- Transient amnesias
- Transient global amnesia
- Transient epileptic amnesia
- Head injury
- Alcoholic blackouts
- After electroconvulsive therapy
- Post-traumatic stress disorder
- Psychogenic fugue
- Amnesia for offences
- Persistent memory disorder
- The Korsakoff syndrome
- Herpes encephalitis
- Severe hypoxia
- Vascular disorders
- Head injury
- Other causes of an amnesic syndrome
- Neuropsychological aspects
- Confabulation disorders
- Neurochemistry and neuropharmacology of memory disorders
- Further reading
Amnesic disorders can be broadly classified across two orthogonal dimensions. Along the first dimension, there can be transient or discrete episodes of amnesia as opposed to persistent memory impairment. On the second dimension, memory loss can result from either neurological damage or psychological causation, although admixtures of these factors are, of course, very common. The notion of confabulation has traditionally been associated with amnesic syndromes, particularly the Korsakoff syndrome, although it may have a separate basis, and false memories are now known to arise in a number of different situations. With the advent of drugs purporting to influence memory, there is increasing interest in the psychopharmacology of memory disorders. In this article, these topics will be considered in turn.
Transient global amnesia
Transient global amnesia most commonly occurs in the middle-aged or elderly, more frequently in men, and it results in a period of amnesia lasting several hours. It is characterized by repetitive questioning, and there may be some confusion, but patients do not report any loss of personal identity (they know who they are). It is sometimes preceded by headache or nausea, a stressful life event, a medical procedure, or vigorous exercise. Hodges and Ward (1) found that the mean duration of amnesia was 4 h and the maximum was 12 h. In 25 per cent of their sample, there was a past history of migraine, which was considered to have a possible aetiological role. In a further 7 per cent of the sample, the patients subsequently developed unequivocal features of epilepsy (there had been no focal signs or features of epilepsy during the original attack) and the memory loss was therefore attributed, in retrospect, to previously undiagnosed epilepsy. There was no association with either a past history of vascular disease, clinical signs suggestive of vascular pathology, or known risk factors for vascular disease. In particular, there was no association with transient ischaemic attacks. In 60 to 70 per cent of the sample, the underlying aetiology was unclear.
In instances where neuropsychological tests have been administered to patients during their acute episode of transient memory loss, (1,2) the patients showed a profound anterograde amnesia, as expected, on tests of both verbal and non-verbal memory. However, performance on tests of retrograde memory was variable. Follow-up studies showed either complete or almost complete recovery of memories, several weeks to months after the acute attack.
The general consensus is that the amnesic disorder results from transient dysfunction in limbic–hippocampal circuits, crucial to memory formation. For example, Stillhard et al.(3) reported severe bitemporal hypoperfusion during an episode of transient global amnesia using single-photon emission CT (SPECT). Positron emission tomography (PET) in patients with transient global amnesia gives findings consistent with the SPECT results.
Transient epileptic amnesia
This refers to the minority of patients with transient global amnesia in whom epilepsy appears to be the underlying cause of the syndrome. (1) Where epilepsy has not previously been diagnosed, the main predictive factors for an epileptic aetiology are brief episodes of memory loss (an hour or less) with multiple attacks. (1) It is important to note that standard electroencephalography (EEG) and CT findings are often normal. However, an epileptic basis to the disorder may be revealed on sleep EEG recordings.(4)
Patients with transient epileptic amnesia may show residual deficits in between their attacks, associated with their underlying neuropathology. Kopelman et al.(4) found a moderate degree of residual anterograde memory impairment in their patient. Multiple small regions of signal alteration were subsequently found in the medial temporal lobes in this patient, as well as medial temporal hypometabolism on a fluorodeoxyglucose ( FDG) PET scan. Kapur et al.(5) described a single case, in whom they found a residual interictal retrograde amnesia, in the presence of only minor anterograde memory impairment. They interpreted this as a case of ‘isolated retrograde amnesia'. Epilepsy may, of course, give rise to automatisms or postictal confusional states. Where there is an automatism, there is always bilateral involvement of the limbic structures involved in memory formation, including the hippocampal and parahippocampal structures bilaterally as well as the mesial diencephalon. Consequently, amnesia for the period of automatic behaviour is always present and is usually complete.
In head injury, it is important to distinguish between a brief period of retrograde amnesia, which may last only a few seconds or minutes, a longer period of post-traumatic amnesia, and islands of preserved memory within the amnesic gap. (6,7) Occasionally post-traumatic amnesia may exist without any retrograde amnesia, although this is more common in cases of penetrating lesions. Sometimes there is a particularly vivid memory for images or sounds occurring immediately before the injury, on regaining consciousness, or during a lucid interval between the injury and the onset of post-traumatic amnesia.
