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The slowly changing voltage of the brain and the electrocorticogram
THE SLOWLY CHANGING VOLTAGE OF THE BRAIN AND THE ELECTROCORTICOGRAM l ELI S. GOLDENSOHN, M.D.*, ROBERT L. SCHOENFELD, M.D. and PAUL F. A. HOEFER, M.D. Deflartment of Neurology, Columbia University College of Physicians and Surgeops, and the Neurological Institute of New York
INTRODUCTION Slowly changing voltages of the brain have been measured by Burge et d. (1936)) Burr and Harman (1939), Dusser de Barenne and McCulloch (1939)) Harman (1941)) Libet and Gerard (1941), and LeHo (1944 and 1947). Burge et al. and Burr and Harman fouad that general anesthesia caused voltages from the brain to shift pocltively with ref’erence to the sciatic nerve. Dusser de Barenne an’d McCulloch found a slow positive voltage drift in areas of the cortex associated wi.th decreased responsiveness to electrical stimulation. LeZo stated that decreased responsiveness to electrical and chemical stimulation in areas of the cortex deve!oped coincident,ly with the appearance of an initial negative v&age variation folslowed by a longer positive voltage change. LeZo also described a negative volltage variation of the brain in response ‘to prolonged anemia. In this study an attempt was m,ade to measure the slowly changing voltages between the brain and the sciatic nerve occurrjng during anoxia, carbon dioxide excess, and asphyxia and to correlate these changes with si~mmnltaneous changes in the electrocorticogram. METHOD Seventy-two procedures were performed on 19 mongrel dogs. Light surgical anesthesia was induced with 20 mg./Kg of Pentothail sodium. No Pentothal sodium was given during procedures. A parietal lobe of the cerebral cortex ‘and the proximal third of a sciatic nerve were exposed. Matched Ag-AgC1 electrodes, with polarization voltages of less than 300 pV, suspended in saline filrled medicine droppers were used. D.C. voltages were picked up with a Toennies differential amplifier having a gain of ten. The output -__-
’ This work was assisted
by a grant from the NaInstitute of Mental Health. ‘Public Health Service Research Fellow of the National Institute of Mental Heahh. Present address: Universtiy of Colorado School of Medicine, 4200 E. 9th Avenue. Denver, Colorado. tional
of the Toennies amplifier was zeroed ‘by balancing against a negative battery and brought out at low impedance by means of a cathode follower stage. D.C. volltages were indicated on the meter of a Misllivac chopper amplifier which followed the Toennies. The zero drift averaged less than 65 pV/min. A balancing control permitted zero adjustment during the procedure. D.C. voltages were monitored continuously. Continuous electrocorticograms and electrocardiograms were taken. The “non-polarizable” aectrodes were used for bipolar EEG recording. An 18 gauge needle placed in the back was used as a common ground. Up to one volt in series with the ground lead produced no visible deflection in the D.C. amplifier output. The animal was attached, by means of a tracheal canula, to an 18 L. mixing chamber, equipped with a flutter valve and breathing bag. The desired gases were admitted into the chamber at 8 to 12 L. per min.
RESULTS D.C.
VOLTAGES AND ELECTROCORTICOGRAMS
1. Control: In 72 runs on 19 animals the co&x was positive with reference to the sciatic nerve in aY but two instances. The average control D.C. voltage was 6.8 mV. The range of voltages for the entire series was -1.9 ‘to + 18.8 mV. During the cOntrol period ‘the D.C. voltage in any given animal showed only small variations. The EEG also s’howed a good deal of variability from animal to animd. Although the anesthesia was maintained as light as passiible the records generally showed the characteristic slowing associated with barbiturate anest,hesia. The domiaant frequencies were 8-16 per sec. at 5OpV. or more. Large amounts of 4-8 per sec. waves were present and often dominated the record. A considerable amount of 16-36 per sec. llow voltage activity was present and some 2-4 per sec. activity was also seen. 2. Carbon Dzoxide The inhalation of 20% CO, in 0, for 5 min. in 9 runs on 3 animals, increased the voltage between the brain and the sciatic nerve from an
232
E.S. GOLDENSOHN, R. L. SCHOENFELD and P. F. A. HOEFER
average value of 7.0 to 12.1 mV. After 15 rain. of inhalation of thi,s mixture the voltage reached 16.0 inV. Upon the removal of CO., and the substitution of O.e for 15 min. the voltage fell to 6.7 inV. The increase in voltage during the inhalation of 20% CO~ ranged from 5.0 to 12.5 mV and averaged 9.0 mV. Thus the effect of breathing 20% COz was to more than double the control D.C. voltage. The inhalation of 30% CO~ in 02 for 5 min. in 17 run~s on 8 animals, increased the voltage from the average control value of 5.7 to 11.1 mV. After 15 min. the voltage reached 14.0 inV. At the 15th min. of recovery under 100% Ou i,t had fallen :to 3.9 inV. The average increase for this series was 8.3 mV, ranging from 4.2 to 17.1 mV. Figure 1 exhibits the D.C. voltage changes during the inhalation of 30~/, CO2 at one rain. intervals. The inhalation of 40% CO2 in O2 for 5 min. in 16 runs on 6 animals, increased the voltage from 5.9 to 15.4 inV. At the 15,th rain. of inhal,at'ion, it reached 20.3 mV and it fall to 6.3
mV at the 15th min. of recovery. When 40% COy in O., was given to the anesthetized dog, respiratory arrest frequently occurred during the experimental period. When this happened CO., was withdrawn and 0.2 substituted. The average rise in voltage was 14.4 mV. The increases ranged from 4.2 ,to 17.1 mV. In table I the effects of various concentration,s of CO., upon the D.C. voltages are given in detail. The initial change in the EEG in response to the inhalation of CO~ was invariably a prompt diminution of voltage and an increase in freq.uency. The predominant frequencies were 12-35 per sec. with some low voltage fast activity up to 50 per sec. After 15 min. of the inhalation of 20 or 30% CO2 in O~ this activity was still presen,t but at much lower voltage than in the control. Forty per cent COe in O2 caused similar progressive changes but before the 15th rain. the recoM had become almost flat and only some very low vol,tage fast acti,vity was usually d,iscernible. At the 15th rain. of recovery from the inhalation of all concentrations of CO2 used the records were similar to the control in both frequency and amplitude.
