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THE AMNESIA OF CEREBRAL CONCUSSION
1359
Hypothesis THE AMNESIA OF
CEREBRAL CONCUSSION
*
INTRACELLULAR orientation of macromolecules is now recognised as an essential characteristic of living matter. Interruption of function is thus likely to follow impacts sufficient in magnitude to cause disarrangement of orientated macromolecules. Moreover such accidents might derange intracellular activities without producing visible evidence of gross injury. This indeed happens in cerebral concussion, when nervous activity is arrested by excessive acceleration1 or retardation of the cerebral substance, although signs of injury may be invisible to the unaided eye. However, careful microscopic examination,22 made on the neurones of concussed animals, reveals almost immediate fragmentation and agglutination of Nissl substance with chromatolysis as a later sequel. RETROGRADE AMNESIA
Concussion is usually succeeded by amnesia of the actual moment of accident and also of the immediately preceding events. This retrograde amnesia is a remarkable feature of concussion, and indicates that the neuronal processes, involved in recording recent happenings, are less indelibly impressed on memory than those connected with longpast episodes. A similar impermanence of record for recent events is often evident in old age, when, as in concussion, the recent traces are more readily erased from memory. NATURE OF CONCUSSION AND MEMORY
The number of theories which have been advanced to explain cerebral concussion gives a fair estimate of our ignorance about its real mechanism. Some views suppose that compression of blood-vessels or spaces containing cerebrospinal fluid deprive the neurones of essential nutriments such as glucose 3 or oxygen.4 It is also possible that intracellular movement of fluids may remove substrates (such as glucose) from their enzymes, so that metabolism is temporarily arrested. Physiologists account for memory as a kind of pattern of resonance dependent on local electrical circuits throughout the cerebral cortex.5 The permanence of memory is explained by plastic changes at synapses, which are affected by usage so that the efficiency of synaptic function is increased by continued activation.6The need for some kind of material or structural foundation, to explain persistence of memory after prolonged anaesthesia sufficient to abolish all electrical activity, was recognised by Adrian,5 although he accepted in part the hypothesis of a resonance pattern. But, after concussion, memory for more remote events is usually quite unaltered and permanent, if consciousness ever returns, although electrical activity of the entire cortex may temporarily be
suspended.7 MACROMOLECULAR COMPOSITION AS BASIS OF MEMORY
If a mere pattern of impulses were the real basis for memory and thought, then with the coma of concussion, *This paper was first submitted for publication in January, 1959, before our Hypothesis series was started.—ED.L. 1. 2. 3. 4. 5.
Denny-Brown, D., Russell, W. R. Brain, 1941, 64, 93. Windle, W. F., Groat, R. A., Fox, C. A. Surg. Gynec. Obstet. 1944, 79, 561. Dixon, K. C. Lancet, 1940, ii, 360. Cannon, W. B. Amer. J. Physiol. 1901, 6, 91. Adrian, E. D. The Physical Background of Perception; p. 92. Oxford, 1947.
6.
Eccles, J. C. The Neurophysiological Basis of Mind; p. 266. Oxford,
7.
Williams, D., Denny-Brown,
1953.
D.
Brain, 1941, 64,
223.
