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Brain, Vol. 125, No. 10, 2152-2190, October 2002
© 2002 Oxford University Press

Review Article

Disorders of memory

Michael D. Kopelman

Neuropsychiatry and Memory Disorders Clinic, University Department of Psychiatry and Psychology, Guy’s, King’s and St Thomas’ Medical School (KCL), London, UK

Correspondence to: Michael D. Kopelman, Neuropsychiatry and Memory Disorders Clinic, University Department of Psychiatry and Psychology, Guy’s, King’s and St Thomas’ Medical School (KCL), St Thomas’ Campus, London, SE1 7EH, UK E-mail: michael.kopelman{at}kcl.ac.uk

Received October 30, 2001. Revised April 2, 2002. Second revision April 18, 2002. Accepted April 20, 2002.

	Summary

Top Summary Introduction Varieties of amnesic syndrome What is impaired and... Explicit and implicit memory Do temporal lobe, diencephalic... How independently semantic is... What determines the pattern... Can retrograde amnesia ever... Does psychogenic amnesia involve... How and when do... Conclusions References

 
This paper reviews disorders of memory. After a brief survey of the clinical varieties of the amnesic syndrome, transient and persistent, selected theoretical issues will be considered by posing a series of questions. (i) What is impaired and what is spared in anterograde amnesia? (ii) Do temporal lobe, diencephalic and frontal lobe amnesias differ? (iii) How independently semantic is semantic memory? (iv) What determines the pattern and extent of retrograde memory loss? (v) Can retrograde amnesia ever be ‘isolated’? (vi) Does psychogenic amnesia involve the same mechanisms as organic amnesia? (vii) How and when do false memories arise? Commonalities as well as differences across separate literatures will be emphasized, and the case for a more ‘dynamic’ (interactionist) approach to the investigation of amnesia will be advocated.

Keywords: amnesia; anterograde; confabulation; psychogenic; retrograde

Abbreviations: AA = anterograde amnesia; FDG PET = [¹⁸H]fluoro-deoxy glucose PET; GABA = gamma-amino butyric acid; K = ‘know’; PTA = post-traumatic amnesia; PTSD = post-traumatic stress disorder; R = ‘remember’; RA = retrograde amnesia; SPECT = single photon emission tomography; TEA = transient epileptic amnesia; TGA = transient global amnesia; TPP = thiamine pyrophosphate; WAIS-R = Wechsler Adult Intelligence Scale—Revised; WMS-R = Wechsler Memory Scale—Revised

	Introduction

Top Summary Introduction Varieties of amnesic syndrome What is impaired and... Explicit and implicit memory Do temporal lobe, diencephalic... How independently semantic is... What determines the pattern... Can retrograde amnesia ever... Does psychogenic amnesia involve... How and when do... Conclusions References

 
‘So we beat on, boats against the current, borne back ceaselessly into the past.’

(F. Scott Fitzgerald, The Great Gatsby, 1925.)

‘The places that we have known belong now only to the little world of space on which we map them for our own convenience. None of them was ever more than a thin slice, held between the contiguous impressions that composed our life at that time; remembrance of a particular form is but regret for a particular moment; and houses, roads, avenues are as fugitive, alas, as the years.’

(M. Proust, Remembrance of Things Past, 1913.)

The literature on memory and its disorders has proliferated, particularly since the advent of recent neuroimaging techniques. However, controversy remains concerning certain broad issues, selected examples of which will be considered in turn in this review, following a brief survey of the clinical disorders that give rise to an amnesic syndrome. The focus of the review will be on neuropsychological studies of patients with disorders of episodic or semantic memory, and there will be only brief reference to functional neuroimaging studies of healthy individuals.

	Varieties of amnesic syndrome

Top Summary Introduction Varieties of amnesic syndrome What is impaired and... Explicit and implicit memory Do temporal lobe, diencephalic... How independently semantic is... What determines the pattern... Can retrograde amnesia ever... Does psychogenic amnesia involve... How and when do... Conclusions References

 
The amnesic syndrome can be defined as: ‘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’ (Victor et al., 1971).

The Korsakoff syndrome can be defined as the same but with the following phrase added: ‘... resulting from nutritional depletion, notably thiamine deficiency.’

In fact, Victor et al. (1971) 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 (1889), whose cases (with hindsight) can all be viewed as having suffered nutritional depletion, whether of alcoholic or non-alcoholic causation. Various disorders can give rise to an amnesic syndrome, including herpes encephalitis, severe hypoxia, certain vascular lesions, head injury, deep midline tumours, basal forebrain lesions and occasionally early dementia.

The Korsakoff syndrome
As just mentioned, the Korsakoff syndrome is the result of nutritional depletion, i.e. thiamine deficiency. Korsakoff (1889) 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’ is intact in the Jamesian sense of recall over a matter of seconds (Zangwill, 1946), 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 (Kopelman, 1989; Parkin et al., 1990b). Korsakoff (1889) 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.’ However, he also noted repetitive questionings, 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 that reflected the problem with 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 ophthalmoplegia. Not all these features are always present, and the ophthalmoplegia in particular 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 (Cutting, 1978a), and such cases are more likely to come to the attention of psychiatrists: in these cases, there may be either no known history or only a transient history of Wernicke features. There are also reports that the characteristic Wernicke–Korsakoff neuropathology (see below) is diagnosed much more commonly at autopsy in alcoholics than in life (Torvik et al., 1982; Harper, 1983), implying that many cases are being missed.