Table I
D. C. VOLTAGES OF CEREBRUM WITH REFERENCE TO SCIATIC NERVE IN NINETEEN DOGS
Animal No.
A 3, 4, 14
Bejore No. o/ Runs
Gas
During moV,,
~
o- 1153
During mV'
After ,,,l7 15"
Cha,,ge mV
16.0
6.7
+9.0
9
CO2 20%
A 1, 2, 15-20
17
CO2 30%
5.7
11.1
13.4
14.0
3.9
+g.3
A 5-8, 10-13
16
CO: 40%
5.9
15.4
17.8
20.~-
6.3
+ 14.4
21
N2 100%
9~0
6.6
1.2
9.1
7.g
16
CO= 20, 30 ^^ 40% ---~.e--
--
I
A 7, 8, 10-15 16.3 - - _16. _9
9
N= 95% CO21 5%1
33
1.5
--3.3
8
CO2 30%
3.8
7.4
9.3
A 16-20
9.53.5
+7.7 --6.6
12.2
3.1
+8.4
SLOWLY CHANGING VOLTAGE OF BRAIN AND EEG
••
15
u~
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"~'\\ .
.
.
.
IE
o
,0
s
~-~-'
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so
-~s
MINUTES
Fig. 1 The slowly changing voltage of the brain with reference to the sciatic nerve during the inhalation of carbon dioxide in oxygen. 3. 100% Nitrogen (anoxia) In 21 runs on 8 animals at the 10th min. of the d~livery of 100% N2 into the mixing chamber the voltage had fallen from an average of 9.0 to 1.2 mV. The N2 admiin,is~ration was conti,nued un,til respiratory arrest ensued sometime before the 12th min. At the 15th min. of recovery with 100e/e O2 the voltage had returned .to 9.1 mV. The average decrease i,n voltage was 7.8 mV; ranging from 2.0 to 16.8 mV. The most significant decline in voltage occurred rather abruptly between the 7th and 12~h min. in contrast to the voltage rise found with the inhalation of CO2 in which the voltage change was g r a d u a l W h e n the voltage was most negative at or near the time of respiratory arrest, the voltage
,/~
201
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-
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I\
+'+7\ ....... .o,.. I \ .a
"-
V
\
o~- . . . . . . . . . . . . . . . . . . .
1
I ~d
-4
IC) ' ~20 '
310
40
50
60
'
7JO--"
8hO ' 9+0
MINUTES
Fig. 2 Typical record of a continuous series of voltage changes of the brain with reference to the sciatic nerve during the inhalation of carbon dioxide in oxygen, oxygen, and nitrogen.
