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Regional cerebral blood flow response during rest and memory activation in a patient with global amnesia
BRAIN
AND
LANGUAGE
Regional
9, 129-136 (1980)
Cerebral Blood Flow Response during and Memory Activation in a Patient with Global Amnesia
Rest
FRANK WOOD, REBECCA ARMENTROUT, JAMES F. TOOLE, LAWRENCE MCHENRY, AND DAVID STUMP
A college professor with a classical amnesic syndrome is described. He has a WAIS IQ of 130, but dramatic memory loss for episodes ranging from a few seconds ago all the way back to portions of his childhood. The amnesia was of sudden onset, 2 years prior to the current memory tests and regional cerebral blood flow measurements. The etiology is believed, though not conclusively proven, to be medial thalamic infarction. rCBF measurements were taken on six separate occasions, four resting baseline, one memory activation, using the previous procedure of Wood, Taylor, et al., and one carbon dioxide activation. The resting baseline showed extremely low flows throughout the cortex, with some hyperfrontal response on the first baseline. With CO, activation, however, there was brisk, uniform reactivity, with all sites showing increased flow. This suggested that there were no prominent areas of impaired vasomotor control or probable ischemic damage in the cortical surface. During memory activation. there was also a generalized increase in flow, especially in the frontal areas. This was in sharp contrast to the pattern for normals, described by Wood, Taylor. et al., which shows a slight overall decrease in flow from baseline to memory activation. The results are interpreted in light of Talland’s proposal that the amnesic syndrome reflects an arousal failure, with premature closure and shutdown of memory processing, especially at retrieval. Here the arousal failure is interpreted as an inadequate restriction or focusing of cortical activation, with resulting pathologically diffuse flow increases.
The case reported here is an especially pure example of the amnesic syndrome. The patient is a 65year-old college professor, who had been active and vigorous in his profession until the day of the acute onset of his permanent, global amnesia, at age 63. On that day, there had been no prior symptoms of any kind, when he suddenly fell over from a sitting Address reprint requests to Dr. Frank Wood, Section of Neuropsychology, Department of Neurology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC. 27103. Supported by USPHS Grant NS 00665513. 129 0093-934X/80/010129-08$02.00/0 Copyright @ 1980 by Academic Press, Inc. All rights of reproduction in any form reserved
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position with acute confusion, some slurring of speech, and general weakness. He never fully lost consciousness and within a day the weakness and speech slurring cleared, leaving a dense, global amnesic syndrome. An EEG taken at the time showed questionable general slowing, but no focal abnormalities. The patient was referred to us 15 months after the initial episode. During that time, there had been no further episodes, but the amnesia had persisted unchanged. In the 9 months following the initial referral, numerous investigations were undertaken. The EEG was completely normal, as was the CT scan. A sodium amytal interview was conducted, with no change in the dense amnesia. A full scale IQ of 130 was obtained, but essentially total failure was demonstrated on any tests involving memory. Classically, the patient was able to carry on intelligent conversations, including general discussions about the subject matter of his research and teaching career. He could not remember events of even a few seconds ago, after distraction, and had a retrograde amnesia extending back into his childhood. Before considering his rCBF data and certain other neuropsychological and neuroradiological findings, it will be useful to review briefly why the amnesic syndrome presents an interested challenge for rCBF analysis. The amnesic syndrome is nature’s operational definition of memory. In pure cases there is intact intelligence-as measured on conventional tests-with normal use of language, acceptable social graces, and retention of most learned skills. Compared to their premorbid personalities, many amnesics are somewhat passive, docile, and flat of affect; but they show no obvious psychopathology or distortion of personality. Some have mild and isolated perceptual and motor difficulties, but the single obvious deficit is gross memory loss for events ranging from a few seconds ago to many years ago. Cases of the amnesic syndrome are rare, compared to the far more common neuropsychological syndromes involving selective or generalized impairment of intelligence, but no correspondingly severe loss of memory, at least for day-to-day events. This apparent dissociation between memory and other processes has made the amnesic syndrome an object of intense clinical and experimental scrutiny, across the last two decades. See recent reviews by Kinsbourne and Wood (1975), Warrington and Weiskrantz (1973), and Cermak, Butters, and Get-rein (1973). See also the basic monographs and edited collections by Talland (1965), Whitty and Zangwill (1966), Talland and Waugh (1969), and Barbizet (1970). The most common etiology for the amnesic syndrome is prolonged alcoholism, resulting in the Wernicke-Korsakoff syndrome. One series of postmortem examinations has led to the conclusion that the critical lesion for this particular syndrome is the medial dorsal nucleus of the thalamus (Victor, Adams, & Collins, 1971). The medial temporal lobes, bilaterally, have also been implicated in surgical (Scoville &
