulsions varied in the prodromal, tonic and (.Ionic phases of the fit. The prodromal phase was characterized by discharges of irregular, high-voltage (as much as 1 mV.), delta waves (1.5 to 3 c/see.) mixed with spikes and
appeared sporadically on this irregular background. The clinical concomitants of this phase of the discharge were blepharospasm, twitching of the mouth, and one or more strong myoclonic jerks producing abrupt flexion of the u p p e r limbs and of 4en of the lower limbs, head and trunk. These myoelonie jerks generally were bilateral, although sometimes they were asymmetric. Because of the
DEPTH
ELECTROGRAPH¥
AND CONVULSIVE
lack of cooperation of our psychotic patients, it was not possible to test conclusively the state of consciousness during this phase of the discharge. Following the appearance of slow waves and spikes during the prodromal phase of the fit, the recording suddenly decreased greatly in voltage (fig. 1, section A:). At this time, a low-voltage, fast discharge was often (tis(~ernible that. developed after a few seconds into a rhythmic discharge of higher voltage
717
PATTERNS
area, while in other areas a similar discharge is only at the onset or the recording is still a p p a r e n t l y flat. In some regions of the depths of the brain, the slow waves and spikes of the prodromal phase passed ahnost directly into the rhythmic discharge of the tonic phase without a p p a r e n t intermediate flattening of the recording. Not only the development but also the voltage, forln and frequency of the discharge varied to some extent from one area to another.
GENERALIZED SEIZURE PROVOKED BY INJECTION
OF
15 ml.
OF
PENTYLENETETRAZOL (METRAZOL)
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7Fig. 2 ( C a s e 2 ) . E l e c t r o g r a p h i e p a t t e r n of s e i z u r e p r o d u c e d b y M e t r a z o l . S e c t i o n A~ s t a r t e d t; see. a f t e r i n j e c t i o n of 15 ml. of M e t r a z o l . S e c t i o n A.. i s c o n t i n u o u s w i t h At. T h e r e w a s a n i n t e r v a l of 30 see. b e t w e e n s e c t i o n s A+ a n d B, a n d a n i n t e r v a l o f 40 see. b e t w e e n B a n d C. T h e r e w e r e no s i g n i f i c a n t q u a l i t a t i v e d i f f e r e n c e s b e t w e e n t h e c l i n i c a l c o n c o m i t a n t s of t h i s nnd the previoas seizure (fig. 1).
(up to 2 inV.) and of lower frequency (about 10 c/see, in fig. 1), which gradually slowed down (to about 8 c/see, in figure 1). This electrographic p a t t e r n corresponds to the generalized tonic spasm usually described as the " t o n i c " phase of the seizure. It should be pointed out that the a p p a r e n t flattening aud the subsequent rhythmic discharge do not occur simultaneously in all cerebral areas. A high-voltage, rhythmic dis(.harge already may be well developed in one
Following this, the rhythmic discharge gradually became discontinuous, breaking down into bursts of multiple spike discharges separated by intervals of quiescence or by a slow swing (fig. 1, section B). The intorvals between the r e c u r r e n t bursts generally increased in duration until tile discharge ended and isoelectricity ensued (fig. 1, section C). Clinically, this pattern corresponded to the " c h m i ( , " phase of the fit, and each burst <)f nmltiple spikes was associated with a
718
GIAN E M I L I O CHATRIAN and MAGNUS C. P E T E R S E N
movement. The passage f r o m the r h y t h m i c to the r e c u r r e n t discharge was gradual, as was clinically the passage f r o m the rigidity of the tonic stage to the r h y t h m i c jerks of the clonic phase. D u r i n g the early p a r t of the elonic phase, the discharges generally occurred synchronously in all areas explored, while (luring the last p a r t of the seizure the dis-
GENERALIZED
SEIZURE
BY
i
induced seizures (fig. 2) a p p e a r e d to be practically indistinguishable front each other. While no information is available as to the depth eleetrographic p a t t e r n d u r i n g the prodrmnal phase and the first 2 to 6 see. of the tonic phase of electrically induced seizures, the rest of the convulsive discharge provoked by electric shock was fairly similar to that
PROVOKED
ELECTRO-SHOCK
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Fig. 3 (C'~se 2). Electrographie pattern of seizure produced by eleetrosboek. Section A (tonic phase) started approximately 5 see. after the end of the stimulating eurrcnt. Tlms, the
pattern should be compared with tlmt of the last part of section A: in figures 1 and 2. Between sections A and B (elonie phqse), the interval was 5 see.; between B and C (end of elonie plmse and beginning of coma), the interval was 7 see. ,.harges often showed some degree of independence in the various areas (fig. 2 and 3, seetion C). The convulsive p a t t e r n s induced by a given eonvulsant were repeated almost identically f r o m one seizure to another in the same patient. Also, the electrographic patferns recorded f r o m the depths of the brain in the same patient during seizures produced by Indoklon (fig. 1) and d u r i n g Metrazol-
provoked in the same patient by Metrazol or Indoklon (fig. 3). The general p a t t e r n of the seizure diseharge recorded f r o m different patients a f t e r administration of the same or of different eonvulsants was essentially the same (fig. 1-5). However, some individual variations were noted concerning the frequency, voltage, f o r m and duration of the discharge.