The Korsakoff syndrome is unusual among memory disorders in that there is a distinct neurochemical pathology with important implications for treatment. Following animal research in the 1930s and 1940s, and the important observations of de Wardener and Lennox (1947) and others in malnourished prisoners-of-war, thiamine depletion was established as the mechanism giving rise to the acute Wernicke episode, and the subsequent (Korsakoff) memory impairment. However, the genetic factor, predisposing certain heavy drinkers to develop this syndrome before hepatic or gastro-intestinal complications, remains unclear. It was thought that a transketolase gene might account for this, because transketolase is the enzyme that requires thiamine pyrophosphate (TPP) as a co-factor. Such a gene has been identified (McCool et al., 1993), but it does not account for all the properties of transketolase and only very weakly for predisposition to the Korsakoff syndrome. Moreover, it remains unclear how thiamine depletion produces the particular neuropathology found in Wernicke–Korsakoff patients, although Witt (1985) pointed out that six neurotransmitter systems (including acetylcholine, GABA, glutamate) are affected by thiamine depletion, either by reduction of TPP-dependent enzyme activity or by direct structural damage (see also Butterworth, 1989). Whatever the precise mechanism, treatment as soon as possible with high doses of parenterally administered multi-vitamins is essential. The Wernicke features respond well to high doses of vitamins, and such treatment can prevent the occurrence of a chronic Korsakoff state (Victor et al., 1971; Lishman, 1998). The small risk of anaphylaxis is completely outweighed by the large risk of severe brain damage if such treatment is not administered.

The characteristic neuropathology in what is often known as the ‘Wernicke–Korsakoff syndrome’ consists of neuronal loss, micro-haemorrhages and gliosis in the paraventricular and peri-aqueductal grey matter (Victor et al., 1971). However, there has been debate as to which particular lesions are critical for the chronic memory disorder to arise. Victor et al. (1971) 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 mamillary bodies were implicated in all the Wernicke cases, whether or not there was subsequent memory impairment. However, Mair et al. (1979) provided a careful pathological and neuropsychological description of two Korsakoff patients, whose autopsies showed lesions in the mamillary bodies and the anterior and midline thalamus, including the paratenial but not the medial-dorsal nuclei. Mair et al. suggested that the lesions they described might ‘disconnect’ a critical memory circuit running between the temporal lobes and the frontal cortex. Mayes et al. (1988) obtained very similar findings in two further Korsakoff patients, who were also very carefully described both neuropsychologically and at autopsy. More recently, Harding et al. (2000) found neuronal loss and atrophy in the mamillary bodies and medial-dorsal thalamic nucleus of 13 Wernicke patients, whether or not they developed (Korsakoff) amnesia. Comparison of eight Korsakoff with five ‘Wernicke only’ patients showed differences confined to the anterior principal thalamic nucleus, suggesting that atrophy in this structure is critical for the development of amnesia.

There is also neuropathological evidence of general cortical atrophy in Korsakoff patients particularly involving the frontal lobes (Torvik et al., 1982; Harper et al., 1987), and this is associated with neuropsychological evidence of ‘frontal’ or ‘executive’ test dysfunction in these patients (Leng and Parkin, 1988; Jacobson et al., 1990; Shoqeirat et al., 1990; Kopelman, 1991).

There have been a number of neuroimaging studies in the Korsakoff syndrome. CT scan studies indicated a degree of general cortical atrophy, particularly involving the frontal lobes (Shimamura et al., 1988; Jacobson and Lishman, 1990). MRI studies have indicated more specific atrophy in diencephalic and frontal structures (Jernigan et al., 1991; Colchester et al., 2001). The findings in single photon emission tomography (SPECT) and PET studies have been more variable, some studies showing widespread hypoperfusion and hypometabolism (Hunter et al., 1989; Paller et al., 1997), other studies showing very little change relative to healthy controls (Martin et al., 1992). White matter and diencephalic changes have also been implicated (Reed et al., 2002).

Victor et al. (1971) reported that 25% of Korsakoff patients ‘recovered’, 50% showed improvement through time and 25% remained unchanged. Whilst it is unlikely that any established Korsakoff patient shows complete recovery, the present author’s experience is that substantial improvement does occur over a matter of years, if patients refrain from alcohol: it is probably correct to say that 75% of Korsakoff patients show a variable degree of improvement, whilst 25% show no change.

Herpes encephalitis
This can give rise to a particularly severe form of amnesic syndrome (Wilson and Wearing, 1995). The majority of cases are said to be primary infections, and a history of a preceding ‘cold sore’ on the lip is uncommon. There is characteristically a fairly abrupt onset of acute fever, headache and nausea. Seizures can occur, and there may be behavioural changes. The fully developed clinical picture with neck rigidity, vomiting, and motor and sensory deficits may take several days to emerge (Peto and Juel-Jensen, 1996). Diagnosis is by a raised titre of antibodies to the virus in the CSF, but often this is missed and a presumptive diagnosis is made on the basis of the clinical picture as well as severe signal alteration in the temporal lobes on MRI brain imaging, associated with loss of tissue volume, haemorrhage and oedema.

Neuropathological and neuroimaging studies show that there is usually extensive bilateral temporal lobe damage (Hierons et al., 1978; N. Kapur et al., 1994; Yoneda et al., 1994; Colchester et al., 2001) although, occasionally, the changes are surprisingly unilateral (Stanhope and Kopelman, 2000). There are often frontal changes, most commonly in the orbito-frontal regions, and there is a variable degree of general cortical atrophy. The medial temporal lobe structures are particularly severely affected, including the hippocampi, amygdalae, and the entorhinal, perirhinal and parahippocampal cortices. Evidence from studies of bilateral temporal lobectomy (Scoville and Milner, 1957; Milner, 1966), as well as animal lesion studies (Zola-Morgan et al., 1989; Murray et al., 1993; Zola et al., 2000), has indicated that these structures are particularly critical in memory formation.

The chronic memory disorder in herpes encephalitis shows many resemblances to that in the Korsakoff syndrome, consistent with the fact that there are many neural connections between the thalami, mamillary bodies and the hippocampi (Aggleton and Saunders, 1997). 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 (Damasio et al., 1985; Phillips et al., 1987; von Cramon and Schuri, 1992).