REST AND
MEMORY
ACTIVATION
IN AMNESIA
131
Milner, 1957) and vascular (Benson, Marsden, & Meadows, 1974) cases. However, the most extensive studies have been done on the Korsakoff cases, with their apparent medial thalamic location of lesion. It was Korsakoff patients who formed the basis for Talland’s (1965) extensive and now classical work, which led him to the conclusion that a certain failure of arousal lay at the heart of the amnesic syndrome. Specifically, he proposed that the memory search cycle was prematurely shut down, resulting in a failure to carry it to its full conclusion. While he entertained the notion that this premature shutdown of arousal and search might operate both at registration and retrieval, he later tended (Talland, 1968) to conclude that the major burden of the difficulty lay at the retrieval stage. The notion of an abnormality in arousal is perhaps the only theory of the basis of the amnesic syndrome which makes face valid neuroanatomical sense, given the known participation of the medial thalamus in the diffuse, nonspecific projection systems believed to play a central role in arousal. See the recent review by Pribram and McGuinness (1975). Regional cerebral blood flow measures may be responsive to arousal levels. This is the implication of the rather uniform flow increases, from quiet resting baseline to multiple psychological activation, demonstrated by Meyer and his colleagues. See their paper elsewhere in this volume. In our laboratory, also, we have found this to be a reliable effect, easily replicable. This generalized, regionally uniform flow increase results from a constantly changing, multiply demanding psychological activation task. Apparently, there is a separate and independent type of arousal response, which is regionally more specific to the frontal lobes. This response habituates over repeated tests, and is thought to reflect the initial adoption of set by the subject, along with his or her general attention to the task and its surroundings. See the discussion of this hyperfrontal response by Risberg, elsewhere in this volume. This is also a familiar and commonly replicated phenomenon. In a previous paper by Wood, Taylor et al., elsewhere in this volume, it was reported that subjects showed neither a generalized nor a frontal type of arousal response to a rather fast paced recognition memory task. In fact, there were decreases in flow, compared to the resting baseline, especially in the occipital regions, where the decreased flow was highly inversely correlated with accuracy of memory performance during the rCBF measurement procedure. This implies that the arousal and memory search cycle described by Talland would not result in generalized cortical or local frontal flow increases. It would be of interest, therefore, to consider what types of arousal responses would be shown by a global amnesic patient. The patient reported here is believed to have a medial thalamic lesion. The evidence for that is not conclusive, but it is suggestive. On angiog-
132
WOOD ET AL.
raphy, he shows filling of the posterior cerebral arteries from the carotid circulation. No occlusions in the distribution of those arteries are demonstrated. However, there is only very slight communication, or none at all, between the distal end of the basilar artery and the posterior cerebral arteries, bilaterally. In addition, the distal end of the basilar artery itself is considerably narrowed, and the thalamic striate arteries are not well visualized. The pneumoencephalogram tomograms did suggest some atrophy of the medial aspect of each thalamus, with some attentuation of the massa intermedia. The patient was discharged with the diagnosis of medial thalamus atrophy. Clinically, the patient does manifest a passive and underaroused affect, typical of many amnesics. Serendipitously we also noticed that whenever we took videotape recordings of this patient’s performance under bright television lights, he consistently became more active in conversation, although his amnesia was not measureably improved. He underwent extensive neuropsychological tests, especially involving memory. They exceed the scope of this paper, but can be summarized essentially as demonstrating no other obvious focal deficits, but a classical pattern of memory loss, with retrograde amnesia. rCBF RESULTS
We have a total of six regional cerebral blood flow studies on this patient. They were done in pairs, on 3 different days, separated by a month between the first and second pair and by 3 months between the second and third pair of tests. In each pair, the first test was a resting baseline, with eyes closed. The second tests in each pair were a resting baseline, a recognition memory activation, and a carbon dioxide activation, respectively, across the three testing dates. The memory activation procedure was identical to the one previously described by Wood, Taylor, et al. It is a probe recognition paradigm, testing memory for auditorily presented words, delivered through earphones at the rate of one word every 2.5 sec. Half of these words are from a list which the subject heard and repeated 5 min prior to the test, and the task for the subject is to indicate with his left finger if the word he hears is from the list presented 5 min previously. The carbon dioxide activation procedure involves inhaling 5% CO, in air, throughout the rCBF test. CO, is a strong cerebral vasodilator, and in normals this procedure induces a generalized increase in blood flow, uniform across all regions. Localized failure of this response suggests impaired vasomotor control, and this is often the result of ischemic damage. The results from these 3 days and six tests are tabulated in Table 1. Consider first the results from Day 1, which involved two successive resting baselines. The first thing to be said about them is that the flows are
