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Pure Retrograde Amnesia Exists But What is the Explanation?
PURE RETROGRADE AMNESIA EXISTS BUT WHAT IS THE EXPLANATION? John R Hodges (MRC cognition and Brain Sciences Unit, Cambridge, UK)
A symposium on the topic of focal retrograde amnesia (FRA) held at the annual European Cognitive Neuropsychology meeting in Bressanone some 8 years ago provoked a heated debate between the participants. One camp argued in favour of an organically based syndrome of retrograde amnesia in the absence of significant anterograde amnesia, while others argued with equal vigour that such cases could be explained by psychogenic factors. At that time relatively few cases had been reported in the literature and in many instances it was not possible to decide between these apparently different explanations. Since the debate, an increasing number of cases with FRA have been described (see Kopelman and Kapur, 2001). Sellal et al. (2002, this issue) add to this growing literature by reporting a new case with clearly impaired retrograde amnesia extending back at least 10 years but normal performance of standard tests of anterograde amnesia. The noteworthy features in this instance are: (i) the retrograde memory loss involved not only autobiographical memory but also knowledge of famous people, recent vocabulary and even the patient’s ability to write his usual adult signature; (ii) a SPECT scan demonstrated hypoperfusion of the right temporal lobe; (iii) the degree of head trauma was slight; and (iv) recovery of the “lost memories” occcurred after a period of three months. The debate is over: there is no longer any reasonable doubt that FRA is a definite syndrome with an organic basis, as proven by the finding of an abnormal SPECT scan in Sellal et al’s case. Or is it? Unfortunately things are not that simple and even if we do accept the existence of FGA, the most intriguing question remains unanswered: how can we explain this syndrome in the context of current models of long-term memory? The multitude of studies showing changes on functional (and more controversially) structural brain imaging in the classic psychiatric syndromes of schizophrenia, affective illness and even anxiety and obsessive-compulsive disorder surely undermines this naïve dichotomy. The classic “neurological” syndrome of transient global amnesia (TGA) also provides informative illustration of the fallacy of this, as most other, dichotomies. A number of SPECT, PET and diffusion weighted MRI studies have now convincingly demonstrated marked changes in the medial temporal lobes during TGA. The neuropsychological findings are also clearly compatible with severe, yet temporary, dysfunction of the hippocampal complex – profound anterograde episodic memory impairment with variable and temporally graded remote memory loss, but preservation of working and well-established semantic knowledge (see Hodges, 1998). Yet, there is also evidence that TGA can be Cortex, (2002) 38, 674-677
Cortex Forum
675
precipitated by an extreme emotional stress and/or physical exertion including occasionally sexual intercourse. An explanation for this paradox is that acute neurotransmitter changes may be induced by psychogenic factors, which in turn cause acute, but reversible, metabolically induced “shut down” of medial temporal lobe structures. However, this attractive hypothesis is still unproven. How are we to explain the opposite pattern: the abrupt onset of isolated and sometimes extensive retrograde memory loss following seemingly minor head trauma? Explanations of this, and other amnesic states, are typically caste in terms of loss of stores vs. impaired retrieval but in the context of autobiographical memory such a model is overly simplistic. Autobiographical memories consist of different elements (people, places, sounds, fragments of conversation etc) which are distributed widely across different cortical regions. Autobiographical memories do not, therefore, really exist in the sense of a “store” localised to one part of the brain. Following this line of reasoning, it is possible to imagine a number of different patterns of pathology which could result in autobiographical memory loss. First, diffuse widespread cortical damage to separate regions from which the individual elements are drawn. Such damage would not, however, cause FRA but rather retrograde amnesia together with other typical cortical syndromes such as language disturbance, apraxia, visuo-spatial or perceptual deficits. Since autobiographical memories are highly visual then damage to areas of the brain responsible for visual imagery are perhaps most likely to cause this pattern. Indeed, Rubin and Greenberg (1998) have put forward just such an argument to explain the frequent co-occurrence of loss of visual imagery and FRA in the context of right posterior brain damage. The loss of older autobiographical memories in patients with semantic dementia, who have atrophy of the anterior temporal lobe(s), might also reflect the fact that autobiographical memory depends upon the integrity of semantic knowledge (Hodges and Graham, 2001). A second possible explanation is in terms of impaired connectivity of brain regions. If the reconstruction of autobiographical memories depends upon drawing together the appropriate elements from distributed cortical areas then pathology which disrupts long cortico-cortical tracts could lead to FRA. This is the hypothesis we proposed to explain the FRA in case JM who had a number of discrete cortical infarcts, as a result of cerebral vasculitis, which