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Cortical and subcortical electrograms in anesthesia and anoxia in man
CORTICAL A N D S U B C O R T I C A L ELECTROGRAMS IN ANESTHESIA A N D A N O X I A IN M A N 1 T. OKUMA, M.D., Y. SHIMAZONO, M.D. and H. NARABAYASHI, M.D. Department of Neurology and Psychiatry and Institute o[ Brain Research, Tokyo University School of Medicine, Tokyo, Japan (Received for publication: May 13, 1957) Recent advance, in the study of depth elect r o g r a p h y on the h u m a n subjects ( H a y n c et al. 1949; Spiegel et al. 1951, 1956; Delgado ,4 al. 1953, 1956; Sere-Jacobsen et al. 1953, 1955, 1956; Okuma ct al. 1954; Heath 1954; Schwartz et al. 1956; etc.) has provided much knowledge on the brain in various functional states. This report covers the effect on the cortical and depth electrograms by administration of intravenous and intranmscular barbiturates, rectal chloral hydrate, subcutaneous and intravenous Benadryl, inhalation of tri~hloroethylene and pure nitrogen gas. The effects of intravenous barbiturate and sub~,utaneous scopolamine hydrobromide on the electrogram were reported earlier (Okuma ct a[. 1954). I n the light of these findings the mmral mechanisms underlying altered eons¢'iousness will be discussed and action of drugs on the central nervous system will be r~'eonsidered.
central region into the medial thalamus and other subcortical structures according to their coordinates and was fixed to the skull as illustrated in figure 1. In most cases monopolar reeordings with reference cat' electrodes and bipolar recordings with electrodes linked in sequence were used and occasionally conw~ntional scalp E E G s simultaneous with the
~D
TECHNIQUE Recording of cortical and depth electro~rams was performed on 74 patients (parkinsonism 43; double athetosis 9; epilepsy 7; feeblemindedness 4; other organic brain diseases 11) in whom stereoencephalotomy on the basal ganglia was indicated and whose electrograms could be registered in the resting state. Patients with normal or almost normal r,mline E E G s were selected. l)ur technique using multi-lead needle electrode was described previously (Okmna el al. 1954). A multi-lead needle electrode 1 ram. in diameter with 8 recording tips at intervals of I cm. was inserted stereotaxically from the
Fig. 1 ~chematical diagram of a multi-lead needle electrode. Electrode I lies in the medial nucleus of the thalamus and electrode 8 on the surface of the central cortex. Distance of electrodes is 1 cm.
1 Presented at the 3rd Annual Meeting of the Japan EEG Society (April, 1954) and at the 5th Meeting of the German EEG Society (September, 1955~.
¢.orti~al and depth recordings were obtained. All eleetrograms were recorded with an 8~,hannel Sanei Model I electroencephalograph (time constant 0.3). Surgical placement of the depth electrode was carried out under local anesthesia. Eleetrograms of the cortex and deeper structures as well as scalp were registered for about 20 rain. in the non-anesthetized state as a control. Techniques of inducing anesthesia and anoxia are described in detail under each paragraph.
609 ]
ill0
T. OKUMA, Y. SttIMAZONO and H. NARABAYASHI RESULTS
I. Intravenous and intramuscular injection of thiope~tal sodium. As reported previously, when 2.5 per cent solution of thiopental sodium was injected intravenously at the rate of 2 ee. per rain., fast activity in the cortical eleetrogram with rising amplitude appeared early followed by a gradual decrease in frequency. In a few minutes alpha activity disappeared and was replaced by 2 to 6/see. waves in cortical and depth eleetrograms as the subject loses conseiousncss. Figure 2 shows eleetrograms of a patient in whom thiopental sodium was injected intravenously and who was ordered to pull on a
before pull injection. ~ $~
pull t -
&~
shown to the right of figure 2, high voltage slow waves of 2 to 6/see. appeared in both cortical and depth electrograms, but they were suppressed and replaced by fast activity dm'ing the period in whieh the subject was pulling the string and appeared only ill the intervals of those pulling actions. The subje(:t ,ould m) longer respond to the call " 6 7 " and m) response was seen on the tracing's, which show~,d continuous slow waves of 2 to 6/see. thoroaftev. Effect of intramuscular injection of tho same drug on the cortical and depth electrograms (fig. 3) is somewhat different from that caused by intravenous administration and is noted in table I. The spindle burst appeared simultaneousl.v and ahnost synchronously in tho (.ortical and
pull
$6
no response
6Z
4 w~,~uw, a~ 7 '*'~'~%V.ff"* l- 2",-""".'~ ~'~"
..
tool,V
RO ~ ' ~ ' , # ' ~ ¢ Fig. 2 Effect of intravenous thiopental sodium. Left: before injeeti(,n. Right: stage of transition to the loss of consciousness (the amount injected is 0.2 g.). The line at the top of the tracing is lowered when the subject pulls the string in response to the examiner's calling of numbers. Note that when the subject pulls the string, slow waves are replaced by fast activity. Tho subject could not respond to the call 67 and slow waves predominate :~fterwards. string following examiner's calling of numbers (when the string is pulled a signal is recorded on the E E G tracing). As narcosis deepened fast activity with increasing voltage appeared in surface and also in depth electrode traeings. Alpha activity, however, persisted in the cortical and depth electrograms as long as the subject could pull on the string, though it showed gradual slowing. I n the stage of transition to uncouseiousness, as
thalanlie electrograms but the amplitude of cortical spindle bursts was larger than that of the thalamie eleetrogram ill both monopolar and bipolar recordings. These spindle waves reversed their phase in both eortical and thalamie levels when recorded bipolarly. Eleetrographie changes at the time of intramuscular injection of thiopental sodium are summarized as follows: the enhancement of cortical fast activity is less than that by intra-
CORTICAl, AND SUBCORT[CAL ELECTROGRAMS IN ANESTHESIA venous injection, though slight increase in amplitude is observed initially, and the wave pattern changes resemble those of natural sleep except for the large cortical fast activity. The electrogram of the caudate nucleus during barbiturate anesthesia is shown in figure 4. A multi-needle c a r r y i n g 4 electrodes was inserted in the head of the eaudate before
15
injection
rain.
611
low voltage fast activity. Intravenous inje~.tion of 2.5 per cent thiopental sodium at the rate of 2 cc. per min. produced gradual suppression of eaudate nucleus alpha activity and appearance of 4-7/see. waves. When the:subject reached the deepest stage of anesthesia, 0.5 to 3/see. slow waves of 100 to 200 ~\'. or over predominated. The stage of a,~tivation of 10 rain.
min.
3
i
L
LQ
I Sec
Fig. 3 Effect of intranmscular thiopental sodium (0.5 g.). When the subject becomes drowsy (7 min.), fast activity in the cortical region increases, while alpha activity in the cortex and depth is depressed. Ten minutes after the beginning of injection fast activity shows reduced voltage again and slow waves of around 6/see. appear in both regions. Lower tracings show spindle phase. Phase reversal both in the level of cortex m~d depth. nucleus. Electrodes 10 and 11 (electrodes distance 1 era.) were in the caudate, 13 was on the surface of the premotor cortex and 12 1 era. below the surface. As shown on the left in figure 4, clectrograms from the eaudate and thalamus were similar, containing chiefly alpha activity mixed with a small amount of
the caudate oll which Schneider ct al. (1!152) had reported on cat was not observed in man. lI. Rectal administration of chloral hydrate, Eleetrographic changes produced by rectal administration of ehloral h y d r a t e (aqueous solution of 3 g. of chloral hydrate) are similar
612
T. OKUMA, Y. SHIMAZONO and H. N A R A B A Y A S H [ TABLE I ELECTROGRAPHIC CHANGES BY I N T R A M U S C U L A R
THIOPENTAL
SODIUM
Time after injection
Before
7-10 rain.
10-15 rain.
15 nfin.
State of the subject
Awake
Drowsy
Very light sleep
Light sleep
Cortical
Alpha activity 13-3(~/see. :let.
l)ecrease of alpha act. 13-20/see. act. suppressed and replaced l/y 21-30/sec. ;let.
4-7/sec. act. nfixed with low voltage 21-3(I/see. act.
Slfin(lle burst 12-14/sec.
Of
l)eerease of Mpha
4-7/see. act.
Spindle burst 12-14/see.
(G'
:~
e l e c t r o g r : l llll
Th,dmnic eleetrogram
Alpha activity
:let,
21-3(I/sec. act. increased.
to those by intramnscuiar barbiturate (fig. 5) and are noted briefly in table I[. They are summarized as follows. In the initial stag(, fast activity in the cortical layer slightly increases its amplitude and reduces its frequency. This slight enhancement of cortical fast activity is similar to that seen under anesthesia by intramuscular barbiturate. The enhancement is more pronounced than that seen in the initial stage of natural sleep but less evideltt than that produced by intravenous harbiturate. Then cortical and depth electro-
before injection 2
I min.
grams gradually show r e d u c e d aml)litmh. again and later the wave pattern in general becomes v e r y s i m i l a r to t h a t of natm-al
sh'el).
l I I. Inhalation, of lrichloro('thylcm'. Trichloroethylene has t)een used r e c e n t l y for a short time anesthesia in s u r g e r y aml gynaeeology. It can be inhaled easily by use of a simple m o u t h piece whieh covers th,. m o u t h and the nose. In o r d e r to s(~(q|l'(' as l>uro a r e s p o n s e to t r i c h l o r o e t h y h m c as i)o~-sibh,, n o s e d a t i v e d r u g w a s g i v e n p r i o r to th,. examination.