REST AND
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IN AMNESIA
TABLE 1 IS1 (INITIAI SLOPE INDEX) VALUES ON SIX DIFFEREYT rCBF TESTS IN 4~ AMNESIC PATIENT
Regional site
Initial day Baseline, baseline
I month after initial day Baseline, memory activation
4 months after initial day Baseline, CO,
Left hemisphere Superior frontal Lateral frontal Broca’s area Mid-Rolandic Wernicke’s area Angular gyrus Superior parietal Occipital pole
44, 30 42, 35 53, 36 35. 35 41.37 33. 35 46.37 36.43
34.41 37,51 35. 46 34.39 34.39 37. 32 33.44 38.42
36,50 44, 59 45,55 39. 55 36,4l 32,47 33,so 37.45
Right hemisphere Superior frontal Lateral frontal Broca’s area Mid-Rolandic Wernicke’s area Angular gyrus Superior parietal Occipital pole
38,33 48.34 31.39 36, 34 44, 37 35.44 37.31 33.30
41, 36 35,42 37.46 38,38 38.37 34,41 31.43 39,4l
31,50 41.49 38,5l 32. 54 35.56 29.39 37.51 38 ,5l
41.3, 36.0 37.8, 35.3
35.3, 41.8 36.6. 40.5
37.8, 50.3 35.1,50.1
Left hemisphere mean Right hemisphere mean NOIO. All ISIS are multiplied
by 100
generally quite low. While we do not as yet have extensive age norms for the resting baseline, we can use the least squares regression line for predicting mean hemispheric ISI from age, which was reported for a group of 14 neurologically normal patients, in the Wood, Taylor et al. study. Using the regression lines found in that study, we would predict ISIS of .53 and .48, respectively, for the left and right hemisphere means. These predicted values are slightly lower than those actually obtained by the three patients in that sample who were over 55. By comparison, then, the resting ISI values for this patient are substantially lower than our data and experience have led us to expect for 65-year-old normals. There are some changes from the first to the second resting baseline. (They were separated by a 30-minute rest.) Essentially, there was a hyperfrontal response in the left and right hemispheres, more pronounced on the left and restricted to the lateral frontal site on the right. This response habituates by the second baseline, which shows a fairly uniform and low pattern of flows for all sites. This hyperfrontal response remains
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habituated on the resting baseline of the second day, which occurs 1 month later. It partly reappears on the third day, 3 months later. It is instructive next to consider the last session, in which there was a carbon dioxide activation. The results show a large and rather uniform increase in flow, for all sites, compared to the resting baseline. If anything, the percentage of increase is larger than average. The principal conclusion to be drawn from the uniformly brisk reactivity of this patient to CO2 stimulation is that there are no regions of impaired vasomotor control and therefore no regions of obvious infarction demonstrated. The low baseline flows of this patient, therefore, do not mean widespread cortical disease or dysfunction. (That is, of course, corroborated both by the CT scan, showing no structural tissue damage, and by the superior performance of this patient on the Wechsler Adult Intelligence Scale, reported above .) The memory activation procedure resulted in some generalized as well as specifically frontal flow increases. The patient was instructed to try his best to remember, and to give a signal for each word in the task. He did give 16 out of 40 “yes” signals, but his accuracy of performance did not differ significantly from chance. (It can be reported, however, that he did not discharge the task flippantly or casually; he appeared to be trying to remember the words.) Compared to the performance of normal patients, reported in the previous Wood, Taylor, et al. paper, the response of this patient to the memory task is abnormal by virtue of the general and specifically frontal flow increases. As to the occipital site, whose flows were especially highly inversely correlated with accuracy in the study with normals, this patient showed no obvious pattern. By absolute standards, the occipital flows are quite low, but in the context of the flows at other sites in the memory activation run, the occipital flows are among the higher ones. The pattern is also abnormal by virtue of the extremely low flows in the left angular gyrus region, compared to the higher flows in the homologous right hemisphere region. Each normal in the Wood, Taylor, et al. study showed the opposite: higher left than right angular gyrus flows, during memory activation. CONCLUSIONS
It will take many more individual and group comparisons before all the relevant features of the normal and amnesic response to this task can be sorted out, and we will not attempt to interpret all of the features of the rCBF response of this patient. Specifically, for example, we think the angular gyrus findings may be relevant to the line of research conducted by Fedio and Van Buren (1978) with regard to the disruption of memory retrieval (but not registration) by electrical stimulation of the left parietotemporal region, but we will not argue that here. The data from this patient, however, are relevant to the arousal failure