Post-traumatic amnesia is generally assumed to reflect the degree of underlying diffuse brain pathology, in particular rotational forces giving rise to axonal tearing and generalized cognitive impairment. The length of post-traumatic amnesia is predictive of eventual cognitive outcome, (8) psychiatric outcome, (7) and social outcome. (8) However, the duration of post-traumatic amnesia is often not well documented in medical records, and these relationships are often weaker than is generally assumed. In addition, contusion to the frontal and anterior temporal lobes is a common consequence of head injury. Various authors have described a disproportionate degree of retrograde memory loss associated with damage to these structures, although an interaction of psychological and neurological factors cannot be excluded in such cases.
Post-traumatic amnesia needs to be distinguished from the persisting anterograde memory impairment, which may be detected on clinical assessment or cognitive testing long after the period of post-traumatic amnesia has ended. Moreover, forgetfulness is a common complaint within the context of a post-traumatic syndrome, which may include anxiety, irritability, poor concentration, and various somatic complaints. Commonly, these complaints persist long after the settlement of any compensation issues. (9)
Alcoholic blackouts are discrete episodes of memory loss for significant events, which should not be confused with withdrawal seizures or other ictal phenomena. Alcoholic blackouts are associated with severe intoxication, usually in the context of a history of prolonged alcohol abuse. Goodwin et al. (10) described two types of blackout—the fragmentary and the en bloc. However, alcohol-induced state-dependent experiences can be viewed as related phenomena, and it has been suggested that the three represent gradations of alcohol-induced memory impairment. In state-dependent effects, subjects when sober cannot remember events or facts from an episode of intoxication, which they recall easily when they again become intoxicated. In fragmentary blackouts, the subjects are aware of their memory loss on being told later of an event, there are islands of preserved memory, and the amnesia tends to recover partially through time by shrinkage of the amnesic gap. In en bloc blackouts there is an abrupt beginning and end to the period of memory loss, and the lost memories are very seldom recovered. Blackouts may be more common in binge drinkers, because they are related to a high blood alcohol level. Hypoglycaemia may also be a contributory factor, at least in some cases.
After electroconvulsive therapy
This is an iatrogenic form of transient amnesia. Benzodiazepines (11) and anticholinergic agents (12) can also give rise to transient memory loss in more moderate form.
Subjects tested within a few hours of electroconvulsive therapy ( ECT) show a retrograde impairment for information from the preceding 1 to 3 years, a pronounced anterograde memory impairment on both recall and recognition memory tasks, and an accelerated rate of forgetting. (13) When retested approximately 6 to 9 months after completion of a course of ECT, memory returns to normal on objective tests. However, complaints of memory impairment can persist, and they may be evident three or more years after a course of ECT has been completed. (14) It seems that patients with persistent complaints of memory loss tend to be those who have recovered least well from their depression, (13,14) although their complaints tend to focus upon the period for which there was an initial retrograde and anterograde amnesia.
Verbal memory appears to be particularly sensitive to disruption. Unilateral electroconvulsive therapy to the non-dominant hemisphere produces considerably less memory impairment than bilateral ECT, although it is important to identify the non-dominant hemisphere by a valid procedure. Recent studies have attempted to minimize memory disruption by either making changes in premedication or the concomitant administration of other substances, for example glycopyrrolate, physostigmine, thyroxine, dexamethasone, acetylcholine, or other substances. In general, these agents have produced little or no benefit. The most effective methods of avoiding memory deficit consist of either electrode placement over the frontal rather than the temporal lobes or ECT to the non-dominant temporal lobe. In the view of this author, any marginal therapeutic benefits of bilateral ECT are outweighed by the minimization of adverse effects using the non-dominant unilateral technique.
Post-traumatic stress disorder
As is well known, it is characterized by intrusive thoughts and memories about the traumatic experience. However, there may be instances of brief memory loss, distortions, or even frank confabulations. For example, a victim of the Herald of Free Enterprise disaster at Zeebruge described trying to rescue a close friend still on board the ship, when other witnesses reported that the close friend had, in fact, not been seen by the victim from the moment the ship turned over. These cases are, of course, confounded by other factors, such as head injury or hypothermia. Nevertheless, it is of interest that post-traumatic stress disorder symptoms can occur, even when a subject is completely amnesic for an episode. (15) Post-traumatic stress disorder victims can show deficits in anterograde memory on formal tasks many years after the original trauma, and there is also evidence that they may show loss of hippocampal volume on magnetic resonance imaging (MRI) brain scan. The latter has been attributed to effects upon glucocorticoid metabolism, although these findings have to be interpreted with caution in view of the rather crude measurements employed and the wide variability in MRI hippocampal volume estimates even in healthy subjects.
