BRAIN AND COGNITION 33, 14–17 (1997)ARTICLE NO. BR970881

Amobarbital Memory Testing: Some Personal Reflections

BRENDA MILNER

McGill University, Montreal, Quebec, Canada

The decision to assess memory, and not merely speech, after intracarotidinjection of sodium amobarbital, in patients who were candidates for an ante-rior temporal lobectomy, arose in response to an urgent clinical need. Al-ready in the early 1950s, it had become apparent that there was risk to mem-ory in the operation of unilateral temporal lobectomy (including the bulk ofthe hippocampus and parahippocampal gyrus) in patients with preexistingdamage to the hippocampal region of the opposite hemisphere (Milner, 1966;Milner and Penfield, 1955; Penfield & Milner, 1958). Observation of pro-found and lasting anterograde amnesia in the patient HM as a sequel to bilat-eral medial temporal-lobe excision confirmed and strengthened this view(Scoville & Milner, 1957). As a result, from then on, all patients at the Mon-treal Neurological Institute with bilateral independent temporal-lobe electro-graphic abnormality, or with radiological or clinical evidence of such bilat-eral damage, were refused operation. The fact that this policy would excludemany people whose seizures might have been controlled, or significantlyreduced, by removal of the more active epileptogenic area led Theodore Ras-mussen to suggest, during one of our weekly seizure conferences, that theintracarotid-amobarbital procedure might be adapted to the study of memory,and thereby allow us to screen out those patients for whom the proposedoperation carried risk of producing an amnesic syndrome. The underlyinghypothesis was that no memory deficit (as defined by our tests) should beseen after unilateral amobarbital injection, unless there was already a lesioninvolving the hippocampal zone of the opposite hemisphere. If there weresuch a lesion, then the temporary inactivation of the normal hemisphere bythe action of the drug should produce transiently the amnesic state character-istic of patients with bilateral medial temporal-lobe damage.

Brenda Milner introduced memory evaluation into the original amobarbital procedure. Thisinvited essay provides her personal historical perspective on those early days of the IAP. Thiswork was supported by the Medical Research Council of Canada. Address correspondenceand reprint requests to Brenda Milner, Sc.D., Montreal Neurological Institute, 3801 UniversityStreet, Montreal, Quebec, Canada H3A 2B4.

140278-2626/97 $25.00Copyright 1997 by Academic PressAll rights of reproduction in any form reserved.

AMOBARBITAL MEMORY TESTING 15

It was not at all clear to us at the time that such an extension of the amobar-bital procedure from speech to memory would prove either feasible or valid.Whereas we could be confident that the carotid injection would affect thecortical speech areas, provided we obtained the expected contralateral hemi-paresis, it was far less certain that the hippocampal region would be inacti-vated in those cases (and they would be the majority) in which the posteriorcerebral artery was not filled. This question was particularly troubling be-cause, when memory testing was first introduced, we were still making ourinjections into the common carotid artery, and without angiographic control.We were thus unaware of the precise distribution of the drug. A second causefor concern was that our experience with speech testing had shown that theeffects of the amobarbital injection wore off quite rapidly (in a matter ofminutes), yet a short time lapse between stimulus presentation and stimulusretrieval was essential if we were to have a meaningful memory test.

In designing our original memory protocol in 1959, I was looking for atask that the amnesic patient, H.M., would fail, but that an aphasic patientwould be able to pass. The actual procedure is described in full elsewhere(Milner, Branch, & Rasmussen, 1962; Milner, 1975, 1978). The essentialfeatures were, first, the use of dually encodable stimuli as memoranda (linedrawings of common objects) and second, the interpolation of an effectivedistractor task (mental arithmetic and reverse repetition of a new digit se-quence) between stimulus presentation and attempted retrieval. The materialwas presented as soon as the preliminary speech testing had been completed(approximately 3 min post-injection). Memory was tested after the distrac-tion, and again when the effects of the drug had cleared. An unexpectedfinding in this early series was the frequent failure of free recall of materialpresented when one hemisphere was inactivated by the drug, even when theinjection was ipsilateral to the lesion, a finding that is consistent with thepoor free recall shown by patients with cerebral commissurotomy (Milner,Taylor, & Jones-Gotman, 1990), despite normal performance on recognitiontests. In the amobarbital procedure, we were satisfied to accept recognitionfrom a multiple-choice series as proof of success, since amnesic patients failrecognition as well as recall tasks.

The results for our first 123 cases were encouraging in that anterogradeamnesia (defined as two or more recognition errors for material presentedwhile the drug was active) was seen after 22% of injections contralateral tothe side of a temporal-lobe epileptogenic lesion and never after ipsilateralinjections, nor after either injection in non-temporal-lobe cases. Moreover,our results were clearly dissociable from dysphasia, since patients frequentlyrecognized later objects that they had been unable to name shortly after theinjection, and, conversely, patients might fail to recognize later objects thatthey had named correctly.

Although the orderliness of these results implied that the method had somevalidity, we were surprised that the incidence of amnesia after injection con-

16 BRENDA MILNER

tralateral to a known medial temporal-lobe lesion was still relatively low,and, given the imperfections of the method, we worried lest our data mightinclude some false negative results.

