Evidence that electroconvulsive shock alters memory retrieval rather than memory consolidation

EXPERIMENTAL

Evidence Memory

20, 3-20 (1968)

NEUROLOGY

That Electroconvulsive

Retrieval

Shock Alters

Rather Than Memory HAROLD

Department

of

Salt Received

C. NIELSON

Psychology, Lake City, Febmary August

*

University Utah 84112

14; revision 14, 1967

Consolidation

of

Utah,

received

Four experiments reported here suggest that most experiments claiming that electroconvulsive shock (ECS) disrupts memory consolidation are confounded because of differences in activity levels and brain excitability states that exist between the experimental and control animals when they are tested for retention. Results of the first experiment showed that ECS increased open field activity levels. The effect of ECS upon brain excitability levels was determined in the second experiment by measuring the intensity of an electrical stimulus, delivered to a subcortical area, that would elicit a conditioned response. A transient decrease lasting 4 days was produced. Recovery of a learned response following ECS administration was investigated in the third experiment; the response was the avoidance of stepping off a platform. There was recovery when ECS induced increases in activity levels were controlled, and the recovery followed the same time course as the changes in brain excitability. A fourth experiment demonstrated that when activity levels and brain excitability states were equalized, ECS did not produce even a transient disruption of the avoidance response. These experiments show that ECS does not disrupt memory fixation which is dependent upon a neural reverberation process for consolidation, but suggest that memory retrieval may depend upon brain excitability states. The hypothesis is offered here that the neurological aspect of learning may involve changes in levels of brain excitability as reflected in the thresholds of functional neural systems, that retention implies a maintenance or reconstruction of these modifications of brain excitability, and that failure of retention occurs whenever brain excitability is modified away from that established by the training procedure. Introduction

There are currently three major proposals advanced to explain the effects of electroconvulsive stock (ECS) upon learned behavior. (;) One is that, by interfering with neural “reverberatory” activity and a neural “fixation process,” or the consolidation of the memory trace, ECS produces retro1 Work performed at the Veterans Administration Hospital, Sepulveda California, and the Department of Anatomy, University of California at Los Angeles, and supported in part by USPHS grant MH 07037. 3

4

NIELSON

grade amnesia (RA) for events immediately preceding its administration. The amount of RA produced is purported to he a function of the amount of time elapsing before the fixation process is arrested. Glickman (24) has reviewed the literature on this view. (ii) Another explanation of ECS effects comes from Coons and Miller (9) who have suggested that ECS induces fear which is sufficiently intense to disrupt behavioral performance, and it is this fear-induced disruption of performance which is assumed to reflect RA. (Z) Lewis and Maher (29) have argued for a third interpretation: That ECS produces a massive inhibition, part of which becomes associated with the environmental stimuli present at the time of ECS administration. The conditioned inhibition in turn is purported to produce a reduction in both fear and activity when the subject is returned to the environment where ECS was administered. Experiment

1

My first experiment was undertaken to investigate certain aspects of the latter hypothesis. The major experimental support for conditioned inhibition comes from an experiment by Adams and Lewis (1) who investigated the effect of ear clips, through which the ECS was delivered, upon the reacquisition of an active avoidance response. Briefly their procedure was to give the rats acquisition training and ECS, then extinction training, and then reacquisition training but with some of the rats having alligator clips attached to their ears during the reacquisition training. The rats with clips attached made fewer avoidance responses during the retraining trials than those without ear clips. Adams and Lewis interpreted these results as a demonstration of conditioned inhibition induced by the ear clips. Recent experiments have demonstrated, however, that animals receiving foot shock followed by ECS had higher activity Ievels than controI animals that received only foot shock (5, 6, 8, 31). It was appropriate, therefore, to re-explore the basis for the conditioned-inhibition hypothesis. The attachment of alligator clips to a rat’s ear also might logically be assumed to depress the animal’s activity and thereby interfere with the acquisition of an active avoidance response even without being associated with ECS. METHOD

OF EXPERIMENT

1

The subjects were eighty male Wistar rats weighing between 1.50-200 g at the start of the experiment. They were housed two to a cage and maintained on food and water ad libitum. One the first day of the experiment, small alligator clips were attached to the ears of all the rats. They were then

5

MEMORY

placed directly onto the grid floor of a step-down apparatus, and given 2 set of unavoidable foot shock. Immediately upon the termination of the shock, half of the rats were given an ECS. The alligator clips were removed from all of the animals and they were returned to their home cages. The following 2 days the animals were tested in the open field, one 3-min trial each day, for levels of activity and emotionality. Half of the convulsed and half of the nonconvulsed animals had alligator clips attached to their ears while they were in the open field. Ambulation and defecation in the open field were recorded for each animal. The step-down apparatus was a square translucent Plexiglass box, 79 cm on each side with walls 35.5 cm high, and a grid floor. An 11.5 cm by 11.5 cm platform, 5 cm above the grid floor, was located in the center of the box. A current of 1 ma was placed on the grid floor for 2 sec. Immediately after the termination of the foot shock, ECS was administered by passing a 600 ma current for 0.3 set through the alligator clips attached to the ears. The ECS was delivered from an Offner Model 733 ECS apparatus, which delivers the current on a high-frequency carrier to prevent tissue polarization, The ECS threshold used with this unit is approximately 200 ma when delivered for 0.3 sec. The open field apparatus, used to measure activity and emotionality, was located in a different room than the step-down apparatus. It was 120 cm in diameter surrounded by a black wall 45 cm high. Constant illumination was provided over the entire field by 21 evenly spaced 25-w light bulbs elevated 60 cm from the floor. A complete description of the open field apparatus is available (35). OPEN