Contrary to what was postulated in the 1980s, there appears to be no difference between Korsakoff patients and herpes encephalitis patients in terms of forgetting rates (Kopelman and Stanhope, 1997), but herpes patients show better ‘insight’ into the nature of their disorder (Kopelman et al., 1998a) and a ‘flatter’ temporal gradient to their retrograde memory loss (i.e. less sparing of early memories). They may have a particularly severe deficit in spatial memory, especially when the right hippocampus is implicated (Kopelman et al., 1997). Semantic memory is more commonly affected in herpes patients, and this results from the involvement of the left infero-lateral temporal lobe, producing impairments in naming, reading (‘surface dyslexia’) and other aspects of lexical-semantic memory. Right temporal lobe damage may lead to a particularly severe impairment in face recognition memory or knowledge of people (e.g. Eslinger et al., 1996).

Severe hypoxia
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 pipe from a car. Drug overdoses may precipitate prolonged unconsciousness and cerebral hypoxia, and this quite commonly occurs in heroin abusers. A recent review has provided a timely reminder that the neuropathological and cognitive consequences of hypoxia are variable and can be widespread (Caine and Watson, 2000), a point widely accepted in clinical practice but sometimes neglected in the neuropsychological literature.

Zola-Morgan et al. (1986) described a patient who, following repeated episodes of hypoxia and cardio-respiratory arrest, developed 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, whereas the rest of the brain appeared relatively normal. Press et al. (1989) reported hippocampal atrophy on MRI in three amnesic patients, and Kopelman et al. (2001) found medial temporal lobe atrophy in hypoxic patients although these patients also showed reduced glucose metabolism in the thalami on [¹⁸H]fluoro-deoxy glucose PET (FDG PET) (Reed et al., 1999; compare Markowitsch et al., 1997b). 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 (Fazio et al., 1992; Aggleton and Saunders, 1997). A recent finding of fornix atrophy and memory deficits following carbon monoxide poisoning (Kesler et al., 2001) is consistent with this view.

Vascular disorders
Vascular disorders can particularly affect memory, as opposed to general cognitive functioning, in (i) thalamic, medial temporal or retrosplenial infarction, and (ii) sub arachnoid haemorrhage.

In an elegant CT scan study, von Cramon et al. (1985) showed that it was damage to the anterior thalamus that was critical in producing an amnesic syndrome (compare with Harding et al., 2000). 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 circulation. More recently, Van der Werf et al. (2000), in a review of the literature, argued that it is damage to the mamillo-thalamic tract, which projects into the anterior nuclei of the thalamus, that is critical in producing an amnesic syndrome. A relatively pure lesion of the anterior thalamus produces anterograde amnesia (AA) with minimal retrograde amnesia (RA) (Graff-Radford et al., 1990; Parkin and Hunkin, 1993; Kapur et al., 1996a). Cases of more extensive RA (Hodges and McCarthy, 1993) or dementia have been described, probably reflecting the extent to which fronto-cortical projections are implicated in the infarction.

The hippocampi are supplied by the anterior and posterior choroidal arteries, branches of the internal carotid and posterior cerebral arteries, respectively (Walsh, 1987). Unilateral infarction tends to give rise to material-specific memory loss and bilateral damage to global amnesia (O’Connor and Verfaellie, 2002). The retrosplenium is also supplied from the posterior cerebral artery, and infarction or haemorrhage can produce amnesia by disrupting connections to anterior thalamus, entorhinal and parahippocampal cortices (Valenstein et al., 1987; Maguire, 2001).

Subarachnoid haemorrhage following rupture of an aneurysm can result in memory impairment, whether the anterior cerebral or posterior cerebral circulation in the Circle of Willis is involved (Richardson, 1989, 1991). Ruptured aneurysms in the anterior communicating artery can implicate the basal forebrain and ventro-medial frontal structures. Gade and others have argued that it is whether or not the septal nucleus of the basal forebrain is damaged that determines whether a persistent amnesic syndrome occurs in such patients (Gade, 1982; Gade and Mortensen, 1990). Others have attributed the florid confabulation that sometimes occurs to associated ventro-medial frontal damage (e.g. De Luca and Cicerone, 1991; Moscovitch and Melo, 1997; Gilboa and Moscovitch, 2002).

Head injury
Head injury can give rise to either transient or persisting amnesia. It is important to distinguish between RA, which is usually (but not necessarily) relatively brief, post-traumatic amnesia (PTA), and ‘islands’ of preserved memory within the amnesic gap (Russell and Nathan, 1946; Lishman, 1968, 1973, 1998). Occasionally, PTA may exist without any RA, 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 PTA.

PTA is generally assumed to reflect the degree of underlying diffuse brain pathology, in particular rotational forces giving rise to diffuse axonal injury. King (1997) has reported that PTA can be assessed with reasonable reliability; the length of PTA is predictive of eventual cognitive (Brooks, 1984), psychiatric (Lishman, 1968), and social outcome (Russell and Smith, 1961; Brooks, 1991). However, the duration of PTA is often not well documented in medical records, and these relationships are often weaker than is generally assumed. PTA needs to be distinguished from persisting anterograde memory impairment, which may be detected on clinical assessment or cognitive testing long after the period of PTA has ended. Levin et al. (1988a) found that, during PTA, head injury patients showed accelerated forgetting of learned information, whereas after PTA forgetting rates were normal (compare with Baddeley et al., 1987).

Damage to the frontal and anterior temporal lobes by direct trauma results in contusion, haematoma and haemorrhage. Contre-coup damage, intracranial haemorrhage and hypoxia can all result (Teasdale and Mendelow, 1984). Rotational and acceleration–deceleration forces may produce shearing or tensile stretching of axons with subsequent gliosis (Strich et al., 1956; Oppenheimer, 1968). The resulting intra-axonal changes lead to a failure in axoplasmic transport, axonal swelling, and, ultimately, to disconnection, de-afferentation and loss of synaptic boutons over a matter of hours or days (Blumbergs et al., 1995; Povlishock and Christman, 1995).