DEPTH E LECTROGRAPHY AND CONVULSIVE PATTERNS TABLE
I
Duration of Generalized Seizures Provoked b,v Various Convulsants Duration, seconds
Case
Convulsant
Total seizure proper
Prodomal Tonic phase phase
Clonic phase
5 8 5 9 {i
16 17 '2'2 18 2l 2O
38 16 19 2'2 22 2O
54 33 4t 40 43 4O
5
I
Indokltm
2
Indoklon Metrazol
9 8
21 22
94 60
115 82
:~ Metrazol
14 10 11
12 12 15
25 25 42
37 37 57
6
4
11 12
25 28 23 21
36 41) 39 3l
1 {i
?,7 24 37
54 36 53
4
5 3
Metrnzol
4
16
Elect roshoek
--
10
Eh~etrosho(,k
--
17 12
Eleet rosho(.k
--
14
26
40
"2 Elect rosho(.k
....
18
37
5;5
1 Electroshock
-
19
21
40
The accompanying table summarizes the d a t a c o n c e r n i n g the d u r a t i o n of t h e p r o d r o real, t o n i c a n d elonie p h a s e s of eaeh s e i z u r e a n d 1he t o t a l d u r a t i o n of t h e s e i z u r e p r o p e r (toni(. a n d elonie p h a s e s ) r e c o r d e d in t h e p r e s e n t s t u d y . A c c o r d i n g to t h i s table, t h e t o t a l d u r a t i o n of the s e i z u r e a p p e a r s to be influenced by individual differences rather than b y the n a t u r e a n d t h e m o d e of a d m i n i s t r a t i o n of the e o n v u l s a n t . I'ostconrulsicc Patterns. Following the l a s t b u r s t of spikes, t h e r e c o r d i n g b e c a m e f l a t or of e x t r e m e l y low v o l t a g e (fig. 1, 2 a n d 3, section C ; fig. 4 a n d 5, section D ) . T h i s a p p a r e n t f l a t t e n i n g was o f t e n s i m u l t a n e o u s i n all electrodes. H o w e v e r , t h e d i s c h a r g e f r o m one a r e a o c c a s i o n a l l y o u t l a s t e d t h a t f r o m the o t h e r r e g i o n s b y s e v e r a l seeonds (as m u c h as 13 se,. in one M e t r a z o l - i n d u e e d s e i z u r e in case 2). W h i l e t h e r e c o r d i n g s w e r e a p p a r e n t l y
719
flat, the patients were unconscious, cyanotic and flaccid, and showed an extensor plantar r e s p o n s e . One or m o r e b i l a t e r a l l y s y n c h r o nous, m u l t i p l e s p i k e d i s c h a r g e s sometiines al)p e a r e d on t h e f l a t p o s t i e t a l r e c o r d i n g ; these discharges usually were associated with a strong bilateral myoelonic jerk. A f t e r 10 to 90 see., h i g h - v o l t a g e ( u p to 450 ~V. ), i r r e g u l a r , d e l t a w a v e s (1 to 3 e/see. ) appeared in the recording. This disturbance i n v o l v e d all t h e e l e c t r o d e s b u t was niore p r o n o u n c e d in the m o s t a n t e r i o r r e g i o n s of t h e d e p t h s of the b r a i n . No c o n s t a n t phase r e l a t i o n s h i p s were d e m o n s t r a b l e f o r these slow w a v e s in the v a r i o u s r e c o r d e d a r e a s (fig. 6 a n d 7, section E ) . The d e l t a w a v e s g r a d u a l l y became m i x e d w i t h a n d t h e n w e r e r e p l a e e d b y m o r e r h y t h m i e t h e t a w a v e s (5 to 7 e/se,..) t h a t in t u r n g r a d u a l l y w e r e r e p l a c e d b y ~he p r e i e t a l r h y t h m s . These c h a n g e s were m)t s i m u l t a n e o u s in all c e r e b r a l a r e a s b m p r o ceeded f r o m t h e m o r e p o s t e r i o r to the m o r e a n t e r i o r p o r t i o n s . Thus, d e l t a or t h e t a waves or both o f t e n w e r e still p r e s e n t in the d e p t h s of t h e f r o n t a l lobe while t h e p r e e o n v u l s i v e p a t t e r n s a l r e a d y h a d r e a p p e a r e d in the most p o s t e r i o r e l e c t r o d e (fig. 6 a n d 7. sections I:. G a n d H ) . W h e n t h e p r e i e t a l r h y t h m s became d o m i n a n t , signs of consciousm~ss r e a p p e a r e d , a l t h o u g h sonletimes the p a t i e n t s were still confused. COMMENT
