MemoryAutopsy Findings and Commentson the Role of Hippocampus in Experiential Recall

Wilder Penfield, MD, FRCS, Gordon Mathieson, MB, ChB, FRCP(C)

A clinician may report his goodresults. He must report his bad

results. He should report what helearns. In 1956, I decided that I mustpublish the cases of two patients whohad suffered a grave and totally unex-

pected loss of recent memory as theresult of partial left temporal lobec-tomy in treatment of focal epilepsy. Iasked Brenda Milner, ScD, my associ-ate in Psychology, to help me.

During the preparation of our re-

port, William Scoville, MD, describedto me the psychotic patients on whomhe had operated, removing both hip-pocampal zones in one procedure,with untoward results similar to myown. Our talk took place during a

meeting of neurosurgeons (the properplace for discussion of unhappy re-

sults!). He had used an anterior ap-proach to each temporal fossa andemployed deep suction to remove thecerebral tissue.

Since his experience seemed to con-firm our previous conclusion that onlybilateral loss of the hippocampuscould deprive a man of his capacity toscan and recall his experiences, I sug-

gested, on my return to Montreal,that Dr. Milner might postpone our

publication, although it was alreadylong overdue, while she applied hercarefully planned psychological teststo Dr. Scoville's patients. The patternof memory loss in his patients andmine proved to be remarkably sim¬ilar.

Eventually our report1 was sent tothe Archives, but it did not appearuntil 1958, whereas the paper by Sco¬vine and Milner2 appeared in 1957.

Milner and I had assumed that thisparticular form of memory loss oc¬curred because our two patients hadsuffered from a previously destructive(but unsuspected) lesion in the hippo-campal zone of the opposite hemi¬sphere. This was presumed to havetaken place at the time of birth whenherniation of the undersurface of thetemporal lobes occurs all too oftenthrough the incisura of the tentoriumand when local ischemia, to which thehippocampus is susceptible, can beproduced on one or both sides.3·4

Milner and I had already carriedout a careful psychological study ofmore than 90 other patients beforeand after unilateral temporal lobec-tomy. There had been no evidence ofgeneral loss of memory in any ofthese patients. We concluded, then,that under normal conditions removalof one hippocampal area would not

produce the memory loss, that one

hippocampus can duplicate the workof the other, and that, normally, ei¬ther can carry on when its fellow isremoved. Since 1970, Milner5 hasshown that differences detected bycareful testing are characteristic ofleft as distinguished from right tem¬poral lobectomy.

In 1964, one of the two patientsdied, whose cases we had publishedbecause of severe memory loss follow¬ing unilateral temporal excision. Thiswas patient 1, a civil engineer. Hiswife, whose loyalty and under¬standing I had learned to admirethrough the years told me that herhusband had died of a heart attack.She was willing to permit autopsy.

In the meantime, I had retiredfrom neurosurgery and was pre¬occupied with other writing. Con¬sequently, it was not until 1968, in re¬

sponse to an invitation from theRoyal Society of Medicine, that I re¬

turned to the problem of memory andmade passing reference to the engi¬neer's autopsy results.

This brief reference did not satisfythe former Director of the MontrealNeurological Institute, Theodore Ras-mussen, who for some years had beenurging Mathieson and me to publishthe findings from the autopsy in care¬ful detail. Now, however, it is thanksto a similar, although independent,

Accepted for publication Dec 24, 1973.From the Department of Neurology and

Neurosurgery, Montreal Neurological Institute,McGill University, Montreal.

Reprint requests to Department of Neurologyand Neurosurgery, Montreal Neurological Insti-tute, McGill University, 3801 University St, Mon-treal 112, Quebec, Canada (Dr. Penfield).

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suggestion from the Editor of the Ar¬chives that we have turned from"good intentions" to action. Since re-

examining these autopsy details, Ihave discovered how meaningful theyare. For this reason, I am adding a re¬

view of the clinical problem and com¬

ments that are relevant to the physi¬ology of man's memory mechanisms.

Fig 1.—Left hemisphere showing medial, inferior, and lateral surfaces of the temporallobe. Cortical excision at time of operation in 1946 is indicated by the fine broken line.Excision at the second operation in 1951 is shown by the dotted line. This was the sur¬

geon's postoperative drawing. Autopsy now indicates that at least 1 cm more of hippo¬campus and hippocampal gyrus were spared (case 1, the engineer).

Rolando TissureInsula andbrain stemremoved

X >

Clinical ReviewThe preoperative clinical history of

patient 1 is as follows: In 1940, a 35-year-old engineer began to have mo¬

mentary lapses in conversation asso¬

ciated with evident confusion. Threeyears later the episodes had becomelonger and more complex, and were

described by his wife as consisting of

a staring appearance of the eyes, fol¬lowed by head turning, usually to theright, and aimless movements of theright hand and arm together withswallowing movements.

