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Bilateral depression in photic-evoked response as a late effect of unilateral visual cortex X-irradiation
BRAIN RESEARCH
389
B I L A T E R A L DEPRESSION IN P H O T I C - E V O K E D R E S P O N S E A S A LATE E F F E C T OF U N I L A T E R A L VISUAL C O R T E X X - I R R A D I A T I O N
A. L. CARSTEN, W. F. CAVENESS, L. ROIZIN AND J. MACHEK
(A.L.C.) MedicaI Department, Brookhaven National Laboratory, Upton, Long Island, N.Y., 11973, (W.F.C.) N.I.N.D.S., National Institutes of Health, Bethesda, Md. 20014, and ( L. R., J. M.) Columbia Unicersit),, College of Physicians and Surgeons, New York, N. Y. 10032 (U.S.A.)
(Accepted December 24th, 1969)
INTRODUCTION In a recently published monograph 2 the authors have reported in detail the functional and morphological changes following X-ray exposure of the visual cortex in the rhesus monkey. At the time of that publication data were only available to 44 weeks after exposure. However, since that time additional data have become available extending the observations to 144 weeks after irradiation. The purpose of this report is to briefly review the early findings and supplement them with long term observations. MATERIALSAND METHODS Eight groups of 3 monkeys, 24 months of age, were exposed to 3,500 rads of 250 kV X-rays localized to the visual cortex of the right occipital lobe. Using the technique previously described the exposure was limited to the right visual cortex to a depth of no greater than 1 cm. In all animals the left visual cortex was spared to serve as an unirradiated control. The techniques of inducing and evaluating evoked responses in the occipital lobe, or more exactly the visual cortex, through the use of photic stimulation of the retina have been well defined and clinically appliedT, s. In a similar manner, the Grey Walter type frequency analyzer has found application in evaluating the frequency distribution of wave forms in the normal and abnormal EEGI,9, H -14. A combination of these previously described techniques 2 has been applied to gain a greater degree of exactness in measuring EEG changes following X-irradiation. Using the apparatus shown in Fig. I, animals were exposed to a 140 sec program of alternating 10 sec periods of photic stimulation and rest. The 7 periods of stimulation were at fixed frequencies of 3, 6, 9, 10, 14, 20 and 30 flashes/sec. The resulting evoked and resting responses were displayed on the write-out of the EEG machine and simultaneously recorded on magnetic tape for subsequent frequency analysis. Brain Research, 20 (1970) 389-400
390
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Fig. 1. Block diagram of photic stimulation and frequency analysis apparatus.
RESULTS E E G observations
From the 16-channel write-out of the EEG machine, the two channels of bipolar recordings that are of primary interest were those receiving their input from the right and left parieto-occipital leads. These leads cover the region where wave patterns associated with the photic-evoked responses are maximally recorded and where, on the right, the radiation dose was delivered. For purposes of illustration, in subsequent figures the EEG write-out will be limited to that from these two channels, their spectrum analysis by the BNI frequency analyzer, and the record of the photic pulse. Base line recordings for each animal were obtained for a period of at least 3 months prior to irradiation. From these tracings, variations in amplitude of the evoked response were noted not only between animals but also from day to day in the same animal. These variations did not involve differences in amplitude of response between the right and left side in the same animal in the same recording, but rather total amplitude of response on both sides. In general, the amplitude of right and left response was essentially equal in unirradiated animals. An example of a typical pre-irradiation record is given in Fig. 2. Following irradiation the same degree of variability was evident as in the preirradiation records. However as opposed to our earlier report where data were available on a large number of animals making a summation technique readily applicable, in this case data are only available on two animals beyond 44 weeks. Therefore summation is not reasonable. As representative of the pattern of change seen in these animals the complete record of response is shown for each animal at a single frequency, i.e., animal 278 at frequency 6 and animal 279 at frequency 10 (Fig. 3). Brain Research, 20 (1970) 389-400
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As previously reported for individual monkeys, considerable variation was noted in the pattern of response, particularly for the early times after exposure. However, overriding this variability, was seen a very definite pattern of right side depression which began to develop in both animals at 15-20 weeks after exposure. This increased in severity until approximately the 25th week (Fig. 4) after which it remained constant throughout the observation period of 144 weeks. However, the factor of most interest, which was previously unreported, is that beginning at approximately the 50th week a marked periodic bilateral depression is seen. This contralateral depression on the unirradiated left side c~ntinues to develop in severity, with some modification until approximately the 80th week at which time extreme and severe depression is seen on both the right irradiated and left control side. By 90 weeks after irradiation a severe, constant bilateral depression is evident (Fig. 5). Except for slight variations this marked bilateral depression continued throughout the 144 week observation p.~riod (Figs. 6 and 7). With minor exceptions, the right and left EEG write-out and the frequency analyzer output were similar for the 90-144 week period on both animals. The only consistent difference was the slightly greater prevalence of low frequency delta rhythms on the right side in the one animal (No. 279). The presence of these 'injury' related forms was also reported as a consistent finding at earlier time periods after exposure.