233
often showed momentary fluc,tuations of several mV for a period of a few ,seconds. After one rain. of respiratory arrest the animal was resusdtated to the stage where spontaneous respiration was resumed. The voltage rose rapidly toward the baseline early in the recovery period. Various concentrations of CO~ in O2 were administered ti) ,this same .series of animals. In 16 runs the vol,tage rose from an average of 9.2 to 16.9 mV i,n 15 m,in., and returned to 9.5 mV at the 15th min. of recovery. The mean increase was 7.7 .mV as con.trasted with an average drop of 7.8 mV in the same animals with anoxia. Figure 2 contrasts ,the effects of anoxia (N2) with 4 0 % CO~ on D.C. voltages in the same animal. During the inhalation of N2 the EEG ,showed l itt.le change in the first few min. About 5 min. are required for the O2 ,tension in the chamber to fall to anoxic levels. After 5 to 7 min. the EEG showed slowing and medium to high voltage 1-6 per sec. activity became prominent. Between the 7th and 121~h min. the EEG waves began to lose ampl.i,tude and the record soon became isoelectr.ic. This occurred at abou,t the same ,time that the D.C. v~ltage of the brain reached its greatest relative negativity. These electrical changes were u.sualty coincident with the onset of respiratory arrest and cardiac arrhythm, ia. At the 15,th mi~. of recovery the EEG rhythm as well as the D.C. voltages had returned to their control v~ues. 4. 9 5 % Nz and 5% C02 (anoxia) Anoxia obtained with the inhalation of a mixture of 9 5 % N2 and 5% CO~ in 9 runs with 4 animals produced a voltage change from the average control of 3.3 to - - 3 . 3 mV at .the lOth min. At the 15th min. of recovery breathing 100% 02 the voltage returned to 3.5 mV. The voltage changes were similar to those seen in l~he 100% N2 series. The decrease i,n voltage averaged 6.6 mV; the decreases ranged from 4.2 to 10.1 inV. In table I the effects of anoxia on the D.C. voltages are given in detail. The EF_~ changes were not substantially different from those seen with 100% N2.
5. Asphyxia Four animals were kitled by clamping the trachea after breath,ing 100% O2 for 15 to 30 min. At the 5th min. after ',the trachea was clamped, the D.C. voltage had risen from 3.3 to 5.5 mV.
234
E.S. GOLDENSOHN, R. L. SCHOENFELD and P. F. A. HOEFER
95~ a 2 ~
P'¢" lqg,?iVSt¢
5S CO2
?',~-t l a ~
10Olg N2
D.C. IrOL"J~GI~ mro
an,.
*l.J
-1.5
--
~
-
5
-
-
LO-
~
O°O
Recov:~ .3.1
*l.1
,1.6,
]O$ CO2 in 0 2
•o.7 '
V
"
~
/~pHT~Ia
- o - ~
°8.2
*9.6
~
-
5
-
~
-
lO -
~
,o,6 -1.5
-
---
~
'
~
'
-
~
' ~
-2.6
R~:o,m:7 *I.I
-
15
I am, o
a.
IIm
~.
Fig." 3
Simultaneous record of the electrocorticogram and ~he slowly changing voltage of the brain with reference to the sciatic nerve during the inhalation of gas mixture s and during asphyxia. At the 10~h rain. the voltage was 4.2 inV. At the 15'th rain. i,t had fallen .to 0.9 inV. In ,two of the animals the voltage of .the 'bra'in was negati;ce in reference to the sciatic nerve at the 15,h rain. In these two animals, the voltage tended to climb toward zero soon af,ter c~inical death. The initial changes in .the EEG response after damping of the trachea were similar to ~hose seen with the administration of high coneen,tr~,tions of CO=. As signs of severe O5 deficiency developed the record .became isoelectric. Figure 3 shows typical EEG and D . C . vol.tage changes with .the inhalation of 30% CO.~, 100% N~ and 5% CO~, and with asphyxia. EKG
Duri,ng the inhal,abion o f 20% CO2 in 02 a typical EKG showed only minor changes. Slight depression of the S-T segment and a decrease in
voltage of the P wave were seen. There was ,no significant change in heart rate. In a typical record using 40% COs in which .the control record showed T wave 4nversion, the T wave becan~e up-right but of very low voltage and the S-T segment became elevated. There was no significant change in heart rate° A typical anoxia (N2) record showed the S-T segment and junction slightly depressed and the T wave diphasic in the con,trod. N o change was seen in the first 5 rain. At the 9th rain. the S-T junction was isdelect;ic, the S-T segment still depressed and the P wave vol,tage decreased. A t the 10th mi,n. pulsus bigemin.us appeared, ~he S-T segmen.t and junction were elevated, t~he T wave tLpright and tall, and the P wave vol,tage further decreased. At this time the heart rate slowed appreciably. In all ca'ses afiter 15 min. of recovery the EKG records were essen.tially the same as the controls.