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hypothesis proposed by Talland and to the possible relationship of amnesic syndrome to the functioning of the medial thalamus. If we assume that this patient does have media1 thalamic disease as the cause of his amnesia, then his generally low baseline flows can be interpreted as indicating low arousal. While there are many other possible interpretations, it is at least clear that widespread, generalized cortical atrophy cannot be the explanation. The CT scan does not show it, and the intact intelligence of the patient contradicts it. Furthermore, chronically low arousal is a fit description of the clinical state of this patient. His ability to mobilize a hyperfrontal response, however, both on the first resting baseline and on the memory activation task, furthers the suggestion that the hyperfrontal response is a different type of arousal response, and that it is not impaired in the amnesic syndrome. We cannot tell whether the flow increases in the memory activation state are general arousal increases or specific processing increases. Nevertheless, we can say that these are abnormal: normals who successfully execute the task tend not to show such increases. It may be that the cortical flow increases, during memory activation. in this patient reflect a poorly focused, imprecise, and therefore generalized arousal and use of cortical process mechanisms. The amnesic deficit cannot be attributed to failure of cortical arousal: that is evidently a much too simple idea. General cortical arousal and activation, indeed, appear to be inconsistent with accurate memory processing. It may be, therefore, that memory requires inhibition and restriction, hence sharp focusing, of cortical arousal or activation. Perhaps medial thalamic disease induces amnesia by prohibiting such focusing. This is equivalent to a kind of premature shutdown of the memory search cycle, as Talland proposed. The major difference is that the premature shutdown is interpreted here as equivalent to a failure to restrict and focus the process, as though breadth precludes depth. See also Redding, 1967, and Swonger and Rech, 1972. It seems likely that an amnesic patient would show cortical flow increases during the execution of other intellectual tasks, which he might perform well. Unfortunately, we do not have such data. Were such data forthcoming, however, it could still be interpreted in the context of the genera1notion of arousal failure, if it is remembered that memory retrieval is, virtually by definition, a low probability event, compared to almost any task where the main features of the task are available in the present environment. Thus, it can be argued that it takes more arousal toperationally defined as response to novelty or uncertainty; Pribram & McGuiness, 1975) to remember an earlier event than it does to calculate any present solution. At least, it may require more arousal to retrieve episodic memories than it does to retrieve semantic ones, which are by definition well rehearsed and not novel. (See Kinsbourne & Wood, 1975, for a more
136
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complete discussion of the relationship of the episodic versus semantic memory distinction to the amnesic syndrome.) In summary, this amnesic patient shows low flows in the resting baseline, with some hyperfrontal response in the first resting baseline and in the memory activation task. In the memory activation task, also, he shows additional generalized flow increases, unlike normals who are correctly executing the task. We believe that chronically low arousal, manifested by low cortical flows in the resting baseline but reflected by unduly generalized flow increases in the memory activation state, could explain the broad pattern of these data. No doubt, the nature of the arousal failure is specific and may not be any longer aptly described by such a global term as arousal. This case, however, does suggest that the mechanism of premature closure (or inadequate focusing) may well deserve further investigation. REFERENCES Barbizet, .I. 1970. Humtrn memory and it.r ptrthology. San Francisco: Freeman. Benson, F., Marsden, C. D., & Meadows, J. 1974, The amnesic syndrome of posterior cerebral artery occlusion. Acttr Neuro/ogictr Scandintwictr, 50, 133-145. Cermak, L., Butters, N., & Gerrein, J. The extent of the verbal encoding ability of Korsakoff patients. Neu,op.s~cho/o,~ict. 11, 85-94. Fedio, P., & Van Buren, J. M. 1978. Electrical stimulation during memory processing. In International Neuropsychological Society Meeting, Minneapolis, MN, February 2-4. Kinsbourne, M., & Wood, F. 1975. Short term memory and the amnesic syndrome. In D. Deutsch and J. A. Deutsch (Eds.), Short trr~n mr,nory. New York: Academic Press. Pribram, K., & McGuiness, D. 1975. Arousal, activation, and effort in the control of attention. Psychological Review. 82, 116-149. Redding, F. K. 1967. Modification of sensory evoked cortical potentials by hippocampal stimulation. Elecfruencephalography und Clink& Neurophysiology, 22: 74-83. Scoviile, W., & Milner, B. 1957. Loss of recent memory after bilateral lesions in the hippocampal area. Journrrl of Neurology. Neurosur~cer~, and P.cychiatry. 20, 1l-21. Swonger, A. K., and Rech, R. H. 1972. Serotonergic and cholinergic involvement in habituation of activity and spontaneous alteration of rats in a Y maze. Journal of Comparative
and Physiological
Psychology,
81: 509-522.
Talland, G. 1965. Deranged memory. New York: Academic Press. Talland, G. 1968. Disorders of’nremor~ and learning. London: Penguin. Talland, G., & Waugh. N. (Eds.) 1969. The pathology ofmemory. New York: Academic Press. Victor, M., Adams, R. D., & Collins, G. H. 1971. Wc~rnicke-KorstrkoffSyndromet A clinical and ptrrhological study of 245 patients. 82 naith post mortrm e.utrminations. Philadelphia: Davis. Warrington, E., & Weiskrantz, L. 1970. Amnesic syndrome: Consolidation or retrieval. Nrrrur-e f Londorr).
228, 628-630.