Histopathology observations Histopathological studies were planned as a supplement to the functional investigations. Their primary aim was to determine the localization, development and the overall character of the central nervous system lesions. The monkeys in this series were sacrificed 144 weeks following irradiation and tissues prepared for evaluation as previously described 2,4,5. Macroscopic" observations. Both monkeys showed depilation in the irradiated occipital scalp. The skin appeared atrophic, wrinkled, scaling and showed areas with cicatrization. The subjacent skull presented areas of necrosis with cavity formation. The exposed meninges were thickened, opaque, and adherent to the underlying cerebral cortex. Microscopic observations. The expected changes in radiation necrosis of the type developing at approximately 18-20 weeks were seen in a greater degree at 144 weeks. Previous to this the defect was one mainly of impairment of the dendritic plexus, which had been observed as early as 4 weeks after expc.sure, without the degenerative or proliferative changes which appear at later times. Beyond 28 weeks histological examination indicated severe cytoarchitectural disorganization, with residual areas of necrosis, cavitation, gliosis and necrosis containing deposits of calcium. These changes, summarized in Table I, were all more severe than seen in the animals sacrificed at earlier times after irradiation. The left, unirradiated side exhibited only minor chromatolytic changes to the extent that is sometimes seen with age, physiological stress, fatigue or certain vitamin deficiencies.
Brain Research, 20 (1970) 389-400
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Fig. 6. Typical example of most severe form of bilateral depression in monkey 279, 128 weeks after irradiation at 6 c/see.
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DISCUSSION At 144 weeks following exposure o f the right visual cortex to 3,500 rads of X-irradiation there is a profound alteration in cytoarchitecture o f the irradiated area. This is associated with the degenerative and proliferative changes o f 'radiation necrosis'. O f special interest are (a) the loss of pyramidal cells; (b) the alteration o/' the dendritic ramifications in those that remain; (c) the loss and alteration of the extrinsic as well as the intrinsic fiber systems within the cortex; (d) the presence of patches of
less affected cells and processes and; (e) the lack of significant changes in the contralateral homologous cortex. In previous observations, such structural changes were evident in kind if not in degree from the 20th week following irradiation and were accompanied by distinct functional change, i.e. a marked loss in amplitude of the photic-evoked response from the affected area. What had not been demonstrated in the observations that were terminated at 44 weeks was that this loss in voltage not only persisted, but beyond
90 weeks was accompanied by an equally dramatic depression in the evoked response .from the non-irradiated homologous visual cortex. For the latter no structural basis has been .found. Until further evidence is uncovered we must assume that this effect is transmitted to the normal cortex from that damaged by the radiation. This is o f considerable theoretical interest and perhaps of practical importance. The transmission of paroxysmal activity from a discharging lesion, with overt cortical pathology, to the h o m o l o g o u s cortex in the opposite hemisphere bringing about a 'mirror focus' has been observed as a clinical phenomenon and thoroughly demonstrated in iabora-
Brain Research, 20 (1970) 389---400
UNILATERAL VISUALCORTEX X-IRRADIATION
399