5 rain.
~
*.I SE't_ '
:Fig. 4 Progressive changes of the electrogranl of the caudate nucleus under intravenous thiopenta! sodium. 2: thalamus. 6, 8: central cortex. 10, 11: eaudate. 12, 13: premotor cortex. Electrograms of the eaudate show similar changes to those of the thalamus. See text.
CORTICAL AND SUBCORTICAI~ EI~ECTROGRAMS IN A N E S T H E S I A
61:l
TABLE I I ELECTROGRAPHIC CHANGES BY RECTAL CHLORAL HYDRATE Time after
Before
10 min.
15 rain.
30 rain.
Awake
l)rowsy
Very light sleep
IAght sleep
Alpha activity ]3-30/see. "tot.
13-20/sec. act. reduced and 21-30/ sec. act. predomin-
4-7/see. act. Period of 13-20/ see. activity alternated with th,qt of
,~l,indh, burst
ndministration ~t~te of the
subject Cortical electrogram
nted
21-30/see. in 106(~ set'.
Thalamic
Alpha activity
Alpha act. reduced
electrogr.m~
4-7/see. act. and low voltage 21-30/
Sldmlle burst
se('. 3('t.
Figure 6 shows a ease studied on electro,:raphic changes brought about by inhalation of trichloroethylene. The outline of the (4ranges is noted in table III. Thirty seconds after the subject lost conseiousness, inhalation was discontinued and the subject was allowed to respire in the air. It was about 10 see. later when the subject
-.~2"-~a@,~
responded to the command to open his eyes. Cortical and thalamic eleetrograms changed their pattern abruptly as the ,~nbjeet regained consciousness. The voltage of fast activity in the cortex and alpha activity in cortical and depth eleetrograms showed marked increase simultaneously with the reappearance of alpha activity in the scalp EEG. ~ Cortieai
" ~ ' % ~ F ~'~'~'~
tOO~'V ! se&.
~V
Fig. 5 Changes induced by rectal chloral hydrate (3 g.). When the subject becomes drowsy (10 rain.), low voltage fast activity increases with disappearance of alpha activity. During very light sleep (15 rain.) stage of higher voltage fast activity alternates with that of lower voltage. Then slow waves of 4-7/see. appear in cortex and depth (25 min.). This stage is followed by spindle phase (30 rain.).
61-t
T. O K U M A , Y. S H I M A Z O N O a n d tI. N A R A B A Y A S H I TABLE
III
ELECTROGRAPHIC CHANGES BY T RICHL OROE T HYL E NE (BIPOLAR RECORDING) Tim(, a f t e r inhlilation
Befor(,
Stilt(, o f till, sul,je(,t
Aw:tk(,
( !orti(':ll
Ali)ha activity 13-30/see. :let.
Low voltage all)h:, ;,('t.
~,hwt l-o~ l':t lil
Th:il:lniic I'] (!('t I'O~TH
III
~0 so(..
INttALATI()N
9(I-159 st'('.
25!) set.
Slight turbidity of OOllStqOUSlleSS I)tlt resI)onsibh~
l'nr(,spmlsiv(, t[, ,.:ill tlv Ilill|l( ~
Voltage reduction of alpha and 13 20/see. act. 21-30/see. :,et. predominated
Almost sanl(, ;~s :II~ so('. Random 4-7/s(,(.. activity
4-7/se('. :wtivity
l)e(q'oilse of alpha :,(!t. l,ow voltage 21-311/ sec. act.
Randoni 4 7/se(.. activity
Almost flat with h)w 4 7/%,c. :wtiv ity
electrogram, however, showed more fast activity of 13 to 20/see. with lower voltage and less alpha activity than that of pre-inhalation period. The voltage of thalamic alpha activity was also lower in that stage. It was about 5 rain. later when wave p a t t e r n recovered to the pre-inhalation level. In this series of experiments, the authors have no ease~ w h o w a s follo~ed~,.~p,,to deeper stage of anesthesia characterized by appearance of large delta waves because of the restriction of experimental conditions. The electrographic changes by trichloroethylene iuhalation are characterized by the 1)arallel depression of fast and alpha activities in the (,ortieal and thalanfic eleetrograms. It makes a sharp contrast to those caused by intravenous barbiturate. The subject suffers from a slight degree of disturbance of consciousness when cortical and depth electrograms are predominated by slow waves of around 6/see.
IV. Nubcuta~mous and intravenous injection of Bc~mdryl. Benadryl, one of anti-histanfinies and a derivation of ethanol amine, has the ehemical structure similar to proeaine. I t is well-known that B e n a d r y l has sedative or narcotic effect on the eentral nervous system and drowsiness or sleepiness is a ehief side-effect of the drug. Some authors think that B e n a d r y l affects the cerebral cortex and others suggest it blocks
l,redon,imlted R(,mark:0)h' volt:,g,, r(,du('tion [)t' II,-:W st,(., activity
the function of tile subcortical struetm'e tTanaka 1951). When Benadryl is injected subcutaneously. most of the subjects show more or less alteration of consciousness ranging front slight drowsiness to sleep-like state, though there is considerable individual variation in the s(,nsitivity to the narcotic effect of the drug. Intraw, nous injection has more intense (,fled and some cases are i n d u c e d t o a s t a t e o f deeper anesthesia. Changes of the cortical and depth eh'drograms of a t y p i e a l case in which 60 mtz. of Benadryl was given subcutaneously (fig. 7i are noted in table IV. Intravenous injection of Benadryl has similar influence on the cortical and thalamie electrograms to subcutaneous injection, though the process of anesthesia a(tvam,es mor,' rapidly. As shown in the table, subcutaneous and intravenous Benadryl cause depression of alpha and fast activities both in cortical aml thalamic electrograms, and general course o~' electrographic changes is similar to that of natural sleep. The marked enhancement of cortical fast activity seen at the time ()f intravenous barbiturate anesthosia is not obsevved
V. Inhalation of pure nitrogc~, (.]a.~. There have been many studies of the erred of anoxia or hypoxia on the electrical activity of the brain and the state of (,onsciousm,s~.
CORTICAL AND SUBCORTICAL ELECTROGRAMS IN ANESTHESIA but r e l a t i o n s h i p s b e t w e e n the e l e c t r o g r a p h i c (.ha nges of t h e c e r e b r a l c o r t e x a n d d e e p e r .~tructures a n d a l t e r a t i o n of consciousness have not y e t been i n v e s t i g a t e d on the h m n a n subject. In o u r cases, n i t r o g e n gas was i n h a l e d by us~, of a r u b b e r m o u t h piece w i t h two o u t l e t c o v e r e d w i t h valves, w h i c h p r e v e n t n i t r o g e n before
1 to 10 a n d t h e t i m e w h e n he d i s c o n t i m t e d to c o u n t was t a k e n as a s i g n of loss of consciousness. A f t e r a few m i n u t e s of r e s p i r a t i o n in the air with scalp and depth electrodes and a m o u t h piece a t t a c h e d on the s u b j e c t , nitrogmt gas was sent to the m o u t h piece. F i g u r e 8 shows a t y p i c a l course of electrog r a p h i c c h a n g e s at the t i m e (>f nitrogm) i,~-
inhalation 9 0 SeC*
30 sec.
3-4
~'<:.'~I','~,~"~ " ~ ' ~
....
iso sec
615
"'
~,
,,
~, "
"~--
,'.~,,',~.~A,~,~~,.~
2so ~ec.
30
see. postinhal.
loo,,v.
/ oo2~ v---.--
! see.
:pig. 6 Recording during inhalation of trichloroethylene. Note progressive reduction of volt'tge of cortical fast activity. Alpha activity in the cortex and depth also disappears gradually. :Large rhythmical swings of the base line in the lower tracings are artifacts due to increased puls-/tion of the brain. gas f r o m m i x i n g w i t h e x p i r e d air. T h e m o u t h piece was c o n n e c t e d to a l a r g e D o u g l a s b a g f i l l e d w i t h n i t r o g e n gas. T h e s u b j e c t was o r d e r e d to c o u n t on his f i n g e r s f o l l o w i n g t h e e x a m i n e r ' s r e p e a t e d c a l l i n g s of n u m b e r s f r o m
h a l a t i o n r e c o r d e d b y m o n o p o l a r method. The o u t l i n e of t h e e l e c t r o g r a p h i c chan~'es is n o t e d in t a b l e V. A b o u t 55 see. a f t e r the b e g i n n i n g of inh a l a t i o n w h e n t h e s u b j e c t could c o u n l on
616
T. OKUMA, Y. SHIMAZONO and H. NARABAYASHI TABLE IV ELECTROGRAPHIC CHANGES BY SUBCUTANEOUS B E N A D R Y L
Time after injection
Before
I0 rain.
15 mill.
2(1 rain.
Stqte of the subject
Aw',ke
Drowsy
Very light sleep
Light sleep
Cortical
Alpha activity. 13-30/see. act.
Alpha and 13-20/ see. act. reduced in voltage and replaced by 21-30/ see. act.
4-T/see. act. 21-30/see. act. decre}] sed
S1)indle burst 12-14/se,..
of
Alpha qctivity
Alpha activity decreased
4-T/see. aet.