I t a p p e a r s f r o m o u r r e c o r d s t h a t th~ irr e g u l a r slow w a v e s a n d s p i k e s t h a t charm.t e r i z e the p r o d r o m a l p h a s e of seizures in(lu(.~,d b y M e t r a z o l or I n d o k l o n r e p r e s e n t a well-individualized pattern that constantly precedes the onset of t h e f i t p r o p e r . T h i s s u g g e s t s t h a l s y n c h r o n o u s d i s c h a r g e of s m a l l n e u r o n a l g r o u p s is p r o v o k e d b y t h e d r u g b e f o r e t h e w i d e s p r e a d s y n e h r o n i e i t y of the t o n i c p h a s e is p r o d u c e d . I t is r e g r e t t a b l e t h a t , d e s p i t e t h e e a r l y d e s c r i p t i o n s of Cook a n d W a l t e r (19381. S t r a u s s et al. (1938, 1939, 1940) t / u b i n a n d W a l l (1939), D a v i s a n d S u l z b a e h ( 1940 ), a n d G o o d w i n et al. (1940), l i t t l e a t t e n t i o n often is p a i d to t h i s p a t t e r n in d e s c r i b i n g the E E G c o r r e l a t e s of t h e c o n v u l s i v e seizure. The s t r i k i n g s i m i l a r i t y f o u n d b e t w e e n the p r o d r o m a l d i s c h a r g e s of s e i z u r e s i n d u c e d b y I n d o k l o n a n d b y M e t r a z o l , as well as the sire-
720
GIAN EMILIO CHATRIAN and MAGNUS C. PETERSEN
i l a r i t y b e t w e e n the c o n v u l s i v e p a t t e r n s p r o p e r p r o v o k e d b y t h e i n h a l a t i o n of I n d o k l o n . b y the i n t r a v e n o u s i n j e c t i o n of M e t r a z o l a n d b y electroshock, m a y i n d i c a t e t h a t these a g e n t s act on the h u m a n b r a i n t h r o u g h a c o m m o n o p e r a t i n g m e c h a n i s m . W h e t h e r t h i s e f f e c t is p r i m a r i l y c o r t i c a l or s u b e o r t i e a l or c o r t i c a l a n d s u b c o r t i e a l a t the same t i m e is still u n certain. In a s t u d y on h u m a n s u b j e c t s , W a d a (1948) f o u n d e v i d e n c e s u g g e s t i v e of a p r i -
t i c i p a t i o n of the s u b e o r t i c a l s t r u c t u r e s i n t h e seizure p r o p e r a p p e a r s to be s e c o n d a r y to e v e n t s in t h e c e r e b r a l (tortes. R e l a t e d to this p r o b l e m a r c the i n v e s t i g a t i o n s of I l u n t e r a n d I n g v a r (1955), who f o n n d t h a t the v i s n a l c o r t e x p l a y s a l e a d i n g role in the d e v e l o p n i e n t of M e t r a z o l - i n d u c e d " i r r a d i a t i o n " of v i s u a l i m p u l s e s a n d the p r o d u c t i o n of seizures. ()u the basis of s t u d i e s on the e o n v u l s a n t a c t i v i t y in isolated p r e p a r a t i o n s of c e r e b r a l cortex, l ' r e s t o n (1!}55) suggeste
R
GENERALIZED SEIZURE PROVOKED BY
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INHALATION OF 1.5 ml. OF HEXAFLUORODIETHYL ETHER (INDOKLON)
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.