tory preparations t0. The transmission of theta and delta activity from local physical or thermal trauma is not uncommon, and such transmission has been demonstrated following irradiation of the hand-face area in the monkey 4. It is somewhat easier to visualize a remote effect of an active process such as a paroxysmal discharge or theta and delta activity than simply a loss in voltage of an evoked response, particularly as the latter has been attributed to loss in neurons and impaired circuitry 3. If we attribute the loss in voltage in the non-irradiated cortex to the interdependence of homologous areas in the two hemispheres, we are dealing with a dimension in time quite out of the range of that required for the establishment of a mirror focus or contralateral appearance of theta and delta activity from acute local injury. Whether this is a negative influence from lack of functioning neuronal tissue in the irradiated area or a positive influence from the remaining elements is not clear. It is within reason that a sustained shift in the steady membrane potential or a sustained membrane conductance change could occur in the non-irradiated cortex as a consequence of the alterations on the irradiated side. Either could function to reduce the voltage change from any given synaptic input. Certainly the irradiated area is not static. Structurally there remain patches of neuronal tissue that are less damaged than the surrounding tissue, and the evoked response, though markedly reduced in voltage, is regularly elicited. Further, there is evidence of old and recent destruction in the irradiated area, e.g. calcium-like deposits and fresh lipid products. Whatever the basic mechanism for initiating this remote influence, the mode of transmission is probably via area 18 and the corpus callosum. An alternate route would be via the intralaminar or other midline integrative systems. Obviously, further precisely designed observations are required if this phenomenon is to be elucidated. Once understood it should be serviceable in the detection and localization of brain damage from ionizing radiation. ACKNOWLEDGEMENTS The authors wish to thank Mr. Kenneth Hess for his continuing effort in obtaining accurate and complete E E G records, and Miss S. Kogan for the histological preparations; Mr. Dimitri Stefani for the development and integration of new equipment into the analysis system. This research was sponsored by the United States Atomic Energy Commission and the National Institute of Neurological Diseases and Stroke, National Institutes of Health.
REFERENCES 1 BICKFORD,R. G., Scope and limitations of frequency analysis, Electroenceph. clin. Neurophysiol., Suppl. 20 (1961) 9-13. 2 C^RSr~N, A. L., Pathogenesis of X-irradiation effects in the monkey cerebral cortex. Irradiation and functional changes, Brain Research, 7 (1967) 5-27. 3 CAVENESS,W. F., CARS'rEN,A. L., RoIzIN, L., ANDSCHAD[,J. P., Pathogenesis of X-irradiation effects in the monkey cerebral cortex, Brain Research, 7 (1968) 1-120. 4 C^wr,r~ss, W. F., RoIZIN, L., Ir,rN~, J. R. M., Ar,rDCARSrEN,A., Delayed effects of X-irradiation of the central nervous system of the monkey. In T. J. HALEYANDR. S. SNIDER(Eds.), Response Brain Research, 20 (1970) 389--400
400
,',. I,. ('ARSTEN et al.
of the Nervou.s System to Ionizing Radiation, Little, Brown and Co., Boston, Mass., 1964, pp. 448 475. 5 Cox, W. H.. Impr~ignation des ccntralcn Ncrvcns>stcms mit Quecksilbersalzen, Arch. mikr. .4nat.,37(1891) 16 21. 6 Got,Gl, C.. Di una nuova reazione apparentementc nera delle cellulc nervose cerebrali ottenuta col bicloruro di mercurio, Arch. Sci. reed., 3 (1879) 1-7. 7 GOLLA, F., AYt) WINTER, A., Analysis of cerebral responses to flicker in patients complaining of episodic headache, Electroenceph. olin. Neurophysh~l., I1 (1959) 539-549. 8 IL'YANOK, V. A., Effect of intensity and pulsation depth of flickering light on the electrical activity of the human brain, Biophysics, 6 (1961) 77-82. 9 KNOT]', J. R., Some comments on automatic low frequency analysis, Electroenceph. clht. Neurophysiol., Suppl. 20 (1961) 22-24. 10 MOaREt~t., F., Physiology and histochemistry of the mirror focus. In H. H. JASPER, A. A. WaRn, JR. A.',;D A. PoPl-: (Eds.), Basic Mechanisms of the Epilepsies, Little, Brown and Co., Boston, Mass.. 1969, pp. 357 370. 11 SmPTOy, H. W., Engineering considerations in the design of waveform analysers of the Waltertype, Electroem'eph. olin. Neurophysiol., Suppl. 20 (1961) 25-27. 12 WAL]'Ea, W. G., Intrinsic rhythms of the brain. In J. FIEt.D, H. W. MAGOUN aND V. E. HAt,L (Eds.), Handbook of Physiology, Sect. I, Neurophysiology, Vol. I, Amer. physiol. Soc., Washington, D.C., 1959, pp. 279.-29~,. 13 WALTER, W. G., Frequency analysis, Electroenceph. clin. Neurophysiol., Suppl. 20 (1961) 14-21. 14 WALTER, W. G., E'r SHIPTOX, J., La pr6sentation et I'identification des composantes des rythmes alpha, Electroenceph. olin. Neurophysiol., Suppl. 6 (1957) 177-184.
