Dr. Ewan Cameron - The Process of Remembering (1963)

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B,tt. J. Pial. (1963), 109, 325-340

The Processes of Remembering

The Thir ty -S ev en th Maud sle y Lec tu re , d el iv er ed b efo re t he Roya l Medic o-Ps yc ho lo gic al

A ss oc ia tio n, 1 4 Xov em be r, 1 96 2

By D. EWEN CAMERON

I have been deeply moved by your invitation to deliver this year's M audsley Lecture.

@ Founded to. commemorate so distinguished aman, it has become most properly one of theh on ou rs o f p sy ch ia try .Those who have presented this Lecture on

earlier occasions have clearly turned to thegreat themes of their own life work. Each man

@ has found in the writings of Henry Maudsleythoughts and plans already foreshadowing theadvances which the lecturer has brought intobeing more than three-quarters of a centurylater. For Maudsley had a penetrating mindwhich struck sw iftly and indsively down tothe fundamentals o f human natu re.In his Physiology of M ind, published in 1876,

M audsley had already seized upon the fact ofthe cardinal position that memory plays inthe total behaviour of man. He pointed out thatâ€œ¿Nomental development would be possible

without it. For if a man possessed it not, hewould be obliged to begin his conscious lifefresh with each impression made upon him

@ and would be incapable of any education.â€•H e also foresaw â€”although the im mense range

@ of data which we now possess was lacking tohimâ€”that it is not images or ideas of objectsthat are stored, but rather changes in some

@ organic substrate of the brain. He recognized,in a word, that â€œ¿codingâ€•akes place andindeed he saw this long before that phrase

A had been coined. He was clearly and pro

foundly interested in the process w ith whichmany of us are presently concerned, namely

the retriev al o f sto red in fo rm atio n.The word â€œ¿ ememberingâ€•overs not one

@. but a multiplicity of functions. They lie in a

long range and are varied in nature. First and@ most commonly thought of as remembering

325

are those functions which serve our needs forprecise recovery of information in the exactform in which it was laid downâ€”an address,a formula, a date. Then we pass over to thecurious, evolving, moving, changing kind ofrem em bering w hich is required for the learning

of a skill. This kind of remembering allows usto replace one modification by the next andalmost always to produce in response to thesame cue the most recent modification. Anexcellent example is furnished by the learningof a new top spin drive in tennis.Passing on to the far end of the range, we

find lying there those m em orial functions w hichperm it us to change our recollections of the pastso that the past becomes more endurable, morereconcilable with the image of ourselves whichwe find at least tolerable. These functionsappear to be governed by our emotions andby the remoulding powers exercised by our

ongoing concept of ourselves and of our w orld.So we come to forget that we stole from ourmother's purse as a child, or we may discoverâ€”¿ikeD arw in building his theory of the originof speciesâ€”that unless we are careful immediately to record as they occur all ideascontrary to the theory, they are remarkablysoon forgo tt en .Intelligence m ay be the prideâ€”the tow ering

distinction of man; emotion gives colour andforce to his actions; but memory is the bastionof his being. W ithout memory, there is nopersonal identity, there is no continuity to thedays of his life. Memory provides the raw

material for designs both small and great.Thus, governed and enriched by memory, allthe enterprises of man go forw ard.Last year's distinguished Lecturer spoke on

remembering and I make no apology for

2

Thie One



326 [MayHE PROCESSES OF REMEMBERING

returning to the theme, for memory has becomewithin the last few years one of the great areasof intensive study. Promise murmurs from the

p io neerin g lab orato ries th at m atters con cern in grememberingâ€”over which mankind has pondered for I ,500 years by recordâ€”may be ontheir w ay to solution.What are these basic problems of remem

bering? Let me first state them as they wereconsidered by the Greeks. Plato (i) around354 B.C . was deeply concerned as to howmemory traces were formed and stored. Headvanced the idea that there is an analogybetween this and the process of imparting animpression to a block of wax. He saw the waximpression and the memory trace share acommon destinyâ€”in som e cases quickly fading

â€”¿sometimes being preserved throughout alifetimeâ€”or yet again being misplaced formoments, for days or forever. Other G reeksraised the question of how memories areretrieved. O r again, what is the difference, ifany, betw een know ledge w hen it is first recordedand the same know ledge later recalled ?â€”clearly our own problem , stated in other w ords,of secondary elaboration. And finally, theGreeks wondered how memory is related tothat elusive faculty-our sense of time.W ith our vastly increased store of informa

tion about the human organism , we have beenable, as a first step, to sharpen and reshape

these questions. Let me state them in terms ofthree great areas of enquiry, each containinghardly less important questions w ithin it.The first is one which in far earlier times

could not be set up because of the lack ofanatomical knowledge. This is, where in thebrain are memory traces recorded and stored?The second great area of enquiry is, what is itthat serves as a substrate for memory? Whatis the substance which, like Plato's wax block,actually receives and holds the memory trace?The third area of search is, how does themachinery of the memorial process work? Howdo we perform this great range of functions

coding and decoding, precision of recall,evolving recall as required in skills and thegreatly m odified recall of otherw ise unacceptable m em ory traces?W ithin this vast and vastly intricate area

there lie the questions of the nature of retrieval,the curious enigma of the differing ease ofrecognition and recall, the mechanisms of

retroactive and proactive inhibition and theintriguing phenomena of anterograde andposterograde amnesia. Here too, lie the fascinating puzzles of how the incoming sensoryimpulses are coded for recording and how,on retrieval, this coding is converted into the 4d ata o f c on sc io us ne ss â€ ”th e p ro ce ss o f re ad ou t.Now let us look down on to these three great

areas of exploration, follow the men at workin them , see what tools they are using, notewhat they have now discovered, and trace theirplans for further exploration.In the first area at which we lookâ€”the

arena where men are working to discover

w here memory traces are recorded and broughtto their final storage areasâ€”there still rem ainsgreat confusion and contradiction. This confusion is characteristic of a great wide-flungresearch area in which all the facts have notyet been found; all the connections between theintricate array of findings have not yet beentraced ou t.A long series of men worked in this field all

throughout the i 9th century. During thisperiod the clinical neurologists took the leadmen such as Prochaska and Gall who soughtto find where memories are stored in the brainchiefly on the basis of their clinical findings.

