Memory Dysfunction

The new england journal of medicine

review article

current concepts Memory Dysfunction

Andrew E. Budson, M.D., and Bruce H. Price, M.D.

From the Geriatric Research Education emory function is vulnerable to a variety of pathologic Clinical Center, Edith Nourse Rogers Me- processes including neurodegenerative diseases, strokes, tumors, head trau- morial Veterans Hospital, Bedford, Mass., m ma, hypoxia, cardiac surgery, malnutrition, attention-deficit disorder, de- the Department of Neurology, Boston Uni- 1,2 versity, Boston, and the Department of pression, anxiety, the side effects of medication, and normal aging. As such, memory Neurology, Division of Cognitive and Be- impairment is commonly seen by physicians in multiple disciplines including neurol- havioral Neurology, Brigham and Wom- en’s Hospital, Boston (A.E.B.); and Har- ogy, psychiatry, medicine, and surgery. Memory loss is often the most disabling feature vard Medical School, Boston, and McLean of many disorders, impairing the normal daily activities of the patients and profoundly Hospital, Belmont, Mass. (B.H.P.). Address affecting their families. reprint requests to Dr. Budson at GRECC, Bldg. 62, Rm. B30, Edith Nourse Rogers Some perceptions about memory, such as the concepts of “short-term” and “long- Memorial Veterans Hospital, 200 Springs term,” have given way to a more refined understanding and improved classification Rd., Bedford, MA 01730, or at abudson@ systems. These changes result from neuropsychological studies of patients with focal partners.org. brain lesions, neuroanatomical studies in humans and animals, experiments in animals, N Engl J Med 2005;352:692-9. positron-emission tomography, functional magnetic resonance imaging, and event- Copyright © 2005 Massachusetts Medical Society. related potentials. Memory is now understood to be a collection of mental abilities that depend on several systems within the brain. In this article, we will discuss the following four memory systems that are of clinical relevance: episodic memory, semantic memory, procedural memory, and working memory (Table 1). We will summarize the current understanding of memory from the point of view of functional neuroimaging and studies of patients with brain insults, which should aid clinicians in the diagnosis and treatment of the memory disorders of their patients. As therapeutic interventions for memory disorders become available, clinicians will increasingly need to be aware of the various memory systems in the brain. A memory system is a way for the brain to process information that will be available for use at a later time.3 Different memory systems depend on different neuroanatomical structures (Fig. 1 and 2). Some systems are associated with conscious awareness (explicit) and can be consciously recalled (declarative),4 whereas others are expressed by a change in behavior (implicit) and are typically unconscious (nondeclarative). Memory can also be categorized in many other ways, such as by the nature of the material to be remembered (e.g., verbal5,6 or visuospatial5,7).

Episodic memory refers to the explicit and declarative memory system used to recall personal experiences framed in our own context, such as a short story or what you had for dinner last night. Episodic memory has largely been defined according to the inability of people with amnesia due to lesions of the medial temporal lobe to remember experiences that healthy people can remember. Thus, this memory system depends on the medial temporal lobes (including the hippocampus and the entorhinal and perirhinal cortexes). Other critical structures in the episodic memory system (some of which are

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current concepts

Table 1. Selected Memory Systems.