Memory is commonly the last cognitive function to show improvement following an acute trauma (Conkey, 1938), and patients can show the characteristic features of an amnesic syndrome (Baddeley et al., 1987; Levin et al., 1988b). Disproportionate RA has been described (see below), particularly in association with damage to the frontal or anterior temporal regions. Forgetfulness is also a common complaint within the context of mild concussion (Lishman, 1988; Fleminger, 2000). Whilst research studies show that recovery from mild head injury is typically expected 1–3 months post-injury, some patients demonstrate symptoms far beyond this time (Barth et al., 1996): long periods of disability and enduring post-concussion symptoms are related, in part, to individual vulnerabilities. In such cases, complaints characteristically persist long after the settlement of any compensation issues (Merskey and Woodforde, 1972; Miller, 1979; Tarsh and Royston, 1985).

Recent controversy has concerned whether severe head injury and amnesia exclude the possibility of post-traumatic stress disorder (PTSD) symptoms. O’Brien and Nutt (1998) argued that a head injury causing coma and severe amnesia prevents the ‘re-experiencing’ symptoms of PTSD. However, McMillan (1996) described 10 patients with head injury of varying severity, in whom PTSD arose. These 10 patients reported ‘windows’ of experience, in which emotional disturbance was sufficient to cause PTSD, even though PTA was of relatively long duration (three patients had PTAs of more than 2 weeks). These ‘windows’ involved recall of events close to impact when RA was brief (e.g. of a lorry bearing down), or of distressing events soon after the accident (when PTA was short) or of ‘islands’ of memory (e.g. hearing the screaming of others). Others reported distressing recollections that appeared to be self-generated or that had been reported to the patient by others. McNeil and Greenwood (1996) reported PTSD symptoms in a young traffic accident victim, who had an RA of 2 days and a PTA of 4 weeks. Despite these cases, the topic remains controversial, and some authors have even disputed whether victims of mild head injury can have PTSD (for review, see Harvey et al., 2002).

Transient global amnesia
Transient global amnesia (TGA) most commonly occurs in the middle-aged or elderly, more frequently in men, and results in a period of amnesia lasting several hours. As is well known, it is characterized by repetitive questioning, and there may be some confusion, but patients do not report any loss of personal identity. It is sometimes preceded by headache or nausea, a stressful life event, a medical procedure, intense emotion or vigorous exercise. Hodges and Ward (1989) found that the mean duration of amnesia was 4 h and the maximum 12 h. In 25% of their sample, there was a past history of migraine, which was considered to have a possible aetiological role. In a further 7%, the patients subsequently developed unequivocal features of epilepsy in the absence of any previous history of seizures. There was no association with either a past history of or risk factors for vascular disease, nor with clinical signs indicating a vascular pathology. In particular, there was no association with transient ischaemic attacks. In 60–70% of the sample, the underlying aetiology was unclear.

Somewhat similarly, Miller et al. (1987), in a sample of 150 men and 127 women, found that the mean duration of the episode was 6.2 h, ranging from 2 to 12 h. A seizure disorder was noted in eight patients and, as in the Hodges and Ward (1989) report, the incidence of cerebro-vascular events (stroke) was no higher than would be expected in this age group.

Where neuropsychological tests have been administered to patients during their acute episode of transient amnesia (Kritchevsky et al., 1988; Hodges and Ward, 1989), the patients have shown a profound AA on tests of both verbal and non-verbal memory, but RA was variable, usually being relatively brief but occasionally prolonged, and worse for recall of episodes than facts (Evans et al., 1993; Guillery et al., 2000). Following the attack, Kritchevsky and Squire (1989) reported that there was complete recovery after several weeks. Miller et al. (1987) stated that ‘a selective verbal memory deficit’ was found ‘in a few patients. .. [although] persisting memory complaints or frank dementia following TGA were seldom noted.’ However, Hodges and Oxbury (1990), in a follow-up of 41 cases at 6 months, found statistically significant impairments on tests measuring the recall of stories, famous faces, and autobiographical memories.

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. (1990) reported severe bitemporal hypoperfusion during an episode of TGA using SPECT and, after recovery from the episode, cerebral perfusion returned to normal. Evans et al. (1993) obtained similar findings, also in a SPECT study, with recovery to normal 7 weeks later. Fujii et al. (1989) used FDG PET in TGA patients 3 months after the episode, obtaining normal findings in all but one of the patients. Simons and Hodges (2000) and Goldenberg (2002) have cited evidence that changes on diffusion-weighted MRI might indicate ischaemic disfunction in these brain regions.

Transient epileptic amnesia
This refers to the minority of TGA cases in whom epilepsy appears to be the underlying cause (Heathfield et al., 1973; Fisher, 1982; Miller et al., 1987; Hodges and Ward, 1989). The main predictive factors for an epileptic aetiology are brief episodes of memory loss (1 h or less) and multiple attacks (Miller et al., 1987; Hodges and Warlow, 1990; Kapur, 1990). It is important to note that standard EEG and CT scan findings are often normal. However, an epileptic basis to the disorder may be revealed on sleep EEG (Kopelman et al., 1994a). Kapur (1990) coined the phrase ‘transient epileptic amnesia’ (TEA) to describe such attacks: this is a useful term, although it does not distinguish between episodes that are ictal (Palmini et al., 1992; Vuilleumier et al., 1996) and those that are post-ictal in nature (Tassinari et al., 1991).

Patients with TEA may show residual deficits in between their attacks, associated with their underlying neuropathology. These may involve anterograde memory (Kopelman et al., 1994a) or aspects of remote memory (Kapur et al., 1986, 1989; Zeman et al., 1998). Most commonly, the patients complain of ‘gaps’ in their past memory. It seems plausible that the patients may have had brief runs of seizure activity in the past: these would have been undetected clinically but resulted in faulty (anterograde) encoding of very specific items in autobiographical memory (Kopelman, 2000a). An alternative interpretation is that the current epilepsy somehow prevents the retrieval of old, autobiographical memories (Kapur, 2000; Manes et al., 2001).

Epilepsy may, of course, give rise to automatisms or post-ictal confusional states (Logsdail and Toone, 1988; Fenwick, 1990; Lishman 1998). 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 (Fenton, 1972). Consequently, amnesia for the period of automatic behaviour is always present and is usually complete (Knox 1968; Fenwick, 1990, 1993).