In 1946, at the age of 41, he wasadmitted to the Montreal Neurolog¬ical Institute. Episodes of confusionand automatism, each lasting aboutfive minutes, were observed. Betweenattacks neurological examinationshowed no abnormality. An electroen¬cephalogram discovered slow andsharp waves, localized in the left tem¬poral region. A pneumoencephalogramshowed moderate enlargement but no

focal deformity of either lateral ven¬

tricle.The patient had had no major con¬

vulsive attacks. His habitual seizureswere ushered in by a sudden illusionthat things seemed to him "silly" or"absurd" or "unreal." After exclaim¬ing perhaps at this strangeness, heseemed to remember no more. Hiswife then observed that he stared andwas unresponsive, made automaticfumbling movements with his hands,movements of mastication with hismouth, and turned his head to theright. Toward the close of an attack,he carried out what appeared to bestereotyped actions in what seemedto be an automatic state, for all ofwhich he had amnesia after "comingto himself." At home, he might havegone out on the porch, made an obser¬vation of the thermometer and ba¬rometer located there, and returnedto the house to record his observa¬tions in the appropriate book, but hewould have no recollection of theseactions. Thus, the amnesia mightcover as much as 15 minutes.

The pattern of these seizurespointed clearly to an origin in one

temporal lobe. We had not yet con¬

cluded, as did Feindel and Penfieldlater,6 that this sort of automatismcould be reproduced by electricalstimulation of the periamygdaloid re¬

gion, nor did we realize at that timethe importance of removing the hip-pocampal area if one hoped to arrestsuch seizures by surgical excision.

(There is a discussion of the prob¬lem presented by this patient in thebook published by Penfield and Jas¬per.7)

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Since the patient's head turned tothe right following the stage of star¬ing, and since the EEG pointed to dis¬charge in the left temporal region, itwas assumed that the cause might befound in the left temporal fossa. Fi¬nally, since the engineer feared theattacks would cost him his position as

manager of a large office staff, we de¬cided to explore the left temporal re¬

gion.First Operation.—The first operation

was carried out on Aug 14, 1946. Afew scattered adhesions were foundin the subdural space, and there was

opacity of the arachnoid membrane inthe fissure of Sylvius. These abnor¬malities are often seen as the resultof incisural herniation at birth.

The anterior 4 cm of temporal lobewere removed (anteroposterior mea¬

surement from the curve of middlefossa in front to the line of cut). Mea¬suring around the temporal lobe sur¬

face, the length would be about 6 cm.

(See the broken line on the inferiorand lateral surfaces of the temporallobe in Fig 1.) Because I feared thatremoval might produce aphasia, thehippocampal zone, including theuncus, was left intact.

At the time this operation was per¬formed, we were in the process ofmapping out by electrical inter¬ference and cortical excision the bor¬ders of the major speech area (Wer-nicke) in the temporal lobe. We werestill not sure of the frontier forspeech on the under and inner surfaceof the lobe. For that reason we hadoften removed this area in the non-dominant hemisphere but never onthe side where speech was localized.Regarding the hippocampus, we were,of course, in doubt about the functionof this unique and strangely struc¬tured area of the brain.

The patient recovered from oper¬ation without event. There was post¬operative aphasia that soon clearedcompletely. During the five years fol¬lowing this first operation, the engi¬neer's seizures were less frequent butessentially unchanged in pattern. InSeptember 1951, however, he hadsome distressingly long attacks ofepileptic automatism, which he fearedwould cost him his employment. Hewas ready, he said, "to take a chance

on anything."At the age of 46, he was readmitted

to the Montreal Neurological Insti¬tute alert, well oriented, and withgood memory. Herbert Jasper carriedout a series of three electroencephalo-graphic studies which showed occa¬

sional sharp waves recorded from theleft temporal region but occasionallyarising from both temporal regionsand, on one occasion, the sudden ap¬pearance of a 5/sec rhythmic dis¬charge from the right temporal re¬

gion before spreading to the left side.We concluded, nevertheless, that hisseizures were arising from the medialstructures of the left temporal lobethat had been left in place at the timeof his first operation.

I was still hesitant to remove theleft hippocampus, but it had beendone so often without unfavorableresults on the right, and we had, bythat time, learned a good deal moreabout speech localization that itseemed to be safe. Finally, I decidedto take the plunge and perform thisexcision, believing that there was anexcellent chance of saving him fromhis attacks of automatism.

Second Operation.—On Sept 28,1951, the second craniotomy was car¬

ried out. I exposed, under local anes¬

thesia, the hippocampal zone that hadbeen left intact at the first operation.Recording electrodes were placed on

the hippocampus and hippocampalgyms. The resultant electrocortico-gram showed the spike dischargesthat come characteristically from an

epileptogenic focus.Then I stimulated the tissue with

an electrode. An attack of whatseemed to be epileptic automatismfollowed immediately. My associate,William Feindel, who was observingthe patient at the moment, describedit as typical of his habitual attacksof automatism. When the stimulatorwas applied, the patient said: "I felt a

tremble over near the west side of themonument." Feindel asked him wherethat was. He replied, "On the road toAlbany." Shortly afterward, when theattack was over, it was quite clearthat the patient had no recollection ofthe conversation. It is difficult to saywhat the exact anatomical localiza¬tion of my stimulator may have been.

