Amnesia Research Paper

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Through the study of amnesic patients, cognitive neuroscience  has advanced  our  understanding  of the processes that underlie learning and remembering. Memory is now understood  to be a collection of functional  systems,  with  each  contributing  uniquely to the storage and retrieval of information.  The study of neurological populations  with lesions that interfere with the function  of specific components  of memory has revealed distinct  roles for these memory systems. This understanding  has provided the theoretical foundation  for evidence-based treatment  approaches.


  1. Introduction
  2. The Contribution of Patient H.M.
  3. Impaired Memory in Amnesia: Declarative Memory
  4. Preserved Aspects of Memory in Amnesia: Nondeclarative Memory
  5. Amnesic Syndromes
  6. Neuropathology of Amnesia
  7. Approaches to Treatment of Amnesic Disorders

1. Introduction

In 1606, Shakespeare’s Lady Macbeth described memory as ‘‘the warder  of the  brain,’’ as a function  that somehow  stands  apart  from the  brain’s other  cognitions  while  bearing  witness  to  them.  She made  this reference while planning to induce a temporary amnesia in the king’s attendants by getting them drunk. Her aim  in  doing  so  was  to  ensure  that  the  attendants would not recall the events surrounding  her husband’s intended  murder  of the king. She knew that after the deed   was  done   and   their   alcohol-induced   stupor passed off, they would  be left witness to a blank,  to a  discontinuity  in  their  experience,  and  not  to  the murder.  For memory to be capable of keeping an account of the swift interplay of sensations, perceptions, and thoughts that make up events and thereby give experience its continuity,  memory must itself have an underlying  continuity.  If it  did  not,  there  would  be nothing  for people to ‘‘go  back to’’  that  would  allow them  to  witness  an  earlier  event  again,  and  Lady Macbeth would have had nothing to fear from any witnesses to her husband’s intended  crime. Now, four centuries later, modern cognitive neuroscience is going beyond   description.    It   investigates   how   memory enables  people  to  actively  bring  the  past  into  the present moment, thereby allowing them to experience their personal persistence through  time.

The fact that  memory can fail has been known  for millennia,  but  its  failure  was not  specifically called ‘‘amnesia’’ (from the Greek for forgetfulness) until relatively recently  in 1786.  In current  common  use, amnesia  refers loosely and  interchangeably  to  either one of two quite  different states or to both  of them. First, it refers to a state in which memories that were available for recall in the past have been lost and are no longer available in the present.  Second, it refers to a state in which current  experiences are not being kept account of and duly recorded, with the result that they will not be available for recall in the future. The first usage is reflected in the Oxford English dictionary definition of amnesia as ‘‘loss of memory’’ and roughly coincides with retrograde amnesia, whereas the second usage is reflected in the Merriam–Webster  dictionary definition   as  ‘‘forgetfulness’’  and  roughly  coincides with anterograde amnesia. The loss of previously consolidated memories, on the one hand, and the inability to create and retain new memories, on the other,  are states that can occur separately. However, more often than  not, both  occur  together  in the same individual following a single event, hence the tendency to refer to either or both of them without distinction by means of the same term ‘‘amnesia.’’

In addition to its common meaning, the term ‘‘amnesia’’  has both  a general sense and  a specific sense in current  scientific literature.  In general, it refers to any pathological loss of the ability to acquire or recall information. In that sense, it encompasses psychogenic amnesia, posttraumatic  amnesia following closed head injury, memory loss that occurs along with other major cognitive impairments in progressive degenerative neurological  disorders  such  as  Alzheimer’s disease, and isolated global memory loss that characterizes the amnesic syndromes. In its more restricted use, it refers specifically to these latter syndromes, and it is in this sense that the term is used in what follows.

Early investigation  of the amnesic syndromes  proceeded both by means of clinical case descriptions and through  the correlation of lesion analyses with deficits found through  neuropsychological  investigations. The most widely known of the early case studies was of the patient ‘‘H.M.,’’ and it is through studies of his memory function  that  the  current  understanding   of amnesia began to unfold.

2. The Contribution Of Patient H.M.

At 9 years of age, H.M. suffered a head injury followed by seizures that became more frequent and more severe over the subsequent 18 years. In 1953, as a treatment of last resort, he underwent  an experimental  neurosurgical operation  in which  a large portion  of the  medial temporal  region of his brain was removed bilaterally. That extensive resection was successful in reducing his seizures, but it left him with an unexpected devastating memory loss.