Summary
The above examples do not, of course, comprise a comprehensive list of the disorders which give rise to transient or persistent amnesia. What they have in common is that temporary or permanent dysfunction or damage in medial temporal/diencephalic circuitry (or in the basal forebrain cholinergic inputs to that circuitry) produces the amnesia. The remainder of this article concerns theoretical issues that arise in our understanding of the functioning of this circuitry and its interaction with frontal lobe and temporal neocortical mechanisms.

	What is impaired and what is spared in anterograde amnesia?

Top Summary Introduction Varieties of amnesic syndrome What is impaired and... Explicit and implicit memory Do temporal lobe, diencephalic... How independently semantic is... What determines the pattern... Can retrograde amnesia ever... Does psychogenic amnesia involve... How and when do... Conclusions References

 
As is well known, a distinction is usually drawn between so-called ‘working memory’, which holds information for brief periods of time (a matter of seconds) and allocates resources, and secondary memory in which information is stored on a permanent or semi-permanent basis (James, 1890; Hebb, 1949; Baddeley and Warrington, 1970; Shallice and Warrington, 1970). Secondary memory can, in turn, 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 (allowing that person ‘to travel back mentally in time’) and it is characteristically affected in the amnesic syndrome, whereas semantic memory refers to knowledge of facts, concepts and language (Tulving, 1972). Implicit memory includes classical conditioning, the procedural learning of perceptuo-motor skills and the facilitation of responses in the absence of explicit memory known as ‘priming’. Much neuropsychological research has examined which of these components are affected/spared in amnesia, and the underlying mechanisms of deficit.

Encoding, storage and retrieval
Over the years, there has been extensive debate concerning whether the primary deficit in the amnesic syndrome lies in either (i) the initial encoding of episodic memories, or (ii) some kind of physiological ‘consolidation’ into secondary memory, or (iii) faulty encoding and storage of contextual information, or (iv) accelerated forgetting of information, or (v) in retrieval processes (Warrington and Weiskrantz, 1970; Butters and Cermak, 1980; Meudell and Mayes, 1982).

(i) Faulty encoding
Some theories propose that there is a deficit in the psychological processes involved in the initial ‘registration’ or representation of information. In particular, it has been argued that, whilst Korsakoff patients are able to ‘encode’ the direct, sensory properties of information, they have difficulties in ‘processing’ its more meaningful (semantic) qualities (e.g. Butters and Cermak, 1980). For example, they perform particularly badly at learning word-pairs (e.g. hungry–thin), the recall of which is normally facilitated by thinking of semantic links between the words (Cutting, 1978b; Butters and Cermak, 1980). On the other hand, giving instructions or orienting tasks that encourage the extraction of meaning from a stimulus produces, at most, a relatively small enhancement in the amnesic patients’ subsequent recall of that stimulus, an effect closely similar to that seen in healthy controls (Meudell et al., 1979; McDowall, 1981; Meudell and Mayes, 1982). Consequently, it seems unlikely that a failure to encode semantic information is the fundamental memory deficit in amnesia.

(ii) Faulty consolidation
A second type of hypothesis proposes that there is impairment in the physiological processes that are assumed to occur shortly after an initial representation is laid down in order to establish (‘consolidate’) information into some relatively permanent form (e.g. Meudell et al., 1979; Moscovitch, 1982). These processes were traditionally thought to involve the ‘transfer’ of information from primary to secondary memory, operating during a time-period of something less than a minute. The hypothesis was suggested by the finding that span test scores and other measures of primary memory (requiring the recall of information within a few seconds) were relatively intact in Korsakoff, medial temporal lesion and head injury patients (e.g. Milner, 1966; Brooks, 1984). In one particularly intriguing study, Lynch and Yarnell (1973) interviewed six concussed American footballers within 30 s of their injury and at intervals thereafter. Although they were initially able to give a lucid account of events occurring just before the blow, they subsequently developed a ‘relatively complete’ RA, suggesting that their immediate memories had not been effectively consolidated. A problem with this theory is that it cannot by itself explain why RA of more than a few seconds or minutes should occur unless one postulates a distinct ‘slow’ consolidation process lasting years or decades. This issue will be discussed below.

(iii) Faulty encoding or storage of contextual information
Huppert and Piercy proposed a very specific deficit in amnesic patients’ acquisition of contextual (e.g. temporal/spatial) information (Huppert and Piercy, 1976, 1978), and this idea was adopted by several other groups (e.g. Mayes et al., 1985). There is certainly substantial evidence of disproportionate contextual memory deficits in amnesic patients, but difficulties with this theory include (a) the fact that the pattern of contextual memory deficits may vary substantially across patient groups (e.g. Parkin et al., 1990a), and that disproportionate contextual memory deficits are not always found (Squire, 1982; Cave and Squire 1991); and (b) such deficits have often been attributed (perhaps erroneously) to concomitant frontal lobe pathology, rather than to the medial temporal/diencephalic lesions critical to the development of anterograde amnesia. Recently, this theory has evolved into a more generalized notion of a deficit in binding complex associations (Mayes and Downes, 1997) or memory for relations between items (Cohen et al., 1997). In turn, this notion relates to various distinctions to be considered below: between recall and recognition memory, remembering and knowing, and between explicit and implicit memory.