.
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Fig. 4 (Case 1). Electrographic pattern of seizure produced by hidoklon. Section A was ol)tained before inhalation of Indoklon. Section B 1 (prodromal phase) started 6 see. after beginning of inhalation of 1.5 nil. of Indoklon. Tonic spasm, twitching of the mouth and one strong myoclonic jerk were observed during this phase of the seizure. Between B, :uld B, (tonic phase), the interval was 4 see.; between B2 and C (clonic phase), it was 21 see.; between C ,qnd D (end of clonic and beginning of comatose phase), it w~s 29 sec. m a r i l y c o r t i c a l a c t i o n of M e t r a z o l . H o w e v e r , a c c o r d i n g to this a u t h o r , a g e n e r a l i z e d convulsion d e v e l o p s o n l y w h e n a s t r o n g s u b c o r t i c a l
1 ) r i m a r i l y a c o r t i c a l c o n v u l s a n t or is e q u a l l y e f f e c t i v e at c o r t i c a l a n d s u b c o r t i e a l levels. A s to h l d o k l o n , its p r i m a r y site of a c t i o n w o u l d a p p e a r to be s u b e o r t i e a l ( e e n t r e n e e p h a l i e ) a c c o r d i n g to K r a n t z et aI. (1957 a a n d b ) , b u t this h y p o t h e s i s h a s not been s u l ) s t a n t i a t e d b y d i r e c t s u b c o r t i c a l r e c o r d i n g s . E q u a l l y deb a t e d is the p r o b l e m of the p r i m a r y site of
DEPTH ELECTROGRAPH¥
721
AND CONVULSIVE PATTERNS
action of electric shock on the h u m a n brain. A m o n g others, Bickford and Rome (1949) upheld the concept of a subcortieal origin of the seizure discharge, while Lennox et al. (1951), using cortical and v e n t r i c u l a r electrodes in monkeys and h u m a n subjects, found evidenee suggestive of initiation of the discharge in the eortcx. F u r t h e r investigation
some instances, duration of the tonic and ohmic discharges indicate that the eonwflsive p a t t e r n is f a r more complex t h a n it a p p e a r s in recordings obtained f r o m the surface of the scalp. Regardless of how it is initiated and controlled, the discharge a p p e a r s to develop with some degree of independence in the various cerebral areas and is fairly consistent
GENERALIZED SEIZURE PROVOKED BY ELECTRO-SHOCK
?~++++* + ~; ,+ t+
,+
+~ +t
+~
~++go~+++,:++/gd+g-4', A
B
D
'+;+: 9
't'
l l O O , lI v i II¢ I
+~.....'+-
J.P III
Iloo O v I iiii¢ i
Pig. 5 (Case 1). E l e c t r o g r a p h i c p a t t e r n of seizure produced by electroshock. Section A was obt'fined before electroshock. Section B (tonic p h a s e ) s t a r t e d 4 sec. a f t e r end of s t i m u l a t i n g c u r r e n t . T h u s , this t r a c i n g should be c o m p a r e d w i t h the last p a r t of section B~ in f i g u r e 4. B e t w e e n B a n d C (clonic p h a s e ) , the i n t e r v a l was 13 see.; between C and I) (end of clonic p h a s e of seizure a n d b e g i n n i n g of postiet.d c o m a ) , it w',s 24 sec.