During the years that followed thefirst operation, we had learned to ex¬

pect this type of epileptic responsein the vicinity of the amygdala. Thus,I had evidence of spontaneous dis¬charge and I seemed to have producedone of his typical attacks of auto¬matism, which was followed by am¬

nesia for the event. I removed theuncus and hippocampal zone, includ¬ing with them, as the autopsy shows,the anterior half of the hippocampus(Fig 2).

In spite of all this preoperative evi¬dence that had led us to localize thecause of the seizures in the left tem¬poral region, the patient's attackscontinued, and an EEG, recorded dur¬ing a clinical seizure after operation,showed an onset characterized bysuppression of electrical activity overthe right temporal region, followedby regular 4/sec sharp waves, whichonly later spread to the left side. Anadverse critic might well object, like a

devil's advocate: "The fact that his at¬tacks were not cured after his two op¬erations should make you reconsider.Perhaps, after all, you were wrong.Perhaps the epileptogenic focus wasin the right temporal region all thetime."

If that is true (which I hesitate toaccept), and if we had excised the hip¬pocampal zone on the right side andnot the left, we might have cured thepatient of his attacks and he wouldhave had no difficulty with his mem¬

ory. Such are the doubts that some¬

times assail whatever part it is of a

surgeon's mind that one can call a

conscience!After operation we were stunned to

discover that the patient had a severe

retrograde amnesia. It included, atfirst, all the things he should havebeen able to remember in recentyears. By the time he left the hospi¬tal, the amnesia for the past had im¬proved until it included only what hadhappened in recent months. But more

important than the retrograde am¬nesia was that he could no longer re¬

member the new events of each dayafter he turned his mind to othermatters. On the other hand, hisgeneral intelligence was remark¬ably preserved and he had no

aphasia.

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My associates and I were nowforced to suspect, as I have said, thatthe hippocampus on the other sidehad been destroyed at the time ofbirth and that our removal had thusproduced a bilateral hippocampaldeficit.

However, we continued to carry outunilateral temporal lobectomies in¬cluding medial temporal structures,but with utmost caution. The resultsin the treatment of this form of ep¬ilepsy were, and still are, remarkablysuccessful. We took great care not todo the operation if there was any sus¬

picion of a bilateral lesion. Thus, a

good many patients were cured oftheir seizures.

Then, on Oct 21, 1952, it happenedagain, and the same postoperativedisturbance of memory followed a

left temporal lobectomy. This time,the left anterior temporal lobe hadbeen removed, and with it, the wholehippocampal zone. Since the removalwas carried out at one stage, I couldmake a more reliable judgment as tothe extent of removal of the hippo¬campus. This patient (No. 2) was a

glove-cutter by profession. His oper¬ation was followed by a defect inmemory and in learning that had thesame peculiar pattern as that of pa¬tient 1. But his retrograde amnesiawas more extensive and improvedlittle, if at all.

The misfortune of these two pa¬tients has led Rasmussen and his as¬sociates to devise a test that can

now be used to guard against thedanger of memory loss after removalof the hippocampus. The amobarbitaltest, devised by Wada and Rasmus-sen (1960) to determine speech later-alization, paralyzes the hippocampuson the side of carotid injection for afew minutes. A brief examination ofthe patient, as described by Milner etal,8 can be used to determine whetheror not there is a loss of memory. Apathologic defect in the opposite hip¬pocampus need be feared only whentemporal lobe epilepsy is caused by an

epileptogenic lesion produced by in-cisural herniation at birth.

As years passed, the engineer andthe glove-cutter were severely handi¬capped, of course, by their memoryloss. And yet, amazingly enough, each

of them was able to continue to earnhis living. Brenda Milner studied thepatients exhaustively. Each had pre¬served the memory of his specialskills. There was no impairment ofspeech nor ordinary perception.

The engineer continued to draw ex¬cellent blueprints. While his attentionwas focused on the problem at hand,he could understand and make thedrawings accurately. But if he turnedhis attention to something else andthen turned back to the drawingboard, all memory of what he haddone and proposed to do was a blank.To make up for this, he made copiousnotes by hand, and substituted thesefor what he should have been, andperhaps was, recording in the brain'sown sequential record. If he was

recording it, then the defect was inthe mechanism of recall. The glove-cutter, although he made less elabo¬rate efforts to compensate for his de¬fect, was still an expert glove-cutter.

When seen in 1956, four years afterhis second operation, the engineer'sintelligence quotient rating was 125and memory quotient 94. No improve¬ment with practice occurred duringrepeated administration of the same

memory tests, probably a most con¬

clusive proof of impairment in theability to learn.

Further comment on both cases willfollow in "Neurophysiologic Com¬ment."

