Amnesia (neurological amnesia and functional amnesia) refers to difficulty in learning new information or in remembering the past. Neurological amnesia is characterized by a loss of declarative memory. Declarative memory refers to conscious knowledge of facts and events. In contrast, nondeclarative memory, which refers to a collection of non-conscious knowledge systems, is largely thought to remain intact. The terms explicit and implicit memory are sometimes used and have approximately the same meanings as declarative and nondeclarative, respectively. Neurological amnesia occurs following brain injury or disease that damages the medial temporal lobe or medial diencephalon. Neurological amnesia causes severe difficulty in learning new facts and events (anterograde amnesia). Patients with neurological amnesia also typically have some difficulty remembering facts and events that were acquired before the onset of amnesia (retrograde amnesia). Functional amnesia is rarer than neurological amnesia and can occur as the result of an emotional trauma. It presents as a different pattern of anterograde and retrograde memory impairment than neurological amnesia. Functional amnesia is characterized by a profound retrograde amnesia with little or no anterograde amnesia. In some cases, patients fully recover. Functional amnesia is a psychiatric disorder, and there is no particular brain structure or region whose damage is known to underlie this condition.
Etiology of neurological amnesia
Neurological amnesia results from a number of conditions including Alzheimer’s disease or other dementing illnesses, temporal lobe surgery, chronic alcohol abuse, encephalitis, head injury, anoxia, ischemia, infarction, and the rupture and repair of an anterior communicating artery aneurism. In all of these conditions, the common factor is the disruption of normal function in one of two areas of the brain - the medial aspects of the temporal lobe, and the diencephalic midline. Bilateral damage results in amnesia for all types of material, and unilateral damage results in material-specific amnesia. Specifically, left-sided damage especially affects memory for verbal material, while right-sided damage especially affects memory for nonverbal material (e.g., memory for faces and spatial layouts).
Anatomy of neurological amnesiaWell-studied cases of human amnesia and animal models of amnesia provide information about the neural connections and structures that are damaged. In humans, damage limited to the hippocampus (a structure within the medial temporal lobe) is sufficient to cause moderately severe amnesia. The severity of memory impairment is exacerbated by additional damage to medial temporal lobe structures outside of the hippocampus. (Animal studies later elucidated the critical anatomical components of this memory system. See Below.) One well-studied case (H.M.) had surgery in 1953 to treat severe epilepsy. Most of the hippocampus and much of the surrounding medial temporal lobe cortices were removed bilaterally (the entorhinal cortex and most of the perirhinal cortex). Although the surgery was successful in reducing the frequency of H.M.’s seizures, it resulted in a severe and persistent amnesia. To understand the anatomy of human amnesia, and ultimately the anatomy of normal memory, animal models of human amnesia have been established in the monkey (Mishkin 1982, Squire and Zola-Morgan 1983) ( Figure 1) and in the rodent.
Following lesions of the bilateral medial temporal lobe or medial diencephalon, memory impairment is exhibited on the same kinds of tasks of new learning ability that human amnesic patients fail. The same animals succeed at tasks of motor skill learning, and they also do well at learning pattern discriminations, which share with motor skills the factors of incremental learning and repetition over many trials. Systematic and cumulative work in monkeys, using the animal model, succeeded in identifying the system of structures in the medial temporal lobe essential for memory (Squire and Zola-Morgan 1991). The important structures are the hippocampal region (hippocampus proper, dentate gyrus, and subicular complex) and adjacent, anatomically related structures (entorhinal cortex, perirhinal cortex, and parahippocampal cortex). Damage limited to the hippocampal region causes significant memory impairment, and damage to the adjacent cortex increases the severity of memory impairment. It is also important to note that the discovery that larger medial temporal lobe lesions produce more severe amnesia than smaller lesions is compatible with the idea that structures within the medial temporal lobe might make qualitatively different contributions to memory function. The amygdala, although critical for aspects of emotional learning (Davis, 1994; LeDoux, 1996) and for the enhancement of declarative memory by emotion (Adolphs et al., 1997), is not a part of the declarative memory system itself. The consistency between the available neuroanatomical information from humans and the findings from monkeys have considerably illuminated the description of memory impairment and its anatomical basis. These lines of work have also made it possible to pursue parallel studies in simpler animals like rats and mice. As a result, one can now study memory in rodents and have some confidence that what one learns will be relevant to the human condition. Another important brain area for memory is the diencephalon. The structures important for memory include the mediodorsal thalamic nucleus, the anterior thalamic nucleus, the internal medullary lamina, the mammillary nuclei, and the mammillo-thalamic tract. Monkeys with medial thalamic lesions exhibit an amnesic disorder, and monkeys with mammillary nuclei exhibit a modest impairment. Because diencephalic amnesia resembles medial temporal lobe amnesia in the pattern of sparing and loss, these two regions likely form an anatomically linked, functional system.