by means of simultaneous cortical and subcortical recordings f r o m stereotactieally implanted electrodes a p p e a r s to be needed before the question of the p r i m a r y site of action of these convulsant agents can be satisfactorily answered. The regional differences as to time of onset, voltage, f o r m and frequency and, in
in each area in successive seizures. This agrees with previous findings of Delgado and H a m l i n (1958). As to the postconvulsive patterns, the predominance and longer persistence in the most anterior regions of the brain of the slow distnrbanee that follows electrically indueed convulsions have been attributed by some authors
722
GIAN :EMILIO C H A T R I A N and MAGNUS C. P E T E R S E N
(Boshes et al. 1943) to the fact that the stimulating electrodes arc located close to these areas. In accordance with this, Delgado et al. (1953) found suggestive evidence that during electroshock the current alters the activity of the various parts of the frontal lobe in proportion to the proximity to the plane of application of the stimulating electrodes. However, the following findings are in disagree-
(Blaurock et al., 1950); (3) the studies of Smitt and Wegener (1944), Lorimer et al. (1949) and Hayes (1950), which are in disagreement with previous results of Alexander and LSwenbach (1944), provide convincing evidence of wide diffusion of the current through all portions of the brain. These findings suggest that the frontal predominance of the disturbanue following an electroshock-
ELECTROGRAPHIC PATTERNS FOLLOWING GENERALIZED SEIZURE PROVOKED BY INHALATION OF INDOKLON
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+~:,'-'w@<-;v>,'+i'/v
~--A.V'-','- ',aA-.~.~?z~1,-.v~
4 '~
-
J
j J\l \ fl.< ~+./\l~,z~ :, i>v. . . . . . . . ..]%.A,r',,~
G
H
~~'-%~.A~d~,~ldq , , ~ . ~ . ~ e ~ . 2 " ~
~
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,
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.
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Fig. 6 (Case 1). Postconvulsive electrographie pattern of seizure produced by Indoklon. Section E began 1 rain. after the end of the convulsive discharge; the patient was lying motionless and breathing stertorously. Section F began 4 rain. after the end of the convulsive discharge; the patient was agitated, unresponsive and mumbling, and was scratching his face and body. Section G started 8 rain. after the seizure; the patient was still agitated and confused but was beginning to answer when called by name. Section H started 23 rain. after the end of the seizure; the patient was lying quietly, giving appropriate answers to simple questions.
ment with this hypothesis: (1) tile topographic distribution of the disturbance following seizures induced by Mctrazol or Indoklon is practically identical to that following eiectroshoek; (2) unilateral shock is followed by slow changes that are not significantly different from those provoked by bilateral electroshock (Bergman et at., 1953) or that have focal characteristics which are unrelated to the position of the electrodes
induced seizure, as well as after a convulsion produced by Indoklon or Metrazol, is probably related to the structural and functional organization of the brain rather than to any local elective action of the convulsant. Thus. the disturbance itself may be interpreted as a nonspeeifie response of the brain to the physiologic stress of the convulsion regardless of how it was produced. It is significant that similar changes can be observed as a result of
723
D E P T H ELECTROGRAPHY AND CONVULSIVE P A T T E R N S
a variety of physiologic stresses on the brain, including anoxia, acapnia and hypoglycemia (Roth et al., 1954). SUMMARY
The convulsive patterns provoked by the inhalation of hexafluorodiethyl ether (Indoklon), the intravenous injection of pentylenetetrazol (Metrazol), and the administration of electroshock have been recorded by means of nmltielectrode leads implanted into the brains
dromal phase, and both these agents plus electroshock during the seizure proper act on the human brain through a common operating mechanism; (2) regardless of how it is initiated and controlled, the convulsive discharge develops with some degree of independence in the various parts of the brain, and (3) the predominance and longer persistence in the frontal areas of the slow disturbance following electrically induced seizures are related to the structural and functional organization
ELECTROGRAPHIC PATTERNS FOLLOWING GENERALIZED SEIZURE PROVOKED BY ELECTRO-SHOCK
7
~
E
G
v
~
i I|¢.