Neuropathologic StudyDeath of patient 1 was due to mas¬

sive pulmonary embolism. The brainweighed 1,445 gm. The arteries were

arranged normally and were gener¬ally free from atherosclerosis, apartfrom some dilation of the intracranialportions of the carotid arteries andslight elongation and tortuosity ofthe vertebral arteries. The left tem¬poral lobe surgical removal involvedthe superior, middle, and inferiortemporal gyri, a portion of the occipi-totemporal gyrus, and approximately2 cm (judging by assumed symmetrywith the right side) of the anteriorparahippocampal gyrus, including thewhole of its uncus (Fig 3). Posteriorto the plane of surgical excision, theleft temporal and occipital lobes ap¬peared normal (Fig 4). The right tem¬poral lobe appeared normal external¬ly; in particular, no depression, scar

or atrophie gyrus was present on the

Fig 2—Left hemisphere of human brain, with cortex and white matter dissected awayto unroof the posterior and inferior ventricle exposing the hippocampus and choroidplexus. Inset, Plexus has been removed to give a complete view of the hippocampus.Dotted line shows the estimated extent of removal of the anterior hippocampus in 1951.

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Fig 3.—Posterior aspect of coronal section of brain showing ex¬tent of left temporal lobe removal. Note intact right amygdaloidnucleus (case 1).

Fig 4—Coronal section of cerebrum at a more posterior plane,also viewed from the posterior aspect. Remaining portion of lefthippocampus, posterior to surgical excision, appears normal.Right hippocampus is pale and shrunken (case 1).

external surface of the brain.The cerebrum was cut coronally,

the brain stem and cerebellum hori¬zontally. Slight generalized wideningof the sulci and dilation of the ante¬rior horn and bodies of the lateralventricles indicated some generalizedbrain atrophy (Fig 3 and 4). Well-de¬fined focal lesions in this brain arebest described in three groups: thosein the left temporal lobe, those in theright temporal lobe, and those else¬where, which are considered to be sec¬

ondary.In the left temporal lobe region, the

whole of the amygdaloid nucleus hadbeen removed in addition to thoseportions of the left anterior temporalgyri described above. The excision ofthe left hippocampus extended backso as to leave approximately 22 mm ofits posterior portion (Fig 4). On nakedeye examination, the laminar patternof this remaining portion of the lefthippocampus was preserved. Histo-logically, it was normal except for at¬rophy and gliosis of the alveus. Thepyramidal cell layer was entirely in¬tact, without cell loss in any of itssectors (Fig 5). The stratum oriens,stratum radiatum, and stratum la-cunosum-moleculare also appearednormal. The gyrus dentatus was in¬tact. In contrast, the alveus was con¬

siderably thinned and showed a well-marked gliosis (Fig 6). This gliosis

extended more widely in the left tem¬poral lobe, involving the gyral whitematter generally, although it was lessapparent in the superior temporalgyrus. The cortex of the remainingposterior part of the left temporallobe, including the parahippocampalgyrus, had a normal neuronal popu¬lation and lamination; it was freefrom gliosis.

Of the structures in the right tem¬poral lobe, the amygdala appearednormal both grossly and microscopi¬cally. The cortex of the superior,middle, and inferior temporal gyri,and the occipitotemporal and para¬hippocampal gyri were also normal.In striking contrast, the right hippo¬campus was shrunken, with a max¬imum coronal surface area of 4x7mm. It was pale, firm, and the usuallaminar pattern was only faintly dis¬cernible. Microscopically, there wassubtotal neuronal loss in the pyrami¬dal cell layer (Fig 7). An attenuatedband of neurons survived in the re¬

sistant zone (Rose's field h-2), and in¬dividually these neurons appearednormal, apart from some cytoplasmiclipochrome accumulation. In otherparts of the pyramidal cell layer, onlyvery occasional neurons survived,mostly widely scattered in the end-plate. The neurons of the gyrus den-tatus were reduced in number, espe¬cially in its medial part (Fig 7).

Gliosis was intense throughout mostof the pyramidal cell layer, therebeing only a small region spared atthe site of Rose's field h-2. The alveuswas also gliosed, and there was somediffuse gliosis of gyral white matterin the parahippocampal, occipito-temporal, and inferior temporal gyri(Fig 8).

The cross sectional area of the bodyof the fornix appeared to be reduced,more on the left side than on theright. The anterior commissure hadlost many of its fibers and was in¬tensely gliosed. The thalamic nuclei,including the anterior nuclear groupand nucleus medialis dorsalis, were

normal bilaterally, as were the hy¬pothalamus and other diencephalicstructures. The basal ganglia werewithin normal limits. Sections ofthe cerebral cortex prepared byBielschowsky method demonstratedneither senile plaques nor neurofibril-lary tangle changes. The brain stemand cerebellum showed no mean¬

ingful abnormality.Interpretation of the Pathologic Find¬

ings.—The lesion of the right hippo¬campus is clearly of very long stand¬ing and has the typical pattern ofAmmon horn sclerosis, as describedby Spielmeyer9 and further analyzedby Sano and Malamud,10 who foundthis type of lesion present in thebrains of 29 of 50 institutionalized

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epileptic patients. Patient 1 did notsuffer from major seizures accom¬

panied by apnea so that his hippo¬campal lesion could not be consideredsecondary to hypoxia occurring dur¬ing habitual seizures. We thereforebelieve that the lesion belongs in thecategory of incisural sclerosis, as de¬scribed by Earle et al.3 The thinningand gliosis of the alveus on the leftside may be considered secondary tothe surgical removal of the anteriorpart of the left hippocampus. Like-

Fig 5.—Posterior part of left hippocampus. The pyramidal cell layer and dentate gyrusare intact. The alveus is thin (arrow) (cresyl violet, original magnification 10).

