unit activity in experimental epileptic foci during focal cortical hypothermia

EXPERIMEKTAL NEUROLOGY 37, 164-178 (1972)

Unit Activity in Experimental Epileptic Foci During Focal

Cortical Hypothermia

JOHN I. MOSELEY, GEORGE A. OJEMANN, AND ARTHUR A. WARD,JR.I

Dcpartwmt of Nmrological Surgery, Uuiwrsity of Washiugtou.

Seattle, Washington 98195

Rccriwd Mny 22, 1972

The change in neuronal firing frequency was measured by extracellular mi-

croelectrode recordings during focal cooling of several experimental epileptic

foci, using a Peltier cooling device. The experimental epileptic foci studied included foci in cat sensory motor cortex secondary to tungstic acid, strychnine,

and freezing, and foci in monkey sensory motor cortex secondary to alumina.

Cooling of tungstic acid and strychnine foci was associated with changes in

neuron firing that were similar to those seen in normal cortex similarly cooled.

By contrast, cooling of alumina foci exhibiting spontaneous seizures was in-

variably associated with a single seizure after only a 1-3 C drop in cortical temperature followed by electrical silence persisting until rewarming. Initial

cooling of alumina foci without spontaneous seizures was similar to normal

cortex; however, repeated cooling cycles were associated with changes similar to

those seen in alumina foci exhibiting spontaneous seizures. Frozen foci showed

variable changes with cooling; occasional cells responding in a manner similar to

alumina foci exhibiting spontaneous seizures, others more like normal cortex. These findings were interpreted as suggesting that there are pathophysiologic

differences between the various experimental epileptic foci under normothermic

conditions. Membrane potentials of neurons in tungstic acid and strychnine foci are likely normal. Neurons in alumina foci may be partially depolarized under

normothermic conditions as may some but not all units in foci secondary to

freezing.

Introduction

In a previous paper the effects of focal hypothermia on single nerve cell activity in normal cat cortex were reported (6). This paper reports the effect of similar focal hypothermia on single units in several experimental epileptic models : cortical epileptic foci made with tungstic acid gel, strychnine, freezing, and alumina. The contrast in unit behavior during cooling between these foci and with normal cortex further defines some processes involved in experimental epilepsy.

1 Supported by NIH Grant NS 04053.

164 Copyright 0 1972 by Academic Press, Inc. All rights of reproduction itI any form reserved.

EPILEPTIC FOCI 165

Methods

Cats were used for the studies on strychnine, tungstic acid, and frozen foci. Monkeys (Mamca wullnta) were used for alumina foci. The basic op- erative exposure, and extracellular unit recording procedures were identical to that described preGously (6 ). Both low-frequency (l-100 Hz) and high-frequency (100-500 Hz) components of the activity recorded by the estracellular electrode were derived on some occasions.

The experimental epileptic foci were prepared as follows: tungstic acid was prepared after the method of Black, Abraham, and Ijinrd (2) and injected rapidly under the pia of sensory motor cortex using a 25-gauge nee- dle. Frozen focus was prepared at a similar site with the cataracted cry- ogenic charge.” Strychnine focus resulted from soaking a l-cm-square piece of cotton gauze with strychnine and applving this to sensory motor cortex. The alumina focus was prepared in monkey sensory motor tortes after the technique outlined by Kopeloff (5 ) and Schmidt, I\Tard and Thomas i 11) All of these monkeys developed interictal bursting over the injected focus on scalp EEG within 3 months. Some also developed spontaneous seizures. In those animals that had no spontaneous seizures, Metrozol 0.2 cc iv pre- cipitated focal seizures.

Data were obtained from 15 neurons in five cats with tmigstic acid foci, 13 neurons in four cats with frozen foci, 21 neurons in seven cats with strychnine foci, and 36 neurons in nine monkeys with alumina foci.

The technique of cooling and other components of experimental design are also identical to those described in the previous paper (6 1. Unit recording was obtained during rapid cooling to electrical silence i deep hypothermia) for all foci. Rapid cooling to levels of moderate hypothermia (27-28 C), maintatining this level for some time, n-as studied in the tungstic acid focus only.