Sl)in(lh~ burst 12-14/see.
o t'
ph!(~trogrllln
Thalamie eleetrogram
fingers no more (fig. 8, a), continuous large slow waves of 2 to 5/sec. predominated in the record. The appearance of large slow waves was ahnost simultaneous in cortical and depth electrograms or a little earlier in the former. before
,'
r ~, "
~
'
inhalation of nitrogen gas was discontinued m the same time (fig. 8, b). D u r i n g the period of convulsion, the electrogram was unreadabh, because of artifacts by the movements. After 5 see. convulsion ceased (fig. 8. (,) aml sh., 25 rni~t.
20 rni~
t"i,
V~ ::h4,""'>,'°°":
o o,~V
"
I
.sec
Fig. 7 E f f e c t of subcutaneous }'enadryl (60 rag.). Fast "~nd alpha activities in the cortex and depth show reduced voltage as the subject becomes drowsy (lo rain.). Then 4-7/see. activity (15 rain., very light sleep) and spindle Bursts (20 min., sleep5 appear in all leads.
Loss o f consciousness a p p e a r e d to coincide with the continuous a p p e a r a n c e of those slow waves in the cortical and depth eleetrograms. Five seconds a f t e r the subject lost conscious1less, slight myoclonie convulsion occurred and
waves of 6/see. a p p e a r e d as a burst in cottical and depth clectrograms for 2 to 3 see. The subject begmt to count on fingers again at d (fig'. 8) and the eleetrographie p a t t e r n became similar to that of the pre-inhalati(m
CORTICAL AND SUBCORTICAL ELECTROGRAMS
IN ANESTHESIA
ill7
TABLE V E L E C T R O G R A P H I C CHANGES BY N I T R O G E N Time a f t e r inhalation
Before
.~tate of the subject
Awake
('ortic,l (.Ice? rogralll
Alpha activity.
Voltage reduc- Voltageof alpha Higher voltage
1;~ 3t}/sec. act.
tion and act.
Tlialaniic
Alpha activity
i,ll2c i r o ~ ra lit
10-20 see.
GAS I N H A L A T I O N
m ,~.
45-5(t see.
:
:
:
of alpha 13-20/see.
Voltage tion of act.
reducalpha
period abruptly. For a few minutes after the subject regained consciousness, fast and alpha a(.tivities in cortical and thalamic electrogram~ showed slight increase of voltage and duration. The fact that the subject showed slight euphoria or hypomaniaeal state in this period might be comparable to the similar phenomenon observed during recovery from barbilnrate anesthesia. before I~,~. , ~ tnhalatto~ _ ~ , ~
3(t-40 see.
lo
of alpha and 13-20/sec. act. 4-7/see. act.
Voltage of alpha act. increased
I t i g h e r voltage :alpha act.
H i g h voltage 2-5/see. act. Low voltqge fast act. superiml)osed
tligh
voltage
2-5/see. :let.
Bipolar recording on tile same subject with electrodes linked in series showed similar finding to that of monopolar recording mentioned above, but changes of amplitude and duration of cortical fast activity eouh/ be revealed more clearly and remarkably by bipolar recording (fig. 9). Loss of consciousness was coincident with the appearance of delta waves in thalamic electrogram. These
sec.
~o , e c .
+ ~
+
v
~
'
~
~
+
,
w
~
~
-~ uncon~clou*
~iO~c
Unconscious
and 13-20/see. act. increased Activity of a r o u n d 15/see. predominated
~z~,~'~-~,~
LO_~,~--~~.,-~*~-
55 s e e . -
l~a.
convulsion
~ , • __
__
c.
.
.
.
.
recow~rv 2 rain. gd. I)ost-iniml'ltion
Fig. 8
Chaages d u r i n g n i t r o g e n gas inhalation (nlonopolar r e c o r d i n g ) . F a s t activity in the cortical eleetrogram shows increased amplitude and d u r a t i o n "~nd slow wayes of a r o u n d 6/see. a p p e a r in the cortex and depth (30-40 see.). Then slow waves of 2-5/sec. p r e d o m i n a t e (50 see.) and the subject loses consciousness (a) ; b-c: clonic convulsion; d: the subject regained consciousness.
618
T. ()KUMA, Y. SHIMAZONO and tt. NARABAYASH1
changes of fast activity in the cortex which is easily revealed by use of direct recording can h a r d l y be detected by investigation of ,leetroeneephah)gram led via scalp. COMMENT Electrographie changes induced by various anesthetic drugs are divided into three groups before
and depth eleetrograms disappeared and wa~ replaced by large theta and delta waves when the subject lost consciousness (fig. 10. H and I ) . (2) Inhalation of trichloroethylene, subcutaneous and intravenous injection of Benadryl, subcutaneous injection of scopolamin,~ h y d r o b r o m i d e (reported in previous papa,r. ()kuma ct al. 1!754) produced ~'ra(hml d,,-
%nhalatiol~ 30 see.
~
Sec.
unc ons o i ous
.~o s~
11, a.
c onvul s i on
b.
"
"
"I s e c .
Fig. 9 Changes during nitrogen g'ls inlmlation (bipolar recording). Enh'~ncenwnt of the eorticM fast activity is seen evidently. Loss of consciousness coincides with ;q)pearam,e of large slow w;,ves in the dei)th and cortex. 7 E: monopolar recording. a(.eording to the s t u d y of cortical and depth eleetrograms. (1) W h e n b a r b i t u r a t e was administered intravenously, fast activity in the cortical layer showed remarkable increase of amplitude and duration in the initial stage (fig. ]0, G). Then alpha activity in cortical
pression of cortical fast activity. Alpha activity ill cortical and depth electrograms disa p p e a r e d g r a d u a l l y and was replaced by theta waves (fig. 10, B and C). These changes wet,, similar to those of n a t u r a l sleep. (:3) IG,ctal administration of chloral hydrato and intra-
('ORTICAL A N D
SUBCORTICAL
ELECTROGRAMS
muscular injection of b a r b i t u r a t e t e m p o r a r i l y caused slightly increased amplitude of cortical fast activity initially, with reduced incidence and voltage of alpha activity (fig. 10, E ) . A f t e r a while theta waves p r e d o m i n a t e d in the record (fig. 10, F ) and then a shift to the spindle phase followed. The t h i r d group of wave p a t t e r n is intermediate between the first and the second group. I n most eases a spindle phase oeeured (fig'. 10, D). The difference of wave p a t t e r n in various anesthesias was probably due to several factors. The first was the difference in the anesthetic drug itself. There are considerable variances
IN ANESTHESIA
(-;19
These facts suggest that electrographie changes in anesthesia can be explained not only by the difference in the drug, but in the mode of administration. The method of administration results in variations of d r u g concentration in the blood and brain and influences the rate of increase and decrease of the effective concentration. Nervous system function is p r o b a b l y disturbed more severely with higher concentrations of drug. It is, of course, impossible to compare the action of all anesthetic d r u g s with similar methods of administration, but in the present study each anesthetic, if possible, was given in different
natural sleep, trichloroethyleI~e, ~et~adry], ~copol~ire.
A alpha
fast
~.~-2(/~,2~-~o/,
]
chloral hydrate,
E
~
'" barbiturate
-
1
F
( intramuscular
).
I splndtl phaae
]~'ig. 1(! Nchem:~tical illustration of changes of the cortical and depth elcctrograms in w~rious am'sthesias. See text. between the electrographic changes following intravenous injection of barbiturate, classified as a brain stem narcotic by Pick (group 1 in our division), and those caused by inhalation of trichloroethylene, cortical narcotic (Pick ]927) (group 2 in our division). Subcutaneous injeetion of scopolamine hydrobromide, though classified as a brain stem narcotic by Pick, shows the electrographie changes of the second group. W h e n b a r b i t u r a t e is inj(,eted intramuscularly, enhancement of cortical fast activity is not so remarkable as that produced by the same d r u g administered intravenously, and the changes are classified as the third group in our division.