(iv) Accelerated forgetting
A fourth possibility focuses upon ‘storage’ (retention) rather than learning processes. On the basis of findings in a single-case (HM), Huppert and Piercy (1979) argued that patients with hippocampal lesions show accelerated forgetting, even after material has been adequately learned; however, this was not the case in patients with diencephalic pathology. Some support for this finding has been obtained in other patients with hippocampal pathology (Parkin and Leng, 1988; Frisk and Milner, 1990) and also in Alzheimer patients (Hart et al., 1987). However, there were ceiling effects in the first two of these studies, and a failure to use equivalent measures at different time-periods in the third. Moreover, Freed et al. (1987) failed to replicate Huppert and Piercy’s original observation in HM (Huppert and Piercy, 1979) in HM when he was studied repeatedly across the same time delays; and Kopelman (1985) and McKee and Squire (1992) found no difference in forgetting between diencephalic patients and those with Alzheimer dementia or focal temporal lobe lesions. Recent studies have demonstrated an apparent difference between recognition memory, in which forgetting rates in amnesic patients were normal once initial learning had been accomplished, and recall measures in which amnesic patients showed accelerated forgetting over delays of a few minutes (Kopelman and Stanhope 1997; Christensen et al., 1998; Isaac and Mayes 1999a, b; Green and Kopelman, 2002). However, there were no differences in these latter studies between patients with primarily diencephalic or temporal lobe pathology (Kopelman and Stanhope, 1997; Green and Kopelman, 2002). One interpretation of such findings is that the major deficit in amnesia involves acquisition or learning processes, since impairments in new learning can be detected on standard measures of either recognition or recall memory, but that there is an additional, more subtle impairment in retention (or ‘consolidation’) over a period of minutes, detectable only on recall tests (Kopelman and Stanhope, 1997, 2001; Green and Kopelman, 2002).

(v) Faulty retrieval
Two types of retrieval hypothesis have been postulated. ‘Pure’ retrieval hypotheses postulate a retrieval deficit arising independently of any failure of ‘acquisition’ processes. For example, Warrington and Weiskrantz postulated that amnesic patients are unable to suppress inappropriate responses during recall or recognition tasks (Warrington and Weiskrantz, 1968, 1970). They noted that amnesic patients sometimes respond erroneously to memory tests with what had been the correct replies to previous tasks and, secondly, that the provision of retrieval cues can improve their performance. On the other hand, it has been shown that healthy subjects also exhibit these phenomena when given recall tests at relatively long retention intervals (e.g. a week), suggesting that they may be a consequence of poor memory rather than its cause (Woods and Piercy, 1974; Mayes and Meudell, 1981). Moreover, restricting the number of choices in a recognition or cued recall test does not necessarily improve amnesic patients’ performance relative to controls (Huppert and Piercy, 1976; Warrington and Weiskrantz, 1978). In recent years, the Warrington and Weiskrantz finding of a beneficial effect of cues has been reinterpreted as demonstrating preserved priming in the presence of impaired explicit memory (e.g. Shimamura, 1986), and there is also evidence that intact priming can precipitate interference effects when explicit memory is impaired (Mayes et al., 1987). A modified retrieval hypothesis stresses evidence that retrieval processes are heavily dependent upon the nature of initial encoding, and that retrieval deficits arise as a consequence of an initial encoding impairment (Tulving and Thompson, 1973). Moreover, a retrieval deficit may be important where there is an extensive RA (Weiskrantz, 1985; Kopelman, 1989; see below).

In summary, several studies point to a problem in the initial acquisition or ‘consolidation’ of information with a more subtle impairment in retention (forgetting) detectable only on recall testing. There may also be a secondary deficit in retrieval processes. However, the precise nature of this acquisition deficit remains ill defined. One possibility is that there is a deficit in ‘binding’ different types of material including contextual information, and that this relates to various distinctions drawn within episodic memory, which will now be considered.

Recall and recognition memory
There may be a differentiation between recall and recognition memory. On the basis of a meta-analysis of single case and small group studies of amnesic patients, Aggleton and Shaw (1996) claimed that patients whose pathology was confined to circuitry involving the hippocampi, fornices, mamillary bodies, mamillo-thalamic tract and anterior thalami, showed impairments on recall but not recognition testing. They argued that in such patients, memory based on familiarity judgements (recognition) was intact, whereas recall memory, involving recollection of such contextual features as time and spatial location, was impaired (see also Aggleton and Brown, 1999). They postulated that damage to other structures, such as the perirhinal cortex, was required to produce an impairment in recognition memory. A potential problem with this single-dissociation is that it might simply reflect the severity of amnesia, milder amnesic patients (with less extensive pathology) showing relatively spared performance at recognition memory. Aggleton and Shaw (1996) tried to argue against this by comparing the recognition memory scores of (i) patients with ‘limbic’ lesions and (ii) Korsakoff/‘other’ amnesic patients, where the revised Wechsler Memory Scale (WMS-R) scores of the two groups did not differ significantly. However, there were trend differences in recall scores, several of which were close to ‘floor’, making any interpretation equivocal.

Consistent with the Aggleton hypothesis, Vargha-Khadem et al. (1997) described three patients with a developmental amnesia for everyday events, resulting from brain injury in infancy or early childhood. These patients showed a pronounced loss of hippocampal volume bilaterally, and their neuropsychological test performance showed impairments on recall but not recognition memory, the latter being tested with material that included lists of words, non-words, familiar faces and unfamiliar faces. These findings suggested that, whilst recall of episodic memories (involving a temporal and spatial context) was impaired as a result of these patients’ hippocampal pathology, recognition memory and semantic memory were spared, because they do not necessarily involve recollection of temporal/spatial context: this allowed these individuals to cope within mainstream education (see also Baddeley et al., 2001).

In contrast, Squire and colleagues have shown impaired performance in a series of studies on measures of recognition memory by patients whose pathology was apparently limited to the hippocampal formation: their studies included 29 measures of verbal and non-verbal recognition memory (yes/no, forced-choice; Reed and Squire, 1997) and the Doors and People test (Manns and Squire, 1999). Moreover, Zola et al. (2000) showed that monkeys with lesions limited to the hippocampal region were impaired on two tasks of recognition memory (but see Baxter and Murray, 2001a, b; Zola and Squire, 2001, on animal findings). In human amnesic patients, Kopelman et al. (2001) found no obvious differences between recall and recognition memory tests in the size of their correlations with an MRI measure of hippocampal atrophy.