Brain Research, 20 (1970) 389--400
389
B I L A T E R A L DEPRESSION IN P H O T I C - E V O K E D R E S P O N S E A S A LATE E F F E C T OF U N I L A T E R A L VISUAL C O R T E X X - I R R A D I A T I O N
A. L. CARSTEN, W. F. CAVENESS, L. ROIZIN AND J. MACHEK
(A.L.C.) MedicaI Department, Brookhaven National Laboratory, Upton, Long Island, N.Y., 11973, (W.F.C.) N.I.N.D.S., National Institutes of Health, Bethesda, Md. 20014, and ( L. R., J. M.) Columbia Unicersit),, College of Physicians and Surgeons, New York, N. Y. 10032 (U.S.A.)
(Accepted December 24th, 1969)
INTRODUCTION In a recently published monograph 2 the authors have reported in detail the functional and morphological changes following X-ray exposure of the visual cortex in the rhesus monkey. At the time of that publication data were only available to 44 weeks after exposure. However, since that time additional data have become available extending the observations to 144 weeks after irradiation. The purpose of this report is to briefly review the early findings and supplement them with long term observations. MATERIALSAND METHODS Eight groups of 3 monkeys, 24 months of age, were exposed to 3,500 rads of 250 kV X-rays localized to the visual cortex of the right occipital lobe. Using the technique previously described the exposure was limited to the right visual cortex to a depth of no greater than 1 cm. In all animals the left visual cortex was spared to serve as an unirradiated control. The techniques of inducing and evaluating evoked responses in the occipital lobe, or more exactly the visual cortex, through the use of photic stimulation of the retina have been well defined and clinically appliedT, s. In a similar manner, the Grey Walter type frequency analyzer has found application in evaluating the frequency distribution of wave forms in the normal and abnormal EEGI,9, H -14. A combination of these previously described techniques 2 has been applied to gain a greater degree of exactness in measuring EEG changes following X-irradiation. Using the apparatus shown in Fig. I, animals were exposed to a 140 sec program of alternating 10 sec periods of photic stimulation and rest. The 7 periods of stimulation were at fixed frequencies of 3, 6, 9, 10, 14, 20 and 30 flashes/sec. The resulting evoked and resting responses were displayed on the write-out of the EEG machine and simultaneously recorded on magnetic tape for subsequent frequency analysis. Brain Research, 20 (1970) 389-400
390
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I RECORDER ] MEMORY
Fig. 1. Block diagram of photic stimulation and frequency analysis apparatus.
RESULTS E E G observations
From the 16-channel write-out of the EEG machine, the two channels of bipolar recordings that are of primary interest were those receiving their input from the right and left parieto-occipital leads. These leads cover the region where wave patterns associated with the photic-evoked responses are maximally recorded and where, on the right, the radiation dose was delivered. For purposes of illustration, in subsequent figures the EEG write-out will be limited to that from these two channels, their spectrum analysis by the BNI frequency analyzer, and the record of the photic pulse. Base line recordings for each animal were obtained for a period of at least 3 months prior to irradiation. From these tracings, variations in amplitude of the evoked response were noted not only between animals but also from day to day in the same animal. These variations did not involve differences in amplitude of response between the right and left side in the same animal in the same recording, but rather total amplitude of response on both sides. In general, the amplitude of right and left response was essentially equal in unirradiated animals. An example of a typical pre-irradiation record is given in Fig. 2. Following irradiation the same degree of variability was evident as in the preirradiation records. However as opposed to our earlier report where data were available on a large number of animals making a summation technique readily applicable, in this case data are only available on two animals beyond 44 weeks. Therefore summation is not reasonable. As representative of the pattern of change seen in these animals the complete record of response is shown for each animal at a single frequency, i.e., animal 278 at frequency 6 and animal 279 at frequency 10 (Fig. 3). Brain Research, 20 (1970) 389-400
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393
As previously reported for individual monkeys, considerable variation was noted in the pattern of response, particularly for the early times after exposure. However, overriding this variability, was seen a very definite pattern of right side depression which began to develop in both animals at 15-20 weeks after exposure. This increased in severity until approximately the 25th week (Fig. 4) after which it remained constant throughout the observation period of 144 weeks. However, the factor of most interest, which was previously unreported, is that beginning at approximately the 50th week a marked periodic bilateral depression is seen. This contralateral depression on the unirradiated left side c~ntinues to develop in severity, with some modification until approximately the 80th week at which time extreme and severe depression is seen on both the right irradiated and left control side. By 90 weeks after irradiation a severe, constant bilateral depression is evident (Fig. 5). Except for slight variations this marked bilateral depression continued throughout the 144 week observation p.~riod (Figs. 6 and 7). With minor exceptions, the right and left EEG write-out and the frequency analyzer output were similar for the 90-144 week period on both animals. The only consistent difference was the slightly greater prevalence of low frequency delta rhythms on the right side in the one animal (No. 279). The presence of these 'injury' related forms was also reported as a consistent finding at earlier time periods after exposure.