FIELD

n---n o---o A---A

150s G

z

,’ k i5

NC-ECS NC-NECS C-ECS C-NECS

FIELD

DEFECATION -24

*---------------(J

-22

130

El -I\ 110 w’

Lt-P g

OPEN

AMBULATION

0.

a go-

70’

‘\

‘\

‘\

-20

(J---------------n

‘\

-I_

‘\

--__

I I

‘\

‘. ‘\ -.__ ‘\ -. ‘0 -n

I 2 TRIAL

-16

r-‘:-i::-

16 2

I TRIAL

1. The effect of ECS upon the open field activity of rats that either do or no attached ear clips, received ECS, do not have attached ear clips: NC-ECS; NC-NECS ; no attached ear clips, no ECS, C-ECS ; attached ear clips, received ECS, C-NECS; attached ear clips, no ECS. FIG.

NIELSON

6 RESULTS

OF EXPERIMENT

1

The results for bc&h ambulation and defecation in the open field are shown in Fig. 1. The analysis of variance of ambulation showed a significant “ear-clip” effect (F = 23.49; p <.Ol) ; a trials effect (F = 39.56; p < .Ol). The ECS effect for the two trials approached significance (F = 3.89 ; p < .OS). However, inspection of Fig. 1 shows that ECS did produce an increase in activity on the first trial which was lost by the second trial. Emotionality, as measured by increased open field defecation, was related only to the ear-clip effect (F = 6.82; p < .OS). This experiment demonstrates that the activity of rats with attached ear clips will be reduced, whether the ear clips have been associated with ECS or not. Furthermore, increased emotionality as measured by increased defecation, is associatedwith the ear clips. Experiment

2

There is a growing body of evidence that changes in neural thresholds are associatedwith learning and, as learning develops, that there is a change in the excitability of the neural components comprising a given functional system. Doty and Rutledge (13) demonstrated that the excitability of the flexor system of a limb being conditioned to give a flexion conditioned response (CR) was increased during the presentation of the conditioned stimulus (CS). Doty (12) subsequently suggested that the engram may represent a change in the threshold of the system being conditioned. Support for this has come from Rutledge (41) who has shown that the excitability of a multisynaptic pathway which mediates an interhemispheric delayed response is increased during the pairing of stimuli as is found in conditioning experiments. Thus, some evidence suggests that an increase in neural excitability of specific neural organizations is associated with learning. There is also evidence that when the excitability of a system is reduced the CR may be lost. Kawakami and Sawyer (26) found that when the threshold of a brain region to which an unconditioned stimulus (US) was applied was raised the CR was lost. Nielson and Davis (33) have shown that ablation of the frontal cortex of cats abolished foreleg flexion CR’s that were established with electrical stimulation of reticular system structures as the CS. These CR’s could be re-established but the reticular thresholds were permanently elevated. These experiments suggest that CR’s can be abolished by decreasing the excitability of structures mediating either the CR or the US. If it is assumed that the engram is a change in the excitability level

7

MEiQoRY

of all or part of the brain, then the experiment by Essig and Flanary (15) requires attention. These investigators showed that cats given a series of convulsions had decreased brain excitability levels as measured by changes in ECS threshold. The possibility exists therefore that ECS produces “amnesia” by changing the levels of brain excitability. To explore the effect of a single ECS upon brain excitability levels, the following experiment was conducted. METHOD

2

OF EXPERIMENT

Changes in brain excitability were determined by measuring the change in the intensity of electrical stimulation necessary for the maintenance of CR’s elicited by electrical stimulation of various subcortical areas. These conditioning thresholds (CT) were selected because they are stable and remain so for as long as 2 years (33). Detailed descriptions of the method, procedure, and apparatus appear elsewhere (13, 14, 33, 34). Six cats were habituated to a hammock which allowed free movement of the head and limbs but restricted gross locomotion. When the cats were tolerant of this restrain and remained quiet they were surgically prepared with four pairs of stereotaxically-implanted bipolar electrodes. Placement sites are listed in Table 1. After recovery from surgery the animals were given avoidance training, first with a lOOO-cycle/set tone as the CS, then with a 2-set train of I-msec square

TABLE CONDITIONING

Sites Area septalis Area amygdaloidens basalis Diagonal band of Broca Hippocampus Substantiareticularis mesencephalica Nucl. reticularis Nucl. anteriormedialis Nucl. ventralislateralis Corpusgeniculatummediale

1

THRESHOLDS

N

FOLLOWING

Pre-ECS Day lb .3 .08

.os .08

.06 .06

.12 .06 .O.S

.5 .35 .3 .4 .35 .35 .35 .5 .4

EC9 Post-ECS Day2 Day3 .45 .20

.14 .32 .2

.37 .16 .08 .16 .14

Day 7 .32

.ll

.08 .16

.o!J

.14

.09

.o!?J

.22

.12 .06 .17

.12

.ll .25

.06 .06

4 WheneverN was morethan one, the value reportedis the meanCT in ma. The CS wasa 2-settrain of I-msecpulsesdeliveredat 150/set. b No CR’s were elicited from any structure on the first day. Valuesare CS intensitieswhich wereusedto test for retentionof CR.