One striking finding that came to light in the early studies  of H.M.’s memory loss was that  his profound forgetfulness and loss of personal memories had occurred  without  any damage to his general intellectual ability, attention, and language. This discovery established that normal medial temporal lobe functioning  is necessary  for  the  accumulation  of memories. However, the fact that its dysfunction  does not interfere with the attention,  thoughts, and perceptions that give rise to experiences in the first place suggests that memory  is specifically linked  to  the  function  of the medial temporal lobe. Further  studies of H.M.’s memory impairment led to the current understanding  of the characteristics of hippocampal amnesia. They also revealed that memory, rather than being a unitary capacity,  is composed  of several functional  systems, not all of which are impaired  in amnesia. Those systems  fall  into  two  major  classes.  The  first  group involves nondeclarative  memory,  that  is, the form of memory that functions without awareness. The second group involves declarative memory, that is, the form of memory  that  supports  conscious  retrieval  of experiences. It is the latter form of memory that is impaired in amnesia.

3. Impaired Memory in Amnesia: Declarative Memory

After H.M.’s operation, it became apparent that he had suffered damage to the memory system that supports the  conscious  (intentional)  retrieval  of experiences. Not  only  did  he  fail to  remember  the  events  of his then  current  day-to-day  life, but  he  also  could  not recall  memories  he  had  accumulated  over  much  of his life prior to the onset of his amnesia. This clinical profile of severe anterograde amnesia together with an extensive retrograde  memory impairment  is typical of hippocampal  amnesia.

3.1.  Retrograde Amnesia

H.M.’s inability to recall memories that he had formed prior to the onset of his amnesia extended back approximately  11 years. The density of his retrograde amnesia followed Ribot’s law, a semi quantitative description  offered in 1881 that  states that  the  ‘‘loss of memory is … inversely [related to] the time that has elapsed between any given incident and the fall (injury). … The new dies before the old.’’ H.M. showed just such a temporal  gradient.  His inability to recall autobiographical and public events from shortly before his operation  was total, but his amnesia was found to be less dense as testing probed further back in time and he was able to remember more and more.

Investigation  of patients  with a variety of amnesic syndromes  has demonstrated  that  such  a temporally graded retrograde amnesia is common and that its severity and duration  tend to vary with the size of the brain  lesion.  Retrograde  amnesia  can affect both  the recall of autobiographical  and public events (episodic memory) and the retrieval of facts and concepts (semantic memory) that were known before the onset of amnesia. However, episodic and semantic memory are differentially affected across syndromes. For example, some patients  have severe retrograde  amnesia for events together  with relatively preserved  memory for facts and concepts,  whereas others show the opposite pattern  with severely impaired  semantic  memory but relatively preserved episodic remote memory.

The finding of a graded decrease in the density of memory  loss  as  probing  moves  backward  through time  starting  from  the  onset  of amnesia  establishes two  important   facts  regarding   how  memories   are stored   and   retrieved.   First,   it   establishes   that   a functional medial temporal region is required for permanent  learning of new information.  Second, it indicates that the medial temporal lobe is not the ultimate repository of long-term memories given that long-established  memories  can  survive  and  be  available for recall despite the presence of medial temporal damage. It has since been found that long-term memories  are stored  in the  neocortex,  specifically in the lateral temporal regions. This is confirmed by the fact that  in patients  with lesions in these areas, even old memories can be permanently  lost, so that their retrograde  amnesia  is  not  temporally  graded.  Thus,  the medial  temporal  lobes  and  neocortical  areas  make unique  contributions   to  information  storage.  When an  event  is  originally  experienced,  separate  aspects of the event, such as its perceptual characteristics, emotional  connotations,  and associated thoughts,  are processed  in  initially  unconnected   sites  throughout the cortex, as determined  by the functional specialization of various parts of the brain. The medial temporal lobes, and especially the hippocampus, provide the glue that allows these diverse aspects to be linked together into a single representation.  When a part of any event is recalled again, the hippocampus  is engaged, and it simultaneously reactivates the spatially separated cortical traces that together make up the brain’s representation of the whole event. With repeated activation over time, links are established among the involved neocortical sites. Eventually,  these  separate  neocortical  sites that collectively represent  a single event become interlinked to the extent that hippocampal  activation is no longer necessary for recall of the event as a whole. It is at that point that the consolidated memory can survive medial temporal lobe damage.