Histopathology observations Histopathological studies were planned as a supplement to the functional investigations. Their primary aim was to determine the localization, development and the overall character of the central nervous system lesions. The monkeys in this series were sacrificed 144 weeks following irradiation and tissues prepared for evaluation as previously described 2,4,5. Macroscopic" observations. Both monkeys showed depilation in the irradiated occipital scalp. The skin appeared atrophic, wrinkled, scaling and showed areas with cicatrization. The subjacent skull presented areas of necrosis with cavity formation. The exposed meninges were thickened, opaque, and adherent to the underlying cerebral cortex. Microscopic observations. The expected changes in radiation necrosis of the type developing at approximately 18-20 weeks were seen in a greater degree at 144 weeks. Previous to this the defect was one mainly of impairment of the dendritic plexus, which had been observed as early as 4 weeks after expc.sure, without the degenerative or proliferative changes which appear at later times. Beyond 28 weeks histological examination indicated severe cytoarchitectural disorganization, with residual areas of necrosis, cavitation, gliosis and necrosis containing deposits of calcium. These changes, summarized in Table I, were all more severe than seen in the animals sacrificed at earlier times after irradiation. The left, unirradiated side exhibited only minor chromatolytic changes to the extent that is sometimes seen with age, physiological stress, fatigue or certain vitamin deficiencies.
Brain Research, 20 (1970) 389-400
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2O
14
25 WEEKS POST-IRRADqATION
MONKEY NUMBER 278
15,
16
18
20
22
24
27
30
Fig. 4. Typical example of depression in photic-evoked response from the irradiated side. Animal number 278, 25 weeks after irradiation, 10 c/sec.
FREQUENCY ANALYSER RECORD LEFT SIDE
FREQUENCY ANALYSER RECORD RIGffT SIDE
PHOTIC STIMU1.AT/ON
CHANNEL I"~VO - LEFT SIDE
CHANNEL ONE - RIGHT SIDE
FREQUENCY 10
[-n Z r~
r'-
4~
v
I,.3 C) 1.5 2.0
2'.5
3.0
3.5
4.0
5.0 6.0
7.0_
2O
23
8.0
10
II
12 CYCLES PER SECOND
9.0
4
3
13
14
IS
92 WEEKS POST-IRRADtAI'ION
16
18 _
4
4
20
22
24
3 27
30
2
•
,
Fig. 5. Typical example of late bilateral depression in monkey 278 at 92 weeks after irradiation, 6 c/sec. Note the marked depression with little evidence of delta or theta rhythms.
FREQU1ENCY ANALYSER RECORD LEFT SIDE
FREQUENCY ANAI.YSER RECORD RIGHT SIDE
PHOTIC STIMULATION
CHANNEl. TWO - LEFT SIDE
C H A N N E L ONE - RIGI~r SIDE
FREQUENCY 6
MONKEY NUMIIER 278
Z
-t
Ni
x
©
t-'
.<
t'-'
n'J
_z
~O
FREQUENCY ANALYSER RECORD LEFT SIDE
FREOUENCY ANALYSER RECORD RIGHT SIDE
2 3 4 5 6 7
18
14 16 18 20 CYCIES pER S E C O N D
8 9 I0 II 12
9
22 24 27 30 33
128 WEEKS POST-IRRADIATION
Fig. 6. Typical example of most severe form of bilateral depression in monkey 279, 128 weeks after irradiation at 6 c/see.
