The amnestic syndrome A marked chronic impairment in memory in the absence of other major cognitive deficits

Amnesia is 'forgetfulness' in Greek ("mnemonics). The adverse effect of certain types of brain injury and mental trauma on memory was recognized long ago. But the systematic analysis of amnesia started only in the nineteenth century, with Ribot (1882) and Korsakoff (1887). Till the introduction of "functional neuroimaging, the study of amnesia has been the only practical approach to the investigation of brain substrates of memory in humans. Some information could be also obtained from electrical stimulation of patients undergoing brain surgery, but this was very limited in scope and controversial in interpretation ("engram). The investigation of amnesia is still a very powerful, unique approach to the analysis of human memory: whereas the application of functional neuroimaging could identify correlations between the activity of distinct brain regions and the "performance on memory tasks, the study of amnesiacs could potentially identify those brain structures that are obligatory for normal memory ("criterion, "method).1

Amnesia is not a unitary syndrome (Whitty and Zangwill 1966; Parkin 1987; Mayes 1995). A "taxonomy based on etiology distinguishes among 'organic amnesia', 'substance-induced amnesia', and 'functional amnesia'. These subtypes of amnesia are also known by other names, as explained below.

1. Organic amnesia is a consequence of damage to the brain inflicted by injury, disease (e.g. tumour, stroke, viral infection), or surgical intervention (DSM-IV 1994).

2. Substance-induced amnesia results from the intake of poisons, drugs of abuse, or medications with amnestic side-effects (for example, certain anxiolytics, "lotus). Chronic excessive consumption of alcohol could result in vitamin deficiency and encephalopathy (brain inflammation), which is manifested in Korsakoff's amnesia, at which stage it is also categorized as organic amnesia (Shimamura et al. 1988).

3. Functional amnesia develops after severe mental stress or trauma, or as a result of certain affective disorders. This type of amnesia is also termed 'psychogenic', or 'dissociative' ('dissociative disorders' in general are disruptions in the integrated functions of "consciousness, perception, personal identity, or memory).

The amnestic syndrome impairs learning and memory while leaving other cognitive faculties relatively intact. It is hence distinguished from "dementia, which involves multiple cognitive deficits, and from delirium, which impairs consciousness. Whereas some amnesia are modality specific (e.g. Rubin and Greenberg 1998), the 'amnestic syndrome' is 'global' and independent of sensory modality. Global organic amnesia is chronic; some improvement may be observed over time, but the patient does not regain normal memory. There is also a separate syndrome termed 'transient global amnesia'. This is a benign neurological syndrome in which the onset of amnesia is sudden and the recovery fast (usually < 1 day). Transient amnesia could also follow head trauma or electroconvulsive therapy.

An additional "criterion used to classify amnesia is the temporal window to which the memory loss refers. Here a distinction is made between 'retrograde' and 'anterograde' amnesia. Retrograde (premorbid) amnesia affects memory from the onset of the pathology backward. Anterograde (postmorbid) amnesia affects memory from the onset of the pathology forward. For example, in a typical case of the amnestic syndrome, there is dense anterograde amnesia and usually only a partial, graded retrograde amnesia. Memory of the recent past is commonly affected more than memory of the distant past; this observation is termed 'the law of regression', or 'Ribot's law' (it is noteworthy that Ribot regarded the phenomenon as the manifestation of a Darwinian principle, in which 'progressive destruction advances progressively from the unstable to the stable'; Ribot 1882).

The "classical, most widely cited case of a global amnesia is that of H.M. He became amnestic in 1953 at the age of 23, following 'a frankly experimental operation' (Scoville and Milner 1957) to alleviate uncontrollable epilepsy. The operation removed bilaterally the medial temporal polar "cortex, most of the "amygdaloid complex, the entorhinal cortex, and approximately half of the rostrocaudal extent of the intraventricular portion of the "hippocampal formation (Corkin et al. 1997). The operation reduced the frequency of seizures, but produced a severe, permanent anterograde amnesia, with only a limited effect on memory of events prior to the operation (and no effect on more remote events). Postoperationally, H.M. scored above average on a general intelligence test, showed no decline on immediate memory ("capacity), but was unable to store any new "declarative information. He was, however, capable of learning new "skills. Thus even in this severe case, the amnesia was not really 'global'.