were insufficient to cause any of the classic neuropsychological deficits associated with cortical pathology but, we argued, were interrupting interconnectivity (Evans et al., 1996). Such pathology may also contribute to the extensive autobiographical memory impairment seen early in the course of Alzheimer’s disease. A third possibility is that there exist circumscribed brain regions which have a critical role in the retrieval and reconstruction of autobiographical memories. Such regions might initiate strategic searches, draw together individual elements from cortical areas, cross-check and verify against other plausible memories, and importantly imbue the reconstructed whole with the appropriate feeling of belonging to one’s own past (i.e., autonoetic awareness). Tulving and colleagues have argued, on the basis of extensive studies of patient ML who was left with FRA following severe traumatic brain injury, that the inferior right frontal lobe serves a key role in autonoetic awareness (see Levine et al., 1998; Tulving
676
John R. Hodges
2002). The evidence from other patients with FRA associated with structural brain pathology is far from clear. Many, but not all, have sustained damage to the right frontal or anterior temporal lobe (see Kopelman and Kapur, 2001). Imaging studies in normal subjects have, so far, clarified the situation, and are difficult to interpret due to differences in methodology. Maguire has hypothesised the existence of a widely distributed and left literalised network which includes the hippocampus, medial frontal region and temporal pole. Other PET based studies have found preferential activation of right temporal regions (see Maguire, 2001). A recent FMRI study using the names of personally relevant vs. irrilevant (unknown) people found very consistent activation of the left posterior cingulate (retrospenial) region which is very interesting given the very early involvement of this region in Alzheimer’s disease (Maddock et al., 2001). The question of whether there are brain regions specialised for the retrieval and reconstruction of autobiographical memories, and if so their localisation, remains, therefore, an open question. Returning then to the possible explanation for RGA after minor head injury, either of the latter two mechanisms – disrupted cortico-cortical interconnectivity or impairment of retrieval processes – is possible but is unlikely to be due to straightforward physical brain damage. Severe closed head trauma is associated with diffuse axonal damage and/or focal cortical contusion but in Sellal et al.’s case, as with many others, the head trauma was relatively slight. It is necessary, therefore, to consider less obvious mechanisms for cortical dysfunction, such as the release of excitotoxic neurotransmitters, temporary disruption of diffuse transmitter systems, or hormonal influences. It is, however, highly likely that emotional and other psychological factors are critical for the genesis of FRA. There could well be a “chain reaction” induced by the interaction between physical and emotional factors: mild head injury occurring at a particular time of emotional turmoil leading to mild perturbation of memory which in turn precipitates even greater stress causing further transmitter dysfunction and so on. To state that a patient with FRA has “no evidence of past or current psychiatric or psychological disorder” constitutes lamentably superficial analysis of the complexities of a human’s emotional and psychological life. One thing is in no doubt. FRA is a fascinating disorder worthy of further serious study. An approach combining modern neuropsychological and functional imaging methods together with more sophisticated psychological analysis could be very informative. Of particular interest would be a direct comparison of FRA in different contexts: in association with structural brain injury, following mild head injury and after severe psychological insult (e.g., “fugues” and “shell-shock”). REFERENCES EVANS JJ, BREEN EK, ANTOUN N and HODGES JR. Focal retrograde amnesia for autobiographical events following cerebral vasculitis: a connectionist account. Neurocase, 2: 1-11, 1996. HODGES JR. Unraveling the enigma of transient global amnesia. Annals of Neurology, 43: 151-153, 1998. HODGES JR and GRAHAM KS. Episodic memory: insights from semantic dementia. Philosophical Transactions of the Royal Society London B, 356: 1423-1434, 2001. KOPELMAN MD and KAPUR N. The loss of episodic memories in retrograde amnesia: single-case
Cortex Forum
677
and group studies. Philosophical Transactions of the Royal Society London B, 356: 1409-1421, 2001. LEVINE B, BLACK SE, CABEZA R, SINDEN M, MCINTOSH AR, TOTH JP, TULVING E and STUSS DT. Episodic memory and the self in a case of isolated retrograde amnesia. Brain, 121: 1951-1973, 1998. MADDOCK RJ, GARRETT AS and BUONOCORE MH. Remembering familiar people: the posterior cingulate and autobiographical memory retrieval. Neuroscience, 104: 667-676, 2001. MAGUIRE EA. Neuroimaging studies of autobiographical event memory. Philosophical Transactions of the Royal Society London B, 356: 1441-1451, 2001. RUBIN DC and GREENBERG DL. Visual memory deficit amnesia: a distinct amnesic presentation and etiology. Proceedings of the National Academy of Science USA, 95: 5413-5416, 1998. SELLAL F, MANNING L, SEEGMULLER C, SCHEIBER C and SCHOENFELDER F. Pure retrograde amnesia following a mild head trauma: A neuropsychological and metabolic study. Cortex, 38: 499-509, 2002. TULVING E. Episodic memory: from mind to brain. Annals Review of Psychology, 53: 1-25, 2002. Professor John Hodges. MRC Cognition and Brain Sciences Unit. 15 Chaucer Road. Cambridge CB2 2EF. e-mail: [email protected]