ways and effects on tile (.ortical and del)th eleetrograms were compared. The electrogram following Benadryl does not v a r y much with different routes of administration. Cortical and depth eleetrograms showed g r a d u a l diminution of amplitude without marked enhancement of cortical fast actiw ity even when the drug was giwm intravenously. A p p a r e n t l y the action of Benadryl on the central nervous system is not so strong in a given dose as that of b a r b i t u r a t e and the influence of the d r u g on nervous tissue, does not depend on the method of giving il. These facts indicate that change of the electrical activity of the brain at the time of
620
T. OK UMA, Y. SHIMAZONO and H. NARABAYASHI
anesthesia is a function of several variables: chemical s t r u c t u r e of the drug, effective concentration of the d r u g in blood, the rate of increase and decrease of the concentration, a f f i n i t y of the d r u g to any speeific structure of the brain, etc. Since the initial report by Berger, there have been m a n y studies on the electroencephalogram during anoxic state in man. In general electroencephalographic changes during anoxia or hypoxia m a y be divided into font stages: (1) stage of little alteration in E E G , (2) stage of decreased amplitude and duration of E E G , (3) stage of increased amplitude and duration of E E G and also of regularity of the wave pattern, (4) stage of r e m a r k a b l y increased amplitude and duration of waves with a p p e a r a n c e of large delta waves (Gibbs and Davis 1935; B r e m e r 1936; Davis, Davis and Thompson 1938; Gibbs and Gibbs 1941; 5Iotokawa 1947; Shimazono 1951; Kasamatsn 1952; etc.). The a p p e a r a n c e of delta waves and loss of consciousness are not always simultaneous, and in most cases a p p e a r a n c e of delta waw:s precedes loss of consciousness by several seconds. Using automatic frequency analysis Brazier (1948) reported that the dominant fre(tueney showed gradual slowing at reduced oxygen level. In our study of hypoxia change of cortical fast activity was observed which was undetectable via scalp recordings. Central cortical fast activity showed slight initial depression of amplitude followed by gradual increase of amplitude and duration. In one ease delta waves were not evident and only the slowing and enhancement of cortical fast activity were observed during loss of consciousness. Our findings suggest a correlation between cortical fast activity and eerebral cortical dysfmmti<>n with altered c<>nscionsness. Delta waves a p p e a r f r o m cortex and deep strm,tures ahnost simultaneously or a little earlier in the cortical electrogram as hypoxia progresses ~md loss <>f consciousness coincides with the c<>ntimmns delta waves in the cortex and thalamus. There haw • been m a n y stu
p a r t s of the central nervous system to ischemia were reported by S u g a r and Gerard in 1938. but most of the reports indicate that the electrical activity of the cerebral cortex and subcortical nuclei disappears simultaneously in advancing ischemia (Giinshirt et al. 1952; J u n g 1953; H i r a i et al. 1956). The diverse findings in animal and h u m a n subjects may he due to differences in experimental conditions and v a r y i n g tolerances of h u m a n and animal brains to the hypoxie state. A l p h a activity is recordable f r o m wide areas of the brain and shows parallel changes ill the cerebral cortex and subcortical regions during sleep, anesthesia and other alteration of the level of consciousness. It is suggested that alpha activity bears close relationship to brain functions which maintain consciousness. Our findings also suggest that alpha activity mechanisms in the cortex and subcortieal regions are in close relation, whether or not there may be a reverberating circuit betwee, the cortex and thalamus. D u r i n g sleep, anesthesia and hypoxia theta and delta waves a p p e a r and disappear i , eortieal and depth electrograms almost simultaneously. Spiegel ct al. (1951) reporte(I some cases of petit real epilepsy in which 3/see. spike and wave pattern a p p e a r e d in the thalamic tracing first and from the scalp lead a few seconds later. Knott, H a y n e and Meyers (1950) stated that changes of electrical activity of the brainsely related an(1 may represent the state of brain function as a whole. Natural sleep, triehloroethylene inhalation, subcutaneous B e n a d r y l and scopolamine hydrobromide cause gradual depressi<)n of fast activity in the central cortex as well as alpha activity in cortex and thalanms (fig. 10). thonF,'h the fast activity shows transient sli~a'ht increase of amplitude in some eases. Intravellous barbiturate, w waw~s dnrintz a
CORTICAL AND
SUBCORTICAL
ELECTROGRAMS
IN ANESTH ESIA
621
r a n t i n g anesthesia. The alternation of the vestigated in relation to the neural mechfast and slow p a t t e r n s during that period in- anism u n d e r l y i n g alteration of consciousness. The investigations were carried out on dicates a functional shift f r o m waking state to unconsciousness. These findings are similar patients with neurological disorders, those to those of H a y n e et al. (1949), Sere-Jacobsen being chosen with normal or near normal EEGs. ct ol. (1953, 1955), Biekford et al. (1953) 1. A u g m e n t a t i o n of cortical fast activity and other authors. Cortical fast activity increases slightly in by i n t r a m u s c u l a r thiopental sodium was not amplitude and r e g u l a r i t y a f t e r recovery front so remarkable as that caused by intravenous barhiturate anesthesia and hypoxia even when administration. A f t e r an initial stage of alpha activity r e a p p e a r e d in cortical and sub- slightly increased voltage and duration, am(.ortical tracings, and the subjects show slight plitude of cortical fast activity gradually deeuphoria in this stage. These facts suggest creased. A l p h a activity in cortical and subthat cortical fast activity is not of p r i m a r y cortical regions also disappeared and was resignificance in maintenance of eonseiousness placed by slow waves of around 6/see. In hut rather modifies the state of consciousness. several minutes spindle bursts a p p e a r e d in all In concluding this report, the authors pro- leads. W h e n the subject was awakened slight pose a hypothetical explanation of electro- increase in the voltage of cortical fast activity g'raphic changes in the cerebral cortex and persisted for a while, even though alpha deel)er structures during various kinds of al- activity r e a p p e r e d in cortical and subeortieal teration of consciousness as follows. In the regions. Eleetrographic changes by rectal stag'e in which cortical fast aetivity shows some chloral h y d r a t e were similar to those t)3' inchange but alpha activity persists in eortex t r a n m s c u l a r barbiturate. 2. Inhalation of trichloroethylene caused and thalanms and the subject is awake, fun(.gradual depression of cortical fast activity and tion of the cerebral cortex is ehiefly affected. substituted 4 to 7/see. slow waves for alpha F r o m the stage in which alpha activity disaetivity. Gradual depression of cortical and a p p e a r s and is replaced by slow waves of subcortieal electrograms was also shown by 4 to 7/see. to the stage of spindle burst, the subcutaneous and intravenous B e n a d r y l with subject cannot percept his surroundings sublittle augmentation of cortical activity. jeelively but can be awakened readily by ap3. Inhalation of p u r e nitrogen gas developpropriate stinmli. In such a stage function of eortico-dieneephalic system m a y be affected. ~ed an initial depression of eortieal and suhFinally in the stage in which large delta waves cortical activity followed by a period of inlwedominate in cortical and depth electro- creased voltage and duration. Cortical fast grams and even strong stimulus can h a r d l y activity showed gradual slowing and enhanawaken the subje(:t, the lower p a r t of the t)rain cement with advancing hypoxia. Loss ot' consciousness was ahnost coincident with afl- - caudal h y p o t h a l a n m s or midbrain - - is also affected. It seems unreasonable to divide pearance of delta waves in the cortex and anesthetic drugs into cortical and 1)rain stem depth. A f t e r the recovery of consciousness anesthetics schematic.ally. E f f e c t of various the fast activity tended to remain augmented. 4. Front the findings on the clinical and anesthetic dru~s on the central nervous system electrographie effects of anesthetics and hyIHay be analyzed Inore (dearly from the view poxia, it is sug'gested that alpha a(,tivity me('h1),lint su(.h as mentioned above. anism ix closely related to lnaintenane(! of SUMMARY waking state. Changes of (.ortieal fast activity. At the time of stereoencephah)tomy, elec- on the other hand, have no p r i m a r y signifilroaTams of the central cortex, subcortieal cance for wakefulness or loss of eollseiouslless white m a t t e r and diencephalic nuclei were re- but rather modify the state of consciousness. ('orded together with scalp E E G and effects Neural nleehanism u n d e r l y i n g alteration of of several anesthetics and hypoxia on the eonsciollsness was discussed from this view cortical and depth eleetrograms were in- point.