The major difference between the Vargha-Khadem and Squire findings may be in the severity of the memory disorder in their respective patients. This is somewhat difficult to determine because different tests were employed, but the Vargha-Khadem et al. (1997) subjects had a mean Wechsler Adult Intelligence Scale—Revised (WAIS-R) verbal IQ minus Wechsler (Wechsler, 1945) memory quotient discrepancy of 11.67 points (SD ± 11.15), whereas the Reed and Squire (1997) patients with hippocampal lesions had a mean WAIS-R IQ minus WMS-R general memory index difference of 33.67 points (SD ± 17.92). In this connection, patient YR, reported by Mayes et al. is relevant (Mayes et al., 2001, 2002). YR had bilateral hippocampal atrophy and a 34-point WAIS-R IQ minus WMS-R general memory discrepancy. Across 43 recognition memory tests, YR did show significant impairment relative to controls, but the impairment was very minor (mean z = –0.5) and clinically significant (>2 SD) in only 10% of tests. In contrast, her impairment on recall tests was disproportionately severe (mean z = –3.6) and clinically significant in 95% of tests.

In summary, it has been hypothesized that hippocampal damage produces a deficit only in recall memory, whereas perirhinal pathology implicates recognition memory as well. The possibility that completely spared recognition memory in the hippocampal cases simply reflects a relatively mild memory impairment cannot be excluded. However, there is now at least one case-report suggesting relative sparing of recognition memory in a patient with a fairly severe impairment of recall memory.

Remembering and knowing; recollection and familiarity
Gardiner and Richardson-Klavehn (2000) have distinguished between the subjective states of ‘remembering’ and ‘knowing’. They defined remembering as ‘intensely personal experiences of the past, those in which we seem to recreate previous events and experiences with the awareness of reliving these events and experiences mentally.’ Knowing referred to ‘experiences of the past, in which we are aware of knowledge that we possess but in a more impersonal way . . . no awareness of reliving . . . [a] general sense of familiarity . . . [of] facts, without reliving them mentally.’

Various experimental studies have identified a number of factors differentiating ‘remember’ (R) and ‘know’ (K) memories (Gardiner and Java, 1990; Gardiner and Parkin, 1990; Rajaram, 1993). One issue that arises is whether R memories are (i) a special form of, and have the potential to become K memories (‘redundancy’), (ii) the outcome of two overlapping (‘independent’) processes (one of which is ‘knowing’), or (iii) the manifestation of an entirely separate process (‘exclusivity’). A second issue is how these subjective states (R, K) relate to more objective measures of ‘recollection’ and ‘familiarity’.

In amnesic patients, Knowlton and Squire (1995) found reduced R and K memories (responses) on a recognition memory test, relative to healthy controls. The controls’ performance 1 week later resembled that of the amnesic patients 10 min after stimuli presentation. Moreover, many of the controls’ R responses at 10 min became K responses at 1 week, implying that R and K memories were either redundant or independent, but not mutually exclusive. The authors concluded that amnesic patients show impairments in both the R and K components of explicit memory, and that K responses cannot be identified as reflecting ‘implicit memory’.

Others have argued that recognition memory judgements can be made either on the basis of feelings of familiarity, which may be relatively preserved in amnesia (see above), or on the basis of contextual memories (e.g. when or where something happened) i.e. conscious recollection (e.g. Huppert and Piercy, 1978; Yonelinas, 2001). There have been various attempts to quantify these memory components: for example, Jacoby and colleagues’ process dissociation procedure relies on subjects’ ability/inability to include or exclude items whose source or context is recollected (Jacoby et al., 1993). Yonelinas (2001) has argued that recollection and familiarity are independent processes with very different response characteristics. In recognition memory, recollection produces all-or-none ‘high confidence’ responses when the contextual information retrieved exceeds a certain threshold. Familiarity produces a much more variable pattern of responding according to trace strength (d') and response bias (B) (signal detection theory), and the pattern of these responses (hits : false alarms) at different levels of confidence (response bias) can be plotted on a so-called receiver operating characteristics (ROC) curve.

Yonelinas et al. (1998) emphasized the importance of controlling for response bias in both R/K and process dissociation experiments. They used a signal-detection procedure to recalculate findings from such studies in amnesia (e.g. Verfaellie and Treadwell, 1993; Schacter et al., 1996a), and they also reported their own findings plotting ROC curves in a small group of amnesic patients. Across all three techniques, amnesia produced a pronounced reduction in recollection memory and a smaller but consistent reduction in familiarity responses: this suggested that R and K are subjective states measuring (or reflecting) recollection and familiarity and, conversely, that objective measures of the latter can be used to predict the occurrence of these conscious states (a point contested by Gardiner, 2001).

In summary, the evidence suggests that memories based on ‘recollection’ (and its subjective counterpart, ‘remembering’) are severely impaired in amnesia, and that those based on familiarity judgements (or ‘knowing’) are also significantly impaired, although less severely so.

	Explicit and implicit memory

Top Summary Introduction Varieties of amnesic syndrome What is impaired and... Explicit and implicit memory Do temporal lobe, diencephalic... How independently semantic is... What determines the pattern... Can retrograde amnesia ever... Does psychogenic amnesia involve... How and when do... Conclusions References

 
Despite their severe impairment of explicit or episodic memory, many aspects of implicit memory are preserved in amnesic patients. For example, they show intact acquisition and retention of the classically conditioned eye-blink response (Weiskrantz and Warrington, 1979; Daum et al., 1989), provided no interval is interposed between the offset of the conditioned stimulus and the onset of the unconditioned stimulus (Clark and Squire, 1998). Amnesic patients can also show preserved acquisition and retention of perceptuo-motor skills (procedural memory) (Corkin, 1965; Moscovitch, 1982; Cermak and O’Connor, 1983; Wilson and Wearing, 1995). In contrast, procedural memory is impaired in certain subcortical dementias such as Parkinson’s disease and Huntington’s disease on, for example, pursuit rotor and the ‘Tower of Hanoi’ tasks (Heindel et al., 1988; Saint-Cyr et al., 1988). More recently, Reber and Squire (1999) have demonstrated that skill learning is not a single entity: Parkinson patients were impaired at ‘habit learning’, implicating the neostriatum, but showed intact learning of artificial grammars and dot pattern prototypes, which were postulated to reflect brain regions outside both the neostriatum and the medial temporal lobes.