A symposium on the topic of focal retrograde amnesia (FRA) held at the annual European Cognitive Neuropsychology meeting in Bressanone some 8 years ago provoked a heated debate between the participants. One camp argued in favour of an organically based syndrome of retrograde amnesia in the absence of significant anterograde amnesia, while others argued with equal vigour that such cases could be explained by psychogenic factors. At that time relatively few cases had been reported in the literature and in many instances it was not possible to decide between these apparently different explanations. Since the debate, an increasing number of cases with FRA have been described (see Kopelman and Kapur, 2001). Sellal et al. (2002, this issue) add to this growing literature by reporting a new case with clearly impaired retrograde amnesia extending back at least 10 years but normal performance of standard tests of anterograde amnesia. The noteworthy features in this instance are: (i) the retrograde memory loss involved not only autobiographical memory but also knowledge of famous people, recent vocabulary and even the patient’s ability to write his usual adult signature; (ii) a SPECT scan demonstrated hypoperfusion of the right temporal lobe; (iii) the degree of head trauma was slight; and (iv) recovery of the “lost memories” occcurred after a period of three months. The debate is over: there is no longer any reasonable doubt that FRA is a definite syndrome with an organic basis, as proven by the finding of an abnormal SPECT scan in Sellal et al’s case. Or is it? Unfortunately things are not that simple and even if we do accept the existence of FGA, the most intriguing question remains unanswered: how can we explain this syndrome in the context of current models of long-term memory? The multitude of studies showing changes on functional (and more controversially) structural brain imaging in the classic psychiatric syndromes of schizophrenia, affective illness and even anxiety and obsessive-compulsive disorder surely undermines this naïve dichotomy. The classic “neurological” syndrome of transient global amnesia (TGA) also provides informative illustration of the fallacy of this, as most other, dichotomies. A number of SPECT, PET and diffusion weighted MRI studies have now convincingly demonstrated marked changes in the medial temporal lobes during TGA. The neuropsychological findings are also clearly compatible with severe, yet temporary, dysfunction of the hippocampal complex – profound anterograde episodic memory impairment with variable and temporally graded remote memory loss, but preservation of working and well-established semantic knowledge (see Hodges, 1998). Yet, there is also evidence that TGA can be Cortex, (2002) 38, 674-677
Cortex Forum
675
precipitated by an extreme emotional stress and/or physical exertion including occasionally sexual intercourse. An explanation for this paradox is that acute neurotransmitter changes may be induced by psychogenic factors, which in turn cause acute, but reversible, metabolically induced “shut down” of medial temporal lobe structures. However, this attractive hypothesis is still unproven. How are we to explain the opposite pattern: the abrupt onset of isolated and sometimes extensive retrograde memory loss following seemingly minor head trauma? Explanations of this, and other amnesic states, are typically caste in terms of loss of stores vs. impaired retrieval but in the context of autobiographical memory such a model is overly simplistic. Autobiographical memories consist of different elements (people, places, sounds, fragments of conversation etc) which are distributed widely across different cortical regions. Autobiographical memories do not, therefore, really exist in the sense of a “store” localised to one part of the brain. Following this line of reasoning, it is possible to imagine a number of different patterns of pathology which could result in autobiographical memory loss. First, diffuse widespread cortical damage to separate regions from which the individual elements are drawn. Such damage would not, however, cause FRA but rather retrograde amnesia together with other typical cortical syndromes such as language disturbance, apraxia, visuo-spatial or perceptual deficits. Since autobiographical memories are highly visual then damage to areas of the brain responsible for visual imagery are perhaps most likely to cause this pattern. Indeed, Rubin and Greenberg (1998) have put forward just such an argument to explain the frequent co-occurrence of loss of visual imagery and FRA in the context of right posterior brain damage. The loss of older autobiographical memories in patients with semantic dementia, who have atrophy of the anterior temporal lobe(s), might also reflect the fact that autobiographical memory depends upon the integrity of semantic knowledge (Hodges and Graham, 2001). A second possible explanation is in terms of impaired connectivity of brain regions. If the reconstruction of autobiographical memories depends upon drawing together the appropriate elements from distributed cortical areas then pathology which disrupts long cortico-cortical tracts could lead to FRA. This is the hypothesis we proposed to explain the FRA in case JM who had a number of discrete cortical infarcts, as a result of cerebral vasculitis, which were insufficient to cause any of the classic neuropsychological deficits associated with cortical pathology but, we