Theory took form largely under the leadershipof Flechsig and favoured the localized storageof memories .These workers were later supported by

growing advances made by the conditionedreflex school. The claims of Pavlov and his @ tco-w orkers, how ever, w ere m ade w ithout actualneurological and neurosurgical experim entalevidence. For the Pavlovians, the assumptionthat memories were stored in association areasserved sim ply to complete the structure of theirbasic theory. AA beginning sophistication in the concept

of the storage of memory traces appeared w ith

the discoveries of Henry Head (3) and KurtG oldstein (2) w ho show ed that the disturbancesfound in aphasia and agnosia are not truefailures in remembering, but defects in thecategorization of ideas. Early in the tw entieth



1963] BY D. EWEN CAMERON 32 7

century, the lead in the search for the locationof the storage of memory traces was increasin gly tak en b y th e an im al ex perim en talists

and, in particular, by those who based theirexperiments upon surgical procedures. Forby these means, it was possible to study the

@ function of one part of the brain after anotherw ith respect to the memorial process. The workof the animal experimenters reached the pointof greatest penetration in the researches ofL ashley (4).In 1950, Lashley summarized his work in

an article entitled â€œ ¿ nearch of the E ngram â€•.@ This report exercised profound influence upon

the thinking of men working in this field, andits effects are still felt. He concluded that itw as n ot po ssib le to d em on strate sp ecific lo caliza

tion of the memory trace anywhere within thenervous system and definitively declared that

@, the association areas are not storehouses for

p artic ula r m emorie s.Lashley considered that the memory trace is

recorded by m eans of m ultiple representations.He postulated that the nervous network maydevelop a pattern of activity by the spread ofexcitation much as the surface of a liquiddevelops an interference pattern of spreadingwaves when it is disturbed at various points.

@ This, he felt, would result in the neurons beingsensitized to react in certain combinations,perhaps in complex patterns of reverberatory

circuits reduplicated throughout the area.Furthermore, he gave consideration to thenumber of cells in the brain and concluded

@ that all of the cells must be in almost constantactivity; that there is no excess of cells which

@ can be used for the preservation of specialmemories. He concluded further that recallinvolves the synchronized action of a very

-@ large number of neurons.

His long series of researches were of parti@ cular value in bringing to the fore not only this

fundamental conception, but also in makingclear that much of what previously had beentaken as a disturbance in the storage of memory

traces was actually a disturbance in closelylinked but not identical functions-such as in

@, failure in shifting from one task to another or

in difficulty in m aintaining a constant set w hile@ endeavouring to remember a task. And he

supported the views of Henry Head and KurtG oldstein who, as w e have already pointed out,showed that aphasia and agnosia are to be

considered as primary defects in the organization of ideas rather than as representing theloss of m em ory traces.Hardly had this monumental and apparently

conclusive report been published than it waschallenged by evidence brought forward bythe neurosurgeons. For with the coming of themid-century, information derived from operative procedures on the human subject becameat once much more abundant and far morereliable. It was more reliable for two reasons:the first is that increasingly refined and efficient techniques perm itted operations to becarried out on parts of the human brain into

which the neurosurgeons previously could notventure. The second is that part of the evidencewas derived from varieties of the lobotomyoperation, which was then reaching its acmeof application. This operation was carried outon brains which, if they could not be describedas entirely healthy, were at least free frommassive and pervasive pathologies such astraum atic change, abscesses or tum ours.In 1954, W illiams and Pennypacker (@ )

reported a Korsakoff type of memory deficitoccurring in individuals who had lesions inthe hypothalam ic region. They were followedby a number of workers (Scoville and M ilner,

1957 (6); Whitty and Lewin, 1957, 1960 (v);

Sweet et al., (8)) who rapidly defined aspecific area w hich when bilaterally damagedresults in a persistent failure of recent memoryand an immediate retrograde amnesia of atleast several weeks. The area thus defined is theh ip po cam pal-fo rnix-m ammillary sy stem .A rather interesting light on the possible

specificity of localization was thrown by thew ork of Penfield (@ ) on electrical stim ulationof the temporal lobe. Discussing the memorychanges following on bilateral hippocampallesions, Penfield has suggested that theyinterfere w ith memory recording and that

already established skills are not interferedw ith. It is probably premature, however, tocome to this conclusion inasmuch as one cannotsay to what extent the damage is in the retrievalmechanism rather than in the recording



32 8 [MayHE PROCESSES OF REMEMBERING

enquiry: what serves as the organic substratefor the memory trace? For a considerable timeit has been considered that memories arepreserved in the brain in the form of traces

which are laid down at the time the experienceoccurs and which are reactivated at the momentof remembering. AEarlier workers, in attempting to provide on

theoretic grounds a substrate for the trace,tended to put forward one of several hypotheses. The first was that the trace is laiddown in terms of alteration at the synapse; a jmodification of this was that it is laid down interms of the linking together of a networkof neurons. The third one, which deviatedrelatively little from the first two, was that thetrace is laid down in terms of alteredconductivity.It was not until 1947 that an entirely new

concept arose. This was that the memory traceis laid down in terms of changes in cell protein.This new concept sprang into being with thediscovery that the protein structure of neuralcells is exceedingly complex and that it alsovaries from cell to cell. This at last providedwhat had been sought, namely, a substrate ofsufficient complexity to perm it the recordingof the exceptionally large number of bits ofinformation which the individual possesses inthe form of memories. 4Katz and Haistead in 1950 (ii) stated the

