Further determinants of interhemispheric transfer under spreading depression

Physiology and Behavior, Vol. 7, pp. 65-71. Pergamon Press, 1971. Printed in Great Britain

Further Determinants of Interhemispheric Transfer under Spreading Depression'

A N D R E W L A N G F O R D ~, N E L S O N F R E E D M A N A N D D O U G L A S W H I T M A N

Department of Psychology, Queens University, Kingston, Ontario, Canada

(Received 30 October 1970)

LANOFORD, A., N. FREEDMAN AND D. WHITMAN. Further determinants of interhemispheric transfer under spreading depression. PHYSIOL. BEHAV. 7 (i) 65-71, 1971.--Three hypotheses of interhemispheric transfer of active and passive avoidance responding under spreading depression were examined; generalization decrement, performance decrement, and memory confinement. The finding (Experiment 1) that rats could discriminate bilaterally applied KCI concentrations was not predictable from the memory confinement hypothesis. When rats were trained with one hemisphere depressed by one KCI concentration and tested with various concentrations on the contralateral hemisphere (Experiments 2 and 3), transfer of active avoidance was chiefly a function of rats' ability to perform on test day, though some generalization to the training concentration was present. Rats trained either during high or low amplitude phases of depression showed interhemispheric transfer of a passive avoidance task, whether or not they received interdepression training; time of transfer was however dependent upon rats' ability to perform on the initial training day.

Spreading depression Interhemispheric transfer Generalization

POTAgglUM chloride (KCI) induced spreading cortical depression (SD) has been widely used recently in the study of interhemisphedc transfer of memory. The failure to find transfer when rats are trained on an active avoidance response with one hemisphere depressed and tested with the opposite hemisphere depressed, has recently been interpreted as a generalization decrement phenomenon [9]. This inter- pretation follows from the fact that stimulus conditions are altered by shifting SD from one hemisphere to the other.

An alternative to the generalization decrement explanation of interhemispheric transfer of active avoidance is the memory confinement hypothesis [1]. This hypothesis suggests that the memory trace for active avoidance is stored in the cortex of the undepressed hemisphere and only transfers with interdepression training (IDT). Amount of transfer depends on the amount of time following IDT that the receiving hemisphere is tested (consolidation). According to this view transfer should be most dependent on factors influencing consolidation.

Theoretically when rats are trained on an active avoidance response with one hemisphere depressed by one concentration of KCI applied to the dura and tested for retention on another day with various higher and lower concentrations, three possible outcomes could occur on test day; a generalization gradient about the training concentration (generalization decrement), a monotonic decreasing gradient of test concentration (performance decrement) similar to active avoidance impairment observed with bilateral application of increasing

KCI concentrations [11], or no transfer at any concentration without interdepression training (memory confinemen0.

In contrast to active avoidance, passive avoidance shows positive savings without interdepression training [2]. This phenomenon has been interpreted as being elaborated subcortically. However, it has also been demonstrated that bilateral [3, 6] and unilateral [4] SD preparations undergo phasic improvement of behaviors, temporally related to the spread of the slow potential wave to motor areas of the depressed cortex, every 6-10 min. Thus, apparent transfer of passive avoidance may occur if information is transmitted simultaneously to the depressed and non-depressed cortex during the initial training session.

Though shifting SD from one hemisphere to the other does not provide a completely adequate stimulus dimension for testing the generalization hypothesis, recent evidence suggests that KCI concentrations may be appropriate. Unilateral SD differentially modifies evoked response amplitude [4] in the depressed and non-depressed hemisphere and the amount of attenuation is a function of the concentration of KCI and EEG amplitude at the time of stimulation. Also, training rats with one hemisphere depressed with 15~o KC1 and testing for retention with the same hemisphere depressed by 10, 15 or 20% KCI produces greatest savings when training and test concentrations are identical [7]. Though these experiments do not specifically examine interhemispheric transfer, they suggest that KCI concentrations would provide an adequate stimulus dimension if they are discriminable.

tThis research was supported by grant APA 171 from the National Research Council of Canada to N. Freedman. This paper is based in part upon an undergraduate thesis presented to the Department of Psychology, Queen's University, by A. Langford. Portions of this paper have been presented at the Psychonomic Society Meetings, St. Louis, 1968, and at the International Conference on Interhemispheric Relations, Smolenica, Czechoslovakia, 1969.