The study of H.M., as well as of many other amnesics since then, gave rise to major insights concerning human memory (Squire and Zola 1997; Milner et al. 1998). These studies have demonstrated that the brain

Fig. 2 The missing parts in the brain of H.M., removed in the operation that had resulted in global amnesia. (a) The surgeon's estimate after the surgery (Scoville and Milner 1957). (b) The outcome of the surgical resection as unveiled by magnetic resonance imaging (MRI) 40 years later (Corkin et al. 1997).The upper diagrams depict ventral views of the brain, the lower ones depict coronal sections.A through D in the ventral views mark the planes of coronal sections in the original drawings, but only plane B is shown here. The operation was bilateral but in the drawing one hemisphere is shown intact for comparison. Adapted from Corkin et al. (1997). The case of H.M. drew much attention to the role of the medial temporal lobe in general, and the hippocampus in particular, in long-term memory.

Fig. 2 The missing parts in the brain of H.M., removed in the operation that had resulted in global amnesia. (a) The surgeon's estimate after the surgery (Scoville and Milner 1957). (b) The outcome of the surgical resection as unveiled by magnetic resonance imaging (MRI) 40 years later (Corkin et al. 1997).The upper diagrams depict ventral views of the brain, the lower ones depict coronal sections.A through D in the ventral views mark the planes of coronal sections in the original drawings, but only plane B is shown here. The operation was bilateral but in the drawing one hemisphere is shown intact for comparison. Adapted from Corkin et al. (1997). The case of H.M. drew much attention to the role of the medial temporal lobe in general, and the hippocampus in particular, in long-term memory.

contains distinct declarative (explicit) and nondeclara-tive (implicit) memory systems; and that long-term declarative memory is dependent on medial temporal lobe structures. Additional research has shown that nondeclarative amnesia could result from damage to a different, corticostriatal system (Mishkin et al. 1984; Knowlton et al. 1996; "skill). Support for the above conclusions has also emerged from studies of circumscribed brain lesions in "monkey "models of human amnesia (e.g. Mishkin et al. 1984; Ridley and Baker 1991; Meunier et al. 1993; Zola-Morgan et al. 1993; Gaffan 1994; Leonard et al. 1995). Indeed, the neuroscience of amnesia is characterized by a remarkable degree of integration of human and animal research.

Despite the impressive advances in our understanding of amnesia, many outstanding questions still await resolution (Warrington and Weiskrantz 1982; Mishkin et al. 1997; Nadel and Moscovitch 1997; Squire and Zola 1997; Weiskrantz 1997; Milner et al. 1998; Aggleton and Brown 1999). Among these: Is amnesia due to impairment in the "acquisition, "consolidation, storage, or "retrieval of memory? Although most authorities consider acquisition of information to remain intact in global amnesics, because of the good performance on the immediate memory tasks (see H.M. above), still, even subtle deficits in the way information is encoded and registered could markedly affect later retrieval. Another question is what is the specific contribution of medial temporal lobe structures (such as the hip-pocampal formation and adjacent cortici), and medial diencephalic structures (such as the medial thalamus and the mammillary bodies), to different manifestations of the amnestic syndrome, such as anterograde vs. retrograde amnesia, or "recall vs. "recognition deficits? And what is the contribution to amnesia of other brain areas, such as the basal forebrain ("acetylcholine, "dementia), or the frontal cortex and its interconnections with the diencephalon?

Each amnestic "subject is a unique individual, and probably in none are the lesions confined to a single well-circumscribed functional location in the brain. This makes the research inherently difficult. Animal models do help a lot, but still, it must be proven that what is considered amnesia in a monkey, even more so in a rodent, is sufficiently similar to the human amnesia to warrant adaptation of the conclusions from the animal to the human. Solutions are expected to emerge from the systematic analysis of additional cases of amnesia (e.g. Reed and Squire 1998), using universally accepted batteries of memory tests; from a greater sophistication of such tests in humans, primates, and rodents; and possibly also from a more extensive integration of novel functional neuroimaging methods in the study of amnestic brains.

Selected associaions: Conscious awareness, Declarative memory, Episodic memory, Dementia, Infantile amnesia

1 Reversible disruption of activity by transcranial magnetic stimulation (TMS) might also be used to identify brain areas obligatory for learning and memory (e.g. Grafman et al. 1999; Rossi et al. 2001), but it has not yet been widely employed.

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