A fugue state is a syndrome consisting of a sudden loss of all autobiographical memories and knowledge of personal identity, usually associated with a period of wandering, for which there is a subsequent amnesic gap on recovery. Characteristically, fugue states last a few hours or days, although there are descriptions of complaints of autobiographical memory loss lasting much longer. Whenever such complaints persist, the suspicion of simulation must arise. Fugue states differ from transient global amnesia or transient epileptic amnesia in that the subject does not know who he or she is, and repetitive questioning is not a characteristic feature in fugues.
As discussed elsewhere, (16) fugue states are always preceded by a severe precipitating stress. Second, depressed mood is also an extremely common antecedent for a psychogenic fugue state, and may be associated with manifest suicidal ideas just before or following recovery from the fugue. Third, various authors have noted that there is often a past history of a previous transient neurological amnesia, such as epilepsy or head injury. In brief, it appears the patients who have experienced a previous transient organic amnesia, and who become depressed and/or suicidal, are particularly likely to go into a fugue in the face of a severe, precipitating stress. That stress may consist of marital or emotional discord, bereavement, financial problems, a criminal charge, or stress during wartime. Fugues have been described as a ‘flight from suicide'.
Amnesia for offences
This is a phenomenon commonly brought to the attention of psychiatrists, particularly forensic psychiatrists, although the empirical literature on this disorder is scanty. Amnesia is claimed by 25 to 45 per cent of offenders in cases of homicide, approximately 8 per cent of perpetrators of other violent crimes, and a small percentage of non-violent offenders.(16,17) It is necessary to exclude underlying neurological or organic factors such as an epileptic automatism, postictal confusional state, head injury, hypoglycaemia, or sleep walking. Underlying organic pathology can be grounds for a so-called ‘insane' automatism in English law (if the result of an internal brain disease) or a ‘sane' automatism (if the consequence of an external agent), but otherwise amnesia per se does not constitute grounds for alleviation of responsibility for an offence.
Amnesia for an offence is most commonly associated with the following.
- States of extreme emotional arousal, in which the offence is unpremeditated, and the victim usually a lover, wife, or family member. This is most commonly seen in homicide cases (‘crimes of passion').
- Alcohol intoxication (sometimes in association with other substances), usually involving very high peak levels as well as a long history of alcohol abuse. The victim is not necessarily related to the offender, and the offence may vary from criminal damage, through assault, to homicide.
- Florid psychotic states or depressed mood. Occasionally offenders describe a delusional account of what has happened, quite at odds with what was seen by other observers, and sometimes resulting in confessions to crimes that the person could not actually have committed (a paramnesia or delusional memory). In many other cases, depressed mood is associated with amnesia for an offence, just as it is a common associate of psychogenic fugue.
It should be noted that many of the factors associated with poor recall in offenders (high emotional arousal, alcohol intoxication, violent crime) are similar to those which have been implicated in poor recall by the victims or eye-witnesses of offences. It should certainly not be assumed that offenders claiming amnesia are malingering.
Persistent memory disorder
The amnesic syndrome can be defined as follows:
An abnormal mental state in which memory and learning are affected out of all proportion to other cognitive functions in an otherwise alert and responsive patient. (18)
The Korsakoff syndrome can be defined in the same way but with the addition of the following phrase:
...resulting from nutritional depletion, notably thiamine deficiency.
In fact, Victor et al. (18) used the first description as a definition of the Korsakoff syndrome, but the present author feels that it is important to distinguish between amnesic syndromes in general (for which the Victor et al. definition suffices) and the particular clinical condition described by Korsakoff, (19) whose cases can all be viewed (with hindsight) as having suffered nutritional depletion, whether of alcoholic or non-alcoholic causation. Various disorders can give rise to an amnesic syndrome.
The Korsakoff syndrome
As mentioned, this is the result of nutritional depletion, namely a thiamine deficiency. Korsakoff (19) described this condition as resulting from alcohol abuse or from a number of other causes, but by far the most common nowadays is alcohol abuse.