2Address reprint requests to Dr. N. Freedman, Psychology Dept., Humphrey Hall, Queen's University, Kingston, Ontario, Canada.

65

66 L A N G F O R D , F R E E D M A N A N D W H I I M A N

The present studies investigated; (a) whether various concentrations of durally applied KCI could be discriminated; (b) whether training with one KC1 concentration and testing with various concentrations produces a generalization, performance decrement, or memory confinement; and, (c) whether transfer of passive avoidance could be determined by the presence or absence of EEG indicators of slow potential spread to cortical motor areas.

EXPERIMENT 1

Since further experiments were intended to subsequently test Schneider's [9, 10] stimulus control hypothesis by training rats with one KCI concentration and by testing at various other concentrations, the present experiment determined whether rats could also discriminate between the presence of different KCI concentrations on the dura.

Method

Animals. Twenty-two male hooded rats weighing approximately 300 g were housed individually and maintained on an ad lib food and water schedule throughout the experiment.

Apparatus. An activity wheel with an electrifiable grid floor of t in. stainless steel rods set ½ in, apart was used for Sidman avoidance training. The response measure was 180 ° wheel-turns. To count responses two small permanent magnets were mounted 180 ° apart on the periphery of the wheel. As the magnets rotated past a fixed reed relay the contacts closed momentarily. Contact closure initiated a pulse which was recorded on solid-state (BRS) programming and recording modules. In the second stage of training an additional 7 x 8 x 10 in. wooden box with an electrifiable grid floor of ½ in. stainless steel tubing was used for Pavlovian training [8]. In this box foot shock delivered by a Grason- Stadler Model E6070B Shock Scrambler was associated with the presence of 5 ~ of 1 0 ~ KC1 on the dura. Digital programming and recording modules (BRS) were located in a separate room.

Surgery. The animals were surgically prepared for SD according to a previously described procedure [I 1 ]. Briefly, this involved intraperitoneal anesthetization with 50 mg/kg sodium pentobarbital (Nembutal) and 0.20mg atropine sulphate (Atrosol). The exposed skull was bilaterally tre- phinated 2 mm from the lambdoidal and saggital sutures [5]. Polyethylene tubes (Intramedic, PE320), flared at the skull end, were fixed over the fenestra with cold-cure dental cement (Lang's Jet Acrylic). These tubes permitted direct dural placement of the 5 ~o or 10 ~ KCI solution, or Ringer's for control solution. The tubes were then filled with Ringer's and plugged with cotton pellets to retard evaporation; both Ringer's and cotton were changed daily.

Procedure. Prior to surgery, each rat received pretraining on the activity wheels to establish a response base. Rats were run for one hour each day on a Sidman Avoidance schedule (Response-Shock interval, 20see; Shock-Shock interval, 5 sec) in the activity wheel for three days. Shock intensity was 0 .5mA for 0.5 sec. In this schedule each wheel-turn response of 180 ° postpones shock for 20sec. When the rat does not respond shocks are delivered every 5 sec until a wheel turn response is made. Such schedules produce moderate but smooth rates of responding in one session [3].

Following 24-hr recovery from surgery, rats were retrained in the wheels on the Sidman schedule with Ringer's solution in the tubes, The following three days, rats received Paviovian

discrimination training in the small box. A 5 'J'~o and 10'I~ KCI (by weight) solution served as the CS-r (shocked solution) and C S - (non-shocked solution) respectively, for one group (n :~ 11), and as the CS-- and CS ~- respectively, for another group (n ~ 1 I).