Such concerns made us increasingly aware of the need to know more aboutthe actual distribution of the drug in each case, and accordingly we em-barked, with our neurosurgical colleague, Henry Garretson, on a new seriesof cases in which the injection was made through a catheter placed well upinto the internal carotid artery of one side, and in which a control angiogramwas performed before the amobarbital tests. For the control angiogram, asmall bolus of angiographic contrast dye was hand-injected to mimic theinjection of the amobarbital. This allowed us to visualize the distribution ofthe drug and to assess the symmetry or asymmetry of the arterial circulationto the two cerebral hemispheres. The results from this series closely paral-lelled our earlier results, but also showed that the occurrence of amnesia wasnot contingent upon filling of the posterior cerebral artery. In this connection,it is interesting to note that a recent MRI study by Amaral and Corkin ofScoville’s patient H.M. has shown that the medial temporal-lobe removalwas less extensive than originally thought, the posterior 2 cm of the bodyof the hippocampus and of the hippocampal gyrus being spared, togetherwith the temporal stem. In other respects, the removal corresponded to thesurgeon’s description, and included the amygdala, the entorhinal cortex, andthe anterior parahippocampal gyrus bilaterally. The rostra-caudal extent ofthe ablation was approximately 5.4 cm on the left and 5.1 cm on the right(S. Corkin, personal communication). These anterior medial temporal-lobelesions are thus sufficient to cause a profound and lasting anterograde amne-sia, while leaving other cognitive functions and previously acquired semanticknowledge essentially intact.

The fact that, in a long series of patients studied with the original protocol,we encountered no instance of post-operative amnesia suggested that wehad devised an adequate screening procedure. Nevertheless, in an attemptto increase the sensitivity of our test, we subsequently decided to introduceadditional memoranda (an object and a word) into the speech testing carriedout during the first three minutes after the injection. Since we still set ourcriterion of failure at two recognition errors, the test had clearly becomemore demanding, and the incidence of failure increased, with some pre-sumably false positive results seen following injection ipsilateral to a well-lateralized temporal- or frontal-lobe lesion. Despite this, at the MNI wenow believe that it is desirable to begin to test memory as soon as possibleafter the injection, since Lesser, Dinner, Luders, and Morris (1986) havefound that patients were later able to recognize objects that had been shownto them during the first minutes after injection into the left hemisphere, whilethe patients were not only mute, but also confused, provided the injectionwas ipsilateral to the temporal-lobe lesion.

As amobarbital memory tests become further refined, the question of how

AMOBARBITAL MEMORY TESTING 17

we define failure on these tests remains to be satisfactorily resolved. Fortu-nately, in recent years, the interpretation of these memory tests has becomeless problematic, both because of the information available about the physio-logical effect of injection when the tests are done with EEG control (cf.Jones-Gotman, Bouwer, & Gotman, 1994) and because, more importantly,we now have volumetric measures of the hippocampal region to alert us tothe presence of significant atrophy, which must be taken into account in thesurgeon’s decision whether or not to operate. In retrospect, it is all the moreremarkable that Rasmussen’s proposal yielded such consistent and clinicallyuseful results even in those early years.

REFERENCES

Jones-Gotman, M., Bouwer, M. S., & Gotman, J. 1994. EEG slow waves and memory perfor-mance durnig the intracarotid amobarbital test. Epilepsia, 35, 61–69.

Lesser, R. P., Dinner, D. S., Luders, H., & Morris, H. H. 1986. Memory for objects presentedsoon after intracarotid amobarbital sodium injections in patients with medically intractablecomplex partial seizures. Neurology, 36, 895–899.

Milner, B. 1966. Amnesia following operation on the temporal lobes. In C. W. M. Whitty &O. L. Zangwill (Eds.), Amnesia. London: Butterworths. Pp. 109–133.

Milner, B. 1975. Psychological aspects of focal epilepsy and its neurosurgical management.In D. P. Purpura, J. K. Penry, & R. D. Walter (Eds.), Advances in neurology (Vol. 8).New York: Raven Press. Pp. 299–321.

Milner, B. 1978. Clues to the cerebral organization of memory. In P. Buser & A. Rougeul-Buser (Eds.), Cerebral correlates of conscious experience. Amsterdam: Elsevier/NorthHolland Biomed Press. Pp. 139–153.

Milner, B., Branch, C., & Rasmussen, T. 1962. Study of short-term memory after intracarotidinjection of sodium Amytal. Transactions of the American Neurological Association, 87,224–226.

Milner, B., Taylor, L., & Jones-Gotman, M. 1990. Lessons from cerebral commissurotomy:Auditory attention, haptic memory and visual images in verbal associative-learning. InC. Trevarthen (Ed.), Brain circuits and functions of the mind. New York: CambridgeUniv. Press. Pp. 293–303.

Milner, B., & Penfield, W. 1955. The effect of hippocampal lesions on recent memory. Trans-actions of the American Neurological Association, 80, 42–48.

Penfield, W., & Milner, B. 1958. Memory deficit produced by bilateral lesions in the hippocam-pal zone. AMA Archives of Neurology and Psychiatry, 79, 475–497.

Scoville, W. B., & Milner, B. 1957. Loss of recent memory after bilateral hippocampal lesions.Journal of Neurology, Neurosurgery and Psychiatry, 20, 11–26.