SLOWLY CHANGING VOLTAGE OF BRAIN AND EEG
Respiration and blood color The initial effeot of the inhalation of all concentrations of CO2 used was to marked~ly increase the respiratory rate and amplitude. At equilibri~am, however, the depressant effects of concentrations of CO2 higher than 20% were seen and respiration slowed. The inhalation of 40% CO2 in O2 usually resulted ,in ~pnea before the 15th min. Pial and tongue color were uniformly excellent with all concer~trations of CO2 used. The admission of 100% N2 into .the chamber caused no significant ~teration in blood color or respi.rafion during the first few rain. as the O~ concentration within the chamber was still relatively high. At about the 7¢h rain. of N2 administration a marked increase in rate and amplitude of respiration occurred and blood color rapidly deteriorated. Between the 9th and 12th rain. respiratory .arrest occurred and blood color was very poor. Respiratory ,rate and color changed in essentially .the same manner with 9 5 % N2 - - 5% CO2 mixtures as with 100% N2. DISCUSSION Lorente de N6 (1947) studied the effects of various concentrations of CO2 in O2 ,and 100% N2 on demarcation voltages of peripheral nerve. He found that the surface of a .nerve segment exposed ,to CO2 mixtures became elecl?ro-posi,tive in reference to the surface of the untreated segment; and that in anoxia produced by 100% N2 the surface of the exposed segment became electronegative. Simi.l~rly,, our studies have shown that the inbalation of CO2 in O2 mixtures produced a positive voltage drift of the parietal lobe with reference to the sciatic nerve, and that the inhalation of 100% N2 caused a negative drift. However, Harman (1941) has shown that although the general anesthetics, ~s a rule, cause a posilJive voltage drift of the brain in reference to the sciatic nerve, their effect in most instances i,s to cause a negative change in the d~marca¢ion voltage of peripheral nerve. The fact that anesthetics usually cause the demarcation voltage in peripherail nerve to move in an opposite direction from ,the slow voltages of the brain may be due to the e~0perimental cond,itions employed, or as seems more probable, to the absence of a simple relationship between the slow voltage changes in the central nervous system and nerve membrane voltage.
235
Spiegel and Spiegel-Adolph (1936, 1938) measured the conductivity between eleotrodes imbedded in ,the brain substance as a function of frequency. They found that ,the ratio of high-low/ low frequency conductivity increased with anesthetics and decreased with asphyxia. This was in,terpreted by them to indicate that anesthetics decrease the ion permeability of the brain cells and that asphyxia increases ion permeability. As mentioned previously, the slowly changing voltages of the brain shift positively during anesthesia .and negatively during asphyxia. These findings suggest tha,t the slowly changing voltages of the brain may be in some way dependent upon or at least ¢elated to changes in ion permeability of its cel:lular membranes. At either extreme of slow voltage change, towards Positivity in the case of CO2 excess and anesthesia, or towards .qegativ4ty in the case of anoxia and asphyxia, the EEG is suppressed. The suppression of EEG by CO2 resembles the extinction phenomenon described by Dusser de Barenne and McCulloch (1939), in that they are both characterized by a lowering of tissue pH and a positive voltage drift. The EEG suppression with anoxia probably reflects the inability of rapidly depolarizing nerve cekls ,to fire. The negative drift in the slowly changing voltage which we found to accompany anoxia appears similar to the negative slow voltage change noted by Le~o (1947) in prolonged anemia of the brain. Each of the agen.~s we used produced characteristic and reproducible effects on both the EEG and the slowly changing voltage. For this reason it was Possible to in'fer the changes occurring in the D.C. voltage from simultaneously occurring changes in the EEG. However, a more general relationship between the slowly changing voltage of the brain an.d the EEG could ~aot be found. SUMMARY 1. Simultaneous EEG and slowly changi.ng voltage recorded from the brai,n with reference to the sciatic nerve, were measured during the inhalation of 'CO2 in 02, N2, and during asphyxia. 2. The slowly changing voltage progressively rose during CO~ admin.i,stration, witch the amount and rate of rise maximal for the highest concentration. The slowly changing voltage fell rapidly at critical levels of anoxia.
236
E . S . GOLDENSOHN, R. L. SCHOENFELD and P. F. A. HOEFER
3. The possibility of a rel~tionsh.i,p between the slow voltage changes of the br~in and the permea~bility of t.he surface films of the brain cells was 6i,scussed. 4. EEG suppression can occur witth either an extreme pOsirtiv,e or an extreme negative slow voltage change of .the brain. REFERENCES BURGE, W. E., WICKWIRE, G. C. and SCHAMP, H. M. A study of the effect of different anesthetics on the electrical potential of the brain cortex. Anesth. Analg,, 1936, 15: 261-267. 2.
SPIEGEL, E. and SHEGEL-AOoLP, M. Physiochemical mechanisms in convulsive reactivity. Proc. Soc. Exp. Biol., N.Y., 1936, 34: 799-800.
3.
SPIEGEL, E. and SPIEGEL-ADOLF,M.. Fundamental effects of ar~esth~ics and hypnotics upon the central nervous system. Arch. Int. Pharm., 1938, 58: 419.
4.
BURR, H. S. and HARMAN, P. Jr., Voltage gradients in nervous system. Amer. Neurol. Assn. Trans., 1939, 65: 11. 5. DUSSER de BARENNE, J. D. and McCuLLOCH, W. S. Factors for facilitation and extinction in the central nervous system. J. Neurophysiol., 1939, 2: 319-355. 6. HARMAN, P. J. Jr., Anesthesia and the e.m.f, of the nervous system. Yale J. Biol. Med., 1941, 14: 189-200. 7. LIBET, B. and GERARD, R. W. Steady potential fie[ds and neurone activity. J. Neurophysiol., 1941, 4: 438-455. 8. LEAO, A. A. P. Spreading depression of activity in the cerebral cortex. ]. Neurophysiol., 1944, 7: 35%390. 9. LEAO, A. A. P. Further observation on the spreading depression of activity in the cerebral cortex. J. Neurophysiol., 1947, 10: 409-414. 10. LORENTE DE N6, R. A study Of nerve physiology. New York, The Rockefeller Institute for Medical Research, 1947, 131:496 pp.