NIELSON

8

wave pulses, delivered at a rate of 150/set to the selected brain site. The intensity of the CS was adjusted for each cat so no forced movement was elicited. If this adjustment failed, no further avoidance training was given to stimulation of that structure. The US was a 0.2-set train of square wave pulses, delivered at a rate of 60/set to the right foreleg of the cat, and overlapped the CS by 50 msec. Each cat was given 25 trials daily, spaced 35 set apart, with at least 5 of the trials given periodically to avoid temporal conditioning. When stable CR’s were established, CT’s were determined twice for each structure by lowering the intensity of the CS in blocks of 5 trials until the CR dropped out. The CS intensity that elicited 50% CR’s, was defined as the threshold. Immediately after the last CT determination, each cat was given a single ECS delivered, at an intensity of 700 ma through alligator clips attached to the cats’ ears, from an Offner Model 733 ECS apparatus. Twenty-four hours later the first tests for the retention of the CR’s and determination of the CT’s were conducted with US reinforcement. Tests were continued each day for the next 7 days. The cats were then killed ; their brains removed and sectioned; and the electrode placements were verified accordingly to the atlas of Jasper and Ajmone-Marsan (25). 2 An ECS of 700 ma failed to induce a seizure in one of the six cats. The results from this animal are reported separately. The effect of ECS upon CT’s for the remaining five cats is summarized in Table 1. The effect of the single ECS upon foreleg flexion CR’s can be summarized as follows: Twenty-four hours after ECS, CR’s established to the tone CS were either abolished or elicited so infrequently they could not be distinguished from indiscriminate flexions. The thresholds at nine loci were sufficiently elevated that CR’s could not be elicited with CS intensities at least five times their pre-ECS value. High intensities were not used for fear of producing neural damage. Forty-eight hours after ECS, CR’s to the tone could be elicited but performance was very erratic. Similar results were obtained with electrical stimulation of subcortical structures as the CS. The CT’s were elevated and unstable. Seventy-two hours after ECS, CR’s were readily elicited with either the tone or electrical stimulation of the subcortical structures as the CS. In most instances, the CT’s were slightly elevated but near pre-ECS values. Four days after ECS all CR’s were stable and the CT’s had reached their final post-ECS values, which were at or near their pre-ECS values. There did not appear to be any differential rates of recovery for any particular structure or neural system. The CS intensities used in attempts RESULTS

OF EXPERIMENT

9

MEMORY

to elicit CR’s from subcortical structures were sufficiently high to demonstrate elevated thresholds for both reticular and limbic structures. It is doubtful that differential recovery rates of these systems could demonstrated with this method because the CR’s are abolished from all structures, despite intense stimulation, on the first post-ECS day and they are unstable the second post-ECS day. Nevertheless, these results suggest that ECS alters thresholds throughout the central nervous system. It is unlikely that ECS effects would be related to a selective depression of the motor system which mediates the response because the increased activity levels, shown with grid shock and ECS, suggest increased motor excitability. Furthermore, the loss of the CR on the first post-ECS day cannot be attributed to a disruption of the consolidation process. These animals were well trained; they had been so for several months while CR’s were being established to electrical stimulation of other structures in the same animal and while CT’s were being taken. These results suggest that the “amnesia” effects of ECS may be related to shifts in neural thresholds. No CT shifts were noted in the one animal that failed to have a convulsion with an ECS intensity of 700 ma, the maximum output of the Offner ECS apparatus. This animal was subsequently given a series of shocks at 700 ma, one each day for 10 days, each of which left the animal in a stupor but failed to induce a tonic-clonic convulsion. On the eleventh day the animal was again tested to CT shifts but none were noted. Thus, it appears that a convulsion is necessary to produce these shifts in CT. Experiment

3

The transient changes in brain excitability levels produced by ECS and transient loss of the CR which accompany it, provide some support for the position that the engram may be represented by a change in neural threshold. This is especially true since ECS should not disrupt CR’s that are several months old. This suggests that if the “amnesia” produced by ECS is related to changes in brain excitability, there may be recovery of even a recently established response which has been disrupted by ECS. However, since foot shock and ECS produce animals that are more active such recovery might be difficult to demonthan “foot-shock controls,” strate because of the differences in activity levels, and these changes in activity levels may persist for as long as 8 days (6). Therefore, activity levels should be suppressed to test for recovery from ECS. Madsen and McGaugh (30) reported that ECS produces RA for a passive avoidance response. In their experiment, a rat was placed on a platform and received a foot shock for stepping off it. Half of their rats