Whitty, C., & Zangwill, 0. (Eds.) 1966. Amnesia.
London: Butterworths.
AND
LANGUAGE
Regional
9, 129-136 (1980)
Cerebral Blood Flow Response during and Memory Activation in a Patient with Global Amnesia
Rest
FRANK WOOD, REBECCA ARMENTROUT, JAMES F. TOOLE, LAWRENCE MCHENRY, AND DAVID STUMP
A college professor with a classical amnesic syndrome is described. He has a WAIS IQ of 130, but dramatic memory loss for episodes ranging from a few seconds ago all the way back to portions of his childhood. The amnesia was of sudden onset, 2 years prior to the current memory tests and regional cerebral blood flow measurements. The etiology is believed, though not conclusively proven, to be medial thalamic infarction. rCBF measurements were taken on six separate occasions, four resting baseline, one memory activation, using the previous procedure of Wood, Taylor, et al., and one carbon dioxide activation. The resting baseline showed extremely low flows throughout the cortex, with some hyperfrontal response on the first baseline. With CO, activation, however, there was brisk, uniform reactivity, with all sites showing increased flow. This suggested that there were no prominent areas of impaired vasomotor control or probable ischemic damage in the cortical surface. During memory activation. there was also a generalized increase in flow, especially in the frontal areas. This was in sharp contrast to the pattern for normals, described by Wood, Taylor. et al., which shows a slight overall decrease in flow from baseline to memory activation. The results are interpreted in light of Talland’s proposal that the amnesic syndrome reflects an arousal failure, with premature closure and shutdown of memory processing, especially at retrieval. Here the arousal failure is interpreted as an inadequate restriction or focusing of cortical activation, with resulting pathologically diffuse flow increases.
The case reported here is an especially pure example of the amnesic syndrome. The patient is a 65year-old college professor, who had been active and vigorous in his profession until the day of the acute onset of his permanent, global amnesia, at age 63. On that day, there had been no prior symptoms of any kind, when he suddenly fell over from a sitting Address reprint requests to Dr. Frank Wood, Section of Neuropsychology, Department of Neurology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC. 27103. Supported by USPHS Grant NS 00665513. 129 0093-934X/80/010129-08$02.00/0 Copyright @ 1980 by Academic Press, Inc. All rights of reproduction in any form reserved
130
WOOD ET AL.
position with acute confusion, some slurring of speech, and general weakness. He never fully lost consciousness and within a day the weakness and speech slurring cleared, leaving a dense, global amnesic syndrome. An EEG taken at the time showed questionable general slowing, but no focal abnormalities. The patient was referred to us 15 months after the initial episode. During that time, there had been no further episodes, but the amnesia had persisted unchanged. In the 9 months following the initial referral, numerous investigations were undertaken. The EEG was completely normal, as was the CT scan. A sodium amytal interview was conducted, with no change in the dense amnesia. A full scale IQ of 130 was obtained, but essentially total failure was demonstrated on any tests involving memory. Classically, the patient was able to carry on intelligent conversations, including general discussions about the subject matter of his research and teaching career. He could not remember events of even a few seconds ago, after distraction, and had a retrograde amnesia extending back into his childhood. Before considering his rCBF data and certain other neuropsychological and neuroradiological findings, it will be useful to review briefly why the amnesic syndrome presents an interested challenge for rCBF analysis. The amnesic syndrome is nature’s operational definition of memory. In pure cases there is intact intelligence-as measured on conventional tests-with normal use of language, acceptable social graces, and retention of most learned skills. Compared to their premorbid personalities, many amnesics are somewhat passive, docile, and flat of affect; but they show no obvious psychopathology or distortion of personality. Some have mild and isolated perceptual and motor difficulties, but the single obvious deficit is gross memory loss for events ranging from a few seconds ago to many years ago. Cases of the amnesic syndrome are rare, compared to the far more common neuropsychological syndromes involving selective or generalized impairment of intelligence, but no correspondingly severe loss of memory, at least for day-to-day events. This apparent dissociation between memory and other processes has made the amnesic syndrome an object of intense clinical and experimental scrutiny, across the last two decades. See recent reviews by Kinsbourne and Wood (1975), Warrington and Weiskrantz (1973), and Cermak, Butters, and Get-rein (1973). See also the basic monographs and edited collections by Talland (1965), Whitty and Zangwill (1966), Talland and Waugh (1969), and Barbizet (1970). The most common etiology for the amnesic syndrome is prolonged alcoholism, resulting in the Wernicke-Korsakoff syndrome. One series of postmortem examinations has led to the conclusion that the critical lesion for this particular syndrome is the medial dorsal nucleus of the thalamus (Victor, Adams, & Collins, 1971). The medial temporal lobes, bilaterally, have also been implicated in surgical (Scoville &
REST AND
MEMORY
ACTIVATION
IN AMNESIA
131