There are frequent misunderstandings about the nature of this disorder. ‘Short-term memory', in the sense that psychologists employ it, is intact but learning over more prolonged periods is severely impaired, and there is usually a retrograde memory loss which characteristically extends back many years or decades. (20) Korsakoff himself noted that his patients ‘reason about everything perfectly well, draw correct deductions from given premises, make witty remarks, play chess or a game of cards, in a word comport themselves as mentally sound persons'. (19) However, he also noted repetitive questioning, the extensive nature of the retrograde memory loss, and a particular problem in remembering the temporal sequence of events, associated with severe disorientation in time. As will be discussed below, he gave examples of confabulation reflecting the problem with the temporal sequence memory, such that real memories were jumbled up and retrieved inappropriately, out of temporal context.
Many cases of the Korsakoff syndrome are diagnosed following an acute Wernicke encephalopathy, involving confusion, ataxia, nystagmus, and opthalmoplegia. Not all these features are always present, and the opthalmoplegia responds rapidly to treatment with high-dose vitamins. These features are often associated with a peripheral neuropathy. However, the disorder can also have an insidious onset, and such cases are more likely to come to the attention of psychiatrists; in these cases, there may be either no known history of or only a transient history of Wernicke features. There are also reports that the characteristic Wernicke–Korsakoff neuropathology (see below) is found much more commonly at autopsy in alcoholics than the diagnosis is made in life, implying that many cases are being missed.
The characteristic neuropathology in what is often known as the Wernicke–Korsakoff syndrome consists of neuronal loss, microhaemorrhages, and gliosis in the paraventricular and periaqueductal grey matter. (18) However, there has been debate as to which particular lesions are critical for the manifestation of chronic memory disorder. Victor et al. (18) pointed out that all 24 of their cases in whom the medial dorsal nucleus of the thalamus was affected had a clinical history of persistent memory impairment (Korsakoff syndrome), whereas five cases in whom this nucleus was unaffected had a history of Wernicke features without any recorded clinical history of subsequent memory disorder.
By contrast, the mammillary bodies were implicated in all the Wernicke cases, whether or not there was subsequent memory impairment. However, Mair et al.(21) provided a careful pathological and neuropsychological description of two patients with the Korsakoff syndrome, whose autopsies showed lesions in the mammillary bodies and the midline and anterior portion of the thalamus, but not in the medial dorsal nuclei. Mair et al. suggested that the lesions they described might ‘disconnect' a critical circuit running between the temporal lobes and the frontal cortex, and put forward a hypothesis concerning the functional significance of this circuit. Mayes et al. (22) obtained very similar findings in two further patients with the Korsakoff syndrome, who had also been very carefully described both neuropsychologically and at autopsy. Taken together, these findings suggest that the mammillary bodies, the mammillothalamic tract, and the anterior thalamus may be more important to memory dysfunction than the medial dorsal nucleus of the thalamus, but the issue remains controversial.
There is also evidence of general cortical atrophy particularly involving the frontal lobes in patients with the Korsakoff syndrome, and this is associated with neuropsychological evidence of ‘frontal' or ‘executive' test dysfunction in these patients. (23)
There have been a number of neuroimaging studies of the Korsakoff syndrome. CT scan studies indicated a general degree of cortical atrophy, particularly involving the frontal lobes. (24) MRI studies have indicated more specific atrophy in diencephalic structures. The findings in SPECT and PET studies have been more variable, some showing widespread hypoperfusion and hypometabolism, other studies showing very little change relative to healthy controls, but (usually) some degree of frontal hypometabolism.
Victor et al.(18) reported that 25 per cent of patients with the Korsakoff syndrome ‘recover', 50 per cent show improvement through time, and 25 per cent remain unchanged. Whilst it is unlikely that any established patient shows complete recovery, the present author's experience is that substantial improvement does occur over a matter of years; if restated, it is probably correct to say that 75 per cent of these patients show a variable degree of improvement, whilst 25 per cent show no change.
This can give rise to a particularly severe form of amnesic syndrome. (25) The majority of cases are said to be primary infections, although there may be a history of a preceding ‘cold sore' on the lip. Characteristically, there is a fairly abrupt onset of acute fever, headache, and nausea. There may be behavioural changes. Seizures can occur. The fully developed clinical picture with neck rigidity, vomiting, and motor and sensory deficits seldom occurs during the first week. (26) Diagnosis is by finding a raised titre of antibodies to the virus in the cerebrospinal fluid, but often this is missed and a presumptive diagnosis is made on the basis of the clinical picture as well as severe signal alteration, haemorrhaging, and atrophy in the temporal lobes on MRI brain imaging.
Neuropathological and neuroimaging studies show that there is extensive bilateral temporal lobe damage, (27) although, occasionally, the changes are surprisingly unilateral. There are often frontal changes, most commonly in the orbitofrontal regions, and there is a variable degree of general cortical atrophy. The medial temporal lobe structures are particularly severely affected, including the hippocampi, amygdalae, entorhinal and perirhinal cortices, and other parahippocampal structures. Evidence from studies of bilateral temporal lobectomy as well as animal lesion studies has indicated that these structures are particularly critical in memory formation.