3.2.  Anterograde Amnesia

The nature of the impact of H.M.’s neurosurgery on his cognition   gradually  became  apparent   when  it  was noticed  that  H.M. consistently  failed to recall having eaten a meal and that he failed to develop any ability to get to know the people who provided his daily care. This  anterograde  amnesia  was  so  pervasive  that  he could  hold onto new information  for only a few seconds and then only if there was no distraction.  If his attention was diverted, the information faded away and was not available for recall. As was noted  earlier, the normal functioning of the hippocampus  and surrounding medial temporal lobe structures is crucial for forming and storing new memories. In general, the severity of anterograde amnesia is proportional  to the extent of damage to medial  temporal  structures.  Furthermore, because the hippocampus  receives input from a variety of neocortical regions that process information  in the various  sensory  modalities,  such  anterograde  loss is invariably global; that  is, it involves both  verbal and nonverbal information in all possible modalities of presentation.  Such dense global anterograde  memory impairment  is the  hallmark  of medial temporal  lobe amnesia.

Anterograde  amnesia   is   evaluated   in   the clinic through tasks that measure recall and recognition of information  to which the individual is exposed during a testing session. Recall tasks require that recently learned information be consciously and deliberately retrieved in  response  to  a question,  whereas  recognition  tasks require that previously encountered  information be distinguished  from, and so recognized  among, foils. The recognition format is generally easier for normal individuals because it requires  less retrieval  effort than  does recall. Recognition is thought to be easier for individuals with intact  memories  because recall depends  on conscious  and  effortful recollection,  whereas  recognition can be supported  not only by recollection  but also by familiarity. Familiarity  refers to the sense of knowing that arises when a stimulus is processed with ease. Recollection and familiarity can be distinguished  from one another  experientially.  For example, consider  the situation where a man hears his name being called out while he is in a crowd. He turns and sees the woman who called his name and has a short conversation with her. The woman is familiar to the man, but he cannot recall any context  that  accounts  for that  familiarity. Several days later, the man receives a telephone  call from the woman in which she identifies her place of work and, at that moment, he knows who she is and is flooded with memories  of details  and  events.  Sudden  recollection replaces felt familiarity. In the laboratory, patients with amnesia secondary to medial temporal lobe damage generally show impairments on both recall and recognition  tasks, suggesting that  familiarity and  recollection both  are  impaired.  However,  some  amnesic  patients show  relatively  preserved  recognition   memory,  and this may reflect their residual ability to use familiarity as a basis for remembering.

Patients with lesions involving the frontal lobes, either directly or indirectly, can also have severe deficits in memory. However, although  their performance is impaired  on tasks of free recall, they show normal performance on tasks that require the recognition of previously learned information. This performance  disparity  between  recall  and  recognition  is due  to  the  distinct  roles  of  the  medial  temporal lobes  and  the  frontal  lobes.  The  medial  temporal lobes contribute  to the encoding, storage, and retention of newly learned information, whereas the frontal lobes support the organizational and strategic aspects of memory necessary for developing encoding and retrieval strategies, monitoring and verifying memory output, and setting order within the recalled memories.

4. Preserved Aspects Of Memory In Amnesia: Nondeclarative Memory

H.M.’s severe amnesia notwithstanding, some aspects of his  memory  functioning  were  found  to  be  intact following his  surgery.  In  contrast  to  his  inability  to consciously  retrieve  information  acquired  before and after  onset  of his  amnesia,  it  was  found  that  H.M. showed  evidence  of learning  on  tasks  that  did  not require his awareness of the learning episode.

 4.1.  Procedural  Memory

Careful experimental  study brought  to light that H.M. was able to acquire specific perceptual–motor skills as well as do  normal  individuals.  One  such  motor  task involved his tracing the outline  of a star with a stylus while gaining feedback of his ongoing performance through  the reflection of his performance  in a mirror. H.M. improved  with repetition  exactly as did normal individuals. But for him, each trial was experienced as if it were his first trial, despite his steady improvement. He had no way of knowing that he was getting better at it, as normal people did. This finding was one of the first to show that procedural memory (i.e., the ability to know how)  is  distinct  from  declarative  memory  (i.e.,  the ability to know that something occurred).  It also established that procedural memory does not depend on the integrity of the medial temporal lobes. Procedural memory develops gradually through  repetition  without  any requisite awareness that the skill is being learned.

