term "neurochemistry" and applied it to our clinical and research laboratories and to my position, so that the first person to be officially called a neurochemist was at the MNI. Today there are about a thousand recognized neurochemists around the world, many in various national and international organizations for neurochemistry. I believe that our neurochemistry laboratory was the first research laboratory of the MNI to become individually endowed. Penfield was able to communicate his intuition to W.H. Donner and allowed me the pleasure of imparting some of our enthusiasm to that friendly philanthropist, so in 1951 it became the Donner Laboratory for Experimental Neurochemistry. In 1955 the first comprehensive survey of brain and nerve chemistry appeared. Called "Neurochemistry",1 it was edited in our laboratory in collaboration with I.H. Page and J.H. Quastel. A second edition2 appeared in 1962. Thereafter it became no longer possible to condense the field into a single volume. (An eight-volume "condensation" has lately been edited by Abel Lajtha in New York). Because of wartime concerns my first research assignment at the MNI was to work with Jasper on brain swelling in relation to head injuries.3 This influenced me to become Jasper's pupil in neurophysiology and established the close relation of the Donner laboratory with neurophysiology that has expressed itself in much further work. The interest in brain swelling has remained a major preoccupation of the Donner laboratory and has involved cooperation with other departments within and outside the MNI. Penfield's feeling for the unity of the sciences and their clinical aspects promoted integration of the objectives and the work of the neurochemistry laboratory with other aspects of the MNI and the Montreal Neurological Hospital. Penfield sought to integrate my interests with the major interests of others at the MNI working in the field of epilepsy. He would invite me into
the operating room so that I could appreciate the problems. My awe stimulated a permanent interest in the mechanism of brain function and epilepsy. With Penfield a group of us from various departments of the MNI published a survey of early studies on epileptogenic areas of the brain.4 The introduction to this article referred to Penfield's earlier conclusion that there is a decrease in the richness of the capillary bed within an epileptogenic focus, leading to the possibility of disturbance of homeostasis and consequent local metabolic changes. Penfield also often expressed his idea that an "x-substance" may be produced that triggers the epileptogenic activity. In my opinion these are valid and related ideas. We now know that there are a number of factors - electrolytes, metabolites and transmitter substances - that affect neuronal activity. Their production and release are affected by metabolic conditions, and they, together or individually, could correspond to the "x-substance". Thus almost any study on brain tissue metabolism and the "action substances" of nervous activity is relevant to the problem of epilepsy. One of my first publications from the MNI described a study of the metabolism of focal epileptogenic human brain tissue;5 Penfield was coauthor. Much of our early work68 on brain tissue metabolism, electrolytes, transmitter substances and active amino acids has been forgotten but it has led to rapid and exciting developments in many other laboratories. And such work in many of these other laboratories is being carried out by our former students and coworkers. Meanwhile in our laboratory Wolfe has become an authority on, and contributor to basic understanding of, various neurologic diseases,9'10 and Pappius has carried on our old interest in brain swelling and has become a leading authority on cerebral edema.'1"2 Penfield's legacy to neurology is part of his more universal legacy. His scientific books and his historical novels and other writings have pleased and
informed many of us. I have been especially affected by "The Mystery of the Mind".13 I have believed that the mystery will remain, but Penfield showed that concrete thinking, based on remarkable observation and anatomic-physiologic knowledge, can be applied to the mystery. With neurochemical knowledge now added I believe the mechanisms behind the mystery are soon to be at least definable in much clearer detail. The influence of Penfield has been felt in tangible ways in his personal works and in his organization and encouragement. But I, and I think others, have felt his presence in less definable ways. There was warmth, yet with controlled severity, an expectation of excellence and a benign dominance that keyed one up and also made one feel part of a whole vital enterprise. An era has ended. We must live without Penfield. But he has made sure that we can. References I. ELuorr KAC:
Neurochemistry, PAGE IH, QUASTEL JH (eds), Springfield, IL, CC Thomas, 1955, p 900 2. Idem: Neurochemistry, 2nd ed, PAGE IH, QUASTEL JH (eds), Springfield, IL, CC
Thomas, 1962, p 1035 3. ELLIOTT KAC, JASPER HH: Measurement of
experimentally induced brain swelling and shrinkage. Am J Physiol 157: 122, 1949
4. POPE A, MORRIs AA, JASPER H, et al: Histochemical and action potential studies on epileptogenic areas of cerebral cortex in man