The nature of neurological amnesia
Impairment in declarative memory
It is important to appreciate that amnesic patients are not impaired at all kinds of long-term memory. The major distinction is between declarative and nondeclarative memory. Declarative memory is the kind of memory impaired in amnesia, and it refers to the capacity to remember the facts and events of everyday life. It is the kind of memory that is meant when the term “memory” is used in ordinary language. Declarative memory can be brought to mind as a conscious recollection. Declarative memory provides a way to model the external world and in this sense it is either true or false. The stored representations are flexible in that they are accessible to multiple response systems and can guide successful performance under a wide range of test conditions. Lastly, declarative memory is especially suited for rapid learning and for forming and maintaining associations between arbitrarily different kinds of material (for example, learning to associate two different words).
Amnesia is characterized by profound difficulty in new learning, and this impairment is referred to as anterograde amnesia. In the circumscribed form of amnesia (when damage is restricted to the medial temporal lobe or midline diencephalon), patients have intact intellectual functions and intact perceptual functions, even on difficult tests that require the ability to discriminate between highly similar images containing overlapping features (Levy et al., 2005; Shrager et al., 2006). In some patients with memory impairment, visual perceptual deficits have been described (Lee et al., 2005a,b). In these cases, damage might extend laterally, beyond the medial temporal lobe, and quantitative brain measurements are needed in order to understand what underlies these deficits.
Amnesic patients are impaired on tasks of new learning, regardless whether memory is tested by free (unaided) recall, recognition (e.g., presenting an item and asking whether it was previously encountered or not), or cued recall (e.g., asking for recall of an item when a hint is provided). For instance, in a standard test of free recall, participants are read a short prose passage containing 21 segments. They are then asked to recall the passage immediately and after a 12-minute delay. Amnesic patients with damage to the medial temporal lobe do well at immediate recall but are impaired at the delay, usually recalling zero segments (Squire and Shimamura, 1986). Amnesic patients are also impaired on recognition tests where a list of words is presented, and participants try to decide (yes or no) if each word had been presented in a recent study list (Squire and Shimamura, 1986). Similarly, recognition is impaired when items are presented together, and participants decide which of the items had been presented previously (Bayley et al., 2008). Lastly, in a cued recall task, individuals study a list of word pairs, such as ARMY-TABLE. During test, they are presented with one word from each pair (ARMY), and they are asked to recall the word that was paired with it (TABLE). Amnesic patients are impaired on this task as well.
The memory impairment in amnesia involves both difficulty in learning factual information (semantic memory) as well as difficulty in learning about specific episodes and events that occurred in a certain time and place (episodic memory). The term semantic memory is often used to describe declarative memory for organized world knowledge (Tulving, 1983). In recalling this type of information, one need not remember any particular past event. One needs only to know about certain facts. Episodic memory, by contrast, is autobiographical memory for the events of one’s life (Tulving, 1983). Unlike semantic memory, episodic memory includes spatial and temporal landmarks that identify the particular time and place when an event occurred. Both episodic memory and semantic memory are declarative. The memory deficit in amnesia is global, in that it encompasses all sensory modalities (e.g., visual, auditory, olfactory). That is, memory is impaired regardless of the kind of material that is presented and the sensory modality in which information is presented.