4.2.  Repetition Priming

Priming is another form of learning that occurs without conscious awareness. It is defined as a bias or facilitation in identifying or responding to certain information to which one has been exposed previously. In contrast to procedural learning, the effect of priming can be seen following a single exposure. In a typical priming task, an individual is asked to view a list of words or pictures. The individual  is then  asked to perform a seemingly unrelated task such as naming words or identifying degraded pictures.  Unbeknownst  to the individual,  some of the stimuli in the second task were part of the list of stimuli that were seen in the first task, whereas others are presented  for  the  first  time.  Priming  is  in  evidence when naming or identification of previously seen stimuli occurs faster or more accurately than does identification of stimuli not seen previously. Amnesic patients  show intact priming across a broad variety of tasks. Sometimes priming reflects facilitation of the processes that support the perception  of stimuli, whereas other times priming reflects the facilitation of processes that support conceptual analysis (i.e., meaningful interpretation) of stimuli. Both perceptual  priming  and  conceptual  priming  are independent   of medial  temporal  structures,  and  both depend on distinct neocortical regions.

5. Amnesic Syndromes

Amnesia can  result  from  a variety  of etiologies  that cause damage to various regions of the brain. For example, diencephalic  amnesia, the memory disorder of  patients  with  Korsakoff’s syndrome,  arises  from damage to structures  that make up the diencephalon, particularly the mammillary bodies, the anterior thalamic nuclei,  and  the  medial  dorsal  thalamic  nucleus. Basal forebrain amnesia, in contrast,  arises in patients with  a history  of rupture  and  repair  of an  anterior communicating  artery (ACoA) aneurysm and is caused by damage  to  structures  of the  basal  forebrain,  the septum, and frontal brain regions. The following is an overview of the  clinical characteristics  of five of the more common amnesic syndromes.

5.1.  Herpes Simplex Encephalitis

Herpes simplex encephalitis (HSE) is an acute inflammation of the brain caused by a herpes simplex virus infection. Some patients recover fully following infection, but most are left with a cluster of cognitive deficits that include a memory disorder.  The heterogeneous  pattern of these cognitive impairments  reflects the extent  and variability of damage to the brain. Among those patients who  recover,  a small number  are left with  a circumscribed amnesic syndrome similar to that of H.M. The fact that  these  two  forms of amnesia  share  a clinical profile is not surprising  given that  the herpes simplex virus preferentially affects medial temporal  brain structures, including the hippocampus  and adjacent entorhinal, perirhinal, and parahippocampal  cortices. In all post encephalitic  patients, the extent of any anterograde memory  impairment  is proportional  to the  amount  of damage to the medial temporal  lobes. Although some patients  are incapable of any new learning, others  can learn and can benefit from increased study time, external cues, and/or repeated exposure. Because the herpes virus can affect the brain asymmetrically, the pattern  of anterograde memory loss will also depend on the laterality of damage. The greater the damage to the right temporal region, the greater the difficulty in performing nonverbal/ visual memory tasks (e.g., memory for faces), whereas the greater the damage to the left temporal  region, the greater the deficit in verbal memory.

Postencephalitic  patients  with damage extending  to the lateral temporal  lobes, the region where memories are permanently stored, will have dense retrograde amnesia for autobiographical  and public information  with little or no temporal gradient. Damage to the right anterior temporal region interferes primarily with retrieval of autobiographical  memories, whereas damage to the left temporal cortex impairs semantic memory.

5.2.  Anoxia

Amnesia can result from damage to, or death of, brain tissue due to a lack of oxygen supply to the brain. This can be caused either by reduced blood flow, such as in cardiac arrest or strangulation,  or by normal perfusion with hypoxic blood secondary to respiratory distress or carbon monoxide poisoning. When the oxygen supply to brain tissue is disrupted,  compensatory mechanisms that maintain cerebral homeostasis are triggered immediately. These protective autoregulatory mechanisms, although  effective in adjusting  for sudden  short-lived changes,  will eventually  fail in  the  face of sustained oxygen   deprivation.   Oxygen   deprivation   for   3   to 8 minutes  will trigger the release of excitatory  neurotransmitters that can result in damage to the hippocampus. Shorter events may also damage regions that  are perfused by terminal vascular branches or that lie in the watershed  regions because these areas are deprived  of oxygen early on.  Longer lasting  events  will result  in neuronal  damage that  extends  to the  cerebellum,  the basal ganglia, the thalamus, and neocortical areas. The outcome  following an anoxic event depends  on many factors, including  the cause and duration  of the event as well as the age and health  status of the individual.