6'2'2
T. OKUMA, Y. StIIMAZONO and H. NARABAYASHI REFERENCES
llICKFORD, R. (~'.~ FAULCONER, A., JR., SEM-JAC.)BSEN, C. W., PETERSEN'~ W. C.~ DODGE, H. W. and SCH~UGG, F. J. Some effects of barbiturate •mesthesia on the depth eleetrogvam. Proc. S t a f f Meet., Mayo Clin., 1953, 28: 162-165. ]{RAZIER, M. A. B. Physiological mechanisms underlying the electrical activity of the brain. J. Neurol. Ne~lros~rg. Psychiat., 1945, J t : 118-133. B~EMER, F. Action de l'anoxSmie, de l'hypercapnGe et de l'acapn@ sur l'activit6 ~leetrique du cortex c~rGbral. C. R. Soc. Biol., 1936, i23: 1256-1261. I)aVlS, P. A., 1)Avis, H. and THONPSON, J. W. Progressive changes in the human electroencephalogram under low oxygen tension. Amer. J. Physiol., 1938, 123: 51-52. DFLGADO, J. M. R , ALEXANDER, L. and HAMLIN, H. Effects of electroshock on the cortical and intracerebral electroactivity of the brain in schizophrenic patients. Conf. Neurol., 1953, 13: 287-294. I)ELGADO, J. M. R. and HAMLIN, ~I. Surface and depth electrography of the frontal lobes in conscious patients. EEG Clin. Neurophysiol., 1956, 8: 371-384. (I:XNSHIRT, jr{., DRANSJ~'ELD, L. und ZYLKA, W. I)as Hirnpotentialbild und der Erholungsriickstand am Warmbliitergehirn nach kompletter Ischiimie. Arch. Psychiat. Ztsehr. Neurol., 195~, 189: 109125. (IIBBS, F. A. an(l (~IBBS, E. [~. Atlas of Eleetroe~eephalography. Lew A. Cummings Co., C:md)ridge, Mass., 1941. HAYNE, R., BELINSON, l~. and GIB~S, F. A. Electrical activity of sul)corticnl areas in epilepsy. EEG Clin..~*europhqsiol., 1949, 1: 437-445. [{EATIt, R. (]. Studies in Schizophrenia: a Multidisciplinary Approach to Mind-Brain Relationships. Cambridge, tIarvard University Press, 1954. ]tIRAI, T., ENDO, S. and SAITO, Y. Electroencephalographic study on the artificial hit>crnation. Especially on relation to the circulatory arrest of the I>rain. Brai~ and Nerve, Tokyo, 1956, 8: 515-539. J ux~, R. Hirnetektrische Befunde bet KreislanfstSrungen und Hypoxiesch;dden des Gehirns. Verhandlungen, d. Deut. Gesellsehaft f. Kreislaufforschung. 1953, 19: 170-196. KASAMATSU, A. Studies on the loss of consciousness induced by N~-gas inhalation. Psyehiat. N¢:~trol. Jap., 1952, 54: 575-604. KNOTT, J. R., HAYNE, R. and ~IEYERS, }I. R. Physiology of sleep: Wave characteristics and temporal relations of human electroencephalograms simultaneously recorded from the thalamus, the corpus striatum an
NARABAYASHI,]{., OKUMA, T. and SHIKIBA, S. Procaine oil blocking of the globus pallidus. Arch. Ne~rrol. Psyehiat., Chicago, 1956, 75: 36-48. MoRuzzI, G. and MAGOUN, ]-I. W. Brain stem reticular formation and activation of the EEG. EEG Cli~*. Nevrophysiol., 1949, 1: 455-473. ~OTOKAWA~ K. Electroencephalographp. Nanjo ('(,. Tokyo, 1947, p. 211. OKUMA~ T.~ SHIMAZONO~ Y.~ ]0UKUDA, T. ~tn(I NARABAYASIII, ]{. Cortical and subcortical recordings in non-anesthetized and "tnesthetized periods in nmn. EEG Cli~. Neurophysiol., 1954, 6: 269-286. PICK, E. P. Ueber schlaf und Schlafmittel. Wic~t Kli~. Wsehr., 1927, 10: 1=63. SCHNEIDER, J.~ WORINGERt E., BROGLY, G. et (iL(~OR. P. Etudes des variations de l'activit6 61ectriquc du cortex cGrdl)ral et de certaines formations sous eorticales chcz 37 chats soumis 'X l'influence des anesthGsiques gGnGraux usuels. Le rGle des syst~mes d'intGgration et (le projection diffuse (ltlns lc m@anisme d'une anesthGsie gdn(~r'fle. Rer. Neurol., Paris, 1951, 85: 178-188. SCHWARTZ, B. n., SEM-JACOBSEN~ C. W. :|nd PETER SEN, M. C. Effects of mescaline, LSI)-25 and adrenochrome on depth electrograms in man. Arch. Neurol. Psychiat., Chicago, 1956, 75: 579 587. ~EM-JACOBSEN, C. W.~ BICKFOI¢D, R. (~., PETERSEN, M. C. and I)ODGE, H. W. JR. 1)epth distributio~ of normal electroencephalographie rhythms, l'roc. S t a f f Meet., Mayo Clin., 1953, 2 8 : 1 5 6 161. SEM-JACOBSEN~ (J. W.~ PETERSEN, M. C., [~AZARTE. J. A., DODGE, It. W. Ja. and ttol~5~A.X, C. B. Electroencephalographie rhythms from the depth of the frontal lobe in 60 psychotic p.Ltients. EE(; Clin. :Veurophysiol., 1955, 7: 193-210. SEM-JACOBSEN, C. \V.~ PETERSEN, ~ . C., DODGE, 11. ~W. JR., LAZARTE, J. A. lind HOLMAN, C. }~. E'lec troencephalograi>hic rhythms from the depths of the 1)ariet'tl, occipital and temporal lobes in man. EEG Cli'n. N~ urophysiol., 1956, 8: 263-278. SHIMAZONO, ~1~. Eleetroencephalographic studies (u, the disturbance of consciousness. I's]tehiat. Ncurol. Jap., 1951, 53: 169-204. SPIEGEL, E. A., WYClS, It. T. and REYr% V. Di enceph'flic mechanisms in petit mql epilepsy. EE(; Clin. Neurophysiol., 1951, 3: 473-475. SPIEGEL, E. A., WYClS, 1t. T., BAIRD, I l l , II. W. and SZEKELY, E. G. Functional state of basal gangli~ in extrapyramidal and convulsive disorders. Arch. Neurol. Psychiat., Chicago, 1956, ?5: 167-174. SI;GGAR, O. illld GERARD, R. W. Anoxia qnd brab, potentials. J. Ncurophpsiol.. 1938, 1: 558-572.
Reference: OKUMA, T., SHIMAZONO,3tr. and NARABAYASHI,II. Cortical and subcortical electrograms in anestln.sia and anoxia in man. EEG Clin. Neurophysiol., 1957, 9: 609-622.
central region into the medial thalamus and other subcortical structures according to their coordinates and was fixed to the skull as illustrated in figure 1. In most cases monopolar reeordings with reference cat' electrodes and bipolar recordings with electrodes linked in sequence were used and occasionally conw~ntional scalp E E G s simultaneous with the
~D
TECHNIQUE Recording of cortical and depth electro~rams was performed on 74 patients (parkinsonism 43; double athetosis 9; epilepsy 7; feeblemindedness 4; other organic brain diseases 11) in whom stereoencephalotomy on the basal ganglia was indicated and whose electrograms could be registered in the resting state. Patients with normal or almost normal r,mline E E G s were selected. l)ur technique using multi-lead needle electrode was described previously (Okmna el al. 1954). A multi-lead needle electrode 1 ram. in diameter with 8 recording tips at intervals of I cm. was inserted stereotaxically from the
Fig. 1 ~chematical diagram of a multi-lead needle electrode. Electrode I lies in the medial nucleus of the thalamus and electrode 8 on the surface of the central cortex. Distance of electrodes is 1 cm.
1 Presented at the 3rd Annual Meeting of the Japan EEG Society (April, 1954) and at the 5th Meeting of the German EEG Society (September, 1955~.
¢.orti~al and depth recordings were obtained. All eleetrograms were recorded with an 8~,hannel Sanei Model I electroencephalograph (time constant 0.3). Surgical placement of the depth electrode was carried out under local anesthesia. Eleetrograms of the cortex and deeper structures as well as scalp were registered for about 20 rain. in the non-anesthetized state as a control. Techniques of inducing anesthesia and anoxia are described in detail under each paragraph.
609 ]
ill0
T. OKUMA, Y. SttIMAZONO and H. NARABAYASHI RESULTS
I. Intravenous and intramuscular injection of thiope~tal sodium. As reported previously, when 2.5 per cent solution of thiopental sodium was injected intravenously at the rate of 2 ee. per rain., fast activity in the cortical eleetrogram with rising amplitude appeared early followed by a gradual decrease in frequency. In a few minutes alpha activity disappeared and was replaced by 2 to 6/see. waves in cortical and depth eleetrograms as the subject loses conseiousncss. Figure 2 shows eleetrograms of a patient in whom thiopental sodium was injected intravenously and who was ordered to pull on a
before pull injection. ~ $~
pull t -
&~
shown to the right of figure 2, high voltage slow waves of 2 to 6/see. appeared in both cortical and depth electrograms, but they were suppressed and replaced by fast activity dm'ing the period in whieh the subject was pulling the string and appeared only ill the intervals of those pulling actions. The subje(:t ,ould m) longer respond to the call " 6 7 " and m) response was seen on the tracing's, which show~,d continuous slow waves of 2 to 6/see. thoroaftev. Effect of intramuscular injection of tho same drug on the cortical and depth electrograms (fig. 3) is somewhat different from that caused by intravenous administration and is noted in table I. The spindle burst appeared simultaneousl.v and ahnost synchronously in tho (.ortical and
pull
$6
no response
6Z
4 w~,~uw, a~ 7 '*'~'~%V.ff"* l- 2",-""".'~ ~'~"
..
tool,V
RO ~ ' ~ ' , # ' ~ ¢ Fig. 2 Effect of intravenous thiopental sodium. Left: before injeeti(,n. Right: stage of transition to the loss of consciousness (the amount injected is 0.2 g.). The line at the top of the tracing is lowered when the subject pulls the string in response to the examiner's calling of numbers. Note that when the subject pulls the string, slow waves are replaced by fast activity. Tho subject could not respond to the call 67 and slow waves predominate :~fterwards. string following examiner's calling of numbers (when the string is pulled a signal is recorded on the E E G tracing). As narcosis deepened fast activity with increasing voltage appeared in surface and also in depth electrode traeings. Alpha activity, however, persisted in the cortical and depth electrograms as long as the subject could pull on the string, though it showed gradual slowing. I n the stage of transition to uncouseiousness, as
thalanlie electrograms but the amplitude of cortical spindle bursts was larger than that of the thalamie eleetrogram ill both monopolar and bipolar recordings. These spindle waves reversed their phase in both eortical and thalamie levels when recorded bipolarly. Eleetrographie changes at the time of intramuscular injection of thiopental sodium are summarized as follows: the enhancement of cortical fast activity is less than that by intra-
CORTICAl, AND SUBCORT[CAL ELECTROGRAMS IN ANESTHESIA venous injection, though slight increase in amplitude is observed initially, and the wave pattern changes resemble those of natural sleep except for the large cortical fast activity. The electrogram of the caudate nucleus during barbiturate anesthesia is shown in figure 4. A multi-needle c a r r y i n g 4 electrodes was inserted in the head of the eaudate before
15
injection
rain.
611
low voltage fast activity. Intravenous inje~.tion of 2.5 per cent thiopental sodium at the rate of 2 cc. per min. produced gradual suppression of eaudate nucleus alpha activity and appearance of 4-7/see. waves. When the:subject reached the deepest stage of anesthesia, 0.5 to 3/see. slow waves of 100 to 200 ~\'. or over predominated. The stage of a,~tivation of 10 rain.
min.