Results

Tungstic ilcid Focus. Figure 1 is a graph of the firing frequency of a unit in the tungstic acid focus rapidly cooled to the 20-22 C range (deep hypothermia). At 35 C the cell was firing in a burst fashion (A ). \Vith cooling. bursting activity diminished and more random firing occurred, although some bursts remained to 27 C. Electrical silence occurred at 21 C. With rewarming burst activity returned. No seizure activity or high frequency repetitive firing was noted during the cooling or rewarming phases. The cell developed an increase in duration of the action potential (AP) with cooling (Fig. 1, bottom). At 35 C (B) the negative going wave

2 Manufactured by Smith, Miller and Patch, Inc., 902 Broadway, N.Y.

166 MOSELEY, OJEMANN, AND WARD

lasted 0.6 msec, the positive going wave 1.4 msec. At 22 C (E) the nega. tive going wave lasted 1 msec and the positive going wave lasted 4 msec. On rewarming, the precooled action potential duration was regained (F). These effects are the same as those previously described for normal corti. cal units undergoing similar cooling (6).

Figure 2 demonstrates the effect of rapid cooling of the tungstic acid focus to the 27-28 C range and then maintaining it at that temperature (moderate hypothermia). At normal temperatures (35 C) there was bursting activity (A). Spontaneous seizures followed by postictal depres-

2 3 4 5 6 7 8 910

C I

FIG. 1. Top: Change in IO-set samples of firing frequency of a neuron in a tungstic

acid epileptic focus in cat sensory motor cortex which was cooled as rapidly as possible to electrical silence. Bottom : A through F is the shape of the action potential

of this same neuron at the points indicated on the graph above, A and B at 35 C before cooling, C at 29 C, D at 24 C, E at 22 C, and F at 35 C, after rewarming

Cooling was to 20 C where electrical silence occurred. Calibrations: Horizontal: A :20 msec, B-F: 5 msec. Vertical: A :200 pv, B-F: 400 yv.

EPILEPTIC FOCI 167

sion, and later a resumption of bursting activity also occurred at this temperature. At 32 C firing was still present but there was less bursting com- pared to random firing (B) At 25 C after being at that temperature for 4 min, a period of high frequency repetitive firing occurred (C) followed by

E

FIG. 2. Top: Change in firing frequency of a neuron in tungstic acid focus in

sensory motor cortex of cat cooled rapidly to the 28 C level and then maintained that

level for approximately 7 min. Firing frequencies are IO-set samples. Note the marked increase in firing frequency after being maintained at the 28 C level for approxi-

matly 4 min, and the period of electrical silence that follows this until rewarming begins. Below, A-F, shows the spontaneous firing observed in the same neuron dur-

ing the same cooling cycle. A, at 35 C before cooling, shows the bursting unit activity, which becomes more random in B at 32 C during cooling; at C, the firing frequency

after being maintained at 28 C abruptly increases, followed at D by electrical silence

still at 28 C, at E rewarming is beginning at 32 C, F the return to 35 C when the bursting activity recurred. Calibrations : Vertical : 100 pv. Horizontal : 50 msec, except C, 20 msec.


electrical silence persisting for the additional 3 min the cell was maintained at 28 C (D) . Rewarming brought a return of random firing at 32 C (E) followed by bursting activity at 35 C (F). Again, electrical seizures at normal temperature levels were followed by postictal depression but now the length of the electrical silence (lo-45 set) was much shorter than the period of isoelectric activity that could be maintained after the single seizure by keeping the temperature of the focus at 28 C. Again the events during cooling were similar to those recorded during similar moderate hypothermic cooling of neurons in normal cortex in spite of the “epileptic” nature of the cells in the tungstic acid focus.

Strycl&ae Focus. The strychnine focus is characterized by waves of depolarization. After a seizure the depolarization waves tend to be better formed and have a larger amplitude than prior to the seizure. Cooling re- duced the amplitude of these waves but did not always abolish them even at temperatures associated with absence of unit activity. A graphic repre- sentation of the firing frequency for strychnine focus is shown in Fig. 3. A spontaneous seizure occurred at 35 C and extended into early cooling. This was apparently a random event as no other relation between cooling or rewarming and seizures was observed. As cooling progressed, a decrease in unit firing frequency was noted. Burst of units continued until 20 C when no activity was noted. Absence of unit firing persisted until rewarming began. Rewarming gave gradual return of bursting as well as a gradual increase in firing frequency of the cell being recorded. Figure 3 also demonstrates the change in action potential in the units in strychnine focus during cooling. At 35 C the action potential depolarization duration was 1.37 msec (A). At 22 C (D) after taking 2.4 min to cool, this duration increased to 3.9 msec. Rewarming (D) returned the AP depolarization to 1.1 msec. Thus, the strychnine focus behaves generally like normal cortex during cooling in that no seizures were consistently observed during deep hypothermia and the rate of increase in the AP duration is in the general range of that seen with normal cortex cooled similarly. When these foci demonstrated active spontaneous seizure production at normothermic temperature (35 C), cooling did not alter the pattern.