PHOTIC STIMULATION
CHANNEL TWO - LEFT SlOE
CHANNEL ONE - RIGHT SIDE
FREOUENCY 6
MONKEY NUMBER 279
"7
'H
,"3,
t'-
>
",O
O FREQUENCY ANALySER RECORD LEFT SIDE
FREQUENCY ANALYSER RECORD RIGHT SIDE
2 3 4 5 6 7
=
,~
4
14 16 18 20
_
CYCLES PE]RSECOND
8 9 10 II 12
I~.
13
133 WEEKS POST-IRRADIATION
22 24 27 30 33
_.
4
Fig. 7. Typical example of most severe form of bilateral depression in monkey 278 at 133 weeks after irradiation, 10 c/sec. Note lack of delta and theta rhythms in the analysis.
PHOTIC STIMULATION
CHANNEL TWO - LEFT SIDE
CHANNEL ONE - RIGHT SIDE
FREQUENCy 10
MONKEY NUMBER 278
Z
"--4
-t
N &
X
0
t"
N I-
.,x. l.. ('ARSi~N et al.
398 TABLE
I
144 W E E K S A F T E R
iRRADIATION
REMARKS
+ R
278 L
to severe reactions in all parameters *Btock for myelin sheath "was medially off irradiated Moderate
+ ',
.
~ i +l , + ;
+ i • J •
:---;
: .... :::-L:-t--:
"
..
+ ~
~, ,+
+ ,~o,
+ i +' ' .
+ +
I
+ I + ! +
+ +
_ _a_re_a_. . . . . . . . . . . . . . . . . .
Unremarkable.
(+)
÷ R
i
4 4
"
.I "
÷
FII. 1
: *
+
Severe reactions in all parameters. "Block for myelin sheath was medially off irradiated area,
279 L
(+1
Fkl.2,8, O.to
:-i o.... o 0
Unremarkable Nonipeclfic Minimal alterations
. . . . .
. . . . .. . . . .
o
Unremarkable
+
=
Moderate alterations
+ =
+ + = +
Necrosis
÷
Marked alterations
DISCUSSION At 144 weeks following exposure o f the right visual cortex to 3,500 rads of X-irradiation there is a profound alteration in cytoarchitecture o f the irradiated area. This is associated with the degenerative and proliferative changes o f 'radiation necrosis'. O f special interest are (a) the loss of pyramidal cells; (b) the alteration o/' the dendritic ramifications in those that remain; (c) the loss and alteration of the extrinsic as well as the intrinsic fiber systems within the cortex; (d) the presence of patches of
less affected cells and processes and; (e) the lack of significant changes in the contralateral homologous cortex. In previous observations, such structural changes were evident in kind if not in degree from the 20th week following irradiation and were accompanied by distinct functional change, i.e. a marked loss in amplitude of the photic-evoked response from the affected area. What had not been demonstrated in the observations that were terminated at 44 weeks was that this loss in voltage not only persisted, but beyond
90 weeks was accompanied by an equally dramatic depression in the evoked response .from the non-irradiated homologous visual cortex. For the latter no structural basis has been .found. Until further evidence is uncovered we must assume that this effect is transmitted to the normal cortex from that damaged by the radiation. This is o f considerable theoretical interest and perhaps of practical importance. The transmission of paroxysmal activity from a discharging lesion, with overt cortical pathology, to the h o m o l o g o u s cortex in the opposite hemisphere bringing about a 'mirror focus' has been observed as a clinical phenomenon and thoroughly demonstrated in iabora-
Brain Research, 20 (1970) 389---400
UNILATERAL VISUALCORTEX X-IRRADIATION
399
tory preparations t0. The transmission of theta and delta activity from local physical or thermal trauma is not uncommon, and such transmission has been demonstrated following irradiation of the hand-face area in the monkey 4. It is somewhat easier to visualize a remote effect of an active process such as a paroxysmal discharge or theta and delta activity than simply a loss in voltage of an evoked response, particularly as the latter has been attributed to loss in neurons and impaired circuitry 3. If we attribute the loss in voltage in the non-irradiated cortex to the interdependence of homologous areas in the two hemispheres, we are dealing with a dimension in time quite out of the range of that required for the establishment of a mirror focus or contralateral appearance of theta and delta activity from acute local injury. Whether this is a negative influence from lack of functioning neuronal tissue in the irradiated area or a positive influence from the remaining elements is not clear. It is within reason that a sustained shift in the steady membrane potential or a sustained membrane conductance change could occur in the non-irradiated cortex as a consequence of the alterations on the irradiated side. Either could function to reduce the voltage change from any given synaptic input. Certainly the irradiated area is not static. Structurally there remain patches of neuronal tissue that are less damaged than the surrounding tissue, and the evoked response, though markedly reduced in voltage, is regularly elicited. Further, there is evidence of old and recent destruction in the irradiated area, e.g. calcium-like deposits and fresh lipid products. Whatever the basic mechanism for initiating this remote influence, the mode of transmission is probably via area 18 and the corpus callosum. An alternate route would be via the intralaminar or other midline integrative systems. Obviously, further precisely designed observations are required if this phenomenon is to be elucidated. Once understood it should be serviceable in the detection and localization of brain damage from ionizing radiation. ACKNOWLEDGEMENTS The authors wish to thank Mr. Kenneth Hess for his continuing effort in obtaining accurate and complete E E G records, and Miss S. Kogan for the histological preparations; Mr. Dimitri Stefani for the development and integration of new equipment into the analysis system. This research was sponsored by the United States Atomic Energy Commission and the National Institute of Neurological Diseases and Stroke, National Institutes of Health.