Fig. 7 ((~mse 1). Postconvulsive electrographie pattern of seizure produced by electroshock. Sections E, F, G and H started 1, 4, 8 and 23 min. after the end of the convulsive discharge, as in figure 6. The S'mle clinical signs were present.
of five psychotic patients (unmedicated) preceding frontal lobotomy. The patterns observed in these tracings, which were free from muscular contamination, during the prodromal, tonic and clonie phases of the seizure and the postictal period have been described and correlated with the accompanying clinical phenomena. Evidence has been found suggesting that: (1) lndoklon and lV[etrazol during the pro-
of the brain rather than to a local action of the convulsant. Rg;SUM~: Les patterns convulsifs provoqu~s par l'inhalation d'ether hexafluorodiethyl (Indoklon), l'injection intra-veineuse de penthylenetetrazol (M4trazol) et l'administration (l'~lectrochocs ont ~t~ enregistrgs au moyen (l'~lectrodes multiples implan%es dans le cerveau
724
G I A N E M I L I O C H A T R I A N a n d M A G N U S C. P E T E R S E N
de cinq malades psyehotiques (sans m6dieation) a v a n t lobotomie frontale. Les p a t t e r n s observ6s dans ees trac6s qui sent indemnes de tout art6fact musculaire, d u r a n t les phases prodromique, tonique et elonique des krises, et d u r a n t la p6riode postcritique ont 6t6 d6erits et mis en relation avee Its ph6nombnes eliniques qui los aceompagnent. Les observations suggbrent (1) que l ' I n d o k l o n et le M6trazol, d u r a n t la phase de prodrome, et ees deux agents plus !'61eetrothee d n r a n t la crise elle-m~me, agissent sur le cerveau humain p a r un m6eanisme comnmn, (2) clue la d6charge conwflsive se d6veloppe avec un certain degr6 d'ind6pendanee dans les diff6rentes r6gions du eerveau qu'elle que soit la fat:on dent elle a d6but6 ou dent est contrS16e, et (3) que la pr6dominance et la persistanee plus league darts les r6gions frontales des p e r t u r b a t i o n s lentes apparaissant ?~ la suite des crises induites p a r 61eetroehoc sent en relation avee une organisation structurale et fonetionnelle du cervcau plutSt qu'avec une action locale du conwflsivant. ZUSAMMENFASSUNG
Die K r a m p f e n t l a d u n g e n , welehe durch die Inhalation yon H e x a f l u o r o d i e t h y l - A e t h e r ([ndoklon), die intravenSse I n j e k t i o n yon Pentylen-Tetrazol (Metrazol), und die Anwendung yon Elektroschoek h e r v o r g e r u f e n wer(ten, wurden mit implantierten Multielektroden im Gehirn von fiinf psyehotisehen Patienten, welche keine Drogen erhielten, v e t frontaler Lobotomie registriert. Die Bilder dieser Kurven, welche frei yon Muskelartefakt(,n waren, wurden fiir Prodromal-, tonische m~d klonisehe K r a m p f p h a sen sowie fiir (tie postkonwdsive Phase besehrieben nnd in Beziehung gesetzt mit den ldinischen Begleiterseheinungen. Es wnrde Anhalt dafiir gefunden, dass (1) hMoklon und Metrazol wiihrend der Prodromalphase, nnd beide Drogen plus Elektroschoek w:~i.hrend des Anfalles selbst auf das mensehliehe Gehirn durch einen gemeinsamen Meehanisnms operieren, (2) mmbhiingig yon der Art wie der K r a m p f erzeugt und k o n t r o f liert wird, die E n t l a d u n g e n mit einem gewissen Grad von I:nabh~in~:iodkeit in den versehiedenen H i r n t e i l e n sieh entwiekeln, und