Reference: GOLDENSOHN,E. S., SCHOENFELD,R. L. and HOEFER, P. F. A. The slowly changing voltage of the brain and the eloctrocorticogram. EEG Clin. Neurophysiol., 1951, 3: 231-236.
INTRODUCTION Slowly changing voltages of the brain have been measured by Burge et d. (1936)) Burr and Harman (1939), Dusser de Barenne and McCulloch (1939)) Harman (1941)) Libet and Gerard (1941), and LeHo (1944 and 1947). Burge et al. and Burr and Harman fouad that general anesthesia caused voltages from the brain to shift pocltively with ref’erence to the sciatic nerve. Dusser de Barenne an’d McCulloch found a slow positive voltage drift in areas of the cortex associated wi.th decreased responsiveness to electrical stimulation. LeZo stated that decreased responsiveness to electrical and chemical stimulation in areas of the cortex deve!oped coincident,ly with the appearance of an initial negative v&age variation folslowed by a longer positive voltage change. LeZo also described a negative volltage variation of the brain in response ‘to prolonged anemia. In this study an attempt was m,ade to measure the slowly changing voltages between the brain and the sciatic nerve occurrjng during anoxia, carbon dioxide excess, and asphyxia and to correlate these changes with si~mmnltaneous changes in the electrocorticogram. METHOD Seventy-two procedures were performed on 19 mongrel dogs. Light surgical anesthesia was induced with 20 mg./Kg of Pentothail sodium. No Pentothal sodium was given during procedures. A parietal lobe of the cerebral cortex ‘and the proximal third of a sciatic nerve were exposed. Matched Ag-AgC1 electrodes, with polarization voltages of less than 300 pV, suspended in saline filrled medicine droppers were used. D.C. voltages were picked up with a Toennies differential amplifier having a gain of ten. The output -__-
’ This work was assisted
by a grant from the NaInstitute of Mental Health. ‘Public Health Service Research Fellow of the National Institute of Mental Heahh. Present address: Universtiy of Colorado School of Medicine, 4200 E. 9th Avenue. Denver, Colorado. tional
of the Toennies amplifier was zeroed ‘by balancing against a negative battery and brought out at low impedance by means of a cathode follower stage. D.C. volltages were indicated on the meter of a Misllivac chopper amplifier which followed the Toennies. The zero drift averaged less than 65 pV/min. A balancing control permitted zero adjustment during the procedure. D.C. voltages were monitored continuously. Continuous electrocorticograms and electrocardiograms were taken. The “non-polarizable” aectrodes were used for bipolar EEG recording. An 18 gauge needle placed in the back was used as a common ground. Up to one volt in series with the ground lead produced no visible deflection in the D.C. amplifier output. The animal was attached, by means of a tracheal canula, to an 18 L. mixing chamber, equipped with a flutter valve and breathing bag. The desired gases were admitted into the chamber at 8 to 12 L. per min.
RESULTS D.C.
VOLTAGES AND ELECTROCORTICOGRAMS
1. Control: In 72 runs on 19 animals the co&x was positive with reference to the sciatic nerve in aY but two instances. The average control D.C. voltage was 6.8 mV. The range of voltages for the entire series was -1.9 ‘to + 18.8 mV. During the cOntrol period ‘the D.C. voltage in any given animal showed only small variations. The EEG also s’howed a good deal of variability from animal to animd. Although the anesthesia was maintained as light as passiible the records generally showed the characteristic slowing associated with barbiturate anest,hesia. The domiaant frequencies were 8-16 per sec. at 5OpV. or more. Large amounts of 4-8 per sec. waves were present and often dominated the record. A considerable amount of 16-36 per sec. llow voltage activity was present and some 2-4 per sec. activity was also seen. 2. Carbon Dzoxide The inhalation of 20% CO, in 0, for 5 min. in 9 runs on 3 animals, increased the voltage between the brain and the sciatic nerve from an
232