3
i
L
LQ
I Sec
Fig. 3 Effect of intranmscular thiopental sodium (0.5 g.). When the subject becomes drowsy (7 min.), fast activity in the cortical region increases, while alpha activity in the cortex and depth is depressed. Ten minutes after the beginning of injection fast activity shows reduced voltage again and slow waves of around 6/see. appear in both regions. Lower tracings show spindle phase. Phase reversal both in the level of cortex m~d depth. nucleus. Electrodes 10 and 11 (electrodes distance 1 era.) were in the caudate, 13 was on the surface of the premotor cortex and 12 1 era. below the surface. As shown on the left in figure 4, clectrograms from the eaudate and thalamus were similar, containing chiefly alpha activity mixed with a small amount of
the caudate oll which Schneider ct al. (1!152) had reported on cat was not observed in man. lI. Rectal administration of chloral hydrate, Eleetrographic changes produced by rectal administration of ehloral h y d r a t e (aqueous solution of 3 g. of chloral hydrate) are similar
612
T. OKUMA, Y. SHIMAZONO and H. N A R A B A Y A S H [ TABLE I ELECTROGRAPHIC CHANGES BY I N T R A M U S C U L A R
THIOPENTAL
SODIUM
Time after injection
Before
7-10 rain.
10-15 rain.
15 nfin.
State of the subject
Awake
Drowsy
Very light sleep
Light sleep
Cortical
Alpha activity 13-3(~/see. :let.
l)ecrease of alpha act. 13-20/see. act. suppressed and replaced l/y 21-30/sec. ;let.
4-7/sec. act. nfixed with low voltage 21-3(I/see. act.
Slfin(lle burst 12-14/sec.
Of
l)eerease of Mpha
4-7/see. act.
Spindle burst 12-14/see.
(G'
:~
e l e c t r o g r : l llll
Th,dmnic eleetrogram
Alpha activity
:let,
21-3(I/sec. act. increased.
to those by intramnscuiar barbiturate (fig. 5) and are noted briefly in table I[. They are summarized as follows. In the initial stag(, fast activity in the cortical layer slightly increases its amplitude and reduces its frequency. This slight enhancement of cortical fast activity is similar to that seen under anesthesia by intramuscular barbiturate. The enhancement is more pronounced than that seen in the initial stage of natural sleep but less evideltt than that produced by intravenous harbiturate. Then cortical and depth electro-
before injection 2
I min.
grams gradually show r e d u c e d aml)litmh. again and later the wave pattern in general becomes v e r y s i m i l a r to t h a t of natm-al
sh'el).
l I I. Inhalation, of lrichloro('thylcm'. Trichloroethylene has t)een used r e c e n t l y for a short time anesthesia in s u r g e r y aml gynaeeology. It can be inhaled easily by use of a simple m o u t h piece whieh covers th,. m o u t h and the nose. In o r d e r to s(~(q|l'(' as l>uro a r e s p o n s e to t r i c h l o r o e t h y h m c as i)o~-sibh,, n o s e d a t i v e d r u g w a s g i v e n p r i o r to th,. examination.
5 rain.
~
*.I SE't_ '
:Fig. 4 Progressive changes of the electrogranl of the caudate nucleus under intravenous thiopenta! sodium. 2: thalamus. 6, 8: central cortex. 10, 11: eaudate. 12, 13: premotor cortex. Electrograms of the eaudate show similar changes to those of the thalamus. See text.
CORTICAL AND SUBCORTICAI~ EI~ECTROGRAMS IN A N E S T H E S I A
61:l
TABLE I I ELECTROGRAPHIC CHANGES BY RECTAL CHLORAL HYDRATE Time after
Before
10 min.
15 rain.
30 rain.
Awake
l)rowsy
Very light sleep
IAght sleep
Alpha activity ]3-30/see. "tot.
13-20/sec. act. reduced and 21-30/ sec. act. predomin-
4-7/see. act. Period of 13-20/ see. activity alternated with th,qt of
,~l,indh, burst
ndministration ~t~te of the
subject Cortical electrogram
nted
21-30/see. in 106(~ set'.
Thalamic
Alpha activity
Alpha act. reduced
electrogr.m~
4-7/see. act. and low voltage 21-30/
Sldmlle burst
se('. 3('t.
Figure 6 shows a ease studied on electro,:raphic changes brought about by inhalation of trichloroethylene. The outline of the (4ranges is noted in table III. Thirty seconds after the subject lost conseiousness, inhalation was discontinued and the subject was allowed to respire in the air. It was about 10 see. later when the subject
-.~2"-~a@,~
responded to the command to open his eyes. Cortical and thalamic eleetrograms changed their pattern abruptly as the ,~nbjeet regained consciousness. The voltage of fast activity in the cortex and alpha activity in cortical and depth eleetrograms showed marked increase simultaneously with the reappearance of alpha activity in the scalp EEG. ~ Cortieai
" ~ ' % ~ F ~'~'~'~
tOO~'V ! se&.
~V
Fig. 5 Changes induced by rectal chloral hydrate (3 g.). When the subject becomes drowsy (10 rain.), low voltage fast activity increases with disappearance of alpha activity. During very light sleep (15 rain.) stage of higher voltage fast activity alternates with that of lower voltage. Then slow waves of 4-7/see. appear in cortex and depth (25 min.). This stage is followed by spindle phase (30 rain.).
61-t
T. O K U M A , Y. S H I M A Z O N O a n d tI. N A R A B A Y A S H I TABLE
III
ELECTROGRAPHIC CHANGES BY T RICHL OROE T HYL E NE (BIPOLAR RECORDING) Tim(, a f t e r inhlilation
Befor(,
Stilt(, o f till, sul,je(,t
Aw:tk(,
( !orti(':ll
Ali)ha activity 13-30/see. :let.
Low voltage all)h:, ;,('t.
~,hwt l-o~ l':t lil
Th:il:lniic I'] (!('t I'O~TH
III
~0 so(..
INttALATI()N
9(I-159 st'('.
25!) set.
Slight turbidity of OOllStqOUSlleSS I)tlt resI)onsibh~
l'nr(,spmlsiv(, t[, ,.:ill tlv Ilill|l( ~
Voltage reduction of alpha and 13 20/see. act. 21-30/see. :,et. predominated
Almost sanl(, ;~s :II~ so('. Random 4-7/s(,(.. activity
4-7/se('. :wtivity
l)e(q'oilse of alpha :,(!t. l,ow voltage 21-311/ sec. act.
Randoni 4 7/se(.. activity
Almost flat with h)w 4 7/%,c. :wtiv ity
electrogram, however, showed more fast activity of 13 to 20/see. with lower voltage and less alpha activity than that of pre-inhalation period. The voltage of thalamic alpha activity was also lower in that stage. It was about 5 rain. later when wave p a t t e r n recovered to the pre-inhalation level. In this series of experiments, the authors have no ease~ w h o w a s follo~ed~,.~p,,to deeper stage of anesthesia characterized by appearance of large delta waves because of the restriction of experimental conditions. The electrographic changes by trichloroethylene iuhalation are characterized by the 1)arallel depression of fast and alpha activities in the (,ortieal and thalanfic eleetrograms. It makes a sharp contrast to those caused by intravenous barbiturate. The subject suffers from a slight degree of disturbance of consciousness when cortical and depth electrograms are predominated by slow waves of around 6/see.
IV. Nubcuta~mous and intravenous injection of Bc~mdryl. Benadryl, one of anti-histanfinies and a derivation of ethanol amine, has the ehemical structure similar to proeaine. I t is well-known that B e n a d r y l has sedative or narcotic effect on the eentral nervous system and drowsiness or sleepiness is a ehief side-effect of the drug. Some authors think that B e n a d r y l affects the cerebral cortex and others suggest it blocks
l,redon,imlted R(,mark:0)h' volt:,g,, r(,du('tion [)t' II,-:W st,(., activity
the function of tile subcortical struetm'e tTanaka 1951). When Benadryl is injected subcutaneously. most of the subjects show more or less alteration of consciousness ranging front slight drowsiness to sleep-like state, though there is considerable individual variation in the s(,nsitivity to the narcotic effect of the drug. Intraw, nous injection has more intense (,fled and some cases are i n d u c e d t o a s t a t e o f deeper anesthesia. Changes of the cortical and depth eh'drograms of a t y p i e a l case in which 60 mtz. of Benadryl was given subcutaneously (fig. 7i are noted in table IV. Intravenous injection of Benadryl has similar influence on the cortical and thalamie electrograms to subcutaneous injection, though the process of anesthesia a(tvam,es mor,' rapidly. As shown in the table, subcutaneous and intravenous Benadryl cause depression of alpha and fast activities both in cortical aml thalamic electrograms, and general course o~' electrographic changes is similar to that of natural sleep. The marked enhancement of cortical fast activity seen at the time ()f intravenous barbiturate anesthosia is not obsevved
V. Inhalation of pure nitrogc~, (.]a.~. There have been many studies of the erred of anoxia or hypoxia on the electrical activity of the brain and the state of (,onsciousm,s~.