Frozen Focus. Figure 4 illustrates the change in firing frequency of several neurons in frozen foci rapidly cooled to electrical silence. Burst activity (A) and intermittent spontaneous seizure activity were converted to rather slow (lo-lS/sec) repetitive firing (C). Further cooling decreased the frequency of this (D) until absence of unit firing occurred (E). In the units sampled in frozen foci, electrical silence often occurred in the 25-25 C range, but some neurons continued to fire until the temperature reached the 20 C range. Once the isoelectric state was achieved, only rewarming would initiate neuronal activity. Early in the cooling or rewarming phase

EPILEPTIC FOCI 169

high frequency (jOO/sec) repetitive firing might be observed. as in the unit whose frequency is graphed in Fig. 4. In other units, continuous repetitive firing, but only at nloderate frequencies (2S-30/set ), occurred (4-F) : in other units only random spontaneous activity reappeared with

rewarming. Changes in action potential of a third neuron in the frozen focus are also

seen in Fig. 4 ( 1-M 1. At 35 C the XP duration was 3 nisec ( I ). :Zt 30 C

400.

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Ttme from begmnrng of Ttme from begmnrng of coolong I” m,“utes cooling I” ml”“tes

A B C D E -I

FIG. 3. Top: Change in firing frequency of a neuron in the sensory motor cortex of cat to which strychnine has been previously applied, during cooling rapidly to

electrical silence (deep hypothermia). Firing frequencies were sampled for lo-set intervals. A period of repetitive firing is observed prior to the beginning of cooling

with a short period of postictal silence after this; then there is a gradual decrease in

firing frequency until electrical silence occurs at 20 C followed by a gradual return during retvarming. Below, A-E, shows the change in action potential configuration

of another neuron in the same type of focus during similar cooling: A at 35 C,

B at 27 C, C at 25 C, D at 22 C followed by electrical silence at 21 C, and E at 35 C on rexarming. Calibrations: Horizontal: 2 msec. Vertical: 100 TV.


FIG. 4. Top: Firing frequency of a neuron in cat sensory motor cortex in the region of an epileptic focus produced by freezing, during rapid cooling to electrica’

silence at 22 C. Firing frequencies were sampled for lo-set intervals. There is ; gradual decrease in firing frequency on cooling to electrical silence, but during

rewarming a period of high-frequency repetitive firing followed by a brief electrica

silence is seen. Below, A-H, shows a brush pen record of the firing pattern of an other neuron in a similar focus. A is at 35 C, B at 34 C, C at 31 C during cooling

D at 29 C, and E, electrical silence at 28 C. F is at 30 C on rewarming, G at 33 C H at 35 C. Note the increase in firing frequencies, though not to very high fre

quency, both during cooling and particularly rewarming (F) . Horizontal calibratia is 1 sec. I-M show the change in configuration of the action potential in yet anothe

unit in the frozen focus during cooling, I at 35 C, J at 32 C, K at 30 C, L at 27 C and M at 23 C just prior to the appearance of electrical silence. Calibration: Horizon

tal: 5 msec. Vertical: 200 FLY. These three units illustrate the different patterns see in the region of the frozen focus with periods of repetitive firing, rather rarely z

EPILEPTIC FOCI 171

the cell had a greatly prolonged total AP duration of 7 msec (K), at 23 C (H ) just before the cell ceased to fire, the AP duration was lengthened to 12.5 msec (M). 0 n rewarming the normal AP duration resumed.

Thus, cooling the frozen focus differs in some ways from cooling of normal cortex. Electrical silence sometimes was seen at a higher temperature (around 28 C) than occurred during cooling of normal cortex. Repetitive firing sometimes occurred during cooling or rewarming and this was occasionally high frequency. This type of firing was never seen with rapid cooling of normal cortex to the temperature levels associated with electrical silence. In some cases this inconsistent appearance of a period of high-frequency repetitive firing during cooling or rewarming of the frozen focus may be only the chance occurrence of spontaneous nontemperature- related seizures. In others, however, there appeared to be clear association to temperature levels. Cooling the frozen focus was also associated with a more rapid lengthening of the AP duration for a given temperature drop than occurs in normal cortex similarly cooled.