concept in these terms: â€œ¿Neur on snvo lv ed inmemory become fully functional only afterchemical structural changesâ€• and they suggested that a neuron becomes operative in )@virtue of the formation of a new, specificallyoriented, protein molecule. They assumed thatthe molecule was a nucleoprotein and that itacted as a template for the synthesis of proteinreplicas.From this point onw ards, a num ber of w orkers

entered this field, of whom the most active has â€œ¿been H ydÃ©n (12). H e advanced the hypothesisthat the substrate is ribonucleic acid andpointed out that in the many combinationsperm itted by the rearrangement of its fourbases, one has a substance which in principlecould encode zo'3 or more bits of information.He set up a theory as to how the pattern of

mechanism . However, it is quite possible tostate that there may not be such a discordancebetween the views of Lashley and the reportsof these m ore recent w orkers, since this system ,

name ly th e hipp ocam pal-fo rn ix -m ammillarybody circuit, m ight simply be an essentialpathw ay to the general areas of the brain wherememories are recorded and from which theya re r etr ie ve d.Another attack on this apparent enigma

presented by these contrasting findings ofLashley and the neurosurgeons has been madeby those who consider that recording is atwo-stage procedure. Teuber (i o) for instancehas recently stated, â€œ¿Ao ca l p ro ce ss o f in itia lregistration and consolidation precedes a subsequent dispersal involving large portions of thecerebral hemisphere.â€• In the electro-shockprocedure, we have a means of producinggraduated amnesia, and it is of interest to notethat there is a proportional relationship betw eenthe number of electroshocks given within aperiod of time and the extent of the amnesias.It is quite possible, for instance, to produce along-lasting, probably permanent, amnesia bysetting the num ber of electroshock treatm entsto be given within a predeterm ined period.Those of us who have worked on this at theInstitute take the view that this phenomenoncannot readily be understood in terms of consolidation, but can be more easily grasped ifwe consider that the longer a memory traceexists the more connections it develops withother traces. From here we may go on topostulate that those memory traces withn um ero us, lo ng-estab lish ed inter-c on nectio nsare much less easily obliterated than those ofrecent origin. This criticism of the concept ofconsolidation leaves intact the possibility thatrecording may be in the form of a two-stageoperation as already described.We may now leave this first great area,

namely, the location where memory traces arerecorded and stored, with at least the temporary assumptions that they are widely storedthroughout the brain and that the hippocam palfornix-mammillary system probably plays animportant part in the conveying of the neuralimpulses to and from the storage areas.W e now turn to the second great area of n erve im pu lses en terin g th e cell co uld d eterm ine




It seemed reasonable, seeing that DNA isprimarily found in the nucleus, to start with it.W e used this primarily in oral form but to a

lim ited extent also in intravenous form , and gotno results. W e then turned to ribonucleic acid(RNA), both in oral and intravenous form , andbegan at least with the former to get definitealthough lim ited evidence of amelioration ofm em ory deficits in the aged individuals w e w erestudying. However, the earlier intravenoussolutions were so apt to produce severe shocklike reactions, that they were stopped.W e co ntin ued im pro ving o ral admin istratio n,

and as we did so and could give larger andlarger amounts, we began to be increasinglycertain that in a grow ing number of cases wewere able to produce changes which could be

recorded and statistically evaluated by the testinstruments w hich we had devisedâ€”notablythe counting test (i8), certain parameters ofthe conditioned reflex procedure (19) and theW echsler M em ory Q uotient.In 1961, D r. S. Sved, who had joined the

biochemical side of our investigative team , w asable to produce a greatly improved solution ofR NA for intravenous use. This solution yieldedmuch more rapid and much more extensiveresults and we were now able to differentiatebetw een the responsiveness of three categoriesof patients showing organic brain deficits,namely, presenile, arteriosclerotic and senile(20).

The procedure which we presently followcalls for extensive pre-treatm ent evaluation, inwhich we employ the counting test, theW echsler Memory Quotient and the follow ingparam eters of the conditioned reflex procedurewhich have been developed by Dr. Solyom ofour research team into methods for estimationof memory change (2!):(a) Rate of extinction of the orienting reflex;

(b) Speed of acquisition of a conditioned

reflex;(c) Rate of retention of the conditioned reflex;

(d) Rate of extinction of the conditioned reflex;

(e) Capacity for discrim ination between cond itio ne d s tim uli;

( f) Capaci tyo delaya condi tionedeflex .We now employ as well two types of a time

estimation test as developed for us by Mr.

the stability of one of the four bases at a givensite on a pre-existing RNA molecule. He wasnot however able to demonstrate this experi

mentally.Interest in this spread rapidly. M orrell (is),

using a technique whereby the production of anartificial epileptogenic area in the cortex of onehemisphere could produce a mirror epileptogenic area on the cortex of the opposite hemisphere in the same general area, demonstratedthat this resulted in unusually high concentrations of ribonucleic acid in the abnormallyd isch arg in g m irro r fo cu s.D espite this interest, experim entation on the

human subject was strangely absent. In 1956,when we commenced our studies of the role ofRNA in the memorial process of aged in

dividuals, so great are the ranges of scientificliterature that we were quite unaware of the

@ earlier conjectures of Katz and Halstead. Soif the early theorists and microbiochemistsseemed unaware of the possibilities offered byhuman investigation, those of us who wereexperienced in this field w ere equally unaw areof those stimulating ideas which had grown upin the shadow of larger speculations concerningthe structure of proteins and the microm etabolism of cells.For over 20 years we had been working in an

attempt to find some substance which wouldcorrect the memory deficit found in the aged.