The chronic memory disorder in herpes encephalitis is often very severe, (25) but it shows many resemblances to that seen in the Korsakoff syndrome, consistent with the fact that there are many neural connections between the thalami, mammillary bodies, and the hippocampi. (28) Encephalitis, like head injury, can also implicate basal forebrain structures which give cholinergic outputs to the hippocampi; since these are thought to modulate hippocampal function, this may further exacerbate the damage. Contrary to what was postulated in the 1980s, there appears to be no difference between patients with the Korsakoff syndrome and those with herpes encephalitis in terms of rates of forgetting or in the relative effect upon recall versus recognition memory. The patients with herpes appear to have better ‘insight' into the nature of their disorder and a ‘flatter' temporal gradient to their retrograde memory loss (i.e. less sparing of early memories), and they may have a particularly severe deficit in spatial memory when the right hippocampus is involved. (20) However, the similarities in the episodic memory disorder tend to outweigh the differences.
On the other hand, a more extensive involvement of semantic memory is characteristic in herpes encephalitis, and this results from the widespread involvement of the lateral, inferior, and posterior regions of the temporal lobes. Semantic memory refers to a knowledge of facts, concepts, and language. Left temporal lobe pathology in herpes encephalitis commonly gives rise to an impairment in naming, reading (a so-called ‘surface dyslexia'), and other aspects of lexicosemantic memory. Right temporal lobe damage may lead to a particularly severe impairment in face recognition memory or knowledge of people.
Severe hypoxia can give rise to an amnesic syndrome following carbon monoxide poisoning, cardiac and respiratory arrests, or suicide attempts by hanging or poisoning with the exhaust gases from a car. Drug overdoses may precipitate prolonged unconsciousness and cerebral hypoxia, and this quite commonly occurs in heroin abusers. Zola-Morgan et al. (29) described a patient with repeated episodes of hypoxia and/or cardiovascular problems who developed a moderately severe anterograde amnesia. At autopsy 6 years later, this patient was shown to have a severe loss of pyramidal cells in the CA1 region of the hippocampi bilaterally, with the rest of the brain appearing relatively normal. Hippocampal atrophy on MRI has been reported in amnesic patients in whom hypoxia may have been the cause. The author's research group has also produced evidence of medial temporal lobe atrophy in hypoxic patients, but this same group has also found thalamic hypometabolism in hypoxic patients on FDG-PET scanning, and this finding is consistent with other reports. In brief, the memory disorder is likely to result from a combination of hippocampal and thalamic changes, related to the many common neural pathways between these two structures. (28)
There have been claims that selective damage to these circuits produces an impairment in recall memory, but not in recognition memory. (28) However, there are many commonalities in the pattern of episodic memory impairment between patients who have experienced severe hypoxic episodes and those whose amnesic disorder results from the more extensive temporal lobe damage found in herpes encephalitis.
Two types of vascular disorder can particularly affect memory, as opposed to general cognitive functioning, namely thalamic infarction and subarachnoid haemorrhage.
In an elegant CT scan study, von Cramon et al. (30) showed that damage to the anterior thalamus was critical in producing an amnesic syndrome. When the pathology was confined to the more posterior regions of the thalamus, memory function was relatively unaffected. The anterior region of the thalamus is variably supplied by the polar or paramedian arteries in different individuals: both of which are, ultimately, branches of the posterior cerebral artery, that also supplies the posterior region of the hippocampi. When there is a relatively pure lesion of the anterior thalamus, anterograde amnesia without an extensive retrograde memory loss commonly results. However, cases in whom there is also retrograde memory loss, or even a generalized dementia, have been described following thalamic infarction, and this presumably relates to the extent to which thalamic projections are also implicated in the infarction.
Subarachnoid haemorrhage following rupture of a beri aneurysm can result in memory impairment, whether the anterior cerebral or posterior cerebral circulation from the Circle of Willis is involved. Most commonly described in the neuropsychological literature have been ruptured aneurysms from the anterior communicating arteries, because these affect ventromedial frontal structures and the basal forebrain. Gade (31) has argued that it is whether or not the septal nuclei of the basal forebrain are implicated in the ischaemia which determines whether a persistent amnesic syndrome occurs in such patients. Others have attributed the florid confabulation, which these patients often exhibit, to concomitant ventromedial damage. (32)
As discussed above, severe head injury can produce a persistent amnesia which may or may not be associated with generalized cognitive impairment. There may be direct trauma to the frontal and anterior temporal lobes, resulting in contusion and haemorrhaging, contrecoup damage, intracranial haemorrhage, and axonal tearing and gliosis following rotational forces. Memory function is commonly the last cognitive function to improve following an acute trauma, and patients can show the characteristic features of an amnesic syndrome. The phenomenon of ‘isolated retrograde amnesia' has been described in other cases of head injury. In many of the latter cases, there appears to have been a differential rate in recovery between an initially severe anterograde memory loss and the retrograde component; in other cases, it is not at all clear that the neurologists and neuropsychologists describing the patients have taken sufficient account of an interaction between psychological and neurological factors.