which may abolish all electrical activity, our thoughts should disappear, never to return. To account for the re-establishment of electrical patterns and thoughts so similar to those existing before the accident, we must assume that some permanent change is impressed on the macromolecular mozaic of the neurone; this change constitutes memory. The macromolecules of neuronal proteins and lipids compose an assembly of variable pattern complex enough to account for an almost infinite catalogue of thoughts. The pattern of local depolarisation, upon which electrical activity and neuronal intercommunication may depend, would thus initially be based on cellular variation in the internal arrangement of protein molecules. According to this view the pattern of neuronal activity depends on the varying composition of neuronal protein: hence the necessity for abundant protein in the neurone. The cell bodies and dendrites of both cerebral and cerebellar cortex are indeed conspicuously rich in protein. 8-10 Moreover the neurone is endowed, to a unique degree for a cell incapable of division, with facilities for the continuous resynthesis of protein: the soma and dendrites contain large amounts of ribonucleic acid (R.N.A.),ll 12 which is the specific fabricator for cytoplasmic protein. R.N.A. provides the mechanism for the continuous replacement of protein molecules which have but a limited span of life. This hypothesis does not deny that electrical activity initiates nervous messages, but suggests that thought does not merely depend on a pattern of electrical impulses. It seems more likely that there is an underlying pattern impressed on the macromolecular fabric of whole groups of neurones with a gradation of molecular make-up from cell to cell. Such a molecular mozaic could regenerate electrical patterns; even though they may have been eliminated, they can later recur under the dominant influence of intramolecular orientation. The permanence of memory following deep anaesthesia or concussion, which abolish electrical activity, would thus depend on the internal configuration of neuronal proteins and the capacity of specific molecules of R.N.A. to replenish these as they disintegrate during normal cellular katabolism. COMA IN CONCUSSION
If
nervous activity, including consciousness, depends specific pattern in orientated protein molecules, then it is reasonable to suppose that displacement of neuronal macromolecules by trauma should at least temporarily interrupt function. The return of consciousness may depend first on the gradual restoration of previous alignment involving the slow movement of intracellular particles and organelles in viscous fluids. But, if at the same time the synthesis of protein has been interrupted by disorientation of R.N.A., then a considerable time may elapse before the specific configurations of neuronal protein are restored; thus loss of consciousness may occasionally be prolonged. on a
REPLENISHMENT OF NEURONAL MACROMOLECULES
Although R.N.A. is the template on which protein is built, alterations impressed on neuronal protein by fresh impulses reaching the cell may react on the R.N.A. during its synthesis so as to produce a new replicating agent capable of replenishing permanently the changed protein. 8. 9. 10. 11. 12.
Dixon, K. C. J. Physiol. 1953, 120, 267. Dixon, K. C. Quart. J. exp. Physiol. 1954, 39, 129. Dixon, K. C. J. Anat. 1958, 92, 425. Hyden, H. Acta Physiol. Scand. 1943, 6, suppl. 17. Hyden, H. Sympos. Soc. exp. Biol. 1947, 1, 152.
1360 This action of the altered protein on the R.N.A. thus establishes a permanent mechanism for replacement of the new protein, which, in its turn, is responsible for the new patterns of impulses associated thereafter with a fresh addition to memory. Burnet 13 suggested a similar process involving specific complementary patterns of protein and R.N.A. in the power of an antigen to affect the synthetic mechanism for making a new specific antibody. PROPOSED MECHANISM OF AMNESIA AFTER
CONCUSSION
proteins, then replication of the latter would be impossible. Thus recent events would become erased from memory and concussion would be attended by retrograde amnesia. ’"’
’"’
’"’
The view that the permanence of memory after concussion is due to a pattern impressed by previous events on the structure of neuronal proteins, which can be replicated by specific molecules of ribonucleic acid, was advanced in a lecture open to members of Cambridge University given in February, 1958.14
protein molecule is altered in the recording of a new experience, the replicating mechanism for the formation of this altered protein is absent from the cell. Only when the specific R.N.A. capable of synthesising this new protein is moulded, can the cell permanently replicate the changed protein. The process of formation of this master template may depend on precise orientation and alignment between protein and R.N.A. ; concussion may dislocate this orientation. Thus no specific molecules of R.N.A., capable of fabricating proteins corresponding to recently received patterns of impulses, may be added to the cellular stores of replicating agents during the period immediately following concussion. Moreover the recently modified protein may have decomposed before it can again be realigned in a state suitable for inducing the formation of new templates of R.N.A. Thus the possibility of replenishing this modified protein may permanently be prevented. Accordingly after concussion the traces corresponding to recent events may never enter the record of permanent memory, although recovery from coma may be followed by full restoration of memory for more remote happenings.