10

NIELSON

received ECS within 10 set of stepping off the platform while the other half did not. A greater proportion of the convulsed animals stepped off the platform on a subsequent trial. Failure of the convulsed rats to inhibit stepping off the platform was interpreted as RA for the foot shock. However, these results may have been influenced by changes in activity levels. A more recent experiment (39) has shown that convulsed rats have shorter latencies of descent from a platform than do nonconvulsed rats. The question is whether, following ECS, there will be recovery of a passive avoidance response correspondin g to the changes in brain excitability produced by ECS, when the increased activity levels of convulsed animals are suppressed by ear clips. METHOD

OF

EXPERIMENT

3

The subjects were 248 male Wistar rats weighing 150-175 g at the start of the experiment. They were housed two to a cage and were maintained on food and water ad libitzm. One hundred and sixty rats had alligator clips attached to their ears during the experiment, while 88 of them had alligator clips attached to their ears only for a few seconds when ECS was administered. All the rats were given training for a passive avoidance response in the step-down apparatus described in Experiment 1. A current of 1.0 ma was maintained on the grid floor so that the rat received a foot shock when it stepped off the platform. The duration of the shock was 1 set and was followed immediately by ECS for the animals with alligator clips attached to their ears, and within 10 set for those without clips. The ECS was a 600-ma shock, delivered via the ear clips, from an Offner Model 733 ECS apparatus. The 160 animals with ear clips attached during the experiment, were individually removed from their home cages, clips attached, and placed on the platform. When they stepped off the platform and received foot shock, half of them immediately received ECS. The ear clips were removed during the convulsion and the animals were returned to their home cages. Twenty-four hours later, half of the convulsed and half of the nonconvulsed animals were removed from their home cages, ear clips attached, and placed on the platform to test for presence of the passive avoidance response. The remaining 80 animals of this group were similarly tested 96 hr later. The 8% rats that did not have clips attached to their ears when they were on the platform, were placed directly on the plaform. They were immediately picked up from the grid floor after they had stepped off the platform and received shock, and half of them were given ECS. These animals

11

MEMORY

were tested for the passive avoidance response either 24 or 96 hr later, but with no ear clips attached. The scoring procedure was the same as that used by Madsen and McGaugh (30). Any animal that failed to step off the platform within 10 set on the first trial was discarded. Rats were scored as making a passive avoidance response if they remained on the platform for longer than 10 set on the second trial. The results are shown in Table 2, which summarizes the findings for each group. Thirty-seven animals were lost, either because they failed to RESULTS

OF

3

EXPERIMENT

step off the platform within 10 set on the first trial, or they sustained injury during the ECS treatment. The results for the animals tested for retention of the passive avoidance response 24 hr after ECS confirmed the findings of Madsen and McGaugh (30). These animals were less likely to remain on the platform and avoid the foot shock (x2 = 20.88; p < -01 with ear clips ; x 2 = 28.04; p < 01, without ear clips). When the remaining rats were tested 96 hr after ECS was administered, the convulsed animals tested with ear clips attached did not differ from their controls (x2 = 1.34 ; p < .2) and showed recovery of the passive avoidance when compared with the convulsed animals tested 24 hours after ECS (x’ = 9.28 ; p < .Ol). No such recovery was seen when the animals were tested without ear clips (x2 = 3.46; p < .l). The results obtained with the animals trained and tested without ear clips attached would support a traditional disruption of consolidation hypothesis since the convulsed TABLE

2

RECOVERY OF A PASSIVE AVOIDANCE RESPONSE FOLLOWING ECS AS A FUNCTION OF SUPPRESSION OF ACTIVITY LEVELS BY ATTACHING ALLIGATOR CLIPS TO THE ANIMALS’ EARS Retention

test

24 hr Ear ESC Number in cell Number avoiding 70 avoiding No

ECS Number in cell Number avoiding % avoiding

clips

No

96 hr ear

29 5 17

2G 5 25

30 23 76

19 15 79

clips

Ear

clips

39

No

ear

51

20 8 40

34 22 64

20 13 65

‘20

clips

12

NIELSOIV

animals failed to remain on the platform. However, a more likely explanation would be a simple increase in activity, consequent to ECS, which would affect passive avoidance performance by decreasing descent latency from the platform as reported (39). The recovery of passive avoidance performance, when ear clips are attached, and by inference activity levels are suppressed, raises serious questions about the traditional interpertation of ECS effects upon memory consolidation. If ECS did impair memory consolidation there should have been no memory to recover. A similar recovery of a passive avoidance response following administration of ECS has recently been reported by Zinkin and Miller (45). Those investigators tested for the retention of a step-down avoidance response 21, 48, and 72 hr after ECS. They also found “‘amnesia” 24 hr after ECS, but retention 48 and 72 hr later. It may also be significant that Zinkin and Miller also attached ear clips to each rat. Furthermore, it appears that recovery of memory following ECS is not limited to a passive avoidance response. Recovery of a conditioned emotional response has also been reported (10). The fact that ECS produces only transient “amnesia” in some cases strongly suggests that ECS does not interfere with memory consolidation but rather, temporarily interferes with memory retrieval mechanisms. The transient nature of ECS effects upon retention can be seen, however, when high activity levels do not obscure the phenomenon, or when activity levels can be suppressed. Experiment