Traumatic head injury is considered in more detail in this article: The neuropyschiatry of head injury.
Other causes of an amnesic syndrome
Deep midline cerebral tumours can give rise to an amnesic syndrome, (7) and this may be exacerbated by surgical or irradiation treatment for pituitary tumours. Other infections, such as tuberculous meningitis or HIV, may, on occasion, give rise to an amnesic syndrome. In the very early stages, Alzheimer dementia may manifest itself as a focal amnesic syndrome. (33) Surgical treatment to the temporal lobes for epilepsy can result in profound amnesia, if there is bilateral involvement. There is increasing evidence that focal lesions in the frontal lobes can also produce severe memory impairment on aspects of anterograde and retrograde memory. (20) This can occur even in the absence of basal forebrain involvement, but it probably results from particular aspects of memory being implicated, including planning and organization, source and context monitoring, and particular aspects of retrieval processes. (34)
The terms ‘short-term' and ‘long-term' memory should be abolished from psychiatric discourse, as they cause confusion across disciplines. It is more useful to consider current or recent memory versus remote or autobiographical memory. In addition, ‘prospective memory' refers to remembering to do something.
Concepts of memory are considered here: Memory and memory disorders
As described in that chapter, a distinction is generally drawn between so-called ‘working memory', which holds information for brief periods (a matter of several seconds) and allocates resources, and secondary memory, which holds different types of information on a permanent or semipermanent basis. Secondary memory, in turn, can be subdivided into an episodic (or ‘explicit') component, semantic memory, and implicit memory. Episodic memory refers to incidents or events from a person's past, and is characteristically severely affected in the amnesic syndrome. As mentioned previously, semantic memory refers to a knowledge of facts, concepts, and language. The learning of new semantic memories may be affected in the amnesic syndrome. Other aspects of semantic memory (naming, reading, well-established general knowledge, mental calculation, comprehension) are affected in disorders where there is concomitant widespread temporal lobe or generalized cortical pathology, such as herpes encephalitis, Alzheimer dementia, and semantic dementia (a form of frontotemporal dementia). Implicit memory refers to procedural perceptuomotor skills, and to the facilitation of responses in the absence of explicit memory, known as ‘priming'. Both these aspects are characteristically spared in the amnesic syndrome, (35) although the precise extent of sparing does depend on particular features in the experimental design. (36)
Over the years, there has been extensive debate concerning whether the primary deficit in the amnesic syndrome lies in the initial encoding of information, or some kind of physiological ‘consolidation' into secondary memory, or accelerated forgetting of that information, or in retrieval processes. (37) There is still very little agreement about this debate, but, if anything, the consensus is that retrieval problems are secondary to initial encoding and consolidation impairments, (37) at least in anterograde amnesia. Retrieval deficits may be more important where there is an extensive retrograde memory loss, (20) which might account for why there is a poor correlation between scores on anterograde memory measures and retrograde memory measures.