In 1955 Paul Weiss (i@ ) made a report summarizing his work on the neuron in the previousseveral decades. It w as a singularly stim ulating

@ report. He pointed out that the neuronâ€”farfrom being a fixed or relatively static structure

fr â€”¿s constantly in action, and that in particular

it is continually producing material at thenucleated end w hich passes along, disappearingas it goes, towards the term inal structure of theaxon. In a subsequent review of the work of

@ himself and others (15), using both his axon@ damming method and radioactive isotope

tracers, he estimated that the flow occurredat the rate of 2â€”3m illim etres a day. Since there

was some evidence that the substances m ightinclude the nucleic acids, as suggested by the

@. earlier work of HydÃ©n (i6) and Samuels ci al.

(i 7), it was decided to start exploring the use

@ of the nucleic acids in the human subject.



[May30 THE PROCESSES OF REM EM BERING

kept down to a minimum. The advantage ofthe second is to secure a high concentration ofRNA and its breakdown products in the

blood, and the advantage of the third is toprovide a m ore continuous (i.e. daily) adm inistration of RNA and at the same time to avoidthe side-effects. Our more recent studies,however, suggest that the first procedure ispreferable.The side-effects referred to consist primarily A

in nausea and abdominal discomfort, in cramping sensations in the extrem ities and in a fallin bloo d p ressu re. T he se verity o f th e sid e-e ffectsis related to the speed of injection. The fallin blood pressure can be corrected by pressoragents such as aram ine.In 1961 Montanan et al. (23), using ribo

nucleotides in oral form , reported confirm ationof our results.After accumulating a considerable number

of cases, we have found it possible to say thatthe best results are obtained in individualswhose memory disturbance is on an arteriosclerotic basis, the second group is that of thepresenile, A lzheim er's and Pick's disease types,and the third group is the senile. In all threecategories, the best results are obtained w herethe cases are treated in the early stages ofm em ory defect.The results demonstrating the greater effec

tiveness of intravenous as against oral adm inis

tration can be seen on Table I. The results inintravenous administration can be seen onTaole II and the breakdown of the group intopresenile, senile and arteriosclerotic sub-groups @ ican be seen in Tables III, IV and V . Thefurther presentation of the effects upon delayedreflex formation can be seen in Table VI andwith respect to discrim ination there is aportrayal on Table V II. Changes in thedirection of reduction in pathology were foundin a majority of the EEG tracings taken after â€œ¿administration of RNA. These can be seen inillustrative cases recorded in Charts I and II.In the meantime, other types of experi

mentation were now going forward whichbrought further evidence to support the hypothesis that ribonucleic acid is the substrate formemory. Certain of these approaches havealready been discussed, and of the additional

Claude Beaulieu of our research group. Thefirst is based on asking the individual to statewhen 5, 10, 15 and 30 seconds have passed

from the time that a given sound was heardand the second is based on presenting theindividual with given intervals of time andasking him to estimate how many seconds hefe els th ey r ep re se nt.W e have also started to explore dichotic

m em ory tests, w hich involve passing a differentsignal in simultaneously through each ear andasking the individual to repeat them . This test,originally evolved by Broadbent (22), is basedon the fact that one ear habitually shows itselfto be dominant and therefore the data passedthrough the other ear must be held transientlyin a memory storage system . The test is

essentially one to show the efficiency of thiss to ra ge s ys tem .Along with the data, we record the electro

encephalogram and collect a great deal ofreportorial information through the medicalstaff and the social w orkersâ€”the m aterial beingobtained both from the patient and his relatives.Furtherm ore, w e are in the process of developingan occupational therapy battery to assessm em ory change.Once these procedures have gone forward

and once the dimensions and nature of thepatient's memory deficit are defined, w e selectonly those patients w hose deficit is relatively

stationary and w ho are not suffering from mooddisorders or any serious physical conditionwhich might in any way disturb the memorialcapacity of the individual.The subject is then given RNA in a io per

cent. buffered solution, the basic m aterial beingobtained from yeast. W e have employed avariety of intravenous procedures. First weused a low concentration method whereby 10grams of RNA in a 10 per cent. solution wereadded to i ,ooo c.c. of normal saline and givenby slow drip over 6-8 hours. A second methodhas been to administer i o grams of RNAin a xo per cent. solution undiluted over aperiod of 50 minutes. These injections wereusually given three times per week. A thirdprocedure has been to give i gram of RNAin a 10 per cent. solution twice a day. Theadvantage of the first is that side-effects are

A

@1



1963] BY D. EWEN CAMERON 33!

CHART I.â€”The alpha activity is more organized and regular and there is more alpha activity present after

RNA treatment. Moreover, other abnormal activities are decreased.



THE PROCESSES OF REMEMBERING [May

A

4

I

I

33 2

q

t

A

I

CHART 11.â€”The alpha activ ity is more regular and of somewhat higher voltage after RNA treatment. Thea lp ha in dex seem s slig htly h ig he r.



MeansBefore

AfterOral I/V Oral I/VChange Oral/VCounting

test:Upper limit ..Lowerlimit .... ... ..

45@27 39.9 72@57 7847

. 261 I5@6 396 37'627@3O

38@57@ 22@OWechsler

Memory Sca le :Memory quotient.... 72@0 72 â€¢¿2 76 89 8i â €¢¿864â€¢ 89.59TABLE

IIIntravenous

Administration(Total

Group:6)Means

T-Test dfBeforefterpCounting

test:Upper hznit .. ..Lower limit .. .... ..39.9

78@4 38@i815@6 37â€¢6 14>

001

o@o5 forone-tailedestWechsler

Memory Scale:Memory quotient ....72@ 2 8 i â€¢¿8 2@95 10â€¢02 < p<€¢¿oiConditioning

test:

Orienting reflex ..Spe ed o f a cq uisitio n o f c .r.Retentionof c.r. ....

..

..w*

5@7 57 38 514.0 5@8 24

43.@ 64@3 i6N.S.02< p< .01

â€¢¿Ã˜ 2

BeforeAfterCounting

test:Upper lim it .. .. .Lowerlimit .. .. ..