Fig 6.—Left temporal lobe. Alveus and gyral white matter are

gliosed. Pyramidal cell layer of the hippocampus and cortex ofparahippocampal and adjacent gyri are not involved (case 1, Höl¬zer method, original magnification 2.25).

wise, the very extensive gliosis ofwhite matter in the left temporal lobeis likely to be the result of changes atthe margins of the previous excisions.The reduction in size of the fornixmight be expected as this structureforms the efferent pathway of thepyramidal cells of the hippocampus;these were reduced in number bilat¬erally. The changes in the anteriorcommissure are likewise regarded as

secondary to the surgical excisions.This autopsy enables us to confirm

the hypothesis put forward in 1958 byPenfield and Milner1 that the patient(case 2 of that communication) had,before operation, a partial destructivelesion of the contralateral hippocam¬pal zone, and that the second oper¬ation deprived him of hippocampalfunction bilaterally. Furthermore, itenables us to localize this lesion to thepyramidal cell layer, and to a lesserextent, the gyrus dentatus, the para¬hippocampal, and other temporal lobegyri being intact on the right side.The 22 mm of the posterior part ofthe left hippocampus were inade¬quate to maintain normal memoryfunction. It is probable that some, or

perhaps even all, of his seizures arose

in the severely damaged right hippo¬campus.

The presence of an intact rightamygdaloid nucleus is interesting inthat it did not maintain memory func¬tion. This supports the conclusion ofNarabayashi and his colleagues," whohave carried out bilateral stereotaxicamygdalotomy in 21 patients withoutevidence of disturbance in memoryfunction.

Most reported cases in which an

amnestic syndrome has been associ¬ated with bilateral temporal lesionshave had infarcts as their pathologicbasis, usually extensive and involvingmore than the hippocampus alone. Inthe case reported by Glees and Grif¬fith,12 in which only the left hemi-

Fig 7.—Right hippocampus. Subtotal loss of pyramidal neurons

with partial survival in resistant sector (stemmed arrow) andthinning of medial part of gyrus dentatus (arrowheads) (case 1,cresyl violet, original magnification 10).

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sphere was examined histologically,both temporal lobes showed destruc¬tion of the tips and medial parts ofthe temporal lobes, their place beingtaken by a cyst-like structure commu¬

nicating with the temporal horns ofthe lateral ventricle. The left poste¬rior cerebral artery was reported tobe partly occluded by arteriosclerosis.The hippocampal gyrus, the cornu

Ammonis, and parts of the lingualand fusiform gyri were missing. Thefiber population of the fornix was de¬pleted and the structure was gliosed.

Victor and his colleagues11 carriedout a detailed pathologic examinationon the brain of a 59-year-old man whodeveloped a profound amnestic syn¬drome following a second stroke. Al¬though this patient had widespreadinfarcts of varying ages, those con¬sidered meaningful to his remarkablemental state were in the parahippo¬campal gyrus, subiculum, hippo¬campus, and dentate gyrus on theleft, and the parahippocampal gyrusand crus of the fornix on the right. Inaddition, the splenium of the corpuscallosum and the commissure of thefornix were infarcted.

A similar case, with bilateral cere¬bral infarcts involving the hippo¬campi and paracalcarine regions in a

44-year-old man with hyperlipopro-teinemia, was reported by De Jongand his colleagues14 in 1969. Initially,this patient was confused and dis¬oriented as to time and place in addi¬tion to having profound loss of recentand remote memory. Later, however,the memory defect was patchy, but itis clear that after a short lapse oftime, he would forget simple informa¬tion. He died of myocardial infarctionfour months after the onset of hisamnestic syndrome.

More akin to our present cases, butpuzzling in its implication, is the re¬

port by Dimsdale et al15 of a 53-year-old woman who developed a severe

memory disability following righttemporal lobectomy for long-term sei¬zures. She had profound retrogradeamnesia, but intellectual skills not re¬

quiring new learning were largelypreserved. The temporal lobe excisionextended 6 cm from the tip of thelobe; the uncus, amygdala, and Am-mon horn were removed. Blood

Fig 8.—Right temporal lobe. Severe gliosis of hippocampus and some gliosis of whitematter of inferomedial temporal gyri (case 1, Hölzer method, original magnification 2.25).

stained cerebrospinal fluid was ob¬tained on the fourth postoperativeday, and the authors suggest that thiswas the result of a secondary hemor¬rhage into the operative cavity. Theview that this patient's temporal lobelesion was strictly unilateral is basedon clinical, electrographic, and radio-logic evidence, but there are hints inthe case record that possibly a lefttemporal abnormality was present;for example, the occurrence in theEEG record of independent spikesarising from the left sphenoidal elec¬trode.