CORTICAL AND SUBCORTICAL ELECTROGRAMS IN ANESTHESIA but r e l a t i o n s h i p s b e t w e e n the e l e c t r o g r a p h i c (.ha nges of t h e c e r e b r a l c o r t e x a n d d e e p e r .~tructures a n d a l t e r a t i o n of consciousness have not y e t been i n v e s t i g a t e d on the h m n a n subject. In o u r cases, n i t r o g e n gas was i n h a l e d by us~, of a r u b b e r m o u t h piece w i t h two o u t l e t c o v e r e d w i t h valves, w h i c h p r e v e n t n i t r o g e n before
1 to 10 a n d t h e t i m e w h e n he d i s c o n t i m t e d to c o u n t was t a k e n as a s i g n of loss of consciousness. A f t e r a few m i n u t e s of r e s p i r a t i o n in the air with scalp and depth electrodes and a m o u t h piece a t t a c h e d on the s u b j e c t , nitrogmt gas was sent to the m o u t h piece. F i g u r e 8 shows a t y p i c a l course of electrog r a p h i c c h a n g e s at the t i m e (>f nitrogm) i,~-
inhalation 9 0 SeC*
30 sec.
3-4
~'<:.'~I','~,~"~ " ~ ' ~
....
iso sec
615
"'
~,
,,
~, "
"~--
,'.~,,',~.~A,~,~~,.~
2so ~ec.
30
see. postinhal.
loo,,v.
/ oo2~ v---.--
! see.
:pig. 6 Recording during inhalation of trichloroethylene. Note progressive reduction of volt'tge of cortical fast activity. Alpha activity in the cortex and depth also disappears gradually. :Large rhythmical swings of the base line in the lower tracings are artifacts due to increased puls-/tion of the brain. gas f r o m m i x i n g w i t h e x p i r e d air. T h e m o u t h piece was c o n n e c t e d to a l a r g e D o u g l a s b a g f i l l e d w i t h n i t r o g e n gas. T h e s u b j e c t was o r d e r e d to c o u n t on his f i n g e r s f o l l o w i n g t h e e x a m i n e r ' s r e p e a t e d c a l l i n g s of n u m b e r s f r o m
h a l a t i o n r e c o r d e d b y m o n o p o l a r method. The o u t l i n e of t h e e l e c t r o g r a p h i c chan~'es is n o t e d in t a b l e V. A b o u t 55 see. a f t e r the b e g i n n i n g of inh a l a t i o n w h e n t h e s u b j e c t could c o u n l on
616
T. OKUMA, Y. SHIMAZONO and H. NARABAYASHI TABLE IV ELECTROGRAPHIC CHANGES BY SUBCUTANEOUS B E N A D R Y L
Time after injection
Before
I0 rain.
15 mill.
2(1 rain.
Stqte of the subject
Aw',ke
Drowsy
Very light sleep
Light sleep
Cortical
Alpha activity. 13-30/see. act.
Alpha and 13-20/ see. act. reduced in voltage and replaced by 21-30/ see. act.
4-T/see. act. 21-30/see. act. decre}] sed
S1)indle burst 12-14/se,..
of
Alpha qctivity
Alpha activity decreased
4-T/see. aet.
Sl)in(lh~ burst 12-14/see.
o t'
ph!(~trogrllln
Thalamie eleetrogram
fingers no more (fig. 8, a), continuous large slow waves of 2 to 5/sec. predominated in the record. The appearance of large slow waves was ahnost simultaneous in cortical and depth electrograms or a little earlier in the former. before
,'
r ~, "
~
'
inhalation of nitrogen gas was discontinued m the same time (fig. 8, b). D u r i n g the period of convulsion, the electrogram was unreadabh, because of artifacts by the movements. After 5 see. convulsion ceased (fig. 8. (,) aml sh., 25 rni~t.
20 rni~
t"i,
V~ ::h4,""'>,'°°":
o o,~V
"
I
.sec
Fig. 7 E f f e c t of subcutaneous }'enadryl (60 rag.). Fast "~nd alpha activities in the cortex and depth show reduced voltage as the subject becomes drowsy (lo rain.). Then 4-7/see. activity (15 rain., very light sleep) and spindle Bursts (20 min., sleep5 appear in all leads.
Loss o f consciousness a p p e a r e d to coincide with the continuous a p p e a r a n c e of those slow waves in the cortical and depth eleetrograms. Five seconds a f t e r the subject lost conscious1less, slight myoclonie convulsion occurred and
waves of 6/see. a p p e a r e d as a burst in cottical and depth clectrograms for 2 to 3 see. The subject begmt to count on fingers again at d (fig'. 8) and the eleetrographie p a t t e r n became similar to that of the pre-inhalati(m
CORTICAL AND SUBCORTICAL ELECTROGRAMS
IN ANESTHESIA
ill7
TABLE V E L E C T R O G R A P H I C CHANGES BY N I T R O G E N Time a f t e r inhalation
Before
.~tate of the subject
Awake
('ortic,l (.Ice? rogralll
Alpha activity.
Voltage reduc- Voltageof alpha Higher voltage
1;~ 3t}/sec. act.
tion and act.
Tlialaniic
Alpha activity
i,ll2c i r o ~ ra lit
10-20 see.
GAS I N H A L A T I O N
m ,~.
45-5(t see.
:
:
:
of alpha 13-20/see.
Voltage tion of act.
reducalpha
period abruptly. For a few minutes after the subject regained consciousness, fast and alpha a(.tivities in cortical and thalamic electrogram~ showed slight increase of voltage and duration. The fact that the subject showed slight euphoria or hypomaniaeal state in this period might be comparable to the similar phenomenon observed during recovery from barbilnrate anesthesia. before I~,~. , ~ tnhalatto~ _ ~ , ~
3(t-40 see.
lo
of alpha and 13-20/sec. act. 4-7/see. act.
Voltage of alpha act. increased
I t i g h e r voltage :alpha act.
H i g h voltage 2-5/see. act. Low voltqge fast act. superiml)osed
tligh
voltage
2-5/see. :let.
Bipolar recording on tile same subject with electrodes linked in series showed similar finding to that of monopolar recording mentioned above, but changes of amplitude and duration of cortical fast activity eouh/ be revealed more clearly and remarkably by bipolar recording (fig. 9). Loss of consciousness was coincident with the appearance of delta waves in thalamic electrogram. These
sec.
~o , e c .
+ ~
+
v
~
'
~
~
+
,
w
~
~
-~ uncon~clou*
~iO~c
Unconscious
and 13-20/see. act. increased Activity of a r o u n d 15/see. predominated
~z~,~'~-~,~
LO_~,~--~~.,-~*~-
55 s e e . -
l~a.
convulsion
~ , • __
__
c.
.
.
.
.
recow~rv 2 rain. gd. I)ost-iniml'ltion
Fig. 8
Chaages d u r i n g n i t r o g e n gas inhalation (nlonopolar r e c o r d i n g ) . F a s t activity in the cortical eleetrogram shows increased amplitude and d u r a t i o n "~nd slow wayes of a r o u n d 6/see. a p p e a r in the cortex and depth (30-40 see.). Then slow waves of 2-5/sec. p r e d o m i n a t e (50 see.) and the subject loses consciousness (a) ; b-c: clonic convulsion; d: the subject regained consciousness.
618
T. ()KUMA, Y. SHIMAZONO and tt. NARABAYASH1
changes of fast activity in the cortex which is easily revealed by use of direct recording can h a r d l y be detected by investigation of ,leetroeneephah)gram led via scalp. COMMENT Electrographie changes induced by various anesthetic drugs are divided into three groups before
and depth eleetrograms disappeared and wa~ replaced by large theta and delta waves when the subject lost consciousness (fig. 10. H and I ) . (2) Inhalation of trichloroethylene, subcutaneous and intravenous injection of Benadryl, subcutaneous injection of scopolamin,~ h y d r o b r o m i d e (reported in previous papa,r. ()kuma ct al. 1!754) produced ~'ra(hml d,,-
%nhalatiol~ 30 see.
~
Sec.
unc ons o i ous
.~o s~
11, a.
c onvul s i on
b.
"
"
"I s e c .
Fig. 9 Changes during nitrogen g'ls inlmlation (bipolar recording). Enh'~ncenwnt of the eorticM fast activity is seen evidently. Loss of consciousness coincides with ;q)pearam,e of large slow w;,ves in the dei)th and cortex. 7 E: monopolar recording. a(.eording to the s t u d y of cortical and depth eleetrograms. (1) W h e n b a r b i t u r a t e was administered intravenously, fast activity in the cortical layer showed remarkable increase of amplitude and duration in the initial stage (fig. ]0, G). Then alpha activity in cortical
pression of cortical fast activity. Alpha activity ill cortical and depth electrograms disa p p e a r e d g r a d u a l l y and was replaced by theta waves (fig. 10, B and C). These changes wet,, similar to those of n a t u r a l sleep. (:3) IG,ctal administration of chloral hydrato and intra-
('ORTICAL A N D
SUBCORTICAL
ELECTROGRAMS
muscular injection of b a r b i t u r a t e t e m p o r a r i l y caused slightly increased amplitude of cortical fast activity initially, with reduced incidence and voltage of alpha activity (fig. 10, E ) . A f t e r a while theta waves p r e d o m i n a t e d in the record (fig. 10, F ) and then a shift to the spindle phase followed. The t h i r d group of wave p a t t e r n is intermediate between the first and the second group. I n most eases a spindle phase oeeured (fig'. 10, D). The difference of wave p a t t e r n in various anesthesias was probably due to several factors. The first was the difference in the anesthetic drug itself. There are considerable variances
IN ANESTHESIA
(-;19
These facts suggest that electrographie changes in anesthesia can be explained not only by the difference in the drug, but in the mode of administration. The method of administration results in variations of d r u g concentration in the blood and brain and influences the rate of increase and decrease of the effective concentration. Nervous system function is p r o b a b l y disturbed more severely with higher concentrations of drug. It is, of course, impossible to compare the action of all anesthetic d r u g s with similar methods of administration, but in the present study each anesthetic, if possible, was given in different
natural sleep, trichloroethyleI~e, ~et~adry], ~copol~ire.