Milner, 1957) and vascular (Benson, Marsden, & Meadows, 1974) cases. However, the most extensive studies have been done on the Korsakoff cases, with their apparent medial thalamic location of lesion. It was Korsakoff patients who formed the basis for Talland’s (1965) extensive and now classical work, which led him to the conclusion that a certain failure of arousal lay at the heart of the amnesic syndrome. Specifically, he proposed that the memory search cycle was prematurely shut down, resulting in a failure to carry it to its full conclusion. While he entertained the notion that this premature shutdown of arousal and search might operate both at registration and retrieval, he later tended (Talland, 1968) to conclude that the major burden of the difficulty lay at the retrieval stage. The notion of an abnormality in arousal is perhaps the only theory of the basis of the amnesic syndrome which makes face valid neuroanatomical sense, given the known participation of the medial thalamus in the diffuse, nonspecific projection systems believed to play a central role in arousal. See the recent review by Pribram and McGuinness (1975). Regional cerebral blood flow measures may be responsive to arousal levels. This is the implication of the rather uniform flow increases, from quiet resting baseline to multiple psychological activation, demonstrated by Meyer and his colleagues. See their paper elsewhere in this volume. In our laboratory, also, we have found this to be a reliable effect, easily replicable. This generalized, regionally uniform flow increase results from a constantly changing, multiply demanding psychological activation task. Apparently, there is a separate and independent type of arousal response, which is regionally more specific to the frontal lobes. This response habituates over repeated tests, and is thought to reflect the initial adoption of set by the subject, along with his or her general attention to the task and its surroundings. See the discussion of this hyperfrontal response by Risberg, elsewhere in this volume. This is also a familiar and commonly replicated phenomenon. In a previous paper by Wood, Taylor et al., elsewhere in this volume, it was reported that subjects showed neither a generalized nor a frontal type of arousal response to a rather fast paced recognition memory task. In fact, there were decreases in flow, compared to the resting baseline, especially in the occipital regions, where the decreased flow was highly inversely correlated with accuracy of memory performance during the rCBF measurement procedure. This implies that the arousal and memory search cycle described by Talland would not result in generalized cortical or local frontal flow increases. It would be of interest, therefore, to consider what types of arousal responses would be shown by a global amnesic patient. The patient reported here is believed to have a medial thalamic lesion. The evidence for that is not conclusive, but it is suggestive. On angiog-
132
WOOD ET AL.
raphy, he shows filling of the posterior cerebral arteries from the carotid circulation. No occlusions in the distribution of those arteries are demonstrated. However, there is only very slight communication, or none at all, between the distal end of the basilar artery and the posterior cerebral arteries, bilaterally. In addition, the distal end of the basilar artery itself is considerably narrowed, and the thalamic striate arteries are not well visualized. The pneumoencephalogram tomograms did suggest some atrophy of the medial aspect of each thalamus, with some attentuation of the massa intermedia. The patient was discharged with the diagnosis of medial thalamus atrophy. Clinically, the patient does manifest a passive and underaroused affect, typical of many amnesics. Serendipitously we also noticed that whenever we took videotape recordings of this patient’s performance under bright television lights, he consistently became more active in conversation, although his amnesia was not measureably improved. He underwent extensive neuropsychological tests, especially involving memory. They exceed the scope of this paper, but can be summarized essentially as demonstrating no other obvious focal deficits, but a classical pattern of memory loss, with retrograde amnesia. rCBF RESULTS
We have a total of six regional cerebral blood flow studies on this patient. They were done in pairs, on 3 different days, separated by a month between the first and second pair and by 3 months between the second and third pair of tests. In each pair, the first test was a resting baseline, with eyes closed. The second tests in each pair were a resting baseline, a recognition memory activation, and a carbon dioxide activation, respectively, across the three testing dates. The memory activation procedure was identical to the one previously described by Wood, Taylor, et al. It is a probe recognition paradigm, testing memory for auditorily presented words, delivered through earphones at the rate of one word every 2.5 sec. Half of these words are from a list which the subject heard and repeated 5 min prior to the test, and the task for the subject is to indicate with his left finger if the word he hears is from the list presented 5 min previously. The carbon dioxide activation procedure involves inhaling 5% CO, in air, throughout the rCBF test. CO, is a strong cerebral vasodilator, and in normals this procedure induces a generalized increase in blood flow, uniform across all regions. Localized failure of this response suggests impaired vasomotor control, and this is often the result of ischemic damage. The results from these 3 days and six tests are tabulated in Table 1. Consider first the results from Day 1, which involved two successive resting baselines. The first thing to be said about them is that the flows are