44

. 1451432@5Wechsler

Memory Scale:Memory quotient .. ..@92@3Conditioning

test:Orientingreflex .. .S pee d o f ac qu isitio n o f c.r. .Retentionofc.r. .. ..

7@2

.

. 495@2475


T@&a I

In travenous versus Ora l Admin is tra tion

(AllRNA patientsncluded)

* Lesser rank total for W ilcoxon's Rank Test Paired Replicates.

TABLE III

Intravenous Administration

Ar ter iosclero tic Group (4 )

approaches the firstas a group ofexperiments

carried out in the cancer field w ith a pyrim idineanalogueâ€”6-azauracil.ork with thisagent

was initiated by Hakala et al. in 1956 (24).When transferredto the human subject by

W ells et a!. (25), it was found that in additionto marked changes occurringin the brainwave

picture, such as the abolition of fast rhythms,the disorganization of background activity,irregular slow ing and the disappearance of

the response to photic stim ulation, behaviouralchanges also appeared in the form of lethargy,somnolence, confusion and semi-coma. Thesechanges were reversible. No work has yetappeared, however, reporting that attempts



MeansT-TestdfpBeforeAfterCounting

test:Upperlim it ..Lower lim it .... .... ..423 8@69@7 [email protected] 2@9I5 5>@coi@05>p>OO2Wechsler

Memor y Sca le :Memoryuotient....6g@[email protected]

test:.Or ienting reflexSpe ed o f a cquis itio n o fRetenti onofC. R...

C.R.....

..

..52

143

39.068

5.14

6 g .4W@

93@ 5I @ 5N.S.

N.S.> â€¢¿@5

U

w

I

z0

U

2(

se c 0 sQC

C ounting test:Upper lim it .. ..Lower lim it .. .... ..36@0 ,8@888@87@5Wechsler

Memor y Sca le :Memory quot ient...7o6766Conditioning

test:

Orienting reflex ..

Speed of acquisition of c.r.

Retentionofc.r. ......

..6 .6

22

39.54

12@3

77.3

THE PROCESSES OF REMEMBERING [May

TABLE IV

33 4

Intravenous Administration

(P re se nile D em en tia G ro up : 7 )

4

* Lesser rank total for Wilcoxon's Rank Test Paired Replicates.

TABLE V

IntravenousAdministrationS en ile D em en tia G ro up (@ )

Tjuu@xVI

DELAYED REFLEX FORMATION

D PREREATMENTâ€¢¿POST TREATMENT

Means

Before After

â€˜¿1

to measure the presumably accompanyingmemory deficits have been carried out.Related studies have been carried forward

w ith reference to the effects of ribonucleaseupon the ability to retain a learned patternof behaviour. Later, Dingman and Sporn (26),working with rats and studying the effect on

m aze learning, used an analogue, nam ely 8-azaguanine, and found that the capacity to learnwas severely interfered with. Sim ilar resultswere reported by Koenig (27) with respect toa pyrim idine analogue.

I-

A

In still another area, a quite different kindof attack was being made upon the problem of

the relation of RNA to remembering.

McConneil et a!. in 1959 (28) and Corning andJohn in 1961 (29) experimenting with theeffects of ribonuclease (which breaks downribonucleic acid) upon planarians reported thefollowing interestingexperiment: Planarians i



BY D. EWEN CAMERON 335

TA BLE V ii namely, if the contents of the neuron are constantly stream ing towards the end of the axon,

how is it possible to ensure the maintenance of

a fixedmemory trace?However, thissuggestionthat the memory trace may actually be in theglialcellsratherthan in the neuron should only

be takenas highlytentative,inceour informa

tionconcerningthe contentsof the neuron so

streamingisbased on evidencesuppliedby the

electronmicroscopeand alsoon Weiss'extra

ordinary earlier experim ents in constricting theaxon.

S till another possibility should be consideredin endeavouring to understand the curious

phenomenon ofthe continuingflowofmaterial

from the nucleatedpartto the peripheralnd

oftheaxon and thedilemma which thisraises

in attempting to explain how a trace is maintained. This possibility is that although thebasic mass of a substance in the neuron maychange both in amount and in identity

(although not necessarily in nature), yetnonetheless the trace may remain as a designo f o rgani za ti on .

A simpleillustrationf t hi sc an b e s ee n i n

the skin,which remains relativelyonstantin

locationnd in texture,ut which isconstantly

beingrenewed,or againin the eddy and swirl

on thesurfaceof a stream,which remain the

same althoughthe water which forms them is

for eve rcha ngi ng.

In a similarmanner, itis possiblethat amemory trace may endure, although theoriginalNA which was itssubstrateas been

replacedby a new supply.Fluctuationsn the

amount of RNA, such as the increase which hasbeen describedduringneuralactivity,ay be

linkedwith working proposals egardingactiveforgetting.hus itispossiblehatwhen a con

siderable number of new memory traces arebeing formed, as when we are actively experiencing, an increased amount of RNA isrequired,but lesswillbe needed when those

memories createdby our experiencingre no

longernecessaryand have been eliminatedby

a proce ssof acti veforge ttin g.Countlessexperimentssuch as thoseon rote

learning,n immediaterecall,ave shown that

whilememory tracesreendlesslyeingformed

during our waking hoursâ€”andapparentlyto

DISCRIMINATION

1963]

z0z0

(1)Ui

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p

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Dz

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2 3 4 5 6 7 8(TestThals)

(a) Responseto pos it ives t imuli a fte r t rea tment

(b) Responseto pos it ives t imul i be fore t rea tment

(c) Responseto negat ive s t imul i be fore t rea tment

(d) Responseto negat ive s timuli a fter t rea tme@t

can be trained to run a very simple T-maze. Ifthe planarians are then transsected and allow edto regenerate in ordinary pond water, both thepart which regenerates from the head and thatwhich regenerates from the tail end will show acapacity to run the maze. If, however, the head