theory of memory, which is in some respects similar, involving the synthesis of individual proteins by separate molecules of ribonucleic acid, was independently put forward by Hyden.I5
AMNESIA IN OLD AGE
ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE
When first
a
Neurones have no replacements and their metabolic activity is lifelong. They are thus the permanent companions as well as the dictators of the rest of the body. Finally, however, the capacity to mould fresh molecules of R.N.A., corresponding to new proteins modified by fresh sensations, may deteriorate. If this happens, the power to replenish the proteins associated with the recent additions to memory would be impaired, although the capacity to replenish early established configurations, along with lucid memory for remote episodes, would be retained. Memory
for recent events would thus become deterioration.
evanescent
in senile
SUMMARY
1. To account for the permanence of memory, after recovery from the coma of concussion, it is suggested that repetitive patterns of neuronal activity depend on the intramolecular composition of neuronal proteins. The structure of the protein molecules may be modified by impulses reaching the neurones. 2. The permanence of memory may further involve the
continued replenishment of each protein by a replicating molecule of ribonucleic acid, which is originally moulded afresh as a specific complementary pattern to each newly modified protein. 3. Disorientation of neuronal protein from the functional surfaces of the cell may account for the coma and arrest of nervous activity in concussion. The subsequent return of consciousness and memory may be due to realignment of these specific proteins at cellular surfaces. 4. If concussion interrupts the process of generating new templates of ribonucleic acid for freshly acquired 13.
Burnet, F.
M.
Enzyme Antigen and Virus; p. 60. London,
1956.
A
I am very advice.
grateful
to
Dr.
Joseph Needham,
F.R.S., for
helpful
KENDAL C. DIXON M.D., PH.D. Cantab. Fellow of King’s College and Reader in Cytopathology,
Cambridge ADDENDUM
Very recently P. Glees (see Medical News, Nov. 2,1962) has proposed a very similar system to account for the persistence of memory in animals cooled sufficiently to abolish cerebral cortical activity. G. Horn (Mermaid, University of Birmingham, 1952, 18, 17) also suggested that memory is stored in neuronal proteins.
Medical Societies
Tristan da Cunha AT a meeting in London on Dec. 13 speakers described their findings during examinations of 259 of the 286 inhabitants of Tristan da Cunha who were brought to England after the eruption of the volcano in October, 1961. Dr. H. E. LEWIS recalled that a garrison was stationed on the island during Napoleon’s imprisonment on St. Helena, and a few members decided to remain when the garrison was withdrawn. These included Corporal Glass, who had married a Hottentot; and they were later joined by two Englishmen and two sisters and a daughter of one of these sisters. Up to the end of the 19th century there were 15 ancestors, of whom 1 was African and 3 were nearly related; there were now seven surnames in the whole population. Moreover, in 1885, 15 men were drowned, leaving only 7. Inbreeding had therefore been intense. Dr. C. K. THACKER commented on the islanders’ physical resemblance to each other. They were slow in action and speech, and they were free from anxiety. They were reasonably intelligent, but illiterate or semiliterate. Only 17% were found to be free from intestinal parasites, of which trichuris (in 72%) and ascaris (23%) were common, as was Entamwba histolytica (11%). The dye-test for toxoplasmosis was positive in 79%. Other infections had previously occurred as epidemicsjaundice (66% affected) in 1961, chickenpox, and measles. The cardiovascular system was generally normal, but was a usual complaint; and congenital deformities
indigestion
Dixon, K. C. The Food of the Mind. Lecture given on Feb. 7, 1958, in series on History of Biochemistry open to all members of the University of Cambridge. 15. Hyden, H. Biochemical Changes in Glia Cells and Nerve Cells at Varying Activity. Symposium no.III, of Fourth International Congress of Biochemistry, Vienna, September, 1958; p. 83. 14.