(3) das Vorwiegen und die liingere D a u e r der langsamen Wellen naeh E l e k t r o k r a m p f im Stirnhirn mehr der strukturellen und fmlktionellen Organisation des Gehirn zuzuschreiben sind als einer 5rtlichen W i r k u n g des k r a m p f e r z e u g e n d e n Mittels. Tire a u t h o r s e x p r e s s `appreciation to Dr. Charles E. t i e n r y , H a r t f o r d I n s t i t u t e of L i v i n g , H a r t f o r d , Conn., for his valuable s u g g e s t i o n s a n d to Mr. Ctetus S. Pollack, Miss M a r y A. B u s h e y a n d Miss N a n c y T,. Moehnke, R o c h e s t e r S t a t e H o s p i t a l , for their as s i s t a n c e a n d interest. REFERENCES ALEXANDER, I~. ,qlld ],O~,VENBACH, It'. ExDerimentM s t u d i e s on electro-shock t r e a t m e n t : T h e i n t r a cerebr`al v a s c u l a r reaction as ,an imlie,ator of t h e p,ath of tire c u r r e n t and t h e t h r e s h o l d of early c h a n g e s w i t h i n the l>rain tissue. J. :Vm¢ropath. Exper. 5rcurol., 1944, 3: 139-171. BERGMAN, "P. S., ]MPASTATO, ]), I. ,and BERG, S. E l e c t r o e n e e p h a l o g r a p h l c f i n d i n g s in p s y c h i a t r i c p a t i e n t s t r e a t e d with unilqteral electrically in duced seizures. E E G Clin. 5"r~ropby.~'iol., 1953. 5 : 463-464. ~ICKFORD, a . G. and ROI~IE, IT. P. Tire (,lectroenceld,a l o g r a m recorded d u r i n g seizures pro~lucecl t)v electroshock. E E G Clin. Nr~trophy.~iol., 1949, 7: 3~9. I:ILAUROCK, M. ]~., L'ORIMER, ]~. ~]-., ~QEGAL, M. M. `all(| GTm+s, F. A. Focal electroencetlhalographic c h a n g e s in u n i l a t e r a l electric convuNi,m ther'tl)y. A r c h . . ¥ c ~ r o L Psyehiat., Chicago, 1950, a4: 22t)2oil. ]7JOSHES, L. D., DARROW, C. W., SOLOMON', A. P. and ~DATItl~IAN, ,1-. H-. Eleetroencephalogr'll)l,ic s t u d y of the local e f f e c t s of electric shock: A ore l i m i n a r y rellort. Arch. ~rr~l~'ol. P.e?l('hiat., Chlcage, 1943, 50 : 108-11(~. CtIATRIANr, O. ]~1., DODGE, H. W., .JR., PETERGENr, M. (L and B1CKPORD, R. G. A multie]ectrode lead for i n t r a c e r e b r a l recordinffs. E E G (!lira .¥curophysiol., 19~9a, 11 : 165-169. (~I[ATRIAN, G. E.. I)OLLACK, C. S. qlld PETERSRN, ~1['. ('. A 1)rocedure for t)reparing a mnltielectrode ]e:ld for intrflceret)ral recordings. EEG Clin. .Y~'urophysiol., 1959b, I l : 35~-361. CooK, L. (L `and WALTEI¢, W. {r. T h e el,~(.tro-enceplmlou'rmn ill convulsions induced tly c`ardi`azol. J. Xe~rol. Nr~ros,r.q. Psycldat., 1988, l: 180-1~6. ]3Avis. P. A. `and ~qULZBA(',H, W. Ch`anges in the eh,ctrocncei)halo~'r`am d u r i n g M e t r a z o l t h e r a p y . A r c h . . Y c ~ r o l . Ps.ychiat., Chicago, 1940, / 3 : 241355. DF~LC,al)O, d. M. R., ALEXAXDER, L. :rod II,X~ILIY, H. E f f e c t s of electroshock on the cortical and intr`acerebrM eleetroaetivlty of the b r a i n in schizophrenic t m t i e n t s . Con.fibula neurol.. 1953, 13: 287-294. DELGA1)O, .1. ~ . R. :tilt] tTAMIAN, ]1. Direct r e c o r d i n g of s p o n t a n e o u s `and evoked seizures in epileptics. E E G Clim Nm~rophy.*iol., 1958, lO: 443-486.