4

The suggestion by Doty (12), that a change in the excitability of a system being conditioned, as evidenced by a change in threshold, may represent the engram warrants further clarification. This is especially so since there are a number of studies which demonstrate a “dissociation” of learning from recall. The dissociation may result from differences in brain excitability states that existed either at the time of the learning or the recall. Such differences in brain excitabilities may be inferred by different brain thresholds in the different states. Some of these “state- dependent” differences between learning and recall are produced by spreading cortical depression (SCD), drugs, and possibly sleep states. Girden and Culler (23) and Girden ( 17-22)) found that animals rapidly learned a response while they were under the effects of crude curare, but the response could not be elecited while the animals were in the undruggetl state. Girden and Culler (23) applied an electric stimulus to the cortex to produce a twitch of the semitendinosus muscle and found that the threshold of the cortex had been raised. They concluded that the “dissociation of learning” was due to a functional decortication. Recently, Sachs, Weingarten, and Klein (42) have suggested that drugs that produce a com-

MEMORY

13

plete dissociation of learning do so by changing the state of the central nervous system rather than the sensorium. Support for such a view comes from their data as well as from others. Overton (36) has shown dissociation of learning with pentobarbital and atropine but failed to demonstrate it with chlorpromazine. However, these drugs may have opposite central effects. Killam and Killam (27) reported that reticular thresholds were raised and reticular conduction blocked by pentobarbital while chlorpromazine had limited effect upon reticular thresholds but enhanced reticular conduction. Further support for the view that changes in brain excitability, as reflected in shifts of neural threshold might be involved in the performance of a learned response, come from studies of SCD. Transfer of learned responses between normal and depressed cortical states, or vice versa have failed (2, 4, 44). Recently, however, conditions have been described where there was limited generalization between these states (43). Nevertheless, differences in brain excitability states may also play a role in the dissociation of learning and retention seen with SCD, since thresholds of structures of the thalamic reticular system are elevated during SCD (3). Such differences in brain excitability states may also be operating during sleep, and waking states. Reticular thresholds are elevated during sleep, and the degree of elevation appears to be dependent upon the stage of sleep (11, 35) and a dissociation of memory between sleeping and waking states has been reported (16). Th e possibility exists, therefore, that dissociation of learning results from differences in brain excitability states associated with the respective learning or retention states. Whether dissociation may be limited to brain excitability states which may involve particular brain regions, such as changes in reticular thresholds is not known. However, conditions in which there is a dissociation of learning also have shifts in some brain thresholds associated with it. Since the time course of recovery of brain thresholds following ECS roughly follows the time course of recovery of the passive avoidance response, the question is raised as to whether the amnesic effects of ECS might be a dissociation of learning phenomenon. In most ECS studies, the animal is trained while in a normal state, given ECS, tested for rentention, 24 hr later when brain thresholds were raised and brain excitability reduced. Such a situation is fully comparable to the ones in which a dissociation of learning is seen. If amnesia produced by ECS is the result of differences in brain excitabilities existing between the learning state and the recall state, and if, by grid shock and ECS, the threshold is raised prior to step-down training. ECS administered immediately after step-down training should fail to produce a performance decrement. To investigate this, the following experiment was conducted.

NIELSON

14 METHOD

OF EXPERIMENT

4

The subjects were 357 male Wistar rats weighing between 150-175 g at the start of the experiment. They were randomly assigned to one of eighteen different experimental groups, housed two to a cage, and maintained on food and water ad libitum To familiarize the rats with shock avoidance in a learning situation, all the rats were first trained in a T maze to give an active avoidance response. The training procedure and apparatus have been described (35). Following acquisition of the active avoidance response, each animal was given one of three treatments to induce the various brain states: no ECS, ECS immediately after, or ECS 4 hr after acquisition of the active avoidance response. Twenty-four hours after the “brain states” were induced, the rats were trained in the step-down apparatus for the passive avoidance response. Alligator clips were attached to the rats’ ears, they were placed on the platform of the step-down apparatus, and received a 1-set foot shock when they stepped off the platform. When the rat stepped off the platform it received one of three ECS treatments, either no ECS, ECS immediately, or ECS 4 hr later. The animals were tested for retention of this passive avoidance responsewith clips attached to their ears, either 24 or 96 hr after stepping off the platform. The scoring procedure was the same as that used in Experiment 3. The steps in the procedure were: (i) active avoidance learning for the animal to learn to avoid shock ; (ii) ECS treatments to induce the various brain states; (iii) passive avoidance training at various brain excitability states; (iv) ECS treatments, either to disrupt consolidation of the memory of the grid shock associated with stepping off the platform, or to match brain excitability states induced by the first ECS treatments ; and (v) test for retention of the passive avoidance response. RESULTS

OF EXPERIMENT

4

The results were analyzed with both chi-square and general linear hypothesis techniques. Table 3 shows the number and percentage of animals from each group that avoided stepping off the platform. The ECS administered 1 set after the animals stepped off the platform did not produce even a transient impairment of the passive avoidance response. The majority of these animals remained on the platform and even appeared to show better retention than the others (x’ = 4.14, p < .OS). However, there is probably not a real difference between the groups. Animals that were discarded, becausethey remained on the platform on the first trial for longer than 10 set, were more likely to come from groups that received no ECS