E.S. GOLDENSOHN, R. L. SCHOENFELD and P. F. A. HOEFER
average value of 7.0 to 12.1 mV. After 15 rain. of inhalation of thi,s mixture the voltage reached 16.0 inV. Upon the removal of CO., and the substitution of O.e for 15 min. the voltage fell to 6.7 inV. The increase in voltage during the inhalation of 20% CO~ ranged from 5.0 to 12.5 mV and averaged 9.0 mV. Thus the effect of breathing 20% COz was to more than double the control D.C. voltage. The inhalation of 30% CO~ in 02 for 5 min. in 17 run~s on 8 animals, increased the voltage from the average control value of 5.7 to 11.1 mV. After 15 min. the voltage reached 14.0 inV. At the 15th min. of recovery under 100% Ou i,t had fallen :to 3.9 inV. The average increase for this series was 8.3 mV, ranging from 4.2 to 17.1 mV. Figure 1 exhibits the D.C. voltage changes during the inhalation of 30~/, CO2 at one rain. intervals. The inhalation of 40% CO2 in O2 for 5 min. in 16 runs on 6 animals, increased the voltage from 5.9 to 15.4 inV. At the 15,th rain. of inhal,at'ion, it reached 20.3 mV and it fall to 6.3
mV at the 15th min. of recovery. When 40% COy in O., was given to the anesthetized dog, respiratory arrest frequently occurred during the experimental period. When this happened CO., was withdrawn and 0.2 substituted. The average rise in voltage was 14.4 mV. The increases ranged from 4.2 ,to 17.1 mV. In table I the effects of various concentration,s of CO., upon the D.C. voltages are given in detail. The initial change in the EEG in response to the inhalation of CO~ was invariably a prompt diminution of voltage and an increase in freq.uency. The predominant frequencies were 12-35 per sec. with some low voltage fast activity up to 50 per sec. After 15 min. of the inhalation of 20 or 30% CO2 in O~ this activity was still presen,t but at much lower voltage than in the control. Forty per cent COe in O2 caused similar progressive changes but before the 15th rain. the recoM had become almost flat and only some very low vol,tage fast acti,vity was usually d,iscernible. At the 15th rain. of recovery from the inhalation of all concentrations of CO2 used the records were similar to the control in both frequency and amplitude.
Table I
D. C. VOLTAGES OF CEREBRUM WITH REFERENCE TO SCIATIC NERVE IN NINETEEN DOGS
Animal No.
A 3, 4, 14
Bejore No. o/ Runs
Gas
During moV,,
~
o- 1153
During mV'
After ,,,l7 15"
Cha,,ge mV
16.0
6.7
+9.0
9
CO2 20%
A 1, 2, 15-20
17
CO2 30%
5.7
11.1
13.4
14.0
3.9
+g.3
A 5-8, 10-13
16
CO: 40%
5.9
15.4
17.8
20.~-
6.3
+ 14.4
21
N2 100%
9~0
6.6
1.2
9.1
7.g
16
CO= 20, 30 ^^ 40% ---~.e--
--
I
A 7, 8, 10-15 16.3 - - _16. _9
9
N= 95% CO21 5%1
33
1.5
--3.3
8
CO2 30%
3.8
7.4
9.3
A 16-20
9.53.5
+7.7 --6.6
12.2
3.1
+8.4
SLOWLY CHANGING VOLTAGE OF BRAIN AND EEG
••
15
u~
°J'°~.~/,--
~
"t
3o ~ "co2 ~oo ~: @
"~'\\ .
.
.
.
IE
o
,0
s
~-~-'
2~o
so
-~s
MINUTES
Fig. 1 The slowly changing voltage of the brain with reference to the sciatic nerve during the inhalation of carbon dioxide in oxygen. 3. 100% Nitrogen (anoxia) In 21 runs on 8 animals at the 10th min. of the d~livery of 100% N2 into the mixing chamber the voltage had fallen from an average of 9.0 to 1.2 mV. The N2 admiin,is~ration was conti,nued un,til respiratory arrest ensued sometime before the 12th min. At the 15th min. of recovery with 100e/e O2 the voltage had returned .to 9.1 mV. The average decrease i,n voltage was 7.8 mV; ranging from 2.0 to 16.8 mV. The most significant decline in voltage occurred rather abruptly between the 7th and 12~h min. in contrast to the voltage rise found with the inhalation of CO2 in which the voltage change was g r a d u a l W h e n the voltage was most negative at or near the time of respiratory arrest, the voltage
,/~
201
,IO I C02 -
-
~,o=o~
I\
+'+7\ ....... .o,.. I \ .a
"-
V
\
o~- . . . . . . . . . . . . . . . . . . .
1
I ~d
-4
IC) ' ~20 '
310
40
50
60
'
7JO--"
8hO ' 9+0
MINUTES
Fig. 2 Typical record of a continuous series of voltage changes of the brain with reference to the sciatic nerve during the inhalation of carbon dioxide in oxygen, oxygen, and nitrogen.