A alpha
fast
~.~-2(/~,2~-~o/,
]
chloral hydrate,
E
~
'" barbiturate
-
1
F
( intramuscular
).
I splndtl phaae
]~'ig. 1(! Nchem:~tical illustration of changes of the cortical and depth elcctrograms in w~rious am'sthesias. See text. between the electrographic changes following intravenous injection of barbiturate, classified as a brain stem narcotic by Pick (group 1 in our division), and those caused by inhalation of trichloroethylene, cortical narcotic (Pick ]927) (group 2 in our division). Subcutaneous injeetion of scopolamine hydrobromide, though classified as a brain stem narcotic by Pick, shows the electrographie changes of the second group. W h e n b a r b i t u r a t e is inj(,eted intramuscularly, enhancement of cortical fast activity is not so remarkable as that produced by the same d r u g administered intravenously, and the changes are classified as the third group in our division.
ways and effects on tile (.ortical and del)th eleetrograms were compared. The electrogram following Benadryl does not v a r y much with different routes of administration. Cortical and depth eleetrograms showed g r a d u a l diminution of amplitude without marked enhancement of cortical fast actiw ity even when the drug was giwm intravenously. A p p a r e n t l y the action of Benadryl on the central nervous system is not so strong in a given dose as that of b a r b i t u r a t e and the influence of the d r u g on nervous tissue, does not depend on the method of giving il. These facts indicate that change of the electrical activity of the brain at the time of
620
T. OK UMA, Y. SHIMAZONO and H. NARABAYASHI
anesthesia is a function of several variables: chemical s t r u c t u r e of the drug, effective concentration of the d r u g in blood, the rate of increase and decrease of the concentration, a f f i n i t y of the d r u g to any speeific structure of the brain, etc. Since the initial report by Berger, there have been m a n y studies on the electroencephalogram during anoxic state in man. In general electroencephalographic changes during anoxia or hypoxia m a y be divided into font stages: (1) stage of little alteration in E E G , (2) stage of decreased amplitude and duration of E E G , (3) stage of increased amplitude and duration of E E G and also of regularity of the wave pattern, (4) stage of r e m a r k a b l y increased amplitude and duration of waves with a p p e a r a n c e of large delta waves (Gibbs and Davis 1935; B r e m e r 1936; Davis, Davis and Thompson 1938; Gibbs and Gibbs 1941; 5Iotokawa 1947; Shimazono 1951; Kasamatsn 1952; etc.). The a p p e a r a n c e of delta waves and loss of consciousness are not always simultaneous, and in most cases a p p e a r a n c e of delta waw:s precedes loss of consciousness by several seconds. Using automatic frequency analysis Brazier (1948) reported that the dominant fre(tueney showed gradual slowing at reduced oxygen level. In our study of hypoxia change of cortical fast activity was observed which was undetectable via scalp recordings. Central cortical fast activity showed slight initial depression of amplitude followed by gradual increase of amplitude and duration. In one ease delta waves were not evident and only the slowing and enhancement of cortical fast activity were observed during loss of consciousness. Our findings suggest a correlation between cortical fast activity and eerebral cortical dysfmmti<>n with altered c<>nscionsness. Delta waves a p p e a r f r o m cortex and deep strm,tures ahnost simultaneously or a little earlier in the cortical electrogram as hypoxia progresses ~md loss <>f consciousness coincides with the c<>ntimmns delta waves in the cortex and thalamus. There haw • been m a n y stu
p a r t s of the central nervous system to ischemia were reported by S u g a r and Gerard in 1938. but most of the reports indicate that the electrical activity of the cerebral cortex and subcortical nuclei disappears simultaneously in advancing ischemia (Giinshirt et al. 1952; J u n g 1953; H i r a i et al. 1956). The diverse findings in animal and h u m a n subjects may he due to differences in experimental conditions and v a r y i n g tolerances of h u m a n and animal brains to the hypoxie state. A l p h a activity is recordable f r o m wide areas of the brain and shows parallel changes ill the cerebral cortex and subcortical regions during sleep, anesthesia and other alteration of the level of consciousness. It is suggested that alpha activity bears close relationship to brain functions which maintain consciousness. Our findings also suggest that alpha activity mechanisms in the cortex and subcortieal regions are in close relation, whether or not there may be a reverberating circuit betwee, the cortex and thalamus. D u r i n g sleep, anesthesia and hypoxia theta and delta waves a p p e a r and disappear i , eortieal and depth electrograms almost simultaneously. Spiegel ct al. (1951) reporte(I some cases of petit real epilepsy in which 3/see. spike and wave pattern a p p e a r e d in the thalamic tracing first and from the scalp lead a few seconds later. Knott, H a y n e and Meyers (1950) stated that changes of electrical activity of the brain
CORTICAL AND
SUBCORTICAL
ELECTROGRAMS
IN ANESTH ESIA
621
r a n t i n g anesthesia. The alternation of the vestigated in relation to the neural mechfast and slow p a t t e r n s during that period in- anism u n d e r l y i n g alteration of consciousness. The investigations were carried out on dicates a functional shift f r o m waking state to unconsciousness. These findings are similar patients with neurological disorders, those to those of H a y n e et al. (1949), Sere-Jacobsen being chosen with normal or near normal EEGs. ct ol. (1953, 1955), Biekford et al. (1953) 1. A u g m e n t a t i o n of cortical fast activity and other authors. Cortical fast activity increases slightly in by i n t r a m u s c u l a r thiopental sodium was not amplitude and r e g u l a r i t y a f t e r recovery front so remarkable as that caused by intravenous barhiturate anesthesia and hypoxia even when administration. A f t e r an initial stage of alpha activity r e a p p e a r e d in cortical and sub- slightly increased voltage and duration, am(.ortical tracings, and the subjects show slight plitude of cortical fast activity gradually deeuphoria in this stage. These facts suggest creased. A l p h a activity in cortical and subthat cortical fast activity is not of p r i m a r y cortical regions also disappeared and was resignificance in maintenance of eonseiousness placed by slow waves of around 6/see. In hut rather modifies the state of consciousness. several minutes spindle bursts a p p e a r e d in all In concluding this report, the authors pro- leads. W h e n the subject was awakened slight pose a hypothetical explanation of electro- increase in the voltage of cortical fast activity g'raphic changes in the cerebral cortex and persisted for a while, even though alpha deel)er structures during various kinds of al- activity r e a p p e r e d in cortical and subeortieal teration of consciousness as follows. In the regions. Eleetrographic changes by rectal stag'e in which cortical fast aetivity shows some chloral h y d r a t e were similar to those t)3' inchange but alpha activity persists in eortex t r a n m s c u l a r barbiturate. 2. Inhalation of trichloroethylene caused and thalanms and the subject is awake, fun(.gradual depression of cortical fast activity and tion of the cerebral cortex is ehiefly affected. substituted 4 to 7/see. slow waves for alpha F r o m the stage in which alpha activity disaetivity. Gradual depression of cortical and a p p e a r s and is replaced by slow waves of subcortieal electrograms was also shown by 4 to 7/see. to the stage of spindle burst, the subcutaneous and intravenous B e n a d r y l with subject cannot percept his surroundings sublittle augmentation of cortical activity. jeelively but can be awakened readily by ap3. Inhalation of p u r e nitrogen gas developpropriate stinmli. In such a stage function of eortico-dieneephalic system m a y be affected. ~ed an initial depression of eortieal and suhFinally in the stage in which large delta waves cortical activity followed by a period of inlwedominate in cortical and depth electro- creased voltage and duration. Cortical fast grams and even strong stimulus can h a r d l y activity showed gradual slowing and enhanawaken the subje(:t, the lower p a r t of the t)rain cement with advancing hypoxia. Loss ot' consciousness was ahnost coincident with afl- - caudal h y p o t h a l a n m s or midbrain - - is also affected. It seems unreasonable to divide pearance of delta waves in the cortex and anesthetic drugs into cortical and 1)rain stem depth. A f t e r the recovery of consciousness anesthetics schematic.ally. E f f e c t of various the fast activity tended to remain augmented. 4. Front the findings on the clinical and anesthetic dru~s on the central nervous system electrographie effects of anesthetics and hyIHay be analyzed Inore (dearly from the view poxia, it is sug'gested that alpha a(,tivity me('h1),lint su(.h as mentioned above. anism ix closely related to lnaintenane(! of SUMMARY waking state. Changes of (.ortieal fast activity. At the time of stereoencephah)tomy, elec- on the other hand, have no p r i m a r y signifilroaTams of the central cortex, subcortieal cance for wakefulness or loss of eollseiouslless white m a t t e r and diencephalic nuclei were re- but rather modify the state of consciousness. ('orded together with scalp E E G and effects Neural nleehanism u n d e r l y i n g alteration of of several anesthetics and hypoxia on the eonsciollsness was discussed from this view cortical and depth eleetrograms were in- point.
6'2'2
T. OKUMA, Y. StIIMAZONO and H. NARABAYASHI REFERENCES
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