Hypothesis THE AMNESIA OF
CEREBRAL CONCUSSION
*
INTRACELLULAR orientation of macromolecules is now recognised as an essential characteristic of living matter. Interruption of function is thus likely to follow impacts sufficient in magnitude to cause disarrangement of orientated macromolecules. Moreover such accidents might derange intracellular activities without producing visible evidence of gross injury. This indeed happens in cerebral concussion, when nervous activity is arrested by excessive acceleration1 or retardation of the cerebral substance, although signs of injury may be invisible to the unaided eye. However, careful microscopic examination,22 made on the neurones of concussed animals, reveals almost immediate fragmentation and agglutination of Nissl substance with chromatolysis as a later sequel. RETROGRADE AMNESIA
Concussion is usually succeeded by amnesia of the actual moment of accident and also of the immediately preceding events. This retrograde amnesia is a remarkable feature of concussion, and indicates that the neuronal processes, involved in recording recent happenings, are less indelibly impressed on memory than those connected with longpast episodes. A similar impermanence of record for recent events is often evident in old age, when, as in concussion, the recent traces are more readily erased from memory. NATURE OF CONCUSSION AND MEMORY
The number of theories which have been advanced to explain cerebral concussion gives a fair estimate of our ignorance about its real mechanism. Some views suppose that compression of blood-vessels or spaces containing cerebrospinal fluid deprive the neurones of essential nutriments such as glucose 3 or oxygen.4 It is also possible that intracellular movement of fluids may remove substrates (such as glucose) from their enzymes, so that metabolism is temporarily arrested. Physiologists account for memory as a kind of pattern of resonance dependent on local electrical circuits throughout the cerebral cortex.5 The permanence of memory is explained by plastic changes at synapses, which are affected by usage so that the efficiency of synaptic function is increased by continued activation.6The need for some kind of material or structural foundation, to explain persistence of memory after prolonged anaesthesia sufficient to abolish all electrical activity, was recognised by Adrian,5 although he accepted in part the hypothesis of a resonance pattern. But, after concussion, memory for more remote events is usually quite unaltered and permanent, if consciousness ever returns, although electrical activity of the entire cortex may temporarily be
suspended.7 MACROMOLECULAR COMPOSITION AS BASIS OF MEMORY
If a mere pattern of impulses were the real basis for memory and thought, then with the coma of concussion, *This paper was first submitted for publication in January, 1959, before our Hypothesis series was started.—ED.L. 1. 2. 3. 4. 5.
Denny-Brown, D., Russell, W. R. Brain, 1941, 64, 93. Windle, W. F., Groat, R. A., Fox, C. A. Surg. Gynec. Obstet. 1944, 79, 561. Dixon, K. C. Lancet, 1940, ii, 360. Cannon, W. B. Amer. J. Physiol. 1901, 6, 91. Adrian, E. D. The Physical Background of Perception; p. 92. Oxford, 1947.
6.
Eccles, J. C. The Neurophysiological Basis of Mind; p. 266. Oxford,
7.
Williams, D., Denny-Brown,
1953.
D.
Brain, 1941, 64,
223.