and the monkey. Proc Assoc Nerv Ment Dis 26: 218, 1946 5. ELLIoTT KAC, PENFIELD W: Respiration and glycolysis of focal epileptogenic human brain tissue. I Neurophysiol 11: 485, 1948 6. ELLIOTT KAC, WOLFE LS: Brain tissue respiration and glycolysis, in Neurochemistry, 2nd ed, op cit, pp 177-211 7. WOLFE LS, ELLIOTT KAC: Chemical studies in relation to convulsive conditions, ibid, pp 694-727 8. ELLIOTT KAC: 'y-aminobutyric acid and other inhibitory substances. Br Med Bull 21: 70, 1965 9. WOLFE LS: Possible roles of prostaglandins in the nervous system, in Advances in Neurochemistry, vol 1, AGRANOFF BW, APRISON MH (eds), New York, Plenum Pr, 1975,
pp 1-45
10. WOLFE LS, No YING KIN NMK:
Storage
and excretion of oligosaccharides and glycopeptides in the gangliosidoses. Adv Exp Med Biol 68: 15, 1976 11. KATEMAN R, PAPPIUS HM: Brain Electrolytes and Fluid Metabolism, Baltimore, Williams & Wilkins, 1973, p 419 12. PAPPIUS H, FEINDEL W (eds): Dynamics of Brain Edema, Heidelberg, Springer-Verlag,
1976, p 404 13. PENFIELD 'N: The Mystery of the Mind, Princeton, Princeton U Pr, 1975, p 123
The frontal lobe DONALD HEBB,* PH D, D SC, LL D, FRS, FRSC
What Wilder Penfield did with respect to the frontal lobe can be reported simply. Ably backed up by William Cone and the rest of the staff of the Montreal Neurological Institute (MNI) he changed the whole doctrine and *Emeritus professor of psychology and former chancellor, McGill University
theory of frontal lobe function and the basis of so-called frontal-lobe signs. In doing so he made fundamental changes in our conceptions of brain functions. Up to 1940 or 1945 the frontal lobes were considered to be the locus of all that is noble and good about human beings. At various times moral ideas,
emotion, abstract ideas, planning and initiative were localized there, although those who reported loss of some of these attributes following damage to the frontal area were far from agreeing among themselves just which was the crucial attribute. They did agree, however, that the frontal area
CMA JOURNAL/JUNE 18, 1977/VOL. 116
1373
was vital; the large size of the frontal lobes was the distinctive feature of man's brain, it was thought, and this was the basis of man's humanity. What Penfield did was to show that none of the frontal-lobe signs need result from large lesions of the prefrontal area, provided the tissue left behind the area bordering on the lesion, and the rest of the brain - was left in good shape. What had been attributed to simple loss of frontal-lobe tissue was in fact the result of scarring and diffuse damage throughout the cerebrum caused by the pressure of a tumour growing in the confines of the tight box of the skull. I do not suggest that Penfield consciously set out to establish that fact; actually I think he was as surprised as anyone at the excellent status of patients from whom he had removed scar tissue simply for the control of epilepsy. In fact, when he made his extensive bilateral removal of the prefrontal lobes in 1938' he must have thought that he could put an end to the fits but that there was a poor outlook for the patient in other respects. I had to urge him to go talk to the patient to see how good his mental status was. Only then did he see how great a change he had wrought. This patient's intelligence quotient improved from 75 to 80 (evidently varying with subclinical attacks) to 95 or so after the operation. He subsequently enlisted in the Canadian Army and went overseas at a time when headquarters in England was demanding a more careful psychologic screening of recruits. The medical officer examining him saw the scar on his forehead, asked what had caused
it, was told that he had had an accident in a sawmill, and asked if it was giving any trouble. The recruit replied that it was not - and indeed it was not after Penfield had taken out the scarred remnants of both his prefrontal lobes.2 That was the most remarkable of those early cases, but another was in a way equally astonishing, at least to a psychologist. In this instance the operation was performed by William Cone, but it formed part of the same pattern that testifies to the clinical significance of Penfield's study of scar and scar formation. Some time after unilateral removal of most of his left prefrontal lobe, perhaps 5% of the total weight of the cerebrum, the young man made a perfect score on the then new (in 1937) Stanford-Binet test of intelligence - a feat that would not be duplicated by 1 person in 10 OOO.. The frontal lobe work at the MNI was revolutionary in its significance. Nothing like it seemed to be going on elsewhere. The results I was reporting at meetings of the American Psychological Association were received with frank scepticism. (I don't think I was regarded as a liar, just an incompetent.) Everyone else studying cases of damage to the frontal area was able to report failures in intelligence-test performance and some of the frontal-lobe signs. Who was I, a newcomer to clinical investigation, to say otherwise? What they did not realize was that in the cases at the MNI there was little or no pathologic change in the remaining brain tissue. Cases seen elsewhere were mostly ones of tumour removal, possibly with scar formation at the site of operation; but in any event there