REST AND
REGIONAL
MEMORY
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IN AMNESIA
TABLE 1 IS1 (INITIAI SLOPE INDEX) VALUES ON SIX DIFFEREYT rCBF TESTS IN 4~ AMNESIC PATIENT
Regional site
Initial day Baseline, baseline
I month after initial day Baseline, memory activation
4 months after initial day Baseline, CO,
Left hemisphere Superior frontal Lateral frontal Broca’s area Mid-Rolandic Wernicke’s area Angular gyrus Superior parietal Occipital pole
44, 30 42, 35 53, 36 35. 35 41.37 33. 35 46.37 36.43
34.41 37,51 35. 46 34.39 34.39 37. 32 33.44 38.42
36,50 44, 59 45,55 39. 55 36,4l 32,47 33,so 37.45
Right hemisphere Superior frontal Lateral frontal Broca’s area Mid-Rolandic Wernicke’s area Angular gyrus Superior parietal Occipital pole
38,33 48.34 31.39 36, 34 44, 37 35.44 37.31 33.30
41, 36 35,42 37.46 38,38 38.37 34,41 31.43 39,4l
31,50 41.49 38,5l 32. 54 35.56 29.39 37.51 38 ,5l
41.3, 36.0 37.8, 35.3
35.3, 41.8 36.6. 40.5
37.8, 50.3 35.1,50.1
Left hemisphere mean Right hemisphere mean NOIO. All ISIS are multiplied
by 100
generally quite low. While we do not as yet have extensive age norms for the resting baseline, we can use the least squares regression line for predicting mean hemispheric ISI from age, which was reported for a group of 14 neurologically normal patients, in the Wood, Taylor et al. study. Using the regression lines found in that study, we would predict ISIS of .53 and .48, respectively, for the left and right hemisphere means. These predicted values are slightly lower than those actually obtained by the three patients in that sample who were over 55. By comparison, then, the resting ISI values for this patient are substantially lower than our data and experience have led us to expect for 65-year-old normals. There are some changes from the first to the second resting baseline. (They were separated by a 30-minute rest.) Essentially, there was a hyperfrontal response in the left and right hemispheres, more pronounced on the left and restricted to the lateral frontal site on the right. This response habituates by the second baseline, which shows a fairly uniform and low pattern of flows for all sites. This hyperfrontal response remains
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habituated on the resting baseline of the second day, which occurs 1 month later. It partly reappears on the third day, 3 months later. It is instructive next to consider the last session, in which there was a carbon dioxide activation. The results show a large and rather uniform increase in flow, for all sites, compared to the resting baseline. If anything, the percentage of increase is larger than average. The principal conclusion to be drawn from the uniformly brisk reactivity of this patient to CO2 stimulation is that there are no regions of impaired vasomotor control and therefore no regions of obvious infarction demonstrated. The low baseline flows of this patient, therefore, do not mean widespread cortical disease or dysfunction. (That is, of course, corroborated both by the CT scan, showing no structural tissue damage, and by the superior performance of this patient on the Wechsler Adult Intelligence Scale, reported above .) The memory activation procedure resulted in some generalized as well as specifically frontal flow increases. The patient was instructed to try his best to remember, and to give a signal for each word in the task. He did give 16 out of 40 “yes” signals, but his accuracy of performance did not differ significantly from chance. (It can be reported, however, that he did not discharge the task flippantly or casually; he appeared to be trying to remember the words.) Compared to the performance of normal patients, reported in the previous Wood, Taylor, et al. paper, the response of this patient to the memory task is abnormal by virtue of the general and specifically frontal flow increases. As to the occipital site, whose flows were especially highly inversely correlated with accuracy in the study with normals, this patient showed no obvious pattern. By absolute standards, the occipital flows are quite low, but in the context of the flows at other sites in the memory activation run, the occipital flows are among the higher ones. The pattern is also abnormal by virtue of the extremely low flows in the left angular gyrus region, compared to the higher flows in the homologous right hemisphere region. Each normal in the Wood, Taylor, et al. study showed the opposite: higher left than right angular gyrus flows, during memory activation. CONCLUSIONS
It will take many more individual and group comparisons before all the relevant features of the normal and amnesic response to this task can be sorted out, and we will not attempt to interpret all of the features of the rCBF response of this patient. Specifically, for example, we think the angular gyrus findings may be relevant to the line of research conducted by Fedio and Van Buren (1978) with regard to the disruption of memory retrieval (but not registration) by electrical stimulation of the left parietotemporal region, but we will not argue that here. The data from this patient, however, are relevant to the arousal failure