which may abolish all electrical activity, our thoughts should disappear, never to return. To account for the re-establishment of electrical patterns and thoughts so similar to those existing before the accident, we must assume that some permanent change is impressed on the macromolecular mozaic of the neurone; this change constitutes memory. The macromolecules of neuronal proteins and lipids compose an assembly of variable pattern complex enough to account for an almost infinite catalogue of thoughts. The pattern of local depolarisation, upon which electrical activity and neuronal intercommunication may depend, would thus initially be based on cellular variation in the internal arrangement of protein molecules. According to this view the pattern of neuronal activity depends on the varying composition of neuronal protein: hence the necessity for abundant protein in the neurone. The cell bodies and dendrites of both cerebral and cerebellar cortex are indeed conspicuously rich in protein. 8-10 Moreover the neurone is endowed, to a unique degree for a cell incapable of division, with facilities for the continuous resynthesis of protein: the soma and dendrites contain large amounts of ribonucleic acid (R.N.A.),ll 12 which is the specific fabricator for cytoplasmic protein. R.N.A. provides the mechanism for the continuous replacement of protein molecules which have but a limited span of life. This hypothesis does not deny that electrical activity initiates nervous messages, but suggests that thought does not merely depend on a pattern of electrical impulses. It seems more likely that there is an underlying pattern impressed on the macromolecular fabric of whole groups of neurones with a gradation of molecular make-up from cell to cell. Such a molecular mozaic could regenerate electrical patterns; even though they may have been eliminated, they can later recur under the dominant influence of intramolecular orientation. The permanence of memory following deep anaesthesia or concussion, which abolish electrical activity, would thus depend on the internal configuration of neuronal proteins and the capacity of specific molecules of R.N.A. to replenish these as they disintegrate during normal cellular katabolism. COMA IN CONCUSSION
If
nervous activity, including consciousness, depends specific pattern in orientated protein molecules, then it is reasonable to suppose that displacement of neuronal macromolecules by trauma should at least temporarily interrupt function. The return of consciousness may depend first on the gradual restoration of previous alignment involving the slow movement of intracellular particles and organelles in viscous fluids. But, if at the same time the synthesis of protein has been interrupted by disorientation of R.N.A., then a considerable time may elapse before the specific configurations of neuronal protein are restored; thus loss of consciousness may occasionally be prolonged. on a
REPLENISHMENT OF NEURONAL MACROMOLECULES
Although R.N.A. is the template on which protein is built, alterations impressed on neuronal protein by fresh impulses reaching the cell may react on the R.N.A. during its synthesis so as to produce a new replicating agent capable of replenishing permanently the changed protein. 8. 9. 10. 11. 12.
Dixon, K. C. J. Physiol. 1953, 120, 267. Dixon, K. C. Quart. J. exp. Physiol. 1954, 39, 129. Dixon, K. C. J. Anat. 1958, 92, 425. Hyden, H. Acta Physiol. Scand. 1943, 6, suppl. 17. Hyden, H. Sympos. Soc. exp. Biol. 1947, 1, 152.
1360 This action of the altered protein on the R.N.A. thus establishes a permanent mechanism for replacement of the new protein, which, in its turn, is responsible for the new patterns of impulses associated thereafter with a fresh addition to memory. Burnet 13 suggested a similar process involving specific complementary patterns of protein and R.N.A. in the power of an antigen to affect the synthetic mechanism for making a new specific antibody. PROPOSED MECHANISM OF AMNESIA AFTER
CONCUSSION
proteins, then replication of the latter would be impossible. Thus recent events would become erased from memory and concussion would be attended by retrograde amnesia. ’"’
’"’
’"’
The view that the permanence of memory after concussion is due to a pattern impressed by previous events on the structure of neuronal proteins, which can be replicated by specific molecules of ribonucleic acid, was advanced in a lecture open to members of Cambridge University given in February, 1958.14
protein molecule is altered in the recording of a new experience, the replicating mechanism for the formation of this altered protein is absent from the cell. Only when the specific R.N.A. capable of synthesising this new protein is moulded, can the cell permanently replicate the changed protein. The process of formation of this master template may depend on precise orientation and alignment between protein and R.N.A. ; concussion may dislocate this orientation. Thus no specific molecules of R.N.A., capable of fabricating proteins corresponding to recently received patterns of impulses, may be added to the cellular stores of replicating agents during the period immediately following concussion. Moreover the recently modified protein may have decomposed before it can again be realigned in a state suitable for inducing the formation of new templates of R.N.A. Thus the possibility of replenishing this modified protein may permanently be prevented. Accordingly after concussion the traces corresponding to recent events may never enter the record of permanent memory, although recovery from coma may be followed by full restoration of memory for more remote happenings.