233
often showed momentary fluc,tuations of several mV for a period of a few ,seconds. After one rain. of respiratory arrest the animal was resusdtated to the stage where spontaneous respiration was resumed. The voltage rose rapidly toward the baseline early in the recovery period. Various concentrations of CO~ in O2 were administered ti) ,this same .series of animals. In 16 runs the vol,tage rose from an average of 9.2 to 16.9 mV i,n 15 m,in., and returned to 9.5 mV at the 15th min. of recovery. The mean increase was 7.7 .mV as con.trasted with an average drop of 7.8 mV in the same animals with anoxia. Figure 2 contrasts ,the effects of anoxia (N2) with 4 0 % CO~ on D.C. voltages in the same animal. During the inhalation of N2 the EEG ,showed l itt.le change in the first few min. About 5 min. are required for the O2 ,tension in the chamber to fall to anoxic levels. After 5 to 7 min. the EEG showed slowing and medium to high voltage 1-6 per sec. activity became prominent. Between the 7th and 121~h min. the EEG waves began to lose ampl.i,tude and the record soon became isoelectr.ic. This occurred at abou,t the same ,time that the D.C. v~ltage of the brain reached its greatest relative negativity. These electrical changes were u.sualty coincident with the onset of respiratory arrest and cardiac arrhythm, ia. At the 15,th mi~. of recovery the EEG rhythm as well as the D.C. voltages had returned to their control v~ues. 4. 9 5 % Nz and 5% C02 (anoxia) Anoxia obtained with the inhalation of a mixture of 9 5 % N2 and 5% CO~ in 9 runs with 4 animals produced a voltage change from the average control of 3.3 to - - 3 . 3 mV at .the lOth min. At the 15th min. of recovery breathing 100% 02 the voltage returned to 3.5 mV. The voltage changes were similar to those seen in l~he 100% N2 series. The decrease i,n voltage averaged 6.6 mV; the decreases ranged from 4.2 to 10.1 inV. In table I the effects of anoxia on the D.C. voltages are given in detail. The EF_~ changes were not substantially different from those seen with 100% N2.
5. Asphyxia Four animals were kitled by clamping the trachea after breath,ing 100% O2 for 15 to 30 min. At the 5th min. after ',the trachea was clamped, the D.C. voltage had risen from 3.3 to 5.5 mV.
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Simultaneous record of the electrocorticogram and ~he slowly changing voltage of the brain with reference to the sciatic nerve during the inhalation of gas mixture s and during asphyxia. At the 10~h rain. the voltage was 4.2 inV. At the 15'th rain. i,t had fallen .to 0.9 inV. In ,two of the animals the voltage of .the 'bra'in was negati;ce in reference to the sciatic nerve at the 15,h rain. In these two animals, the voltage tended to climb toward zero soon af,ter c~inical death. The initial changes in .the EEG response after damping of the trachea were similar to ~hose seen with the administration of high coneen,tr~,tions of CO=. As signs of severe O5 deficiency developed the record .became isoelectric. Figure 3 shows typical EEG and D . C . vol.tage changes with .the inhalation of 30% CO.~, 100% N~ and 5% CO~, and with asphyxia. EKG
Duri,ng the inhal,abion o f 20% CO2 in 02 a typical EKG showed only minor changes. Slight depression of the S-T segment and a decrease in
voltage of the P wave were seen. There was ,no significant change in heart rate. In a typical record using 40% COs in which .the control record showed T wave 4nversion, the T wave becan~e up-right but of very low voltage and the S-T segment became elevated. There was no significant change in heart rate° A typical anoxia (N2) record showed the S-T segment and junction slightly depressed and the T wave diphasic in the con,trod. N o change was seen in the first 5 rain. At the 9th rain. the S-T junction was isdelect;ic, the S-T segment still depressed and the P wave vol,tage decreased. A t the 10th mi,n. pulsus bigemin.us appeared, ~he S-T segmen.t and junction were elevated, t~he T wave tLpright and tall, and the P wave vol,tage further decreased. At this time the heart rate slowed appreciably. In all ca'ses afiter 15 min. of recovery the EKG records were essen.tially the same as the controls.
SLOWLY CHANGING VOLTAGE OF BRAIN AND EEG
Respiration and blood color The initial effeot of the inhalation of all concentrations of CO2 used was to marked~ly increase the respiratory rate and amplitude. At equilibri~am, however, the depressant effects of concentrations of CO2 higher than 20% were seen and respiration slowed. The inhalation of 40% CO2 in O2 usually resulted ,in ~pnea before the 15th min. Pial and tongue color were uniformly excellent with all concer~trations of CO2 used. The admission of 100% N2 into .the chamber caused no significant ~teration in blood color or respi.rafion during the first few rain. as the O~ concentration within the chamber was still relatively high. At about the 7¢h rain. of N2 administration a marked increase in rate and amplitude of respiration occurred and blood color rapidly deteriorated. Between the 9th and 12th rain. respiratory .arrest occurred and blood color was very poor. Respiratory ,rate and color changed in essentially .the same manner with 9 5 % N2 - - 5% CO2 mixtures as with 100% N2. DISCUSSION Lorente de N6 (1947) studied the effects of various concentrations of CO2 in O2 ,and 100% N2 on demarcation voltages of peripheral nerve. He found that the surface of a .nerve segment exposed ,to CO2 mixtures became elecl?ro-posi,tive in reference to the surface of the untreated segment; and that in anoxia produced by 100% N2 the surface of the exposed segment became electronegative. Simi.l~rly,, our studies have shown that the inbalation of CO2 in O2 mixtures produced a positive voltage drift of the parietal lobe with reference to the sciatic nerve, and that the inhalation of 100% N2 caused a negative drift. However, Harman (1941) has shown that although the general anesthetics, ~s a rule, cause a posilJive voltage drift of the brain in reference to the sciatic nerve, their effect in most instances i,s to cause a negative change in the d~marca¢ion voltage of peripheral nerve. The fact that anesthetics usually cause the demarcation voltage in peripherail nerve to move in an opposite direction from ,the slow voltages of the brain may be due to the e~0perimental cond,itions employed, or as seems more probable, to the absence of a simple relationship between the slow voltage changes in the central nervous system and nerve membrane voltage.