15

MEMORY

TABLE 3 ECS UPON RETENTION OF STEP-DOWN RESPONSE UNDER GRID SHUCK ESC INTERVALS BEFORE AND AFTER STEP-DOWN TRAINING

EFFECT VARIOUS

Step-down ECS Treatment 0 time

1 set

4hr

OF

24-hr step-down retention T-Maze ECS Treatment 0 1 set 4hr 20 8 5 41.5 23 4 13 68.5 20 7 7 53.7

19 3 5 31.2 21 6 10 66.7 20 4 11 68.7

21 2 12 63.2 21 6 10 66.7 21 5 9 56.2 T-MAZE

96-hr step-down retention T-Maze ECS Treatment 0 1 set 4hr Total N in cell N discarded-latency N avoiding o/o avoiding Total N in cell N discarded-latency N avoiding % avoiding Total N in cell N discarded-latency N avoiding % avoiding ECS

20 7 9 69.2 19 11 5 55.6 17 6 5 45.5

19 4 8 53.3 19 4 10 66.7 19 3 7 43.7

21 4 5 29.4 19 1 10 55.5 18 4 8 57.1

4

DELAY

TREATMENT

IMMEDIATE

HOUR,

16-

I RETENTION

d

sNONE

5

I SEC

4 HOURS

NONE

STEP

I

I

I SEC

4

DOWN

ECS

HOURS

1 NONE

-

24

HOUR

A---A

96

HOUR

I I SEC

4

I HOURS

FIG. 2. Mean latencies of a passive avoidance response with ECS treatments before and after a passive avoidance training trial. The similar response latencies are found with similar foot-shock ECS treatments.

action to be significant (F = 2.53; p < .OS). It is apparent that the after the active avoidance response was learned (F = 4.45 ; p < .OS). The latencies of response on the second trial, the passive avoidance retention trial, are shown in Fig. 2 for each group. An analysis of these latenties by the general linear hypothesis method showed only the triple inter-

16

NIELSON

effects of ECS are changed through time and are altered by prior experience. There was no evidence that ECS disrupted a consolidation process. There was support, however, for the position that ECS may produce a dissociation of learning. The ECS did not produce even a transient amnesia, and the most similar response latencies were obtained with the The dissimilar treatments produced same grid-shock ECS treatments. divergent response latencies across time. Discussion

The theories advanced to account for the effects of ECS upon learned behavior generally agree that ECS does disrupt behavorial performance. They disagree, however, as to the underlying causes of this behavorial disruption. Perhaps the most popular of these interpretations is that ECS disrupts reverberating neural activity, which is responsible for the consolidation of the memory trace. This, in turn, is supposed to produce RA for events preceding ECS administration. Furthermore, the amount of RA that is produced is supposed to be directly related to the amount of consolidation time which elapsed between the occurrence of the event and the administration of ECS. The exact time that it takes a memory to be consolidated is, however, in dispute. It has been reported to be as short as 10 to 30 set (7, 37) or possibly as long as 6 hr (28). The results of this experiment clearly do not support a disruption of consolidation hypothesis to explain ECS effects. Rather, they support previous reports (10, 45) showing recovery of a response which should have been erased by ECS. These results are not compatible either with the conditioned-inhibition hypothesis (29) or the fear hypothesis (9). The ECS did not produce inhibition which was associated with the ECS, but rather it produced an increase in activity levels which could be suppressed with alligator clips attached to the animals’ ears. The ECS-induced increase in activity could alter behavorial performance such that, without ear clips to suppress activity, the rats would not stay on a platform to avoid foot shock. It may well be that the increased activity levels, consequent to shock and ECS, is what Coons and Miller (9) interpreted as strong fear because a single ECS has been shown to induce fear (31). Nevertheless, the fear produced by the ECS was not sufficient to disrupt the behavorial performance of the animals in these experiments. These results suggest an alternative interpretation of ECS effects, base<1 upon the states of brain excitability existing at the time of learning or recall. When learning occurs at one state of brain excitability, the animal was then tested for retention of that learning in a different state of brain excitability, induced by ECS, the animal fails to show that learning 24 hr later. However, when activity levels were controlled, there was recovery of