argued, were interrupting interconnectivity (Evans et al., 1996). Such pathology may also contribute to the extensive autobiographical memory impairment seen early in the course of Alzheimer’s disease. A third possibility is that there exist circumscribed brain regions which have a critical role in the retrieval and reconstruction of autobiographical memories. Such regions might initiate strategic searches, draw together individual elements from cortical areas, cross-check and verify against other plausible memories, and importantly imbue the reconstructed whole with the appropriate feeling of belonging to one’s own past (i.e., autonoetic awareness). Tulving and colleagues have argued, on the basis of extensive studies of patient ML who was left with FRA following severe traumatic brain injury, that the inferior right frontal lobe serves a key role in autonoetic awareness (see Levine et al., 1998; Tulving
676
John R. Hodges
2002). The evidence from other patients with FRA associated with structural brain pathology is far from clear. Many, but not all, have sustained damage to the right frontal or anterior temporal lobe (see Kopelman and Kapur, 2001). Imaging studies in normal subjects have, so far, clarified the situation, and are difficult to interpret due to differences in methodology. Maguire has hypothesised the existence of a widely distributed and left literalised network which includes the hippocampus, medial frontal region and temporal pole. Other PET based studies have found preferential activation of right temporal regions (see Maguire, 2001). A recent FMRI study using the names of personally relevant vs. irrilevant (unknown) people found very consistent activation of the left posterior cingulate (retrospenial) region which is very interesting given the very early involvement of this region in Alzheimer’s disease (Maddock et al., 2001). The question of whether there are brain regions specialised for the retrieval and reconstruction of autobiographical memories, and if so their localisation, remains, therefore, an open question. Returning then to the possible explanation for RGA after minor head injury, either of the latter two mechanisms – disrupted cortico-cortical interconnectivity or impairment of retrieval processes – is possible but is unlikely to be due to straightforward physical brain damage. Severe closed head trauma is associated with diffuse axonal damage and/or focal cortical contusion but in Sellal et al.’s case, as with many others, the head trauma was relatively slight. It is necessary, therefore, to consider less obvious mechanisms for cortical dysfunction, such as the release of excitotoxic neurotransmitters, temporary disruption of diffuse transmitter systems, or hormonal influences. It is, however, highly likely that emotional and other psychological factors are critical for the genesis of FRA. There could well be a “chain reaction” induced by the interaction between physical and emotional factors: mild head injury occurring at a particular time of emotional turmoil leading to mild perturbation of memory which in turn precipitates even greater stress causing further transmitter dysfunction and so on. To state that a patient with FRA has “no evidence of past or current psychiatric or psychological disorder” constitutes lamentably superficial analysis of the complexities of a human’s emotional and psychological life. One thing is in no doubt. FRA is a fascinating disorder worthy of further serious study. An approach combining modern neuropsychological and functional imaging methods together with more sophisticated psychological analysis could be very informative. Of particular interest would be a direct comparison of FRA in different contexts: in association with structural brain injury, following mild head injury and after severe psychological insult (e.g., “fugues” and “shell-shock”). REFERENCES EVANS JJ, BREEN EK, ANTOUN N and HODGES JR. Focal retrograde amnesia for autobiographical events following cerebral vasculitis: a connectionist account. Neurocase, 2: 1-11, 1996. HODGES JR. Unraveling the enigma of transient global amnesia. Annals of Neurology, 43: 151-153, 1998. HODGES JR and GRAHAM KS. Episodic memory: insights from semantic dementia. Philosophical Transactions of the Royal Society London B, 356: 1423-1434, 2001. KOPELMAN MD and KAPUR N. The loss of episodic memories in retrograde amnesia: single-case
Cortex Forum
677
and group studies. Philosophical Transactions of the Royal Society London B, 356: 1409-1421, 2001. LEVINE B, BLACK SE, CABEZA R, SINDEN M, MCINTOSH AR, TOTH JP, TULVING E and STUSS DT. Episodic memory and the self in a case of isolated retrograde amnesia. Brain, 121: 1951-1973, 1998. MADDOCK RJ, GARRETT AS and BUONOCORE MH. Remembering familiar people: the posterior cingulate and autobiographical memory retrieval. Neuroscience, 104: 667-676, 2001. MAGUIRE EA. Neuroimaging studies of autobiographical event memory. Philosophical Transactions of the Royal Society London B, 356: 1441-1451, 2001. RUBIN DC and GREENBERG DL. Visual memory deficit amnesia: a distinct amnesic presentation and etiology. Proceedings of the National Academy of Science USA, 95: 5413-5416, 1998. SELLAL F, MANNING L, SEEGMULLER C, SCHEIBER C and SCHOENFELDER F. Pure retrograde amnesia following a mild head trauma: A neuropsychological and metabolic study. Cortex, 38: 499-509, 2002. TULVING E. Episodic memory: from mind to brain. Annals Review of Psychology, 53: 1-25, 2002. Professor John Hodges. MRC Cognition and Brain Sciences Unit. 15 Chaucer Road. Cambridge CB2 2EF. e-mail: [email protected]