@ ends and the tail ends are regenerated in asolution of ribonuclease, the head ends stillshow a capacity to run the maze equal to thatof the head or tail section w hich w as regenerated

in pond water, but the tails perform randomly.A gain shifting the basis of attack, w e find that

in 1960HydÃ©nand Pigonworkingwithrabbits

1 (30) reported that ribonucleic acid concen

trations rise in neurons during activity andperhaps during learning, and that after suchactivity a decreased amount is to be found int he n eu ro ns b ut a n i nc re as eda mo un t i n t he

@ glialcellssurroundingthe neurons.In other

@ words,theirbasicsuggestionsthatribonucleic

acid increasesin amount in neurons during

activ ity,nd theirseco nds ugge stionsthatthe

glialcellspossiblyplay a much more active

partincerebralctivitynd perhapsinmemory

than hashithertoeen supposed.They considerthatth esefindings ivefu rthersupportto the

â€˜¿rontention that the substrate of remembering is

ribonucleiccid.

Thismay be theanswertoa difficultuestion,



33 6 [MayHE PROCESSES OF REM EM BERING

some degree during our hours of sleepâ€”avastly greater proportion of them can no longerbe recovereda few minutes afterthey have

b ee n fo rm ed .It is moreover a matter of common experi

ence that the number of bits of informationwhich impinge upon the individual and towhich he responds by form ing temporarymemory traces is clearly fluctuating. In turn,the individual show s considerable fluctuation inthe extent to which he responds or, as one saysin common language, in the extent to which heattends.Weiss (3m) although clearly basically con

cerned with the presentation of his concept ofperpetual neuronal growth, approaches theproblem of how fixed or relatively fixed m em ory

traces are maintained in a substratum whichmay be constantly moving its location and alsobeing broken up or replaced. He points to thehigh rate of synthesis of proteins and of ribonucleic activity and to the continuous flow ofsem i-solid materials from the nucleated partof the neuron to the end of its axon. He considers that the fact that the neuronal m echanismis undergoing perpetual renewal perm its ofa da ptiv e remo de llin g.He cites the example of the antigen causing

not only the formation of antibody moleculeswhen it is actually present, but resulting inmodifying the cells in a lasting manner so that

they continue to manufacture the same specificantibodies. He suggests that in a sim ilar waythe nuclear production apparatus of the nervece ll m igh t in resp on se to ap pro priate stim ulatio nhenceforth turn to m olecules having a particularconfiguration.It seems not unreasonable to suggest that

nerve impulses evoked by meaningful experience as they pass through the nerve cells mayalter the conform ation of m olecules in a lastingway. One may assume that as these moleculesare reproduced they will tend to be identicalw ith those formed by the original impulse.Here one may see the sketched-in outline of a

theory serving to explain the preservation ofengrams in a field which itself is constantlychanging with respect to the substrate.These things, however, remain highly specu

lative and we should not close the list of

possibilities w ithout pointing to the fact thatwe are only now beginning to discover thepresence in the neuron of a highly complicated

inner structure consisting of a great variety oforganelles. Among these organdies we shouldmention the ribosomes which are reported aspossessing a particularly high RNA content.The role of the various membranes which existw ithin the cells is still largely unknow n. A mongthese membranes is the endoplastic reticulumwhich, while located in the cytoplasm , isthought possibly to have direct communicationwith the nuclear membrane. These organelles,of which reference is being made only to two,constitute what Brachet has termed the â€œ¿cytoskeletonâ€• (32).Finally, quite recently we ourselves have

made a further step forward in so far that wehave begun to examine ribonuclease in theblood of normals and of various individuals inthe aged group who have memory defects. Dr.Sved of our research group has found evidenceth at rib on uclease is ele vated in th ese ind iv id uals.This suggests the hypothesis that a possiblefactor in memory disturbance may be overa cti vi ty o f r ib onuc le as e.As we set out on the survey of the processes

of rem em bering, w e found that over a prolongedperiod of time men have endeavoured to solvethree great questions about these processes. ThefIrst: Where in the brain are memory traces

stored? Second: W hat substrate is used for theirstorage? And the third question we will dealwith in a moment.W ith respect to the first two questions,

however, it cannot be too strongly stated thatthe memorial processes cannot be understoodpurely on the basis of anatomical connectionsor of the biochemical substrate of memory.W ere w e to discover tom orrow that ribonucleicacid is actually the substrate of memory andwere we able to demonstrate how this substrate is used for the coding of memory, wewould still be confronted with the vastlyintricate matter of the total functioning of the

memorial processâ€”a matter which no doubtw ill concern com ing generations of researchers.How does the incoming stimulus produce thememory trace? What is the nature of coding?How is the trace held? What is the role of the

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emotional response? How does the retrievalmechanism find with such remarkable speed,

and in most cases with such extraordinary

accuracy, the tiny datum of information laiddown in a day now far off. How are memorytraces once coded then read out again?Our third question then to which we now

address ourselves is by far the most comprehensive and difficult. It isâ€”placing to one sidethe question of the location of the storehouseof memory and the nature of the substratehow do we remember and forget? The questionshere are numerous, complex and far fromsolution. They include one that is outstandingin its complexity and in its fundamentalnature. For, as we consider the intricate chainw hich runs from perception through recording

of the memory trace and back through decodingof that trace to actual conscious recall, therebreaks in time and again to face us that mostprofound of enigmas, namely, the conversionof neurochemical events into the events ofconsciousness.It is in a sense well that we should be thus

confronted, since undoubtedly some of ourdifficulties in understanding rem em bering arisefrom our having tended to explore the anatom ical, biochem ical and psychological aspectsof this function separately. Whereas, if theprocess is taken as a whole, leads developed inany one part can be of assistance in others. For

instance, it is well known that a stimulussituation must last for a given time for theindividual to respond by developing a memory

v@ trace. This suggests that the necessary neurochemical mechanism requires a certain periodoftime tooperate.Thisin turnmeans thatwe

can elim inate from our questioning any neurochem ical m echanism s w hich take appreciablylo nger to comp lete o peratio n.Or, again, we may point out that repetition

serves to stabilize the memory trace as does theintensity of the m eaning of the stim ulus reaction.This raises conjectures as to the nature of theco ding and sto rag e p ro ced ures.