In addition to impaired new learning, damage to the medial temporal lobe also impairs memories that were acquired before the onset of amnesia. This type of memory loss is referred to as retrograde amnesia. Retrograde amnesia is usually temporally graded. That is, information acquired in the distant past (remote memory) is spared relative to more recent memory (Ribot, 1881). The extent of retrograde amnesia can be relatively short and encompass only one or two years, or it can be more extensive and cover decades. Even when retrograde amnesia is extensive, memories for the facts and events of childhood and adolescence are typically intact. Indeed, severely amnesic patients can produce detailed autobiographical narratives of their early life (Bayley et al., 2003; 2005b; Kirwan et al., 2008).
The severity and extent of retrograde amnesia is determined by the locus and extent of damage. Patients with restricted hippocampal damage have limited retrograde amnesia covering a few years prior to the onset of amnesia. Patients with large medial temporal lobe damage have extensive retrograde amnesia covering decades. When damage occurs beyond the brain system that supports declarative memory, which can result from conditions such as encephalitis and head trauma, retrograde amnesia sometimes can be ungraded, extensive, and include the facts and events of early life. Such extensive deficits can occur from damage to cortical storage sites or cortical regions that are critical for retrieval.
Because the study of human retrograde amnesia is based almost entirely on findings from retrospective tests, the clearest data about retrograde amnesia gradients come from studies using experimental animals, where the delay between initial learning and occurrence of damage can be manipulated directly. Findings from such studies make three important points. First, temporal gradients of retrograde amnesia can occur within long-term memory. Second, after a lesion, remote memory can be even better than recent memory. Third, lesions can spare old weak memories while disrupting strong recent ones, showing that it is the age of the memory that is critical.
The sparing of remote memory relative to more recent memory illustrates that the brain regions damaged in amnesia are not the permanent repositories of long-term memory. Instead, memories undergo a process of reorganization and consolidation after learning, during which time the neocortex becomes more important. During the process of consolidation, memories are vulnerable if there is damage to the medial temporal lobe or diencephalon. After sufficient time has passed, storage and retrieval of memory no longer require the participation of these brain structures. Memory is at that point supported by neocortex, such that memory is intact even when there is damage to the medial temporal lobe. The areas of neocortex important for long-term memory are thought to be the same regions that were initially involved in the processing and analysis of what was to be learned. Thus, the neocortex is always important, but the structures of the medial temporal lobe and diencephalon are also important during initial learning and during consolidation.
Since the discovery of hippocampal place cells in the rodent (O’Keefe and Dostrovsky, 1971), an influential idea has been that the hippocampus creates and uses spatial maps and that its predominant function is to support spatial memory (O’Keefe and Nadel, 1978). As a result, discussions of amnesia have focused especially on the status of spatial memory. It is clear that spatial memory is impaired in human amnesia. Amnesic patients are impaired on tests that assess their knowledge of the spatial layout of an environment, and they are also impaired when asked to navigate to a destination in a virtual environment (Maguire et al., 1996; Spiers et al., 2000). Similarly, the noted patient H.M. was impaired at recalling object locations (Smith, 1988). It is also clear, though, that amnesic patients are impaired on memory tests that have no obvious spatial component, such as recall or recognition of items (Squire and Shimamura, 1986). Furthermore, formal experiments that directly compared spatial and nonspatial memory in amnesic patients showed that the patients were similarly impaired on tests of spatial memory and tests of nonspatial memory. There was not a special difficulty with tests of spatial memory (Cave and Squire, 1991).
As is the case with nonspatial memory, remote spatial knowledge is intact. One well-studied patient with large medial temporal lobe lesions and severe amnesia (E.P.) was able to mentally navigate the neighborhood where he grew up, use alternate and novel routes to describe how to travel from one place to another, and point correctly to locations in the neighborhood while imagining himself oriented at some other location (Teng and Squire, 1999). These findings show that the medial temporal lobe is not needed for the long-term storage of spatial knowledge and does not maintain a spatial layout of learned environments that is necessary for successful navigation. Accordingly, the available data support the view that the hippocampus and related medial temporal lobe structures are involved in learning new facts and events, both spatial and nonspatial. Further, these structures are not repositories of long-term memory, either spatial or nonspatial.