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hypothesis proposed by Talland and to the possible relationship of amnesic syndrome to the functioning of the medial thalamus. If we assume that this patient does have media1 thalamic disease as the cause of his amnesia, then his generally low baseline flows can be interpreted as indicating low arousal. While there are many other possible interpretations, it is at least clear that widespread, generalized cortical atrophy cannot be the explanation. The CT scan does not show it, and the intact intelligence of the patient contradicts it. Furthermore, chronically low arousal is a fit description of the clinical state of this patient. His ability to mobilize a hyperfrontal response, however, both on the first resting baseline and on the memory activation task, furthers the suggestion that the hyperfrontal response is a different type of arousal response, and that it is not impaired in the amnesic syndrome. We cannot tell whether the flow increases in the memory activation state are general arousal increases or specific processing increases. Nevertheless, we can say that these are abnormal: normals who successfully execute the task tend not to show such increases. It may be that the cortical flow increases, during memory activation. in this patient reflect a poorly focused, imprecise, and therefore generalized arousal and use of cortical process mechanisms. The amnesic deficit cannot be attributed to failure of cortical arousal: that is evidently a much too simple idea. General cortical arousal and activation, indeed, appear to be inconsistent with accurate memory processing. It may be, therefore, that memory requires inhibition and restriction, hence sharp focusing, of cortical arousal or activation. Perhaps medial thalamic disease induces amnesia by prohibiting such focusing. This is equivalent to a kind of premature shutdown of the memory search cycle, as Talland proposed. The major difference is that the premature shutdown is interpreted here as equivalent to a failure to restrict and focus the process, as though breadth precludes depth. See also Redding, 1967, and Swonger and Rech, 1972. It seems likely that an amnesic patient would show cortical flow increases during the execution of other intellectual tasks, which he might perform well. Unfortunately, we do not have such data. Were such data forthcoming, however, it could still be interpreted in the context of the genera1notion of arousal failure, if it is remembered that memory retrieval is, virtually by definition, a low probability event, compared to almost any task where the main features of the task are available in the present environment. Thus, it can be argued that it takes more arousal toperationally defined as response to novelty or uncertainty; Pribram & McGuiness, 1975) to remember an earlier event than it does to calculate any present solution. At least, it may require more arousal to retrieve episodic memories than it does to retrieve semantic ones, which are by definition well rehearsed and not novel. (See Kinsbourne & Wood, 1975, for a more
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complete discussion of the relationship of the episodic versus semantic memory distinction to the amnesic syndrome.) In summary, this amnesic patient shows low flows in the resting baseline, with some hyperfrontal response in the first resting baseline and in the memory activation task. In the memory activation task, also, he shows additional generalized flow increases, unlike normals who are correctly executing the task. We believe that chronically low arousal, manifested by low cortical flows in the resting baseline but reflected by unduly generalized flow increases in the memory activation state, could explain the broad pattern of these data. No doubt, the nature of the arousal failure is specific and may not be any longer aptly described by such a global term as arousal. This case, however, does suggest that the mechanism of premature closure (or inadequate focusing) may well deserve further investigation. REFERENCES Barbizet, .I. 1970. Humtrn memory and it.r ptrthology. San Francisco: Freeman. Benson, F., Marsden, C. D., & Meadows, J. 1974, The amnesic syndrome of posterior cerebral artery occlusion. Acttr Neuro/ogictr Scandintwictr, 50, 133-145. Cermak, L., Butters, N., & Gerrein, J. The extent of the verbal encoding ability of Korsakoff patients. Neu,op.s~cho/o,~ict. 11, 85-94. Fedio, P., & Van Buren, J. M. 1978. Electrical stimulation during memory processing. In International Neuropsychological Society Meeting, Minneapolis, MN, February 2-4. Kinsbourne, M., & Wood, F. 1975. Short term memory and the amnesic syndrome. In D. Deutsch and J. A. Deutsch (Eds.), Short trr~n mr,nory. New York: Academic Press. Pribram, K., & McGuiness, D. 1975. Arousal, activation, and effort in the control of attention. Psychological Review. 82, 116-149. Redding, F. K. 1967. Modification of sensory evoked cortical potentials by hippocampal stimulation. Elecfruencephalography und Clink& Neurophysiology, 22: 74-83. Scoviile, W., & Milner, B. 1957. Loss of recent memory after bilateral lesions in the hippocampal area. Journrrl of Neurology. Neurosur~cer~, and P.cychiatry. 20, 1l-21. Swonger, A. K., and Rech, R. H. 1972. Serotonergic and cholinergic involvement in habituation of activity and spontaneous alteration of rats in a Y maze. Journal of Comparative
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Talland, G. 1965. Deranged memory. New York: Academic Press. Talland, G. 1968. Disorders of’nremor~ and learning. London: Penguin. Talland, G., & Waugh. N. (Eds.) 1969. The pathology ofmemory. New York: Academic Press. Victor, M., Adams, R. D., & Collins, G. H. 1971. Wc~rnicke-KorstrkoffSyndromet A clinical and ptrrhological study of 245 patients. 82 naith post mortrm e.utrminations. Philadelphia: Davis. Warrington, E., & Weiskrantz, L. 1970. Amnesic syndrome: Consolidation or retrieval. Nrrrur-e f Londorr).
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