More recently, there has been an emphasis on the specific functions of the hippocampi, prompted by the need in neuroimaging studies to differentiate their role from that of the frontal lobes. One possibility is that the hippocampi particularly contribute to the binding of complex associations; (38) another is that they are involved in the binding together of the distributed features of an episode as a coherent trace, whilst ensuring that there is sufficient pattern separation of similar episodes. (39) The hippocampi may be especially involved in novel or incremental learning, (40) and they may also contribute to retrieval processes. (41) PET and MRI activation studies have emphasized the role of the frontal lobes in learning processes. (42) The frontal lobes are generally thought to contribute to planning and organization in memory, aspects of context and source memory, awareness of memory performance (metamemory), and to particular aspects of retrieval processes. (34)
There are also many controversies concerning the nature of the extensive retrograde memory loss found in many of the above disorders. Modern neuropsychological studies have confirmed that this retrograde memory loss can extend back many years or decades, but that it characteristically shows a ‘temporal gradient' with relative sparing of early memories. The gradient is characteristically steeper in the amnesic syndrome than in dementing disorders such as Alzheimer dementia or Huntington's disease. The relative sparing of early memories may result from their greater salience and rehearsal, such that they have become assimilated within semantic memory. However, differing patterns of retrograde memory loss can certainly occur. Left temporal lobe damage seems to characteristically affect memory for facts and for the more linguistic components of remote memory, (20) whereas right temporal lobe damage more commonly affects memory for the incidents in a person's life. (20)
Confabulation can be subdivided into ‘spontaneous' confabulation, in which there is a persistent, unprovoked outpouring of erroneous memories, and ‘momentary' or ‘provoked' confabulation, in which fleeting intrusion errors or distortions are seen in response to a challenge to memory, such as a memory test. (43)
Confabulation is widely believed to be particularly associated with the Korsakoff syndrome, but this is incorrect. Confabulation arises in confusional states and in frontal lobe disease. (44) The link with frontal lobe pathology has been established in many investigations. (32,45) Spontaneous confabulation is often seen in the confusional state of a Wernicke encephalopathy, but it is rare in the more chronic phases of the Korsakoff syndrome. (18,43) On the other hand, fleeting intrusion errors or distortions (‘momentary confabulation') do occur in the chronic phase of a Korsakoff syndrome, when memory is challenged. However, such intrusion errors are also seen in healthy subjects when memory is ‘weak' for any reason, such as a prolonged delay until recall. (43) They are also seen in Alzheimer dementia and other clinical amnesic syndromes, and they are certainly not specific to the Korsakoff syndrome.
There has been considerable interest of late in the nature of spontaneous confabulations. Moscovitch and Melo (32) argued that it is a product of the following:
- faulty cue-retrieval, meaning that cues can be ambiguous, resulting in retrieval errors in normal subjects but more particularly in subjects whose memory is impaired;
- impaired strategic search, producing misleading cues and thereby inappropriate memories;
- defective monitoring, meaning that the resulting errors are not edited out.
Similar hypotheses have been put forward by Burgess and Shallice (46) and by Schacter et al.(39) A second approach to this topic emphasizes problems in the temporal ordering of memories. This is a very old theory, put forward by Korsakoff himself, as well as many other authorities (see, for example, Victor et al.(18)). In a particularly elegant study, Schnider et al. (47) found that a group of ‘spontaneous confabulators' could be differentiated from other amnesic patients and controls on the basis of their errors on a temporal context memory task, but not on other memory or executive tests.
There have been two recent studies that provide some support for this viewpoint, but they also make it clear that temporal and other context memory deficits cannot account for all instances of spontaneous confabulation. In an analysis of a severely confabulating patient's errors, (48) it was evident that many confabulations (particularly in episodic memory) may plausibly have resulted from the conflation and inappropriate retrieval of ‘real' memory fragments out of temporal sequence, but that others resulted from perseverations (particularly in semantic memory) or from the patient giving instantaneous, ill-considered, and unchecked responses to immediate environmental and social cues. Likewise, Johnson et al. (49) found that several measures of context memory failed to discriminate between a severely confabulating patient and three other patients with frontal lobe lesions. Johnson et al. concluded that confabulation may reflect an interaction between a vivid imagination, an inability to retrieve autobiographical memories systematically, and source or context monitoring deficits.
The notion of ‘confabulation' or ‘false memory' has now been extended to a variety of other disorders, including delusional memory, confabulation in schizophrenia, false confessions, apparently false memories for child sexual abuse, pseudologia fantastica, and dissociative identity disorder. Whilst each of these can potentially be accounted for in terms of a general model of memory and executive function, provided that the social context and some notion of ‘self' is incorporated, there are likely to be differing mechanisms which give rise to these different types of false memory. (50)
Neurochemistry and neuropharmacology of memory disorders
The Korsakoff syndrome is relatively unusual among memory disorders in that there is a distinct neurochemical pathology with important implications for treatment. Since animal studies in the 1930s and 1940s, and the important observations of De Wardener and Lennox (51) and others in malnourished prisoners of war, it has been known that thiamine depletion is the mechanism which gives rise to the acute Wernicke episode, followed by a Korsakoff memory impairment. However, the genetic factor that predisposes some heavy drinkers to develop this syndrome before they develop hepatic or gastrointestinal complications of alcohol abuse remains unclear. In many other alcoholics, the problems are the other way around. There has been much speculation about a transketolase gene, as transketolase is the enzyme which requires thiamine pyrophosphate (TPP) as a cofactor. The transketolase gene was identified in 1993, but no particular allelic variation was found that could account for the biochemical properties of the enzyme. Furthermore, it is not clear how thiamine depletion produces the particular neuropathology found in Wernicke–Korsakoff patients. Thiamine depletion affects six neurotransmitter systems, either by reduction of TPP-dependent enzyme activity or by direct structural damage. Of these neurotransmitters, four (acetylcholine, glutamate, aspartate, and GABA) are directly related to glucose metabolism. Whatever the precise mechanism, treatment as soon as possible with high doses of parenterally administered multivitamins is essential in patients with the Wernicke–Korsakoff syndrome. The Wernicke features respond well to high doses of vitamins, and such treatment almost certainly prevents the occurrence of a chronic Korsakoff state. (7,18) The small risk of anaphylaxis is completely outweighed by the high risk of severe brain damage and the appreciable risk of litigation (not an exaggeration) if such treatment is not administered.