Spared learning and memory abilities
It is a striking feature of amnesia that many kinds of learning and memory are spared. Memory is not a unitary faculty of the mind but is composed of many parts that depend on different brain systems. Amnesia impairs only declarative memory and spares immediate and working memory as well as nondeclarative memory.
Immediate and working memory
Amnesic patients have intact immediate memory. Immediate memory refers to what can be held actively in mind beginning the moment that information is received. It is the information that forms the focus of current attention and that occupies the current stream of thought. The capacity of immediate memory is quite limited. This type of memory is reflected, for example, in the ability to repeat back a short string of digits. Intact immediate memory explains why amnesic patients can carry on a conversation and appear quite normal to the casual observer. Indeed, if the amount of material to be remembered is not too large (e.g., a 3-digit number), then patients can remember the material for minutes, or as long as they can hold it in mind by rehearsal. One would say in this case that the patients have carried the contents of immediate memory forward by engaging in explicit rehearsal. This rehearsal-based activity is referred to as working memory, and it is independent of the medial temporal lobe system. The difficulty for amnesic patients arises when an amount of information must be recalled that exceeds immediate memory capacity or when information must be recalled after a distraction-filled interval or after a long delay. In these situations, when the capacity of working memory is exceeded, patients will remember fewer items than their healthy counterparts.
Motor and perceptual skills
One can learn how to ride a bicycle but be unable to describe what has been learned, at least not in the same sense that one might recall riding a bicycle on a particular day with a friend. This is because the learning of motor skills is largely nondeclarative, and it has been shown that amnesic patients can learn skills at a normal rate. In one experiment, amnesic patients and control participants performed a serial reaction-time task, where they responded successively to a sequence of four illuminated spatial locations. The task was to press one of four keys as rapidly as possible as soon as the location above each key was illuminated. The amnesic patients learned the sequence, as did the normal participants, as measured by their decreased reaction times to press a key when it was illuminated. When the sequence was changed, the reaction times increased for both groups. Strikingly, the amnesic patients had little or no declarative knowledge of the sequence, though they had learned it normally (Reber and Squire, 1994).
Perceptual skills are also often intact in amnesic patients. These include such skills as reading mirror-reversed print and searching a display quickly to find a hidden letter. In formal experiments, amnesic patients acquired perceptual skills at the same rate as individuals with intact memory, even though the patients did not remember what items were encountered during the task and sometimes did not remember the task itself. For example, amnesic patients learned to read mirror-reversed words at a normal rate and then retained the skill for months. Yet, after they had finished the mirror-reading task, they could not remember the words that they had read and in some cases could not remember that they had ever practiced the mirror-reading skill on a previous occasion (Cohen and Squire, 1980).
Priming refers to an improved ability to identify or produce a word or other stimulus as a result of its prior presentation. The first encounter with an item results in a representation of that item, and that representation then allows it to be processed more efficiently than items that were not encountered recently. For example, suppose that a line drawing of a dog, hammer, and airplane, are presented in succession, with the instruction to name each item as quickly as possible. Typically, about 800 milliseconds are needed to produce each name aloud. If in a later test these same pictures are presented intermixed with new drawings, the new drawings will still require about 800 milliseconds to name, but now the dog, hammer, and airplane are named about 100 milliseconds more quickly. The improved naming time occurs independently of whether one remembers having seen the items earlier. Amnesic patients exhibit this effect at full strength, despite having poor declarative memory of seeing the items earlier.