JI~nlil~a Fork. Partial Focus. The partial focus was defined as those monkeys with alumina foci that had focal spiking on scalp EEG but no spontaneous seizures. These animals when stimulated with Metrazol had clinical seizures which began in the focus. Before any cooling, units in the partial focus showed bursting activity. During the initial cooling cycle, these units behaved like units in normal cortex, the AP duration gradually widening and firing ceasing at 20-22 C. On a subsequent cooling cycle, however. these units in the partial focus began to behave like units in the alumina focus with clinical seizures (active focus j . For example, one neuron in the partial focus demonstrated only random firing that persisted during the first cooling cycle to electrical silence at 22 C. On rewarming after this cooling cycle, this neuron showed burst phenomena. During a second cooling cycle, electrical silence occurred at 27 C. On rewarming after this second cycle, a seizure was seen, followed by postictal depression. Cortex at normothermic levels after this second cycle showed bursts and spontaneous seizure activity. Thus, after multiple cooling cycles, some of the partial foci would respond to cooling in the same manner as active alumina foci described below. The effect of deep hypothermia on the neuronal AP duration in the partial alumina focus was similar to that of the frozen focus as illustrated in Fig. 5. Like the frozen foci the rate of AP widening with cooling of the partial alumina focus was generally faster than that obser\-et1 in normal tortes. or tungstic acid or strychnine foci.

high frequency, during cooling or rewarming. and the temperature of electrical silence being at relatively high levels, around 28 C in some units and at much lower levels,

around 2G’Z C in others.


FIG. 5. Top: Change in configuration of the action potential during cooling of a neuron in the region of alumina focus in monkey sensory motor cortex. This is a partial alumina focus, that is, one that can be identified by EEG, but which had no spontaneous seizures although focal seizures could be evoked with the injection of Metrozol. A shows action potentials during a burst at 35 C. Cooling was then carried as rapidly as possible to electrical silence which occurred at 23 C. B is the action potential at 25 C just prior to electrical silence, and C is the configuration at 35 C

after rewarming. Calibrations: Horizontal: 10 msec. Vertical: 150 pv.

Active Focus. The sequence of events that occurred when alumina foci with spontaneous seizures (active foci) were cooled is seen in Fig. 6. Bursting activity was seen at 35 C. The bursts were prolonged with just a single-degree drop in temperature, and then progressed into a seizure with a 2 C temperature drop (B) . Seizures occurred in all units recorded in the active alumina foci with a l-3 C temperature drop. After the seizure. a prolonged state of electrical silence occurred which would last as long as the cooled state was maintained (C). Rewarming gave a return of precooling bursting activity.. At times during rewarming, a seizure would also be seen (D) A second cooling of the same unit produced the same pattern of response. Figure 6 also summarizes these changes in firing frequency with cooling of the active alumina focus, as recorded in another unit. The length of the action potential for these units was slightly increased just before electrical silence. Normal cortex also showed only a slight lengthening of the AP duration with this small a temperature drop. The magnitude of these changes is so small that any difference between alumina focus and normal cortex cannot be distinguished qualitatively from the variability within either group.

In one animal, the active alumina focus was cooled to a temperature below that associated with electrical silence and held there for varying periods of time. The focus was cooled to 26 C in 3.5 min. Electrical silence occurred at 29 C. After holding cortical temperature at 26 C for 10 min, it was rapidly rewarmed to 35 C in 1 min. Bursting activity first returned after 2 min at 35 C and a precooling level of activity returned within 3 min. When this focus was cooled a second time to 26 C and held there for

EPILEPTIC FOCI 173

25 min instead of the previous 10 min. and then once again rapidly heated to 35 C in 1 min, bursting activity first returned only after 3.5 min and was not back to precooling levels until 6 min had elapsed from rewarming.

Thus, with rapid cooling to electrical silence in an active alumina focus, a period of seizures predictably occurred with a 1-3 C. temperature drop.