This patient had a severe verbalmemory defect before operation and,further, had had major seizures withloss of consciousness occurring fairlyfrequently preoperatively. It may bethat these seizures could, in them¬selves, have produced some left-sidedhippocampal damage. The authors of¬fer several possible explanations ofan amnestic syndrome developing inunilateral temporal lobectomy—thatthe lobectomy may be unusuallylarge, ie, that memory loss dependson the amount of hippocampal dam¬age, rather than its bilaterality, andthat some patients may be unusuallyvulnerable to unilateral temporal le-

sions. In any event a final assessmentof this most interesting case mustawait histologie evidence regardingthe condition of the left temporal lobe.

Neurophysiologic CommentThis autopsy study has provided us

with a remarkably clear picture of a

long-standing ischemie lesion in thepreviously untouched right temporallobe. It was of the "Ammon horn scle¬rosis type." At the time of my surgi¬cal removal of his anterior hippo¬campus on the left, patient 1 hadalready suffered destruction of thehippocampus on the right, with re¬

markably little damage in the rest ofthe hippocampal zone. Although our

purpose was only to make his life a

happy and more effective one, thecase of this civil engineer may betreated now as a critical experimentfrom which to draw reliable conclu¬sions.

The right hippocampus was de¬stroyed early in life, almost certainlyat the time of birth. At the age of 41,the anterior half of the left temporallobe was removed. At 46, the anteriorhalf of the left hippocampus was re¬moved together with all of the lefthippocampal gyrus and amygdaloid

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region.Since it had already been amply

proved that the surgical removal ofone hippocampus right or left couldbe carried out without obvious mem¬

ory defect, and since this patient hadhad no such defect before this secondoperation, one conclusion is clear:This memory defect was due to loss offunction in the left anterior hippo¬campus in a man who had no righthippocampal function.

It can also be concluded that, in therecall of experience, the hippocampiplay an indispensable role in memoryrecall, whether that recall is volun¬tary or whether it is the automatic re¬call required for routine recognitionand interpretation. Either hippo¬campus can carry out this essentialrole in the absence of the other.

Two explanatory hypotheses pre¬sent themselves: first, that a record¬ing of the stream of consciousness isformed from day to day, progres¬sively, all through conscious life, inthe hippocampus of one side and a du¬plicate in the other; or, second, that a

record, probably a single recording, isformed elsewhere in the brain whereit can be activated from a distance byneuronal potentials that pass to itfrom the right or the left hippo¬campus alternatively.

In my own experience with electri¬cal stimulation of the cerebral cortexof conscious patients, I have longfaced the necessity of choosing be¬tween these two hypotheses. Initially,I chose the first; but after learningmore about the physiology of corticalstimulation, I was forced to concludethat the second was the true explana¬tion.

Beginning as long ago as 1931, Istumbled, at long intervals, on an

amazing fact. A stimulating elec¬trode, if applied to the temporal cor¬

tex, would occasionally cause a con¬scious patient to report that he was

having an experiential flashback. Init, everything of which he had beenconscious in some earlier period oftime came to him, and the events ofconscious experience moved forwardat a normal pace. For years I could of¬fer no reasonable explanation.

Finally, as I have said, I chose tosubscribe to the first hypothesis and

made what I am sure, now, was themistake of assuming that the recordof consciousness had been establishedsomehow and somewhere in each ofthe temporal lobes. These experien¬tial responses never came from stim¬ulation in any other part of the cere¬bral cortex.

I analyzed this material18 and madea final summary17 at the close of myclinical career. This led to the conclu¬sion that all positive responses tostimulation were activations of dis¬tant areas of gray matter. I wasforced to conclude that, in the case ofexperiential flashbacks, the stimulat¬ing electrode, placed on certain areasof the temporal cortex (interpretivecortex), activated gray matter thatwas located at a distance in the dien-cephalon (the higher brain stem).That centrally located target for acti¬vation with its connections must con¬stitute the neuronal recording of thestream of consciousness. It corre¬

sponds to, or is near to, the gray mat¬ter that every experienced neurolo¬gist knows is indispensable to theexistence of any consciousness at all.A lesion there inevitably producesloss of consciousness.16-19

If that is so, the case reported inthis communication, together withthe evidence provided by other signif¬icant pathologic studies, to which Dr.Mathieson has referred in "Neuro-pathologic Study, show that in thehippocampus of either side there mustbe a mechanism that is essential inthe process of scanning the past andcalling to mind selected material.

It is obvious that pertinent experi¬ence must be summoned automati¬cally if there is to be interpretation ofpresent events. It is also obvious thatthere must be such a mechanism ifthe mind is to make its voluntary se¬lection and recall of experience.