235
Spiegel and Spiegel-Adolph (1936, 1938) measured the conductivity between eleotrodes imbedded in ,the brain substance as a function of frequency. They found that ,the ratio of high-low/ low frequency conductivity increased with anesthetics and decreased with asphyxia. This was in,terpreted by them to indicate that anesthetics decrease the ion permeability of the brain cells and that asphyxia increases ion permeability. As mentioned previously, the slowly changing voltages of the brain shift positively during anesthesia .and negatively during asphyxia. These findings suggest tha,t the slowly changing voltages of the brain may be in some way dependent upon or at least ¢elated to changes in ion permeability of its cel:lular membranes. At either extreme of slow voltage change, towards Positivity in the case of CO2 excess and anesthesia, or towards .qegativ4ty in the case of anoxia and asphyxia, the EEG is suppressed. The suppression of EEG by CO2 resembles the extinction phenomenon described by Dusser de Barenne and McCulloch (1939), in that they are both characterized by a lowering of tissue pH and a positive voltage drift. The EEG suppression with anoxia probably reflects the inability of rapidly depolarizing nerve cekls ,to fire. The negative drift in the slowly changing voltage which we found to accompany anoxia appears similar to the negative slow voltage change noted by Le~o (1947) in prolonged anemia of the brain. Each of the agen.~s we used produced characteristic and reproducible effects on both the EEG and the slowly changing voltage. For this reason it was Possible to in'fer the changes occurring in the D.C. voltage from simultaneously occurring changes in the EEG. However, a more general relationship between the slowly changing voltage of the brain an.d the EEG could ~aot be found. SUMMARY 1. Simultaneous EEG and slowly changi.ng voltage recorded from the brai,n with reference to the sciatic nerve, were measured during the inhalation of 'CO2 in 02, N2, and during asphyxia. 2. The slowly changing voltage progressively rose during CO~ admin.i,stration, witch the amount and rate of rise maximal for the highest concentration. The slowly changing voltage fell rapidly at critical levels of anoxia.
236
E . S . GOLDENSOHN, R. L. SCHOENFELD and P. F. A. HOEFER
3. The possibility of a rel~tionsh.i,p between the slow voltage changes of the br~in and the permea~bility of t.he surface films of the brain cells was 6i,scussed. 4. EEG suppression can occur witth either an extreme pOsirtiv,e or an extreme negative slow voltage change of .the brain. REFERENCES BURGE, W. E., WICKWIRE, G. C. and SCHAMP, H. M. A study of the effect of different anesthetics on the electrical potential of the brain cortex. Anesth. Analg,, 1936, 15: 261-267. 2.
SPIEGEL, E. and SHEGEL-AOoLP, M. Physiochemical mechanisms in convulsive reactivity. Proc. Soc. Exp. Biol., N.Y., 1936, 34: 799-800.
3.
SPIEGEL, E. and SPIEGEL-ADOLF,M.. Fundamental effects of ar~esth~ics and hypnotics upon the central nervous system. Arch. Int. Pharm., 1938, 58: 419.
4.
BURR, H. S. and HARMAN, P. Jr., Voltage gradients in nervous system. Amer. Neurol. Assn. Trans., 1939, 65: 11. 5. DUSSER de BARENNE, J. D. and McCuLLOCH, W. S. Factors for facilitation and extinction in the central nervous system. J. Neurophysiol., 1939, 2: 319-355. 6. HARMAN, P. J. Jr., Anesthesia and the e.m.f, of the nervous system. Yale J. Biol. Med., 1941, 14: 189-200. 7. LIBET, B. and GERARD, R. W. Steady potential fie[ds and neurone activity. J. Neurophysiol., 1941, 4: 438-455. 8. LEAO, A. A. P. Spreading depression of activity in the cerebral cortex. ]. Neurophysiol., 1944, 7: 35%390. 9. LEAO, A. A. P. Further observation on the spreading depression of activity in the cerebral cortex. J. Neurophysiol., 1947, 10: 409-414. 10. LORENTE DE N6, R. A study Of nerve physiology. New York, The Rockefeller Institute for Medical Research, 1947, 131:496 pp.
Reference: GOLDENSOHN,E. S., SCHOENFELD,R. L. and HOEFER, P. F. A. The slowly changing voltage of the brain and the eloctrocorticogram. EEG Clin. Neurophysiol., 1951, 3: 231-236.