was extensive damage throughout the rest of the brain, the result of compression from the growing tumour. And in the frontal region the tumour might get somewhat larger before producing symptoms that would take the patient to his doctor. Adding to the disbelief was my report of increased intelligence after a major brain operation. How could 1 possibly say that taking out more cortex after injury to the brain could raise the intelligence quotient? Obviously this was nonsense. And it took some time for an even more obvious fact to be appreciated - that an active disturbance, depressing functions in the rest of the cortex, can be more damaging than the mere loss of the tissue from which the disturbance originates. It seems to me that this was as important as any of Penfield's contributions to knowledge, this demonstration that a small area of dysfunction could have such widespread deleterious effects and impair thought so much. In this work he was laying a new foundation for the scientific study of brain and mind, a process that went much further in his later study of the temporal lobe, but it was already clear by 1938 that he was doing more than just telling us about the frontal lobe. Neurologically and psychologically he was making a revolution. References
I was impressed, as no one could fail to be, by the experience of being in the operating room when Wilder Penfield was stimulating the exposed temporal cortex of patients who had reported having complex hallucinatory experiences as part of their epileptic seizures. In a small number of such patients Penfield was able to elicit reports of complex experiential phenomena that sometimes, but not invariably, resembled those occurring during the patient's habitual seizures. These observations were later reported by Penfield and Perot,1 who analysed the phenomena separately according to whether they were auditory or visual.
The beautifully orderly and unexpected distribution of points along the first temporal convolution in the right and left hemispheres from which electric stimulation during operation elicited complex auditory experiences is illustrated in Fig. 1. A patient might hear the voice of his cousin in Africa, or he might hear a well known march from Aida and be able to keep time to the music. The sounds would unroll at the rate of normal experience and yet the patient would not be deceived by them; he would remain aware at the same time of being in the operating room at the MNI, replying to Penfield; it was as though there were a moment-
I. HERB DO, PENFIELD W: Human behavior after extensive bilateral removal from the frontal lobes. Arch Neurol Psychiatry 44: 421, 1940 2. HERB DO: Man's frontal lobes: a critical review. Arch Neurol Psychiatry 54: 10, 1945 3. Idem: Intelligence in man after large removals of cerebral tissue: report of four left frontal lobe cases. J Gen Psychol 21: 73, 1939
Memory mechanisms BRENDA MILNER,* PH D, D SC, FRSC
Memory mechanisms and the study of the temporal lobes go hand in hand, as I was to learn quickly on my arrival at the Montreal Neurological Institute (MNI) for the first time in the summer of 1950. My original plan was to study problem-solving and certain aspects of visual perception that I believed might be affected by temporal-lobe lesions. After a few months, however, I realized that one could not afford to neglect memory, because so many exciting clues were coming from patients undergoing operations for the relief of temporal-lobe seizures. In those first days *Professor of neuropsychology, department of neurology and neurosurg.ry, McGill University
1374 CMA JOURNAL/JUNE 18, 1977/VOL. 116
the operating room so that I could appreciate the problems. My awe stimulated a permanent interest in the mechanism of brain function and epilepsy. With Penfield a group of us from various departments of the MNI published a survey of early studies on epileptogenic areas of the brain.4 The introduction to this article referred to Penfield's earlier conclusion that there is a decrease in the richness of the capillary bed within an epileptogenic focus, leading to the possibility of disturbance of homeostasis and consequent local metabolic changes. Penfield also often expressed his idea that an "x-substance" may be produced that triggers the epileptogenic activity. In my opinion these are valid and related ideas. We now know that there are a number of factors - electrolytes, metabolites and transmitter substances - that affect neuronal activity. Their production and release are affected by metabolic conditions, and they, together or individually, could correspond to the "x-substance". Thus almost any study on brain tissue metabolism and the "action substances" of nervous activity is relevant to the problem of epilepsy. One of my first publications from the MNI described a study of the metabolism of focal epileptogenic human brain tissue;5 Penfield was coauthor. Much of our early work68 on brain tissue metabolism, electrolytes, transmitter substances and active amino acids has been forgotten but it has led to rapid and exciting developments in many other laboratories. And such work in many of these other laboratories is being carried out by our former students and coworkers. Meanwhile in our laboratory Wolfe has become an authority on, and contributor to basic understanding of, various neurologic diseases,9'10 and Pappius has carried on our old interest in brain swelling and has become a leading authority on cerebral edema.'1"2 Penfield's legacy to neurology is part of his more universal legacy. His scientific books and his historical novels and other writings have pleased and