Thus, we come to the conclusionthat there are at least three func¬tional units of gray matter involvedin the act of scanning and recall ofexperience: (1) the interpretive cortexof the temporal lobe, (2) the hippo¬campi with their direct connections tothe brain stem, and (3) the experien¬tial recording within the higher brainstem.

These tentative conclusions con-

form with the second explanatory hy¬pothesis proposed above. The proposi¬tion is, then, that neuronal potentialsdo pass from the hippocampi to thecentrally placed experiential record,activating it selectively.

In our stimulation explorations ofthe interpretive cortex, it was clearthat the right (nondominant) tempo¬ral lobe is very much more frequentlyused in judgments of familiarity(déjà vu) and in interpretations oforientation in space than is the left(the dominant) temporal lobe. I sur¬mise then that the right hippocampusis more often employed to scan andrecall experience related to thesejudgments than is the left. On theother hand, Milner5 has shown that,following removal of the left hippo¬campus, there is detectable difficultyin the recall of verbal concepts.

Thus, the hippocampi play an es¬sential role in the recall of experiencefor the automatic mechanism of per¬ception and interpretation. They alsoplay an essential role in the mecha¬nism of conscious recall of experience.

A Speculative PostscriptEver since the days of horse-and-

buggy practice, when a doctor hadmuch time for speculation and reflec¬tion between his visits, the clinicianhas made his own peculiar approachto the truth. He carries at the back ofhis mind certain unsolved problems inhis field of special interest, and hestumbles unexpectedly on clues totheir solution, constructing his own

tentative hypotheses. In that place atthe back of the mind that is reservedfor wonder, he should be, to the bestof his ability, a pathologist, an anat¬omist, and a physiologist. Thus, whendisease or accident presents to himthe perfect experiment, he has a mindprepared and can, perhaps, ask thequestion and get the answer forwhich the problem waits, doing thisbefore the fleeting chance is gone.

Retrograde amnesia is such a prob¬lem. How can a patient lose memoryof experience for recent months andpreserve memory of the distant past?What is the anatomy and the physiol¬ogy that explains this phenomenon?Another question is "Where are theclues or keys that the hippocampus

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must use when it scans and recalls an

experience from the past that is sim¬ilar to the present experience?" Thecritical experiment presented by thecase of the engineer will give us someanswers if we add to it the case of theglove-cutter.

The surgical excision that I in¬tended to carry out in each case wasthe same. But, because I did the oper¬ation in one stage, I could see the an¬atomical outlines more clearly in pa¬tient 2. I am reasonably sure, now,that I removed considerably more ofhis hippocampus than I had of patient1. I certainly went beyond the pointwhere the hippocampus turns inward,that is, beyond the dotted line that in¬dicates the extent of removal in thecase of the engineer (Fig 2).

Now, compare the clinical deficitthat the glove-cutter presented withthat of the engineer. The loss of abil¬ity to recall current experience afteroperation was the same. The loss ofthe ability to learn was complete atfirst, but it improved in the case ofthe engineer. The loss of retrogradememory by the glove-cutter extendedback into the past much farther, as Ishall elaborate.

Two years after operation, if weare to accept the opinion of his fam¬ily, his retrograde amnesia was stillcomplete back to a date four years be¬fore the operation. Convincing evi¬dence of the completeness of thismemory loss was pointed out by hisbrother, who was a physician. The pa¬tient, he said, no longer recognizedthe girl who had been his very closefriend for the last 18 months beforethe operation.

On the other hand, the engineer'sretrograde amnesia, although appar¬ently extensive during the period ofpostoperative swelling, contractedrapidly. By the time he left the hospi¬tal, it blocked out only the fewmonths that immediately precededthe operation.

Like the engineer, the glove-cutterpreserved normal command of speech.He, too, had an adequate postopera¬tive intelligence quotient rating(109), actually a slight improvementover his preoperative record. He, too,preserved his skills, supporting him¬self as a glove-cutter as effectively as

ever. His ability to focus attentionand concentrate was unimpaired. Hecould preserve his awareness of factsfor many minutes, if not distracted,but after turning his attention tosomething else, his memory of thosethings that had made up the streamof his consciousness had vanished.

These men did remember as long as

their attention was not called to othermatters. It might seem then that it isonly the act of scanning and recall inwhich the hippocampus plays its es¬sential role.

The stream of consciousness isrecorded within the brain. It can bereactivated by a stimulating elec¬trode placed on an interpretive areaof the temporal cortex as though itwere a key to a strange tape recordercapable of bringing back sounds andsights and thoughts. If the recorder islocated in the diencephalon as I havesuggested, their keys of access are

formed in the hippocampus of eachtemporal lobe, duplicate keys. Theymay use the interpretive cortex toturn on the recorder, since a man can

normally recall nearly all that hap¬pened to him for the few minutes ofpast time.