There has been an extensive literature on the effects of cholinergic antagonists (such as scopolamine) upon memory. Kopelman and Corn (12) found a pattern of impairment in anterograde memory that closely resembled that seen in the amnesic syndrome. It has been argued that cholinergic blockade produces an effect upon the ‘central executive' component of working memory, but Rusted (52) has concluded that this is not sufficient to account for the drug effect upon memory processes. Although some have argued that the predominant effect of scopolamine is on attention, Curran et al. (53) found that covarying for the sedation or psychomotor effects of the drug did not eliminate the strong drug effects on episodic memory tests, and a similar finding was obtained by Kopelman and Corn. (12) The anticholinesterases physostigmine, tacrine, and donepezil have, of course, been developed and licensed for their effects in Alzheimer dementia, but, in the absence of unequivocal evidence of cholinergic depletion in amnesic syndromes, they have seldom been employed in these disorders.
Despite their very differing pharmacological action, the effects of the benzodiazepines upon memory and attention are remarkably similar to those of scopolamine. When recall or recognition is tested after a delay, benzodiazepines produce a marked anterograde impairment in explicit or episodic memory, similar to scopolamine. (53) As with scopolamine, however, once learning has been accomplished, the rate of forgetting is normal, and benzodiazepines do not produce any retrograde deficits. Procedural learning tasks for both benzodiazepines and scopolamine show similar effects, with learning curves on the active drug generally paralleling those for placebo. (12,54) Benzodiazepine effects can be attenuated by coadministration of the benzodiazepine antagonist, flumazenil.
The effects of catecholamines upon memory have been studied for many years, but the general consensus is that they act upon ‘tonic attentional processes' rather than directly upon the storage or retrieval of memories. In an elegant study, Cahill et al. (55) examined the effects of the b-adrenergic receptor antagonist propranolol on memory for an emotionally arousing story, compared with a carefully matched neutral story. As expected, subjects given a placebo recalled more of the emotional than the neutral story, when tested 1 week later. Subjects given propanolol recalled the neutral story as well as the placebo subjects, but were impaired on the emotional story. Cahill et al. (55) concluded that the enhanced memory for emotional experience is mediated by the b-adrenergic system. However, it is possible that the enhanced memory was mediated by arousal, and that the effect of the drug was on arousal rather than directly upon memory. It has been claimed that clonidine (an adrenergic agonist) produced a small, but statistically significant, benefit in patients with the Korsakoff syndrome on tests of memory and attention, but this finding has not been replicated.
Similarly, some years ago, there was interest in the serotonergic system and alcohol-induced memory impairment. Early reports suggested that zimelidine, a serotonin reuptake inhibitor, reversed the memory impairment in healthy volunteers after the administration of ethanol. Later, it was claimed that fluvoxamine improved memory performance in five patients with the Korsakoff syndrome, and that the improvements correlated significantly with reductions in a cerebrospinal fluid breakdown product. The samples were small, the benefits were minor, and the informal use of this drug by the present author has not produced any noticeable benefit. Nevertheless, 3,4-methylenedioxymethamphetamine (ecstasy) has been reported to produce memory impairments either by direct or indirect effects. My colleagues and I have described one case of severe toxicity, in which a profound amnesic syndrome resulted; the memory impairment in this case was attributed to hypometabolism in the thalamus, particularly the anterior thalamus, which is a serotonin-rich brain region.
Systematic clinical descriptions of amnesic disorders and their underlying pathology have become more detailed and rigorous over the years. In particular, recent advances in neuroimaging (structural, metabolic, and activation) have provided the opportunity to relate particular cognitive abnormalities to specific changes in brain function. The use of pharmacological agents, in parallel with such imaging techniques, may promote the development of pharmacological agents more potent than the meagre array that we have at present for the treatment of severe memory disorder.
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