informed many of us. I have been especially affected by "The Mystery of the Mind".13 I have believed that the mystery will remain, but Penfield showed that concrete thinking, based on remarkable observation and anatomic-physiologic knowledge, can be applied to the mystery. With neurochemical knowledge now added I believe the mechanisms behind the mystery are soon to be at least definable in much clearer detail. The influence of Penfield has been felt in tangible ways in his personal works and in his organization and encouragement. But I, and I think others, have felt his presence in less definable ways. There was warmth, yet with controlled severity, an expectation of excellence and a benign dominance that keyed one up and also made one feel part of a whole vital enterprise. An era has ended. We must live without Penfield. But he has made sure that we can. References I. ELuorr KAC:
Neurochemistry, PAGE IH, QUASTEL JH (eds), Springfield, IL, CC Thomas, 1955, p 900 2. Idem: Neurochemistry, 2nd ed, PAGE IH, QUASTEL JH (eds), Springfield, IL, CC
Thomas, 1962, p 1035 3. ELLIOTT KAC, JASPER HH: Measurement of
experimentally induced brain swelling and shrinkage. Am J Physiol 157: 122, 1949
4. POPE A, MORRIs AA, JASPER H, et al: Histochemical and action potential studies on epileptogenic areas of cerebral cortex in man
and the monkey. Proc Assoc Nerv Ment Dis 26: 218, 1946 5. ELLIoTT KAC, PENFIELD W: Respiration and glycolysis of focal epileptogenic human brain tissue. I Neurophysiol 11: 485, 1948 6. ELLIOTT KAC, WOLFE LS: Brain tissue respiration and glycolysis, in Neurochemistry, 2nd ed, op cit, pp 177-211 7. WOLFE LS, ELLIOTT KAC: Chemical studies in relation to convulsive conditions, ibid, pp 694-727 8. ELLIOTT KAC: 'y-aminobutyric acid and other inhibitory substances. Br Med Bull 21: 70, 1965 9. WOLFE LS: Possible roles of prostaglandins in the nervous system, in Advances in Neurochemistry, vol 1, AGRANOFF BW, APRISON MH (eds), New York, Plenum Pr, 1975,
pp 1-45
10. WOLFE LS, No YING KIN NMK:
Storage
and excretion of oligosaccharides and glycopeptides in the gangliosidoses. Adv Exp Med Biol 68: 15, 1976 11. KATEMAN R, PAPPIUS HM: Brain Electrolytes and Fluid Metabolism, Baltimore, Williams & Wilkins, 1973, p 419 12. PAPPIUS H, FEINDEL W (eds): Dynamics of Brain Edema, Heidelberg, Springer-Verlag,
1976, p 404 13. PENFIELD 'N: The Mystery of the Mind, Princeton, Princeton U Pr, 1975, p 123
The frontal lobe DONALD HEBB,* PH D, D SC, LL D, FRS, FRSC
What Wilder Penfield did with respect to the frontal lobe can be reported simply. Ably backed up by William Cone and the rest of the staff of the Montreal Neurological Institute (MNI) he changed the whole doctrine and *Emeritus professor of psychology and former chancellor, McGill University
theory of frontal lobe function and the basis of so-called frontal-lobe signs. In doing so he made fundamental changes in our conceptions of brain functions. Up to 1940 or 1945 the frontal lobes were considered to be the locus of all that is noble and good about human beings. At various times moral ideas,
emotion, abstract ideas, planning and initiative were localized there, although those who reported loss of some of these attributes following damage to the frontal area were far from agreeing among themselves just which was the crucial attribute. They did agree, however, that the frontal area
CMA JOURNAL/JUNE 18, 1977/VOL. 116
1373
was vital; the large size of the frontal lobes was the distinctive feature of man's brain, it was thought, and this was the basis of man's humanity. What Penfield did was to show that none of the frontal-lobe signs need result from large lesions of the prefrontal area, provided the tissue left behind the area bordering on the lesion, and the rest of the brain - was left in good shape. What had been attributed to simple loss of frontal-lobe tissue was in fact the result of scarring and diffuse damage throughout the cerebrum caused by the pressure of a tumour growing in the confines of the tight box of the skull. I do not suggest that Penfield consciously set out to establish that fact; actually I think he was as surprised as anyone at the excellent status of patients from whom he had removed scar tissue simply for the control of epilepsy. In fact, when he made his extensive bilateral removal of the prefrontal lobes in 1938' he must have thought that he could put an end to the fits but that there was a poor outlook for the patient in other respects. I had to urge him to go talk to the patient to see how good his mental status was. Only then did he see how great a change he had wrought. This patient's intelligence quotient improved from 75 to 80 (evidently varying with subclinical attacks) to 95 or so after the operation. He subsequently enlisted in the Canadian Army and went overseas at a time when headquarters in England was demanding a more careful psychologic screening of recruits. The medical officer examining him saw the scar on his forehead, asked what had caused