Therefore, it is not surprising  to find variability in the clinical profiles associated with anoxic events. Most individuals who have suffered an anoxic brain injury experience a memory disorder along with other cognitive impairments. On occasion, an isolated amnesic syndrome is documented  secondary to a lesion in the  hippocampus.  When  the  lesion is limited  to the CA1 area  of  the  hippocampus,   there  is  moderately severe anterograde  amnesia  together  with  very mild retrograde  loss. When the lesion extends  beyond the CA1 area of the hippocampus  but remains limited to the hippocampal formation, there is severe anterograde memory impairment and more robust retrograde memory impairment  that  can extend  back  more  than  15 years.   More   commonly,   however,   anoxic   patients have a memory  impairment  that  is akin  to that  seen in patients with damage to the frontal brain region due to disruption  of frontal–subcortical  circuits as a result of damage to watershed  zones in the cerebral cortex. Rather than  encoding,  storage, and retention  deficits, these  patients  demonstrate  impairments  at  the  level of the organizational and strategic aspects of memory.

5.2.1. Anterior Communicating Artery Aneurysm

Memory deficits, along with associated behavioral disorders, frequently follow rupture  and surgical repair of an ACoA aneurysm. Such deficits vary from a very mild impairment  to a severe amnesic  disorder  called basal forebrain amnesia. This wide variability reflects the fact that the ACoA perfuses a broad anatomical brain region, all of which  is vulnerable  in the  event  of rupture  to damage from infarction, either directly or secondary to subarachnoid   hemorrhage,   vasospasm,  or  hematoma formation.  Basal  forebrain  amnesia  is usually  due  to damage to the septal nucleus and the subcallosal area. Disruption of hippocampal functioning may play a role in  the  amnesia  of at  least  some  patients  with  ACoA aneurysm because several basal forebrain nuclei contain a large number of cholinergic neurons that innervate the hippocampus   as  well  as  large  neocortical   regions. Disruption  of frontal  network  systems can occur  and may also contribute to the quality of the memory deficit seen in some ACoA aneurysm-related forms of amnesia. The severe deficit in recall found in basal forebrain amnesia shares superficial similarities with the anterograde  memory  impairment  that  characterizes  medial temporal  lobe amnesia. However, the deficit in basal forebrain  amnesia is due  to inefficient encoding  and not  to the  failure of consolidation  that  characterizes

medial temporal  amnesia. As a result,  ACoA patients will benefit from the use of encoding strategies, whereas patients with medial temporal lobe damage will not. Another  difference  is  found  in  the  performance  of ACoA patients  on  recognition  tasks,  where  they  are found to succeed more often than their medial temporal lobe counterparts. This recall–recognition disparity is attributed  to the frontal executive component  of the amnesia that follows ACoA aneurysm, particularly the disruption  of strategic effortful search  processes  that give access to information  stored in memory. Another executive contribution  to the disorder is the tendency of some ACoA patients to score many false positives on recognition tasks, a finding that suggests an additional impairment  in the ability to monitor  the outcome  of a memory search. Retrograde memory is nearly always impaired  in  amnesia  secondary  to  ACoA aneurysm, and it invariably shows a temporal gradient. However, patients  do appear to benefit substantially  more from cueing than do other amnesic groups, suggesting that impaired  retrieval  efficiency contributes  to  both  the anterograde and retrograde aspects of their amnesia.

5.2.2. Stroke

Amnesia is a common consequence of infarction of the posterior  cerebral artery (PCA). It results from neural tissue damage caused by the interruption of blood flow to a large part of the medial temporal  lobes, particularly the posterior  two-thirds of the hippocampus,  the parahippocampal   gyrus,  and  other  critical  pathways that  connect  the  hippocampus  to  surrounding  brain areas.  A more  posterior  extension  of the  lesion  will result in other neuropsychological  deficits in addition to the memory  disturbance,  for example, visual field defects and  other  visual disturbances  that  may affect reading and cause problems with color identification, space perception,  and/or  object  naming.  The  typical memory disturbance associated with bilateral PCA infarction is an inability to establish new memories in the  presence  of preserved  intelligence  and  attention. Retrograde  memory  problems  are also often present. There have been several reported cases of bilateral PCA infarction that spared the medial temporal lobes proper but that involved the occipital lobes bilaterally as well as the  deep  white  matter  of both  the  occipital  and temporal  lobes. These patients  present  with  a visual amnesic syndrome that results from the disconnection between  occipital  cortices  involved in visual processing and temporal  brain regions supporting  memory. There have been other reported cases in which the PCA infarction was unilateral. Patients with infarction of the left PCA present with a selective verbal memory deficit, whereas patients with infarction of the right PCA have preserved verbal memory but impaired  visual processing skills and impaired visual memory.