FIG. 6. Firing frequency during cooling of a neuron in an alumina focus with

spontaneous clinical seizures, in monkey sensory motor cortex during rapid cooling to electrical silence. A spontaneous seizure is observed in the first minute of the record

prior to cooling. A similar seizure occurs immediately on cooling to 30 C, followed by electrical silence maintained for the duration of the time the cortex is at this

temperature. There is another period of high-frequency repetitive firing on rewarming followed by brief silence and then the precooling firing frequency returns. Below,

A-E, demonstrate the pattern of unit behavior in another neuron in a similar focus

cooled a similar way. A is at 35 C, B at 33 C, C, electrical silence at 30 C, D at 34 C on rewarming and E at 35 C after completion of rewarming. Calibrations:

Horizontal : 50 msec. Vertical : 100 hv.


This was followed by electrical silence lasting as long as the cortex was below 30 C. The longer the cortex was kept at this temperature, the longer it took for bursting and seizure activity to resume after rewarming to normothermic levels.

Discussion

In a previous communication (6) we reported two effects of focal hypothermia on units in normal cortex. When units were rapidly cooled only to moderate hypothermic levels, in the 27-29 C range and then maintained at that level over a period of S-10 min, a seizure occurred followed by electrical silence which was maintained until rewarming was started. This was interpreted as indicating that while spike-producing mechanisms remained intact at these temperature levels, gradual depolarization of the cell occurred until the threshold for repetitive firing was crossed. This effect we ascribe to hypothermic inactivation of the pump mechanism eschanging Na+ and K+ cross the cell membrane. On the other hand, if units in normal cortex were rapidly cooled to electrical silence at levels of around 20-22 C, a steady broadening of the action potential (AP) was observed until the unit ceased firing. This inactivation of spike production mechanisms with cooling we ascribed to blocking of the passive exchange of Na+ and K+ ions (through membrane pores).

Cooling of the experimental epileptic foci used the techniques of cooling as rapidly as possible to electric silence. This would be expected to show these progressive changes in action potential duration without seizures. As summarized in Table 1, this pattern was seen only for the tungstic acid z and strychnine foci and the initial cooling of the partial alumina foci. By contrast, the fully developed alumina focus cooled in the same manner, re- sponded with a seizure and then electrical silence until rewarming. This is the pattern seen in normal cortex maintained at moderate hypothermic levels. But, in contrast to normal cortex, in the alumina focus this phenomenon occurred with a minimal temperature drop of only l-3 C and required no prolonged time period at moderate hypothermic levels. The frozen focus appears to occupy an intermediate position in that a period of repetitive firing, only occasionally high frequency, was sometimes observed on cooling or rewarming. Electrical silence sometimes occurred at relatively mod- est temperatures, while on other occasions the units in the focus could be carried down to lower temperatures with a clear lengthening of L1P duration and then cessation of spike production.

These observations suggest that the various agents which produce ex-

2 Tungstic acid focus was also cooled using the technique of cooling rapidly to moderate hypothermic levels and maintaining the temperature there. It showed the

same behavior as normal cortex units, that is, a seizure followed by electrical silence.

EPILEPTIC FOc‘l 175

Smn1.4~~ OF RISJLTS

Type of focu>

Temperature at electrical silence

Alumina

‘I‘ungstic Strych- Normal acid nine Freezing Partial 0 ;\ctive

20-22 c 20-22 c 20-22 c 22-2gc 20-22 c 29-34c

Seizure5 on cooling

or rewarming - - - * - t

Slowing of action

potential just before + + + ++ ++ b

electrical silence

fL On repeated cooling behaved like active alumina focus.

D The small temperature drop at electrical silence interferes with a qualitative assess- ment of the action potential.

perimental epileptic seizures may utilize different physiologic mechanisms. Since in our analysis of cooling normal cortex, it appeared that the changes associated with cooling were principally a result of the progressive inactivation of spike production mechanisms and progressive changes in membrane potential, the observation that the units in the strychnine and tungstic acid foci behaved like those in normal cortex suggests that spike production mechanisms and membrane potential in the units in these foci are probably in the normal range. This conclusion has also been reached for the strychnine focus in cortex from other data recently summarized by Ajmone-Marson (1). Thus, many of the individual units in the cortical strychnine focus may well be normal, at least, in terms of membrane potential and spike generation, and the epileptic phenomenon in that focus are best ascribed to abnormalities in synaptic activation of these units whether this be due to alterations in the actual input to the cell or in the response of the cell to different transmitter substances. No bodv of data is available for the tungstic acid focus to either support or refute the sugges- tion that Lmits in this focus also have relatively normal membrane potential and spike production characteristics.