On Day 1 of discrimination training the CS i was placed in the tubes and the rat received 36 one-mA, one-see inescapable foot-shocks in the box in a half-hour period. On Day 2, the CS-- solution was placed in the tubes, the rat was replaced in the discrimination box and no shocks were given during the half-hour. On Day 3, the CS~ was again placed in the tubes and shocks were administered as on Day 1. Following each discrimination session the CS was flushed from the tubes which were then filled with fresh Ringer's and cotton plugs. The unusual C S + , C S - , C S i Pavlovian procedure was used to maximize the possibility of discrimination (CS+ followed only by CS-- should lead to extinction) while also minimizing possible effects of repeated KCI applications.

Following the three days of discrimination training, rats were returned to the Sidman wheel with either the CS-;- or CS-- present in the tubes for one hour of testing. With typical Pavlovian conditioned stimuli (e.g. tones previously associated with shock) discrete presentations of the C S + during Sidman avoidance responding increase rate of responding relative to the pre-trial rate; the C S - decreases this rate [6, 8, 12, 13]. Of course in the present study discrete trial presentations of the C S ÷ or CS - solutions was technically unfeasible during and after discrimination training. Therefore, rate of Sidman avoidance responding in the presence of these solutions was compared to responding prior to Pavlovian discrimination training.

Gross histological examination. Brains were grossly examined at the time of surgery. In the event of dural injury there is usually excessive bleeding and collapse of blood vessels visible in the pia mater. At the end of the experiment brains were removed to determine whether further injury had occurred through infection or subsequent trauma. Rats with dural and/or cortical injury at either examination were not run. Data from rats which died in the course of the experiment was also not included. Losses for both reasons did not exceed 15 ~o in any of the reported experiments and these rats were replaced to facilitate statistical analysis.

RESULTS AND DISCUSSION

Gross histological examination revealed no visible cortical or dural damage to any of the remaining or replaced rats. The data are reported as the ratio of total responses during pre-discrimination training to the total training and test responses. Thus, a ratio of less than 0.50 indicates more responses to the discriminative solution, while a ratio greater than 0.50 indicates fewer responses to the discriminative solution relative to the last prediscrimination day base rate. The data are represented in Fig. 1. There was a significant difference in responding to the C S + and CS .... solutions (F = 18.98, d r = 1/19,p < 0.001). No significant differences resulted from using 5 ~ or 10 ~ KC1 as the CS + . Figure 1 dear ly shows increased responding to C S + and decreased responding to CS-- , irrespective of whether 5 ~ or 10~o KCI was the C S + .

It was concluded that rats could discriminate the concentration of bilaterally applied KCI on the dura. This finding confirmed and extended the conclusion that SD has certain stimulus control properties [I0].

INTERHEMISPHERIC TRANSFER AND SPREADING DEPRESSION 67

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TRAINING CONCENTRATION FIG. 1. Mean suppression ratios to CS+ and C S - KCI solutions when 10% and 5% KC1, respectively, were the CS+ solutions.

E X P E R I M E N T 2

Since durally applied KCI concentrations could be discriminated, they were used as stimuli in the same manner as wavelengths or line orientations in more typical generalization experiments to examine whether generalization decrement might account for failure of interhemispheric transfer of active avoidance under SD.

Method

Animals. Sixty male hooded rats, weighing approximately 300 g were individually housed and maintained on ad lib food and water throughout the experiment.

Procedure. The surgical procedure was identical to that outlined in Experiment 1. Following 24 hr recovery from surgery, rats were trained in the activity wheels as in Experi- ment l on a Sidman avoidance schedule for 90 min. Shock intensity was 0 . 5 m A and shock duration 0.5sec. One group (n = 30) was trained with 5% KC1 applied to one hemisphere and Ringer's applied to the other; in half the rats the 5% KC! was applied to the right hemisphere, in the other half to the left. A control group (n---- 30) was trained with Ringer's on both hemispheres. Following training, the tubes were flushed with fresh Ringer's, plugged with cotton pellets and they were returned to their home cages.