MEMORY

17

the response that followed the return of normal brain excitability. Furthermore, when brain excitability states were the same during both the training and recall sessions, ECS did not produce any retention deficits. Thus, there was a temporary amnesia when differences existed between the states of brain excitability during learning and recall, but no amnesia was noted when learning and recall sessions were conducted at the same levels of brain excitability. The failure of the animals that were given an ECS, training followed by ECS, and then not tested for retention of the response for 4 days, to step off the platform should be mentioned. Presumably the brain excitability levels had returned to normal within 4 days. These animals had learned with a lowered state of brain excitability but still “remembered” to remain on the plaform when brain excitability had returned to normal. For these animals it seems that ECS does not produce a sufficiently different state of brain excitability to block generalization. Overton (36) showed that the complete dissociation of learning produced by large dosages of drugs is only the extreme form of a continuous phenomenon. Both he, and Schneider and Hamberg (43), who have produced the dissociation of learning with SCD, emphasized the speed with which generalization can occur between those and the normal states. To maintain dissociation, trials must be given in highly drugged states or rapid generalization can occur. The recovery of the response following ECS also supports the contention that some generalization between brain excitability states does occur. The considerations from these and other experiments suggest that many of the agents that have been used to block consolidation of the memory trace may produce changes in brain excitability states and a resulting dissociation of learning, This implies a failure of retrieval of information, rather than a disruption of engram formation. The dissociation of learning phenomenon, while it is assumed to be the extreme case of a continuous phenomenon, also appears to be a general phenomenon, if brain threshold shifts can be taken as an estimate of brain excitability states. Brain excitability shifts have been implicated in learning (12, 13, 41), the loss of a learned response in drug states (23, 42), SCD (3) with brain lesions (32, 33)) and sleep (11, 38). A lowering of certain thresholds- may be a correlate of learning and it appears to be correlated with brain excitability states. These considerations suggest that learning may involve a modification of brain excitability levels and that failures of retention occur when brain excitabilities are different from those established by the training procedure. Such a conclusion, that memory retrieval depends upon the matching of brain excitability states during recall that existed during the learning, fits well with the data on man. Russell and Nathan (40) investigated disturbances of memory in several hundred patients that had

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sustained head injury. They followed the general time course of recovery of memory, and reported a progressive shrinkage of the amnesic period. Their concluding comments suggest that at least some cases of amnesia, following traumatic head injury, may be due to differences in states of brain excitability. “The recall under barbiturate hypnosis, or occasionally in the state of traumatic confusion, of events which cannot be remembered in the normal state of consciousness is of considerable interest. . . . The twilight states of dreaming and toxic or infective delirium are analogous, and in these also there may be recall of experience not available in the state of clear consciousness.” References 1. ADAMS, H. E., and D. J. LEWIS. 1962. Retrograde amnesia and competing responses. J. Camp. Physiol. Psychol. 55: 302-305. 2. BURES, J., and 0. BURESOVA. 1963. Cortical spreading depression as a memory disturbing factor. J. Cow@. Physiol. Psychol. 56: 268-272. 3. BURES, J., 0. BURESOVA, T. WEISS, and E. FIFKOVA. 1963. Excitability changes in non-specific thalamic nuclei during spreading depression in the rat. Electroencephalog. Clin. Neurophysiol. 15: 73-83. 4. BURES, J., 0. BURESOVA, and A. ZAHOROVA. 1958. Conditioned reflexes and Leao’s spreading cortical depression. J. Consb. Physiol. Psychol. 51: 263-268. 5. CHEVALIER, J. A. 1965a. Permanence of amnesia after a single post trial electroconvulsive seizure. J. Con&p. Physiol. Psychol. 59: 125-127. 6. CHEVALIER, J. A. 1965h Inhibition of response to foot shock through competition with a concurrent conditioned response, pp. 133-134. 1n “Proceedings of the 73rd annual convention of the American Psychological Association.” American Psychological Association, Washington. 7. CHOROVER, S. L., and P. H. SCHILLER. 1965. Short-term retrograde amnesia in rats. J. Camp. Physiol. Psychol. 59: 73-78. 8. CHOROVER, S. L., and P. H. SCHILLER. 1966. Reexamination of prolonged retrograde amnesia in one-trial learning. J. Co+np. Physiol. Psychol. 61: 34-41. 9. COONS, E. E., and N. E. MILLER. 1960. Conflict versus consolidation of memory traces to explain “retrograde amnesia” produced by ECS. J. Comp. Physiol. Psychol. 53: 524531. 10. COOPER, R. M., and R. J. KOPPENSAAL. 1963. Suppression and recovery of a one-trial avoidance response after a single ECS. Psychofz. Sci. 1: 303-304. 11. DILLON, R. F., and W. B. WEBB. 1965. Threshold of arousal from “activated” sleep in the rat. J. Cornp. Pltysiol. Psychol. 59: 446-447. 12. DOTY, R. W. 1961. Conditioned reflexes formed and evoked by brain stimulation, pp. 397-412. In. “Electrical Stimulation of the Brain,” D. E. Sheer [ed.]. Univ. of Texas Press, Austin, Texas. 13. DOTY, R. W., and L. T. RUTLEDGE. 1959. “Generalization” between cortically and peripherally applied stimuli eliciting conditioned reflexes. J. Neurophysiol. 22: 428-435. 14. DOTY, R. W., L. T. RUTLEDGE, and R. M. LARSEN. 1956. Conditioned reflexes established to electrical stimulation of cat cerebral cortex. J. NeurophysioZ. 19: 401415.