We have not obtained data on cooling of the penicillin focus. However, studies of unit behavior in that focus suggest that it is very similar to the strychnine focus (9j. and we would espect that it, too, probably would behave with cooling in the same manner as does normal cortex, the tungstic acid and the strychnine focus. Vastola, Roman, and Rosen ( 12 ) focally cooled penicillin foci in cat visual cortex and noted that the epileptic spikes diminished in frequency but not in amplitude in most cases. Both spont-


neous and induced seizures generally diminished below 30-32 C and remained silent as long as the cortex was below this temperature. Although not entirely analogous to the techniques we have used in cooling the other experimental foci, the lack of an increase in spontaneous seizure activity with this rate of cooling would seem to suggest that the penicillin focus was behaving more like the tungstic acid, strychnine foci and normal cortex than like the alumina focus.

In the fully developed alumina focus a temperature drop of 1-3 C was adequate to bring units in this focus to the threshold for repetitive firing. In a normal neuron this sort of temperature drop would be associated with only a 3-4 mv depolarization (8). The units in the alumina focus may be unusually sensitive to cooling so that they get far larger depolarization changes with a small temperature drop, or the focus may be partially depolarized under normothermic conditions so that this small additional depolarization brings an already low resting membrane potential across the threshold for repetitive firing. There is relatively little information from intracellular recording in the alumina focus to confirm or deny such changes in resting membrane potential levels. The available data are con- flicting (10,13).

Cells in the partial aluniina focus do not appear to be as depolarized at normal temperatures as in the active focus. Thus, the initial cooling cycle on this type of focus behaves generally in a manner similar to normal cortex, but this single cycle is now enough to further depolarize cells in the partial focus so that on a second cooling cycle they behave as those in the active alumina focus. Potassium accumulation outside cells during the initial cooling cycle might depolarize cells in partial alumina focus to the same range maintained by the active alumina focus. It was observed that the longer the active alumina focus was cooled, the longer it took for return of seizure activity after rewarming. The longer periods of cooling may be associated with even further depolarization drawing the membrane potential closer to zero (due to extracellular potassium accumulation?). With the reactivation of pumping processes upon rewarming, a longer time is now required to repolarize the membrane to levels greater than the threshold for repetitive firing.

The frozen focus appears to represent an intermediate situation between the alumina focus and the tungstic acid, and strychnine foci and normal cortex. Some of the cells cooled in the frozen focus behaved very similarly to normal cortex. Others behaved in a manlier more reminiscent of the active alumina focus. Thus one would propose that some of the units in the frozen focus, but probably not all, may be partially depolarized. Goldenson (4) has recorded intracellularly from cells in the frozen focus and has found the resting membrane potential, in some cells, to be in the normal

EPILEPTIC FOCI 177

range. However, in our data only a portion of the units in the frozen focus showed changes suggesting depolarization. Thus, a major sampling prob- lem may esist in analyzing unit behavior in this particular experimental epileptic model.

Thus, there is a class of esperimental model of epilepsy (tungstic acid, strychnine and, perhaps, penicillin) which behave in the same way as normal cortex with cooling. There is another class of experimental model of epilepsy (alumina) which shows changes in response to cooling that suggest that the normothermic cell membrane is partially depolarized. Since all the models in the first class produce epilepsy acutely. whereas epilepsy occurs chronically in the second class, one might conclude that the membrane depolarization is associated only with chronic epilepsy. However, the presence of some cells partially depolarized in the frozen focus. which pro- duces seizures acutely. indicate that this is not the case.

It is our impression that the rate of change in duration of action potential (AP) differ between the various experimental epileptic foci, an impression summarized in Table 1. At present this is only a qualitative impression : the partial alumina focus showed more rapid widening of the AP duration for a given temperature drop than did the tungstic acid and strychnine foci. The rate of AP widening with these latter foci seemed to be near the high side of the range for normal cortex. .qgain, the frozen focus appeared to be intermediate between partial alumina and strychnine- tungstic acid foci. These impressions require further confirmation and quantification. If confirmed, it appears that distinctions between the Tar- ious experimental epileptic foci are similar, whether one considers the change in firing frequency with cooling, or the rate of change in AP duration. These changes in AP duration are most likely ascribed to aItera- tions in processes intrinsic to the neuron and its membrane rather than alterations in its input. Thus, it may be that it is an intrinsic neu~-on property that differs between experimental epileptic foci.