On the next day all rats were tested for interhemispheric transfer of the Sidman avoidance task for one hour with one of five KCI concentrations applied contralateral to the hemisphere which received the training concentration and Ringer's on the opposite hemisphere. In the control rats, half the rats received the KCI on the right hemisphere and

half on the left. The logarithmically related test concentrations were 1.0, 2.2, 5.0, 10.8 and 24.0% KCI [11]. Histological procedures were identical to Experiment 1.


NO dural or cortical damage was observed in any of the rats. The data are reported as percentage increase or decrease in responding (Test responses-Training responses/training responses). Positive percentages represent increased wheel turning from training to test; negative percentages, decreased wheel turning; and zero percentage, no change. Figure 2 shows the percentage change in wheel-turn responses as a function of test concentration of KCI. The gradient is seen to be an inverse linear function of test concentration, both for the KCl-trained rats and the Ringer's-trained rats. The two groups did not differ significantly but the concentration effect on test day was significant (F = 6.90, d r = 4/29, p < 0.01). There is no evidence of a substantial peak at 5% for the KC1 rats, nor at 1.0% for the Ringer's-trained rats, as would be predicted if generalization decrement alone were responsible for the transfer results. Thus, the amount of interhemispheric transfer on test day does not appear to be a function of training solution but is a function of KCI concentration used on that day.

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FIG. 2. Mean percentage change in total Sidman avoidance responses as a function of training solution and test KCI concen-

trations.

Results for the Ringer's control group might be considered to be the amount of increment or decrement in motor performance produced by retraining with unilateral concentrations of KCI. Therefore, if the mean for each Ringer's control group were subtracted from the corresponding mean for the KCI trained group, the resultant difference should roughly represent the amount of interhemispheric transfer expected on the basis of other factors such as generalization. (The authors wish to thank V. G. Reed for suggesting this analysis.) Though no appropriate statistic would apply to such data, the form of the function appears to be a generalization gradient with a peak at the 5 % KCI training concentration. Thus, interhemispheric transfer of active avoidance

68 LANGFORD, FREEDMAN AN[) Wt l I IMAN

in the present experiment may be a joint function of generalization decrement (produced by manipulating the difference in concentration from training to tes0, and performance decrement (produced by increasing test concentrations of KC1). Apparently, the more predominant effect in the present experiment was the performance deficit.


To determine whether the generalization effect was specific to the particular training and testing concentrations used, Experiment 2 was replicated using several training concentrations and linear instead of logarithmic test concentrations of KCI.

Method

Sixty additional hooded rats were surgically prepared as in Experiments 1 and 2. Following 24 hr recovery, the rats were trained on Sidman Avoidance as previously with either 5~o ( n = 2 0 ) , 15% ( n = 2 0 ) or 25~0 KC1 (n-----20) in the tube on one side and Ringer's in the other. On the next day they were tested for transfer with either 5, 10, 15, 20 or 25 % KCI in the tube on the contralatcral hemisphere and Ringer's on the initially depressed one. Linear KCI concentrations were used in preference to logarithmic ones of the previous study since a logarithmic relationship was not found.


The data are again reported as the percentage change in responding from training to test situations. Analysis of variance failed to show any significant differences between Training Groups, Concentrations, or Groups x Concen- trations interaction. Figure 3 shows the percentage change in responding from training to test as a function of test concentration of KCI. The mean percentage change in total responding averaged over the three training conctmtrations is an inverse linear function of test KCI concentration as in the previous experiment ( F l i n = 7.58, df--~ 1/45, p < 0.01). In other words, when groups are compared solely on the

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FIG. 3. Mean percentage change in total Sidman avoidance responding as a function of training and test KCl concentration.

basis of test concentration, the data tit the performance decrement hypothesis.

Again, generalization appears to play a relatively insignifi- cant role in the interhemispberic transfer of responses learned under specific KCI concentrations. However, generalization may be a minor factor in the present data as apparent peaks may he noted at 1 0 ~ for the 5% KC1 trained group; at 15% for the 15% KCI trained group; and at 20~/o for the 25% KCI trained group (Fig. 3), though there was no significant group difference.