theory of memory, which is in some respects similar, involving the synthesis of individual proteins by separate molecules of ribonucleic acid, was independently put forward by Hyden.I5
AMNESIA IN OLD AGE
ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE
When first
a
Neurones have no replacements and their metabolic activity is lifelong. They are thus the permanent companions as well as the dictators of the rest of the body. Finally, however, the capacity to mould fresh molecules of R.N.A., corresponding to new proteins modified by fresh sensations, may deteriorate. If this happens, the power to replenish the proteins associated with the recent additions to memory would be impaired, although the capacity to replenish early established configurations, along with lucid memory for remote episodes, would be retained. Memory
for recent events would thus become deterioration.
evanescent
in senile
SUMMARY
1. To account for the permanence of memory, after recovery from the coma of concussion, it is suggested that repetitive patterns of neuronal activity depend on the intramolecular composition of neuronal proteins. The structure of the protein molecules may be modified by impulses reaching the neurones. 2. The permanence of memory may further involve the
continued replenishment of each protein by a replicating molecule of ribonucleic acid, which is originally moulded afresh as a specific complementary pattern to each newly modified protein. 3. Disorientation of neuronal protein from the functional surfaces of the cell may account for the coma and arrest of nervous activity in concussion. The subsequent return of consciousness and memory may be due to realignment of these specific proteins at cellular surfaces. 4. If concussion interrupts the process of generating new templates of ribonucleic acid for freshly acquired 13.
Burnet, F.
M.
Enzyme Antigen and Virus; p. 60. London,
1956.
A
I am very advice.
grateful
to
Dr.
Joseph Needham,
F.R.S., for
helpful
KENDAL C. DIXON M.D., PH.D. Cantab. Fellow of King’s College and Reader in Cytopathology,
Cambridge ADDENDUM
Very recently P. Glees (see Medical News, Nov. 2,1962) has proposed a very similar system to account for the persistence of memory in animals cooled sufficiently to abolish cerebral cortical activity. G. Horn (Mermaid, University of Birmingham, 1952, 18, 17) also suggested that memory is stored in neuronal proteins.
Medical Societies
Tristan da Cunha AT a meeting in London on Dec. 13 speakers described their findings during examinations of 259 of the 286 inhabitants of Tristan da Cunha who were brought to England after the eruption of the volcano in October, 1961. Dr. H. E. LEWIS recalled that a garrison was stationed on the island during Napoleon’s imprisonment on St. Helena, and a few members decided to remain when the garrison was withdrawn. These included Corporal Glass, who had married a Hottentot; and they were later joined by two Englishmen and two sisters and a daughter of one of these sisters. Up to the end of the 19th century there were 15 ancestors, of whom 1 was African and 3 were nearly related; there were now seven surnames in the whole population. Moreover, in 1885, 15 men were drowned, leaving only 7. Inbreeding had therefore been intense. Dr. C. K. THACKER commented on the islanders’ physical resemblance to each other. They were slow in action and speech, and they were free from anxiety. They were reasonably intelligent, but illiterate or semiliterate. Only 17% were found to be free from intestinal parasites, of which trichuris (in 72%) and ascaris (23%) were common, as was Entamwba histolytica (11%). The dye-test for toxoplasmosis was positive in 79%. Other infections had previously occurred as epidemicsjaundice (66% affected) in 1961, chickenpox, and measles. The cardiovascular system was generally normal, but was a usual complaint; and congenital deformities
indigestion
Dixon, K. C. The Food of the Mind. Lecture given on Feb. 7, 1958, in series on History of Biochemistry open to all members of the University of Cambridge. 15. Hyden, H. Biochemical Changes in Glia Cells and Nerve Cells at Varying Activity. Symposium no.III, of Fourth International Congress of Biochemistry, Vienna, September, 1958; p. 83. 14.