But to speak of a "tape recorder"that preserves the experiential recordin the diencephalon, and "keys of ac¬

cess" in the hippocampus, is to use a

gross over-simplification. But it isuseful to hide our ignorance of physi¬ologic detail while it points to thetruth. There must also be summariz¬ing keys of access in (or associatedwith) the hippocampus. Such keys be¬come summarizing units and so corre¬

spond with nonverbal concepts.For example, consider the key of

access that is related to one's conceptof a particular friend, say John Jones.It was established when Jones firstappeared. Years later, when he hadbecome a well-known friend, that keyof access will have changed. It haslines of access to many experienceswith Jones.

The tape recorder in the brain stemis unchangeable if one can judge bythe experiential responses to stimula¬tion. Whether it is activated by reflexaction or by stimulating electrode, itseems to play the same tune. But thesummarizing key of access associated

with the hippocampus changes. It canbe enlarged and altered.

Suppose now that the lines of per¬manently facilitated connection fromthe hippocampus to the tape recorderearly in life are laid down at the pos¬terior end of each hippocampus andmore anteriorly later in life. Onecould understand then why the retro¬grade amnesia of the engineer was ofa few months' duration and that ofthe glove-cutter was about four years.The key of access to the glove cutter'sgirl friend, whom he had known only18 months, was gone completely, butthe concepts of his tools, which he hadused for many years, were not lost.

The foregoing details of my ration¬alization may well prove to be wrong.But the hypothesis proposed is worthtesting. For me, it is a most excitingclue. It might help us to understandwhy injuries to the hippocampus in an

increasing number of published cases

present the syndrome of loss of mem¬

ory of the recent past and preserva¬tion of ability to recall the distantpast.

In summary, then, the engineerwhose autopsy findings are reportedhere suffered a destruction of the neu¬

rons in the right hippocampus, in allprobability at the time of birth. Thedestruction was selective, which ischaracteristic of a "sclerotic is¬chemie" lesion in that location. At 46,when the anterior portion of the lefthippocampus was removed surgically,the patient developed retrograde am¬nesia instantly. It covered somemonths. There was a postoperativeloss of ability to recall each precedingawareness after any diversion of at¬tention to other matters. Thus, he hadlost the capacity to create keys of ac¬

cess. For this, the anterior half of atleast one hippocampus is absolutelyessential. The same seems to havebeen true in the case of the glove-cut¬ter.

These patients lost capacity for vol¬untary recall of recent experience.They lost, also, the capacity for auto¬matic recall of experience that is nec¬

essary for the recognition of peopleand things. With this, it is not sur¬

prising that Milner's tests showedthat both seem to have lost capacityfor new learning as well. On the other

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hand, memory of speech and nonver¬

bal concepts, acquired in the more dis¬tant past, and memory of formerlyacquired skills were not lost.

It may now be surmised that thehippocampi are involved with the in¬terpretive cortex of both temporallobes in the function of scanning andrecall. It is the record of the stream ofpast consciousness that must bescanned. That record is a continuouspattern of neuron connections thathave been permanently facilitatedfor the subsequent passage of neu¬ronal currents. This continuousthread of facilitated passage is theexperiential engram.

I have assumed that this recording

of the experiential past is in the dien¬cephalon, near to or within the mech¬anism that is the brain's counterpartof conscious states. To substantiatethis, I have reviewed my own experi¬ence, hoping to throw some light onthe physiology of consciousness in a

forthcoming study (The Mystery ofthe Mind: A Study of the Physiology ofConsciousness).

These two cases taken togetherprovide a clue to understanding therole played by the hippocampus in ex¬

periential recall. When this is addedto the evidence provided by electricalstimulation of interpretive areas ofthe temporal cortex, a physiologic hy¬pothesis is proposed that would ex-

plain retrograde amnesia. It mightalso explain how it is that pathologicchange in the hippocampus can pro¬duce the pattern of memory loss socharacteristic of forgetfulness in theaged.

Dr. Mathieson carried out the post¬mortem study and wrote the discussion ofpathology. The clinical review and thephysiologic discussion were added by Dr.Penfield.

M. Mouradian, MD, Phelps Memorial Hospital,North Tarrytown, NY, made the brain of patient1 available for autopsy.

Herbert Jasper, MD, performed the electroen-cephalographic studies in patient 1.

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12. Glees P, Griffith H: Bilateral destruction ofthe hippocampus (cornu ammonis) in a case ofdementia. Monatsschr Psychiatr Neurol 123:193\x=req-\204, 1952.

13. Victor M, et al: Memory loss with lesions

of hippocampal formation: Report of a case withsome remarks on the anatomical basis of mem-

ory. Arch Neurol 5:244-263, 1961.14. DeJong RN, Itabashi HH, Olson JR: Mem-

ory loss due to hippocampal lesions: Report of acase. Arch Neurol 20:339-348, 1969.

15. Dimsdale H, Logue V, Piercy M: A case ofpersisting impairment of recent memory follow-ing right temporal lobectomy. Neuropsychologia1:287-298, 1964.

16. Penfield W: The Excitable Cortex in Con-scious Man. Liverpool, England, Liverpool Uni-versity Press, 1958.

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