Amnesia can also be caused by thalamic infarction. In such cases, the severity of the memory impairment is related  to the site of damage within  the thalamus. Lesions that damage the mammillo–thalamic  tract, in particular,  have  been  associated  with  severe anterograde amnesia. Infarction of the medial dorsal thalamic nuclei has also been associated with memory impairments, but it appears that the damage must extend beyond the medial dorsal nucleus to include the mammillo–thalamic tract or anterior  nucleus for the development of a severe amnesic disorder. Because the thalamus  has rich connections  with the frontal lobes, this  anterograde  amnesia  is also accompanied  by an increased  sensitivity  to  interference  and  by  impairments in executive functioning. As with other amnesic syndromes, left-sided lesions result in impairments  on tasks  of verbal  learning,  whereas  right-sided  lesions result in nonverbal/visual memory impairments. Retrograde memory deficits following thalamic infarction are variable; some patients are found to have little impairment  in remote  memory,  whereas others  demonstrate severe long-term memory impairments.

5.2.3. Wernicke–Korsakoff Syndrome

Wernicke–Korsakoff syndrome (WKS) is seen in patients with a history of long-term alcohol abuse in association with poor nutrition and a lack of Vitamin B1 (thiamine). In acute Wernicke’s encephalopathy, patients exhibit confusion,  a gait disorder  (ataxia),  and  abnormal  eye movements (oculomotor palsy). Treatment with large doses  of thiamine  may result  in  improvement  in,  or even reversal  of, some  of these  symptoms.  However, most patients are left with a permanent  dense amnesic disorder referred to as Korsakoff’s syndrome. This amnesic syndrome arises from damage to the thalamic nuclei, the mammillary bodies, and the frontal system.

Patients with WKS suffer from both anterograde and retrograde amnesia. Several explanations  have been proposed to account for their episodic memory impairment. Although early models emphasized their superficial and deficient encoding strategies or their failure to inhibit competition  from irrelevant material at the time of retrieval, current  views agree that an explanation  of their learning deficits is best accounted for by a theory that  integrates  both  encoding  and  retrieval  processes.

The retrograde amnesia in WKS has a steeper temporal gradient than that found in medial temporal lobe amnesia. The  concomitant  presence  of frontal  dysfunction in   Korsakoff’s  patients   is  believed  to  account   for their poorer performance on remote memory tests. Intelligence is usually preserved in Korsakoff’s patients, but there are often associated cognitive and neurobehavioral deficits that are unique to this patient population. In particular,  some combination  of impaired  planning and initiation, passivity, apathy, confabulation, and limited insight is nearly always found. These symptoms are thought to arise from associated frontal dysfunction.

6. Neuropathology Of Amnesia

For centuries, any lapse in the functioning of the warder of the brain’s cognitions was described, and eventually defined, as simple forgetfulness. During the first half of the 20th century,  it was thought  that memory, as the cognition  that  keeps account  of other  cognitions,  was not dependent  on the activity of a circumscribed  brain region  (as are those  other  cognitions)  but  rather  was directly  dependent   on  the  functioning  of the  whole brain. There also emerged an opposing view that held that memory function was localized in the brain. There was no conclusive experimental evidence for either view until, at midcentury, the consequences of H.M.’s surgical resection decided the matter in favor of a localized brain representation  for declarative memory. Later evidence similarly established  distinct  localizations  for priming and  procedural  learning,  two forms of nondeclarative memory. Cognitive neuroscience has since clarified the nature of those localizations in substantial detail.

6.1.  Declarative Memory

Declarative memory is mediated by a group of interconnected  structures  that are part of the extended  limbic system. Within the limbic system, two interacting memory circuits can be identified: the Papez circuit and the basolateral circuit. The Papez circuit is composed of the hippocampus,  the fornix, mammillary bodies, the anterior thalamus,  and the posterior  cingulate gyrus (with additional  connections  to  the  basal forebrain  via the fornix). The basolateral circuit is composed of the amygdala and surrounding perirhinal cortex, the dorsomedial thalamus, and the prefrontal cortex. Although damage to any part of either circuit in isolation will impair memory function,  damage to both circuits will result in a profound amnesic disorder. The contribution  that each circuit  makes  to  memory  function  remains  a matter  of active debate. On one side of the discussion are those who believe that both circuits are involved in all aspects of declarative memory.  Lesions affecting both  circuits would, therefore, be expected to result in more severe amnesia  simply  because  more  of the  relevant  neural tissue would be dysfunctional.  Others suggest that the two circuits make qualitatively different contributions to memory. In particular, they suggest that the hippocampus and related structures  in the Papez circuit support the  recollection  of episodic  information,  whereas  the perirhinal  cortices and related structures  in the dorsolateral circuit support  judgments  of familiarity. In this case, damage to both circuits would impair more functions  than  would  damage to either  circuit  alone and, therefore,   would   explain   current   clinical   findings. Future  studies  of patients  who present  with  selective lesions will be needed to resolve this debate.