In Experiments 2 and 3, the KCI trained groups performed better on test day when shifted from a higher to a lower test concentration and performed worse when shifted from a lower to higher concentration. Thus, though concentrations of KCI met the qualifications for differential stimuli, the presence or absence of transfer in the present active avoidance studies depended mainly upon the rat 's ability to perform on test day, and to a lesser degree upon stimulus differences between the training and test situations.


Performance deficit is not constant over the 3 -4h r depression period induced by 25 % KCI. Indeed, performance recovers and becomes impaired with the repeating spread of depression to relevant cortical areas every 6-10 min on the average [3, 4, 6]. Moreover, the amount of behavioral recovery when the EEG indicates recovery is inversely related to KC! concentration. The present study examined whether transfer of passive avoidance is related to these fluctuations in EEG and, hence, to the rat 's ability to perform during training and testing.

Method

Seventy-two male hooded rats were surgically prepared as in the previous experiments with the following exception. Two EEG recording electrodes of 00-80 stainless steel screws soldered to brass male connector pins were implanted bilaterally in the skull directly anterior to the lambdoidal suture and 4 mm lateral to the midline. A common indifferent electrode of similar construction was implanted in the nasal bone about 5 mm anterior to bregrna.

Following 24 hr recovery from surgery, rats were exposed to several days of training in a step-down apparatus, one trial per day. Table 1 summarizes the procedures used. On the first day, the rats were unilaterally depressed with 25 % KCI in one tube and Ringer's in the other. The Grason- Stadler shock generator was used to deliver a single 1-mA, 1-see foot shock when the rat stepped off a 8 x 8 in. platform onto the grids of a modified step-down apparatus. The trial was initiated when a 8 x 8 x 10 in. Plexiglas box surrounding the platform was lifted. Latency on the platform was auto- matically recorded by contact closures when the Plexiglas box was lifted and terminated when the rat stepped off the platform. While the rat was on the platform, the EEG was continuously monitored on one channel of a Grass Model 5 Polygraph. This data was simultaneously integrated using the Grass Unit Integrator. For one group (n - - 24) the step- down trial was initiated when the slope of the integral decreased to 50 per cent of its initial rate (Low Group); for the other group (n - - 24) the trial started when the slope decreased to 50 per cent of its initial rate and increased again by 50 per cent (High Group). The tubes were then rinsed and filled with Ringer's and the rats placed in their home cage.


T ~ L E 1

TRA1NING AND TESTING CONDITIONS AND INTEItDEPRILSSION CON- DITIONS FOR THE HIGH AND LOW PHASES OF EEG DEPRESSION AND FOR RINGER'S CONTROL GROUPS 1N A ONE-TRIAL STEP-DOWN

PASSIVE AVOIDANCE TASK

Day 1 Day 2 Day 3 Unilateral SD Interdepression Transfer Testing

Training Treatment Contralateral SD

6 High EEG IDT High EEG 6 High EEG IDT Low EEG 6 Low EEG IDT High EEG 6 Low EEG IDT Low EEG 6 High EEG Handling High EEG 6 High EEG Handling Low EEG 6 Low EEG Handling High EEG 6 Low EEG Handling Low EEG 6 Ringer's shock Handling Ringer's 6 Ringer's no shock Handling Ringer's 6 Ringer's shock IDT Ringer's 6 Ringer's shock No IDT Ringer's

On the following day, half the rats from each group received a single interdepression trial (IDT) identical to the previous trial in the step-down apparatus, except rats were non- depressed. The other half were only handled and replaced in their home cage (No IDT). At this time only Ringer's was present in the tubes.

On the third day of training, all rats received a test trial with 25 9/o KCI placed on the hemisphere contralateral to that depressed during initial training, and with Ringer's placed on the other. Again, one half of the animals received the test trial during a high amplitude EEG phase, the other half during low amplitude.