REFERENCES 1 BICKFORD,R. G., Scope and limitations of frequency analysis, Electroenceph. clin. Neurophysiol., Suppl. 20 (1961) 9-13. 2 C^RSr~N, A. L., Pathogenesis of X-irradiation effects in the monkey cerebral cortex. Irradiation and functional changes, Brain Research, 7 (1967) 5-27. 3 CAVENESS,W. F., CARS'rEN,A. L., RoIzIN, L., ANDSCHAD[,J. P., Pathogenesis of X-irradiation effects in the monkey cerebral cortex, Brain Research, 7 (1968) 1-120. 4 C^wr,r~ss, W. F., RoIZIN, L., Ir,rN~, J. R. M., Ar,rDCARSrEN,A., Delayed effects of X-irradiation of the central nervous system of the monkey. In T. J. HALEYANDR. S. SNIDER(Eds.), Response Brain Research, 20 (1970) 389--400
400
,',. I,. ('ARSTEN et al.
of the Nervou.s System to Ionizing Radiation, Little, Brown and Co., Boston, Mass., 1964, pp. 448 475. 5 Cox, W. H.. Impr~ignation des ccntralcn Ncrvcns>stcms mit Quecksilbersalzen, Arch. mikr. .4nat.,37(1891) 16 21. 6 Got,Gl, C.. Di una nuova reazione apparentementc nera delle cellulc nervose cerebrali ottenuta col bicloruro di mercurio, Arch. Sci. reed., 3 (1879) 1-7. 7 GOLLA, F., AYt) WINTER, A., Analysis of cerebral responses to flicker in patients complaining of episodic headache, Electroenceph. olin. Neurophysh~l., I1 (1959) 539-549. 8 IL'YANOK, V. A., Effect of intensity and pulsation depth of flickering light on the electrical activity of the human brain, Biophysics, 6 (1961) 77-82. 9 KNOT]', J. R., Some comments on automatic low frequency analysis, Electroenceph. clht. Neurophysiol., Suppl. 20 (1961) 22-24. 10 MOaREt~t., F., Physiology and histochemistry of the mirror focus. In H. H. JASPER, A. A. WaRn, JR. A.',;D A. PoPl-: (Eds.), Basic Mechanisms of the Epilepsies, Little, Brown and Co., Boston, Mass.. 1969, pp. 357 370. 11 SmPTOy, H. W., Engineering considerations in the design of waveform analysers of the Waltertype, Electroem'eph. olin. Neurophysiol., Suppl. 20 (1961) 25-27. 12 WAL]'Ea, W. G., Intrinsic rhythms of the brain. In J. FIEt.D, H. W. MAGOUN aND V. E. HAt,L (Eds.), Handbook of Physiology, Sect. I, Neurophysiology, Vol. I, Amer. physiol. Soc., Washington, D.C., 1959, pp. 279.-29~,. 13 WALTER, W. G., Frequency analysis, Electroenceph. clin. Neurophysiol., Suppl. 20 (1961) 14-21. 14 WALTER, W. G., E'r SHIPTOX, J., La pr6sentation et I'identification des composantes des rythmes alpha, Electroenceph. olin. Neurophysiol., Suppl. 6 (1957) 177-184.
Brain Research, 20 (1970) 389--400