The finding of temporally graded retrograde amnesia in association with damage to the medial temporal lobe reveals that this brain region plays a critical role in the establishment  of memory  and  also suggests a subsequent slow transfer of memory to other brain regions. The finding that old memories, both autobiographical and semantic, are left untouched  by damage limited to the   hippocampus   suggests  that   memories   are  not stored  there.  Long-term storage takes place in neural networks in the neocortex.

6.2.  Nondeclarative Memory

Nondeclarative   memory   systems  are   supported   by widely varying brain regions, depending on which sensory mode is involved in a given task and whether or not performance of the task involves higher associative functions. For example, evidence from neuroimaging  studies, together  with  clinical  data  from  individuals  who have  suffered  focal  cortical  damage,  has  established that priming finds its substrate in the neocortex. Specifically, the substrate for perceptual  priming is the relevant unimodal cortex (i.e., visual priming in the occipital visual cortex, auditory priming in the auditory cortex), whereas the substrate for conceptual priming is located  in  multimodal  association  cortices.  The same brain regions that are involved in the initial processing of information  are  also  involved  in  the  more  fluent processing that follows repetition, and priming is accompanied by a reduction  in neural activity in these regions.

Although priming manifests after a single exposure to a stimulus, procedural  memory requires a series of repetitions for its manifestation. Consequently, the involvement   of   relevant   brain   regions   and   their changes over time is more complex for procedural memory. The initial acquisition of motor skills engages the  motor/prefrontal cortices,  basal ganglia, and  the cerebellum. Over time, however, two opposite tendencies are evident. On the one hand, as procedural learning develops  and  a skill can be performed  with  less effort, the prefrontal  cortex and cerebellum  gradually become less activated. This repetition  suppression  effect mirrors that seen in the neural substrate for priming. On the other hand, repetition leading to increased skill engages the higher order motor cortex more than it had initially been engaged. This latter finding indicates expanded cortical involvement in the retention of procedural  memory  for motor  tasks that  mirrors  the increased neocortical involvement in the long-term retention  of declarative memories.

7. Approaches To Treatment Of Amnesic Disorders

The treatment  of memory disorders aims at enhancing day-to-day memory  functioning  and  routine  so as to increase  an  individual’s  level  of independence.   The choice  of  treatment   will  depend  on  both  cognitive and  noncognitive  factors. Noncognitive  factors to be considered  include  psychosocial  context  (e.g., family situation, educational background, lifestyle habits) and emotional  factors  (e.g.,  level  of insight,  motivation, neuropsychiatric  symptoms). Of critical importance among these factors are level of insight and motivation. Research has shown that interventions  are unsuccessful in patients who fail to appreciate that their memory is impaired and/or who are unmotivated. In these patients,  efforts  should  initially  focus  on  increasing level of insight  and/or  motivation.  Cognitive  factors that  must  be taken  into  account  include  premorbid abilities and skills and postmorbid  neuropsychological deficits,  including  a clear  delineation  of those  areas of memory  that  are impaired  and  preserved.  Within the  context  of a  holistic  individualized  approach,  a memory   remediation    program   can   be   developed based on current  understanding  of the processes that support  learning and memory.

Several treatment  approaches  for densely  amnesic patients     capitalize     on     nondeclarative     memory processes because this form of memory remains intact in most patients. The ‘‘vanishing cues’’ technique is an example of a treatment  method that recruits preserved implicit perceptual memory processes to teach patients domain-specific facts or concepts. The technique takes advantage  of patients’  preserved  ability  to  complete studied items in response to word fragment cues. In a typical  vanishing  cue paradigm,  patients  are given a definition and are then presented  with as many letters as is necessary to produce the target word. With training, the letter cues are gradually reduced until the patients  can spontaneously  generate  the  sought  after information. Success has been achieved using this technique  in  teaching  patients  computer-related  vocabulary, business-related terms, and novel concepts. Learning by means of this technique  is slow and laborious but can lead to surprisingly good retention, particularly  if the  information  to  be  learned  uses  a knowledge base that is already familiar to the individual. However, a caveat arises from the inherent reliance of the vanishing cues method  on the perceptual  cues given during  learning.  As a result,  generalization  has often been limited, and benefits have been found to be best when the information is used in situations similar to those where learning occurred.