It seems that there are fundamental differences in pathophysiology between different experimental epileptic foci in which the alumina focus, in particular, differs from the strychnine and tungstic acid models. Ward (14) has recently summarized the parallels between the alumina focus and clinical epilepsy. The alumina focus alone, among experimental epileptic foci, has chronically recurring spontaneous clinical seizures as, of course, is the case in human epilepsy. Recent studies by Calvin, Ojemann, and Ward (3) also suggested that interictal burst unit firing patterns in the alumina focus are similar to those that have been recorded in cases of human epilepsy.

In the active alumina focus, it appeared that the time from rewarming to return of seizures was progressively longer, the longer the cooling period.


This effect seems to parallel several reports (7,12) of the effect of cooling human epileptic foci for prolonged periods of time after which a number of patients have not had recurrence of their seizures. Additional documenta- tion of this effect, and the mechanisms underlying it, deserve further in- quiry.

References

1. AJMONE-MARSON, C. 1969. Acute effects of topical epileptogenic agents, pp.

299-319. 112 “Basic Mechanisms of the Epilepsies.” H. H. Jasper, A. A. Ward

and 4. Pope [Eds.], Little-Brown, Boston.

2. BLACK, R., J. ABRAHAM, AND A. A. WARD. 1967. The preparation of tungstic

acid gel and its use in the production of experimental epilepsy. Epilepsiu 8: S-63.

3. CALVIE, W., G. OJEMANN, AND A. A. WARD. 1972. Human cortical neuron in

epileptogenic foci: Comparison of interictal firing patterns to those of

“epileptic” neurons in animals. (in preparation.)

4. GOLDENSON, E. 1969. Experimental seizure mechanisms, pp. 289-298. In “Basic

Mechanisms of the Epilepsies.” H. H. Jasper, A. A. Ward, and .4. Pope [Eds.],

Little-Brown, Boston.

5. KOPELOFF, L., S. BARRERA, AND N. KOPELOFF. 1942. Recurrent convulsive seizures in animals produced by immunologic and chemical means. .-Inter. J. Psychiat.

98: 881.

6. MOSELEY, J., G. OJEMANN, AND A. A. WARD. 1972. Unit activity during focal

cortical hypothermia in the normal cortex. Esp. Nrzrrol. 37 : 152-163.

7. PASZTOR, E., AND I. TOMKA. 1969. Changes in electrocorticographic activity in

response to direct brain surface cooling in epileptic patients. Arta Physiol.

.Icad. Sci. Hmg. 36 : 277-292.

8. PIERAU, F., M. KLEE, AND R. KLUSSMAN. 1969. Effect of local “hyro-hyperther-

mia” on mammalian spinal motoneurons. Frd. Pvoc. 28: 1006-1010.

9. PRINCE, D. 1969. Microelectric studies of penicillin foci, pp. 320-328. Itt “Basic Mechanisms of the Epilepsies.” H. H. Jasper, A. A. Ward, and A. Pope [Eds.],

Little-Brown, Boston.

10. PRINCE, D., AND K. FUTAMACHI. 1970. Intracellular recordings from chronic epileptogenic foci in the monkey. Electror~~cephalogr. Clk Ncwophysiol. 29 :

496-510.

11. SCHMIDT, R., L. THOMAS, AND A. A. WARD. 1959. The hyperexcitable neuron mi-

croelectrode studies of chronic epileptic foci in monkey. J. Nr~rrophysiol. 22:

285-296.

12. VASTOLA, E., R. HOMAN, AND A. ROSEN. 1969. Inhibition of focal seizures by moderate hypothermia. Arch. Neurol. 20 : 160-165.

13. WARD, *4. A. 1966. The hyperexcitable neuron-epilepsy, pp. 379-411. In “Nerve

as a Tissue.” K. Rodahl and B. Issekutz [Eds.], Harper, New York.

14. WARD, .4. A. 1969. The epileptic neuron: Chronic foci in animals and man, pp. 263-298. In “Basic Mechanisms of the Epilepsies.” H. H. Jasper. A. A. Ward,

and A. Pope [Eds.], Little-Brown, Boston.

unit activity in experimental epileptic foci during focal cortical hypothermia

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