With these 8 groups (n = 6 per group) the amount of interhemispheric transfer to presentation of the training trial during high or low EEG amplitude was assessed. Further- more, the effect of a single interdepression trial on the interbemispheric transfer of passive avoidance was determined. Finally, the role of EEG state of the depressed contralateral hemisphere on test day was also examined.

An additional four Ringer's control groups (n = 6 per group) received either shock or no shock during training and either interdepression training or no interdepression training with Ringer's solution present in both tubes.


Since unilaterally depressed rats might tend to remain on the platform because of motor impairment I11], comparisons to non-depressed rats can not be made on the basis of step- down latency. Therefore, results are expressed as percentage change in step-down latency from training to test. Positive transfer is indicated by an increase in latency and negative transfer by a decrease. The mean percentage change in latency and standard deviations for all groups is shown in Fig. 4. In the Ringer's control groups a single step-down shock on training day increased the latency on test day by an average of 24-28 per cent, whereas this latency decreased

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EEG STATE DURING TREATMENT AND TEST

FIG. 4. Top. Per cent increase or decrease in step-off latency from treatment to test session for Ringer's control groups. Bottom. Per cent increase or decrease in step-off latency from treatment to test session as a function of EEG state during these sessions and interdepression training (white rectangles, no IDT; Cross-hatched

rectangles, IDT).

by 17 per cent without shock. Therefore, the present experimental procedures produced passive avoidance. No significant differences were found between experimental groups as a function of EEG state during training or testing, or as a function of interdepression training. A significant increase in latency ( t = 3.34, d r = 47, p < 0.01) of 19 per cent indicated that positive interhemispheric transfer of passive avoidance had occurred in all experimental groups.

On the interdepression day, latency on the platform was indicative of transfer from a unilaterally depressed to bilaterally non-depressed state. Figure 5 shows the per cent increase or decrease in latency for the Low and High trained groups. The group trained under High EEG amplitude increased their latency by 13 per cent indicating that transfer of passive avoidance had occurred. The Low group decreased their latency by 26 per cent and therefore did not show transfer. The difference between these groups was significant (t = 2.44, d f = 22,p < 0.05). Thus, interhemispheric transfer in the High group must have occurred after the first trial; interhemispheric transfer in the Low group could not have occurred until after the interdepression trial.

It is conceivable that a similar process occurred in the groups not receiving interdepression training; that is, the High group underwent transfer after one trial whereas the Low group did not transfer until the second trial was presented to the originally untrained hemisphere.

70 LANGFORD, FREEDM ANANI) WIIITMAN

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FIG. 5. Per cent increase or decrease in step-off latency from treatment to interdepression session as a function of EEG amplitude

during treatment session.

GENERAL DISCUSSION

Experiment 1 demonstrated that rats could discriminate between concentrations of KCI placed on the dura. The mechanism for such discrimination may be central (e.g. differential action of KCl concentrations upon dural receptors, or upon cerebral vasodilation) or more peripheral behavioral consequences of SD (e.g. differential motor impairment, proprioceptive feedback, etc.). The memory confinement hypothesis can not explain this discrimination since in bilateral cortical depression produced by either 5% or 10% KCI the memory trace for discrimination training would have to be stored subcortically, if at all, because cortical function is disrupted. This subcortical memory trace had no opportunity for cortical elaboration on any of the Pavlovian training days or test day, yet discrimination occurred.

Likewise, stimulus control theory makes no specific predictions about this discrimination of bilaterally applied KCI concentrations, though stimulus control probably occurred by modification of the stimulus complex in a manner similar to that suggested by Schneider [9] for unilateral depression. The data is most easily handled by the hypothesis

of differential behavioral impairment produced by the different concentrations. More importantly, this experiment demonstrates that concentrations of KCI (and consequent impairment) can be used as a stimulus continuum to test the generalization decrement hypothesis of interhemispheric transfer.