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C. F., and H. G. FLANNARY. 1964. Repeated electroconvulsions: elevation of threshold proximal and distal to origin. Exptl. Neural. 9: 31-35. 16. EVANS, F. J., L. A. GUSTAFSON, D. N. O’CONNELL, M. T. ORNE, and R. E. SKOR. 1966. Response during sleep with intervening waking amnesia. Science 162: 666-667. 17. GIRDEN, E. 1940. Cerebral mechanisms in conditioning under curare. Am. J. 15. ESSIG,

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18. GIRDEN, E. 1942a. Generalized conditioned responses under curare and erythroidine. J. Exptl. Psychol. 31: 105-119. 19. GIRDEN, E. 1942b. The dissociation of blood pressure conditioned responses under erythroidine. J. Exptl. Psychol. 31: 219-231. 20. GIRDEN, E. 1942c. The dissociation of pupillary conditioned reflexes under erythroidine and curare. J. Exptl. Psychol. 31: 322-332. 21. GIRDEN, E. 1943. Role of the response mechanism in learning and in “excited emotion.” Amer. J. Psychol. 56: l-20. 22. GIRDEN, E. 1947. Conditioned responses in curarized monkeys. Am. J. Psycho!. 60: 571-587. 23. GIRDEN, E., and E. A. CULLER. 1937. Conditioned responses in curarized striate muscle in dogs. J. Comp. Physiol. 23: 261-274. 24. GLICKMAN, S. E. 1961. Perseverative neural processes and consolidation of the memory trace. Psychol. Bull. 56: 218-233. 25. JASPER, H. H., and C. AJMONE-MARSAN. 1954. “A Stereotaxic Atlas of the Diencephalon of the Cat.” National Research Council of Canada, Ottawa. 26. KAWAKAMI, H., and C. H. SAWYER. 1964. Conditioned induction of paradoxical sleep in the rabbit. Exptl. Neural. 9: 470-482. 27. KILLAM, K. F., and E. K. KILLAM. 1958. Drug action on pathways involving the reticular formation, pp. 111-122. Zn “Reticular Formation of the Brain.” H. H. Jasper, L. D. Proctor, R. S. Knighton, W. C. Moshay, and R. T. Costello [eds.] Little, Brown, Boston, Masachusetts. 28. KOPP, R., 2. BOHDANECKY, and M. E. JARVICK. 1966. Long temporal gradient of retrograde amnesia for a well-discriminated stimulus, Science 153: 15471549. 29. LEWIS, D. J., and B. A. MAHER. 1965. Neural consolidation and electroconvulsive shock. Psychol. Rev. 72: 225-239. 30. MADSEN, M. C., and J. L. MCGAUGH. 1961. The effect of ECS on one-trial avoidance learning. J. Camp. Physiol. Psychol. 54: 522-523. 31. MCIVER, A. H., and H. C. NIELSON. 1966. Effects of electroconvulsive shock and grid shock on open field behavior. J. Comp. Physiol. Psychol. 62: 102107. 32. NIELSON, H. C. 1965. Effect of frontal ablation on conditioned responses established to electrical stimulation of limbic and reticular structures, pp. 101-102. In “Proceedings of the 73rd Annual Convention of the American Psychological Association.” American Psychological Association, Washington. 33. Nielson, H. C., and K. B. Davis. 1966. Effect of frontal ablation upon conditioned responses. J. Comp. Physiol. Psychol. 61: 380-387. 34. NIELSON, H. C., J. M. KNIGHT, and P. B. PORTER. 1962. Subcortical conditioning, generalization and transfer. J. Comp. Physiol. Psychol. 56: 168-173. 35. NIELSON, H. C., A. H. MCIVER, and R. S. BOSWELL. 1965. Effect of septal lesions on learning, emotionality, activity, and exploratory behavior in rats. Exptl. Neurol. 11: 147-157.

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OVERTON, D. A. 1964. State-dependent or “dissociated” learning produced with pentobarbital. J. Conlp. Physiol. Psychol. 57: 3-L’. QUARTERMAIN, D., R. M. PAOLINO, and N. E. MILLER. 1965. A brief temporal gradient of retrograde amnesia independent of situational change. Science 149: 1116-1118. ROLDAN, E., T. WEISS, and E. FIFKOVA. 1963. Excitability changes during the sleep cycle of the rat. Electroencephalog. Clin. Neurophysiol. 15: 775-785. ROUTTENBURG, A., and K. E. KAY. 1%5. Effect of one electroconvulsive seizure on rat behavior. J. Comp. Physiol. Psychol. 66: 285-288. RUSSELL, W. R., and P. W. NATHAN, 1946. Traumatic amnesia. Brabc 66: 28G300. RUTLEDGE, L. T. 1965. Facilitation: electrical response enhanced by conditional excitation of ceberal cortex. Scierzce 148: 1246-1248. SACHS, E., M. WEINGARTEN, and N. W. KLEIN. 1966. Effects of chlordiazepoxide on the acquisition of avoidance learning and its transfer to the normal state and other drug conditions. Psychopharmacologia. 9: 17-30. SCHNEIDER, A. M., and M. HAMBURG. 1966. Interhemispheric transfer with spreading depression: a memory transfer or stimulus generalization phenomenon. J. Comp. Physiol. Psychol. 62: 133-136. TAPP, J. T. 1962. Reversible cortical depression and avoidance behavior in the rat. J. Comp. Physiol. Psychol. 55: 306-308. ZINKIN, S., and A. J. MILLER. 1967. Recovery of memory after amnesia induced by electroconvulsive shock. Scicrrce. 155: 102-103.