Adaptation-level effects refer to the finding that experience with one set of stimuli influences how a second set of stimuli is perceived (e.g., their heaviness or size). For example, experience with light-weighted objects subsequently causes other objects to be judged as heavier than they would be if the light-weighted objects had not been presented. Amnesic patients show this effect to the same degree as healthy individuals, even when they experience the first set of objects with one hand and then make judgments with the other hand. However, they have difficulty remembering their prior experience accurately (Benzing and Squire, 1989).
Classical conditioning refers to the development of an association between a previously neutral stimulus (CS) and an unconditioned stimulus (US) and is a quintessential example of nondeclarative memory. One of the best-studied examples of classical conditioning in humans is delay conditioning of the eyeblink response. It is reflexive and automatic and depends solely on structures below the forebrain, including the cerebellum and associated brainstem circuitry (Thompson and Krupa, 1994). In a typical conditioning procedure, a tone repeatedly precedes a mild airpuff directed to the eye. The tone overlaps the airpuff, and they terminate together. After a number of pairings, the tone comes to elicit an eyeblink in anticipation of the airpuff. Amnesic patients acquire and retain the tone-airpuff association at the same rate as healthy individuals. In both groups, awareness of the temporal contingency between the tone and the airpuff is unrelated to successful conditioning.
In trace conditioning, a brief interval of 500-1000 msec is interposed between the CS and the US. This form of conditioning requires the hippocampus (McGlinchey-Berroth et al., 1997). Formal experiments suggest that trace conditioning is hippocampus-dependent because it requires the acquisition and retention of conscious knowledge during the course of the conditioning session (Clark and Squire, 1998). Only those who became aware of the CS-US relationship acquired differential trace conditioning. There was a correlation between measures of awareness taken after the conditioning and trace conditioning performance itself, whereas there was no correlation between awareness and conditioning performance on a delay conditioning task.
Habit learning refers to the gradual acquisition of associations between stimuli and responses, such as learning to make one choice rather than another. Habit learning depends on the neostriatum (basal ganglia). Many tasks can be acquired either declaratively, through memorization, or nondeclaratively as a habit. For example, healthy individuals will solve many trial-and-error learning tasks quickly by simply engaging declarative memory and memorizing which responses are correct. In this circumstance, amnesic patients are disadvantaged. However, tasks can also be constructed that defeat memorization strategies, for example, by making the outcomes on each trial probabilistic. In such a case, amnesic patients and healthy individuals learn at the same gradual rate (Knowlton et al., 1996). It is also true that severely amnesic patients who have no capacity for declarative memory can gradually acquire trial-and-error tasks, even when the task can be learned declaratively by healthy individuals. In this case they succeed by engaging habit memory. This situation is nicely illustrated by the 8-pair concurrent discrimination task, which requires individuals to learn the correct object in each of eight object pairs. Healthy individuals can learn all eight pairs in one or two test sessions. Severely amnesic patients acquire this same task over many weeks, even though at the start of each session they cannot describe the task, the instructions, or the objects. It is known that this task is acquired at a normal (slow) rate by monkeys with medial temporal lobe lesions, and that monkeys with lesions of the neostriatum (basal ganglia) are impaired. Thus, humans appear to have a robust capacity for habit learning that operates outside of awareness and independently of the medial temporal lobe structures that are damaged in amnesia (Bayley et al., 2005a).
Functional amnesia, also known as dissociative amnesia, is a dissociative psychiatric disorder that involves alterations in consciousness and identity. Although no particular brain structure or brain system is implicated in functional amnesia, the cause of the disorder must be due to abnormal brain function of some kind. Its presentation varies considerably from individual to individual, but in most cases functional amnesia is preceded by physical or emotional trauma and occurs in association with some prior psychiatric history (Kritchevsky et al., 2004). Often, the patient is admitted to the hospital in a confused or frightened state. Memory for the past is lost, especially autobiographical memory and even personal identity. Semantic or factual information about the world is often preserved, though factual information about the patient’s life may be unavailable. Despite profound impairment in the ability to recall information about the past, the ability to learn new information is usually intact. The disorder sometimes clears and the lost memories return. Sometimes, the disorder lasts longer, and sizable pieces of the past remain unavailable.
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