Finally, we may point to something that weshall shortly discuss in more detail, namely,

@, that recognition is better preserved than is

recall in organic memory deficits. This againmakes one ask questions and perhaps serves to

pointour questionsn givendirectionss to thenatureofthestorageofthememory trace.

In the courseofour work on remembering,

w e h av e d ev el op ed a w or ki ng c on ce pt o f t hevariousstagesof the memorial processas they

occur at the behaviourallevel.It should be

pointedout that thisisa purely provisional

pictureand probablybearsno more relation

ship to the final portrayal of the stages ofremembering than do the architect's initialsketches to the finally completed building.This working concept is shown on Figure i.

I shall not attempt to deal with the linksseparately, but shall m ake som e overall observations and also deal w ith one or two points inthe process w hich seem particularly prom isingfor stu dy.The primary response is of course an

organismal event. It is based upon psychological, neurophysiological and biochemicalhappenings. Nonetheless, when w e describe its

duration, this is most easily stated in terms of itsneurophysiological events. Thus we may saythat the prim ary response is in operation duringthat period when the inflow of neural impulsesfrom some stimulus commences to the pointwhere their encoding as a memory trace iscompleted. Here is at once an unansweredquestion. Is this the course of all incominginformation or does some become held in ahighly transitory form for perhaps a fewseconds?. . . or up to a minute or two, accordingto some workers,in reverberatorycircuits?

or forperiodsas longas halfto one hour

as suggestedby John (33)?

Broadbent(22),an dnglisnd Sandersonon the basisof the former'sdichotictesting

procedure,have advanced a most explicittatement of memory as a two-stage procedure.And there is now a widely held belief that

S TA GE S O F M EM OR IA L P RO CE SS

Fic.i.



33 8 [MayH E PRO CE SSES O F R EM EM BER IN G

memory isa two-stageprocedureand hence

in the Figure I have at least recorded a linkfor immediate retention and another link for

p ro lo ng ed re te ntio n.The link dealing with active forgetting is

more contentious, and there are those whoclaim , as you know, and to my mind quiteabsurdly, that nothing ever experienced andrecalled no m atter how briefly ls ever forgotten,so that, theoretically, you should be able toremember the fifth poached egg that you atein your life, the third person you met enteringthe railroad station in your home city 3! yearsago, as well as the colour of the tie you wore on16 August, 1952. Moreover, quite apart from

these relatively discrete events, such a theorypostulates recording of every conversation

heard, the frequency of lightning flashes andthunderstorms which one has endured sincebirth, the structure and content of everyreverie, all the songs you have heard and theorder of every fleeting cloud formation everseen and noted.Quite clearly the burden of proof is on those

who assert such a concept. Nature is well know nto be most parsimonious, though if the enddemands it prodigal in the extreme. But nosuch comprehensive and indeed total rem embering of experience is required. W hat is valuableand useful for the individual to retainâ€”beyondthe brief retention necessary to afford con

tinuityâ€”is strictly lim ited. A ll evidence froma great many investigators using a very considerable variety of testing procedures suggestsstrongly that storage space in the brain isreserved for the memory traces of matters setthere under the urgency of their specialemotional significance for us and maintainedthere because of the frequency with whichsuch m em ory traces are called uponâ€”in a w ord,because they are especially meaningful or theyare continually useful to us.Indeed we have some evidence of this in

studies we have carried on in the last two yearson perseveration. The term â€œ¿perseverationâ€•s

used here in the sense that has been employed byBumke, Jaspers and Solder 36, 37), namely,to designate a phenom enon w hich is particularlyapt to appear in the organic brain syndrome.This consists in the patient tending to respond

to a question by means of an answer which hehas just given in reply to a quite different

question. Using the counting test, we found

that perseverationended to interfereithretention, that it usually appeared at the upperlim its of retention, and that it could only be

overcome by means of massivereinforcement

of the stimulus, as where one uses multiplemodalities in attaining initial registration. W econsidered that there are grounds for thinkingthat perseveration is due to a failure in theprocess of forgetting; in other words, that theprevious question and answer had not beenremoved from im mediate retention.Somewhere, and probably in the section

described as prolonged retention, encodingtakes place. Encoding and the formation of

the trace appear to us at least at the presenttime to be functions which are difficult toseparate. s is w ell k nown, men are at this

moment in theprocessof breakingthe genetic

code which employs DNA as its substrate, butw e a re s t il li th ou ta l ea da s t o h ow t o b r ea k

the memory code which we presume is basedupon RNA. It is here that the use of analoguesfor the bases may be of great value.

@A rapidly lengthening series of reports is

appearing on how encoding takes place. Mostof them , however, are derived from studies ofmechanical and sometimes purely theoretical

information. It would also appear that those

attempting these approaches are handicappedby lack of direct experience with behaviouralphenomena.

M ay I lastly pass on to a brief considerationof what also suggests a good leadâ€”this timeto the u nde rstan din g o f d eco din g o r reco llectio n.Ths lead lies within the section of retrieval andconsists in the comparison of the process ofrecalland recognition.ere one may pointto

the very interesting phenomenon that if oneafter another one puts before a patient a seriesof numbers, it is quite easy to demonstrate thetime interval beyond which he cannot recall.If one puts before him four numbers of which

one is that in quest, he will be able to recognizethe correct one over a much more extendedperiod than he can recall correctly. It wouldseem that in the case of recall the stream ofingoing impulses derived from the question is

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11. KATZ, J. J., and HAJSrEAD, W. C. (1950). â€œ¿rotein

organization and m ental function.â€• Com par.