Attention  to  training  contexts  may be  important when  using  techniques  that  take  advantage  of preserved implicit  memory  processes.  Because amnesic patients have no recollection of the learning episodes, they  fail  to  remember   their   mistakes  and  consequently fail to benefit from ongoing error correction. Instead, incorrect responses made during learning are often unconsciously repeated, leading to errors becoming primed and more likely being repeated subsequently. To avoid the perpetuation  of errors through priming, some investigators have emphasized the  importance   of  ‘‘errorless learning’’  for  patients who have explicit memory impairments.  In errorless learning,  the  possibility  of making  errors  is  eliminated  by using  cues  and  prompts  or  by providing the correct answer. The approach has met with some success in  teaching  memory-impaired  patients  both new skills (e.g., use of a memory book, programming of an electronic organizer) and new knowledge (e.g., learning of new words). Errorless learning is thought to operate by strengthening  residual explicit memory, either alone or together with implicit memory. Its applicability as a method to facilitate learning appears to be broad and promising because errorless learning principles  can be applied to a variety of remediation methods.

Other treatment  approaches  capitalize on preserved procedural   learning.  Through   repetition,   skills  and habits  that  are important  for activities of daily living or occupation can be taught. Such skills can range from simple assembly tasks to more complex multistep tasks such  as learning  to type.  A variety of compensatory aids   (e.g.,   notebooks,    scheduling   books,   diaries, alarms)  and augmentative  technologies  (e.g., computers, personal digital assistants, paging systems) rely on procedural  memory. The notebook  is an example of a low-tech aid. It is usually created at the early stage of rehabilitation  and contains  sections  aimed at drilling overlearned  personal  information  (e.g., date of birth, age, address), information about immediate family members (including their telephone numbers), daily schedules, and a daily record of activities. The book is tailored   to   the   individual   and   can   be   gradually increased  in  complexity.  Electronic  organizers,  the most favored external memory aid among normal individuals, are now also being used by memory-impaired patients.   Training   in  the   use  of  such   technology requires lengthy practice sessions, within and outside the rehabilitation  environment,  to foster generalization. Because the acquisition of new skills is time-consuming for  everyone   involved,   careful  consideration   needs to be given as to whether an electronic device is appropriate for an individual  before investing the time and effort.  Factors  that  would  argue  against  it  include dense amnesia associated with poor insight, lack of initiative,  impaired  visual attention,  poor  motor  control, and limited problem-solving  skills. Patients who are good candidates  for this technology are generally younger, have experience in using electronic  devices, and have achieved higher educational  levels. Devices used premorbidly are preferable because familiarity increases the  likelihood  that  they will be used effectively outside the clinic.

The  preceding  examples  illustrate  approaches  that focus on preserved memory systems to teach new skills and habits. Another approach focuses on enhancing impaired forms of memory to improve day-to-day episodic memory by means of internal  strategies. Internal strategies require awareness of the learning method and recall of the strategy itself; therefore, they are of limited use to patients who are moderately or densely amnesic. However, they are useful for patients  who have mild memory deficits secondary to impaired effortful encoding or retrieval, who have good awareness of their deficits, and who have adequate motivation. These patients  are more likely to generalize their  training  to situations that go beyond the clinic setting.

Examples of internal strategies include mental retracing, feature–name association, and verbal elaboration by means of a story or an association—all of which are skills that promote  the use of imagery. The choice of technique  will depend on the memory process that is targeted for remediation. For example, techniques that focus on strengthening  encoding,  and  therefore  storage, are  effective at remediating  consolidation  problems. Story elaboration  is effective in linking together a list of unrelated  words through  the development  of a scenario  that  features the target words. The use of verbal associations is often effective in recalling a surname.  In  all of these  instances,  repeated  use  of the strategy is important  and spaced repetitions,  at different times and in different contexts, generally increases the  likelihood  that  information  will be  learned  and become  conceptually  integrated  within  a  matrix  of old memories. Strategies that are most effective when the  deficit  is at  the  level of strategic  processes  that enhance encoding are those that increase the organizational structure of incoming information. For example, learning how to ‘‘chunk’’ incoming information is helpful in  streamlining  and  organizing  that  information. Organizing information  according  to themes  or categories can also structure learning so that a thematic cue can serve to trigger recall when necessary.

These  remediation  methods  are guided  by knowledge regarding the cognitive processes that support learning  and  memory.  More  than  50  years ago, the early  clinical  findings  with  H.M. and  other  patients informed  the  theoretical  understanding   of the  functional systems that comprise human memory. Current cognitive neuroscience  has evolved from those  early findings   and   now,   in   turn,   can   inform   clinical approaches to remediation that enable amnesics to function more effectively in their daily lives.


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