Priming refers to the facilitation of a response in the absence of conscious awareness (explicit memory) that the stimulus has occurred before. This facilitation can occur across perceptually or conceptually similar/identical stimuli. Many studies have demonstrated intact priming in amnesic patients on tasks such as stem-completion (e.g. Graf et al., 1984; Shimamura and Squire, 1984; Graf and Schacter, 1985), and Hamann and Squire (1997) reported fully intact priming in a profoundly amnesic patient (from herpes encephalitis), despite his performing at chance on recognition memory tests. Such findings have been interpreted as demonstrating that priming is not dependent on diencephalic/medial temporal brain structures, but that cortical regions must be critical (e.g. Shimamura, 1986; Schacter, 1987; Alvarez and Squire, 1995; Reber and Squire, 1999).

Keane et al. (1995) contrasted the performance of two patients on measures of explicit and implicit memory. The first was LH, who had suffered a severe closed head injury 23 years earlier: he had undergone a right temporal lobectomy and insertion of a shunt for hydrocephalus. In addition, he had damage to the right parietal and occipital lobes and a left hemisphere white matter lesion, which extended from the inferior temporal gyrus to just below the occipital horn. The medial temporal structures were spared gross structural damage. The second patient was HM (Scoville and Milner, 1957; Corkin et al., 1997), who became profoundly amnesic following a bilateral medial temporal lobectomy. His MRI showed bilateral pathology including the medial temporal polar cortex, the amygdalae and the entorhinal cortex. The resection involved approximately the anterior 2 cm of the hippocampal formation, and there was atrophy in the posterior 2 cm of the hippocampal fields. The posterior perirhinal and parahippocampal cortices were only slightly damaged. Keane et al. (1995) showed that LH was intact at measures of (explicit) recognition memory, but impaired at perceptual priming (e.g. perceptual identification, word-completion priming). In contrast, HM showed severely impaired recognition memory, but intact perceptual priming. On the basis of these findings, Keane et al. (1995) argued that visuo-perceptual priming depends on the integrity of occipital circuits that were compromised in LH but were preserved in HM. In contrast, explicit recognition memory is critically dependent on intact medial temporal lobes.

An alternative view has been postulated by Ostergaard, who argued that, when a task is easy and subjects achieve high levels of baseline performance (producing the ‘correct’ words to cues in the absence of any primes), the possible magnitude of priming effects is constrained and may not reflect the amount of information available from the study (‘priming’) episode (Ostergaard, 1994, 1998, 1999). When a task was made more difficult, a significant correlation between priming and explicit memory (recognition) scores emerged in healthy subjects (Ostergaard, 1998) and amnesic patients showed a priming impairment not seen on an easier task (Ostergaard, 1999). Moreover, two studies employing quantitative structural MRI (Jernigan and Ostergaard, 1993; Jernigan et al., 2001) found correlations between impaired priming and medial temporal/hippocampal volume loss in mixed groups of amnesic, dementing, and healthy control subjects. Ostergaard and colleagues have concluded that amnesic patients show impaired priming, related to medial temporal damage, after controlling for baseline performance (Ostergaard, 1994, 1999). More recently, Kinder and Shanks (2001) have postulated that a single memory system may underlie apparent ‘dissociations’ in performance on recognition memory and priming tasks, arguing that differential rates of learning between patients and controls and differing task demands across procedures can explain the pattern of results obtained.

Gooding et al. (2000) have put forward a third position. They conducted a meta-analysis of studies of implicit memory for familiar or novel information in amnesic patients and healthy controls. In 36 studies involving 59 separate measures, the patients and controls showed equivalent priming on tests using familiar information (the control group doing better 11 times out of 23 investigations). However, the controls performed significantly better than the amnesic patients on priming tasks involving novel items (18 out of 23 studies) or novel associative information (e.g. unrelated word pairs such as mountain–stamp) (nine out of 13 studies). Somewhat similarly, Chun and Phelps (1999) found that amnesic patients showed normal perceptuo-motor (procedural) skill learning on a visual search task, but unlike healthy subjects, they failed to show additional benefits from contextual cueing: the benefits of this contextual cueing were ‘implicit’ in the healthy subjects because they could not identify the context on subsequent recognition testing. From such findings, Gooding et al. (2000) concluded that the hippocampi are essential for encoding and storing (or ‘binding’) novel information with its associates including context, or in making new associations between established items, whether implicitly or explicitly.

In summary, the conventional wisdom is that priming is spared in amnesia, and that damage to sites of pathology beyond the medial temporal lobes is required to produce impaired priming (e.g. involving occipital circuitry). However, amnesic patients do show impaired priming in certain experimental conditions, e.g. in ‘difficult’ tasks where baseline responding has been controlled or in associative learning. This implicates a contribution of medial temporal/diencephalic structures in priming in these circumstances.

	Do temporal lobe, diencephalic and frontal lobe amnesias differ?

Top Summary Introduction Varieties of amnesic syndrome What is impaired and... Explicit and implicit memory Do temporal lobe, diencephalic... How independently semantic is... What determines the pattern... Can retrograde amnesia ever... Does psychogenic amnesia involve... How and when do... Conclusions References

 
Lesion studies
There has been considerable interest in whether or not the pattern of memory deficits differs across patients with either medial temporal, diencephalic, or frontal pathology. As already mentioned, Huppert and Piercy (1979) argued that temporal lobe pathology gives rise to accelerated forgetting, whereas diencephalic amnesia does not, but this observation has generally not been supported. An alternative hypothesis is that the diencephalon and medial temporal lobes differ in their contribution to context memory. Parkin and others argued that diencephalic lesions produce larger deficits in temporal order memory than does medial temporal lobe pathology, whereas spatial context deficits are larger for the latter group (Parkin et al., 1990a; Hunkin et al., 1994). Other studies have provided some support for these findings, but the findings are generally much less clear-cut (Chalfonte et al., 1996; Kopelman et al., 1997).

Context memory has