P s,c ho l. M on og ra ph s, 2 0, 1 â€ ”3 3.

12. HYD#.N , H. â€œ¿Nu cl ei ca ci ds and p ro te in s. â€ •

in N eu ro ch em is t'y , p p. 2 22 â€ ”2 24 . S prin gfie ld :C has. C . Thom as.

13. MORRELL, F . (1961). Brain Mechanisms and Learning.

E dited b y J . F . D ela fres na ye. O xfo rd : B la ck wd ll,

p p. 3 75 â€ ”3 92 .

14. WEISs, P. â€œ¿T heife h is to ry o f th e n eu ro n.â €•

Paper presented at annual meeting of

A.R.N.M.D.,35,8â€”i8.(i@@). Regional Neurochemistry. Edited by

S . S . K etty and J. E lk is. N ew York : P erg am onP re ss, p p. 2 20 -2 42 .

i6. HYDEN, H. (1950). â€œ¿S pe ct ro sc op ics tu di es on n er ve

cells in development, growth and function.â€•

in G en etic N eu ro lo gy , p p. 1 77 â€ ”1 93 . Un iv ersity o f

C hica go P res s.

17. SAMUELS, A. J. et a!. (,g@ ). â€œ¿D is tr ib ut io n, e xc ha ng e

and m igration of phosphate com pounds in the

nervous system .â€• A mer. J. P hjsw l., 164, 1â€”[email protected],D. E. (I@3):â€œ¿mpairmentfthereten

tion phase of rem em bering.â€• P sychiat. Q uart.,

17, 395.

19. SOLYOM, L., and BEACH, L . (1961). â€œ¿Fu rth er s tu d ie s

u po n th e e ffe cts o f t he a dm in is tr atio n o f r ib on uc le

ic acid in aged patients suffering from m em ory

( re te ntio n) fa ilu re .â €• N eu ro -p sy ch op ha rm ac ol., 2 ,

35 1 -355.2 0. S VE D, S ., a nd WA INRIB ,B . (1 96 2). â €œ ¿Effectsf int raven

and ous administration of ribonucleic acid upon

21. failure of memory for recent events in presenile

and aged individualsâ€• in Recent Advances in

B io lo gic al P sy ch ia tr y. E di te d b yJ . W o rth .

22. BROADBENT, D . E . (1958). Perception and Communication.

London: Pergam on P ress.

23. Mor'rrANMu, M., CuToL.o, E., and MAzzoNi, S.

(ig6i). â€œ¿A cidi ucleinici e derivati: possibilieffeti sa l s istem a n erv osa cen tr ale e a pp lica zio ni

terapeutiche in neurop sichiatria.â€• L 'A rcisepedale

S. Anna di Ferrara, 14, 573â€”582.

24. HAKALA, M. T. (1956). â€œ¿nhibitory activity in 6..

azau radi l,-ura cileth olso ipho nend rel atedcom pounds in the grow th of m ouse lym phom as

a nd sa rcoma s.â €• P ro c. Amer . A . C an cer R esea rch ,

2, 113.

25. WELLS, C. E., AJMor@x-M@sasAN, C., FREI, E., and

TOUHY, J. H. â€œ¿lectroencephalographic

an d n eu ro lo gica l c ha ng es ind uc ed in m an b y th eadministration of I ,2,4-triazine-3, 5(2H,4H)-dione (6-azauracil). E EC C lin. N europhysiol., 9,

325â€”332.

26. DINGM AN, W ., and SP0P.N , M . B. (i96i). â€œ¿Then

corporation of 8-azaguanine into rat brain R NA

and its effect on maze-learning by the rat: aninquiry into the biochem ical basis m emory.â€•

J. Psychiat.Res., @ .27. Kozr'no, H . (196o). â€œ¿Experimental myelopathy pro

duced with a pyrim idine analogue.â€• A .M .A.

A rc h. N eu ro l., 2 , 4 63 â€ ”4 95 .

unable to reactivate the trace, but the trace isstill there, for if this stream of ingoing im pulsescontains a pattern derived from the number

w hich is being sought, it is possible to reactivatethe trace. This clearly brings us to the questionof how the trace is reactivated and opens theway for a series of interesting experimentalapproaches.

And so we complete our review of the greatquestionsithwhich men have struggledrom

the earl iestf timesc oncer ningthisamazi nglypower fulcord which holdstogeth erallthe days

@ o f our liv es.hus a rme d an d sup por ted ,o ur

powers infinitelymplifiedby allthe scientific

devicesof our time,we draw near to the dis

covery of the answ ers to these ancient questions.

W e must in all humility pay tribute to theextraordinary penetration of those men who

@ pondered these questions thousands of yearsago with no devices to aid them , but fortifiedby the fact that if they had but one tool, itw as and remains the most pow erful of allâ€”them ind of m an.

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Biological Memory. Edited by F. 0. Schmitt.

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34 0 THE PROCESSES OF REM EM BERING

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29.Coar@i1No,. C.,andJoNN,E.R. (,@6,).€œ¿ffectsfribonuclease on retention of conditioned response

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1363â€”1365.30. HYD@r4, H ., and PIO0N, A. (@g6o). â€œ¿Acytophysi

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D. Ewen Cameron, M.D.,P.R.C.P.C.),D.P.M.,Directorf theAllanMemorial Institute,hairman

o f th e D ep ar tm en t o f P .@ y ch ia tryo f M cG ill U niv er sity a nd P .@ y ch ia tth t-in -Chie f o f th e R oy al V ic to ria

Hosp it al , Mon tr ea l

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Documents

Dr. Ewan Cameron - The Process of Remembering (1963)