In Experiments 2 and 3, under optimal conditions for generalization decrement, training with one hemisphere depressed by one KCI concentration and testing for interhemispheric transfer with the opposite hemisphere depressed by varying concentrations produced positive transfer to test concentrations lower than training concentrations and negative transfer to those that were higher. Transfer was a monotonic decreasing function of test concentration. According to the generalization decrement hypothesis positive transfer should only have occurred when training and test concentrations were identical. According to the memory confinement hypothesis transfer of active avoidance should only occur with inter-depression training (when memory traces are elaborated in cortex of both hemispheres simultaneously). Since no interdepression training was used in these experiments transfer should not have occurred. The present data, on the other hand, show that interhemispheric transfer depends mainly on the rats ability to perform on test day and performance in turn is dependent upon the KCI concentrations used. These results are not predicted by either of the prevalent views of interhemispheric transfer.

Performance during SD also varies with the EEG state of the motor cortex [3, 6]. Thus, interhemispheric transfer of passive avoidance may also depend upon performance variables. Consistent with experiments using similar techniques [2, 9], Experiment 4 demonstrated apparent interhemispheric transfer of passive avoidance. However, the day of transfer was a function of the EEG state during training; again not predicted by memory confinement or stimulus generalization notions.

Transfer of active avoidance in the present studies was chiefly dependent on the rat 's ability to perform on test days. Performance in turn is dependent upon the relative occurrence of high and low amplitude EEG phases during depression which apparently change in number and effectiveness as a function of KCI concentrations [3, 6]. Conversely, transfer of passive avoidance appears independent of performance, but the time of transfer depends on the EEG state during training. Techniques which ensure constant unilateral depression or which ensure training and testing during low EEG amplitude would eliminate performance variation during the varying EEG states as explanations of inter- hemisnheric transfer.

REFERENCES

1. Albert, D. J. The effect of spreading depression on the consolidation of learning. Neuropsychologia 4: 49-64, 1966.

2. Buret, J., O. Bure~ov~i and E. Fifkovgt. Interhemispheric transfer of a passive avoidance reaction. J. romp. physiol. Psychol. 57: 326-330, 1964.

3. Freedman, N. Recurrent behavioral recovery during spreading depression. J. romp. physiol. Psychol. 68: 210--214, 1969.

4. Freedman, N. and A. Langford. Visual evoked response attenuation by spreading depression. J. romp. physiol. Psyrhol. 69: 362-367, 1969.

5. Freedman, N, and A. Langford. An improved trephine for small animal neurosurgery. Percept. Mot. Skills 211: 750, 1969.

6. Freedman, N., R. Pote, R. Butcher and M. D. Suboski. Learning and motor activity under spreading depression depending on EEG amplitude. Physiol. Behav. 3: 373-376, 1968.

7. Reed, V. G. and J. A, Trowill. Stimulus control value of spreading depression demonstrated without shifting depressed hemispheres. J, romp. physiol. Psychol. 69: 40-43i 1~9.

8. Reseorla, R. and M. Lolordo. Pavloviaa inhibition of avoidance behavior. J. romp. physiol. Psychol. 59: 4 0 ~ 1 2 , 1965.

9. Schneider, A. M. Control of memory by spreading depression : A case for stimulus control. Psychol. Rev. 74: 201-2i5, 1967.


10. Schneider, A. M. and H. Kay. Spreading depression as a discriminative stimulus for lever pressing. J. cornp, physiol. Psychol. 65: 149-151, 1968.

11. Tapp, J. T. Reversible cortical depression and avoidance behaviour in the rat. J. comp. physiol. Psychol. 55: 306-308, 1967.

12. Weisman, R. G. and J. Litner. Positive conditioned reinforce- ment of Sidman avoidance behavior in rats. J. comp. physiol. Psychol. 68: 597-603, 1969.

13. Weisman, R. G. and J. Litner. The course of Pavlovian excitation and inhibition of fear in rats. J. comp. physiol. Psyehol. 69: 667-672, 1969.

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Further determinants of interhemispheric transfer under spreading depression