it, was told that he had had an accident in a sawmill, and asked if it was giving any trouble. The recruit replied that it was not - and indeed it was not after Penfield had taken out the scarred remnants of both his prefrontal lobes.2 That was the most remarkable of those early cases, but another was in a way equally astonishing, at least to a psychologist. In this instance the operation was performed by William Cone, but it formed part of the same pattern that testifies to the clinical significance of Penfield's study of scar and scar formation. Some time after unilateral removal of most of his left prefrontal lobe, perhaps 5% of the total weight of the cerebrum, the young man made a perfect score on the then new (in 1937) Stanford-Binet test of intelligence - a feat that would not be duplicated by 1 person in 10 OOO.. The frontal lobe work at the MNI was revolutionary in its significance. Nothing like it seemed to be going on elsewhere. The results I was reporting at meetings of the American Psychological Association were received with frank scepticism. (I don't think I was regarded as a liar, just an incompetent.) Everyone else studying cases of damage to the frontal area was able to report failures in intelligence-test performance and some of the frontal-lobe signs. Who was I, a newcomer to clinical investigation, to say otherwise? What they did not realize was that in the cases at the MNI there was little or no pathologic change in the remaining brain tissue. Cases seen elsewhere were mostly ones of tumour removal, possibly with scar formation at the site of operation; but in any event there
was extensive damage throughout the rest of the brain, the result of compression from the growing tumour. And in the frontal region the tumour might get somewhat larger before producing symptoms that would take the patient to his doctor. Adding to the disbelief was my report of increased intelligence after a major brain operation. How could 1 possibly say that taking out more cortex after injury to the brain could raise the intelligence quotient? Obviously this was nonsense. And it took some time for an even more obvious fact to be appreciated - that an active disturbance, depressing functions in the rest of the cortex, can be more damaging than the mere loss of the tissue from which the disturbance originates. It seems to me that this was as important as any of Penfield's contributions to knowledge, this demonstration that a small area of dysfunction could have such widespread deleterious effects and impair thought so much. In this work he was laying a new foundation for the scientific study of brain and mind, a process that went much further in his later study of the temporal lobe, but it was already clear by 1938 that he was doing more than just telling us about the frontal lobe. Neurologically and psychologically he was making a revolution. References
I was impressed, as no one could fail to be, by the experience of being in the operating room when Wilder Penfield was stimulating the exposed temporal cortex of patients who had reported having complex hallucinatory experiences as part of their epileptic seizures. In a small number of such patients Penfield was able to elicit reports of complex experiential phenomena that sometimes, but not invariably, resembled those occurring during the patient's habitual seizures. These observations were later reported by Penfield and Perot,1 who analysed the phenomena separately according to whether they were auditory or visual.
The beautifully orderly and unexpected distribution of points along the first temporal convolution in the right and left hemispheres from which electric stimulation during operation elicited complex auditory experiences is illustrated in Fig. 1. A patient might hear the voice of his cousin in Africa, or he might hear a well known march from Aida and be able to keep time to the music. The sounds would unroll at the rate of normal experience and yet the patient would not be deceived by them; he would remain aware at the same time of being in the operating room at the MNI, replying to Penfield; it was as though there were a moment-
I. HERB DO, PENFIELD W: Human behavior after extensive bilateral removal from the frontal lobes. Arch Neurol Psychiatry 44: 421, 1940 2. HERB DO: Man's frontal lobes: a critical review. Arch Neurol Psychiatry 54: 10, 1945 3. Idem: Intelligence in man after large removals of cerebral tissue: report of four left frontal lobe cases. J Gen Psychol 21: 73, 1939
Memory mechanisms BRENDA MILNER,* PH D, D SC, FRSC
Memory mechanisms and the study of the temporal lobes go hand in hand, as I was to learn quickly on my arrival at the Montreal Neurological Institute (MNI) for the first time in the summer of 1950. My original plan was to study problem-solving and certain aspects of visual perception that I believed might be affected by temporal-lobe lesions. After a few months, however, I realized that one could not afford to neglect memory, because so many exciting clues were coming from patients undergoing operations for the relief of temporal-lobe seizures. In those first days *Professor of neuropsychology, department of neurology and neurosurg.ry, McGill University
1374 CMA JOURNAL/JUNE 18, 1977/VOL. 116