Major Anatomical Length of Storage Memory System Structures Involved of Memory Type of Awareness Examples Episodic memory Medial temporal lobes, anteri- Minutes to years Explicit, declarative Remembering a short story, what or thalamic nucleus, mam- you had for dinner last night, millary body, fornix, pre- and what you did on your last frontal cortex birthday Semantic memory Inferolateral temporal lobes Minutes to years Explicit, declarative Knowing who was the first president of the United States, the color of a lion, and how a fork differs from a comb Procedural memory Basal ganglia, cerebellum, Minutes to years Explicit or implicit, Driving a car with a standard trans- supplementary motor area nondeclarative mission (explicit) and learning the sequence of numbers on a touch-tone phone without trying (implicit) Working memory Phonologic: prefrontal cortex, Seconds to minutes; Explicit, declarative Phonologic: keeping a phone num- Broca’s area, Wernicke’s information active- ber “in your head” before dialing area ly rehearsed or ma- Spatial: mentally following a route or Spatial: prefrontal cortex, nipulated rotating an object in your mind visual-association areas associated with a circuit described by Papez in the right medial temporal and right frontal lobes are 19378) include the basal forebrain with the medial most active when learning visual scenes.7 septum and diagonal band of Broca’s area, the ret- One reason that the frontal lobes are important rosplenial cortex, the presubiculum, the fornix, for encoding is that they permit the person to focus mammillary bodies, the mammillothalamic tract, on the information to be remembered and to en- and the anterior nucleus of the thalamus.2 A lesion gage the medial temporal lobes. Dysfunction of the in any one of these structures may cause the im- frontal lobes may cause distortions of episodic pairment that is characteristic of dysfunction of the memory as well as false memories, such as infor- episodic memory system (Fig. 1). mation that is associated with the wrong context14 Memory loss attributable to dysfunction of the or with incorrect specific details.15 Extreme exam- episodic memory system follows a predictable pat- ples of memory distortions include confabulation, tern known as Ribot’s law, which states that events which occurs when “memories” are created to be just before an ictus are most vulnerable to dissolu- consistent with current information,14 such as “re- tion, whereas remote memories are most resistant. membering” that someone broke into the house Thus, in cases of dysfunction of the episodic mem- and rearranged household items. ory system, the ability to learn new information is These differences between deficits in episodic impaired (anterograde amnesia), recently learned memory that occur because of damage to the medi- information cannot be retrieved (retrograde am- al temporal lobes (and the Papez circuit) and those nesia), and remotely learned information is usually that occur because of damage to the frontal lobes spared.9 can be conceptualized in an oversimplified but clin- Studies have shown that the episodic memory ically useful analogy.16 The frontal lobes are analo- system includes the frontal lobes.5,10 Rather than gous to the “file clerk” of the episodic memory sys- being responsible for the retention of information, tem, the medial temporal lobes to the “recent the frontal lobes are involved in the registration, ac- memory file cabinet,” and other cortical regions to quisition, or encoding of information6; the retrieval the “remote memory file cabinet.” Thus, if the of information without contextual and other cues11; frontal lobes are impaired, it is difficult — but not the recollection of the source of information12; and impossible — to get information in and out of stor- the assessment of the temporal sequence and re- age. However, the information may be distorted ow- cency of events.13 Studies have also shown that the ing to “improper filing” that leads to an inaccurate left medial temporal and left frontal lobes are most source, context, or sequence. If, however, the medi- active when a person is learning words,6 whereas al temporal lobes are rendered completely dysfunc-

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Thalamocingulate Cingulate gyrus Prefrontal tract cortex

Anterior thalamic nucleus Fornix

Thalamus Mammillothalamic tract

Mammillary body

Parahippocampal Amygdala gyrus

Hippocampal formation

Figure 1. Episodic Memory. The medial temporal lobes, including the hippocampus and parahippocampus, form the core of the episodic memory system. Other brain regions are also necessary for episodic memory to function correctly.

tional, it will be impossible for recent information mentia and multiple sclerosis, progress in a step- to be retained. Older information that has been con- wise manner. Other disorders of memory, such as solidated over a period of months or years is thought those due to medications, hypoglycemia, tumors, to be stored in other cortical regions and will there- and Korsakoff’s syndrome, can have a more com- fore be available even when medial temporal lobes plicated and variable time course. and the Papez circuit are damaged. For example, Once a disorder of episodic memory is suspect- although patients with depression and those with ed on the basis of a reported inability to remember Alzheimer’s disease may exhibit episodic memory recent information and experiences accurately, ad- dysfunction, the former have a dysfunctional “file ditional evaluation is warranted. A detailed history clerk” and the latter have a dysfunctional “recent should be taken, with particular emphasis on the memory file cabinet.” time course of the memory disorder. Interviewing a Disorders of episodic memory may be transient, caregiver or other informant is usually critical for such as those attributable to a concussion, a seizure, accuracy, since the patient will invariably not re- or transient global amnesia. Static disorders, such member important aspects of the history. A history as traumatic brain injury, hypoxic or ischemic injury, of other cognitive deficits (e.g., attention, language, single strokes, surgical lesions, and encephalitis, visuospatial, and executive) should be elicited. A typically are maximal at onset (or for several days), medical and neurologic examination should be per- improve (sometimes over periods of two years or formed, with a focus on searching for signs of sys- more), and then are stable. Degenerative diseases, temic illness, focal neurologic injury, and neurode- including Alzheimer’s disease,17 dementia with generative disorders. Lewy bodies, and frontotemporal dementia, begin Cursory cognitive testing may be performed by insidiously and progress gradually. Disorders af- asking the patient to remember a short story or sev- fecting multiple brain regions, such as vascular de- eral words, or with the use of instruments such as

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current concepts the Mini–Mental State Examination,18 the Blessed Dementia Scale,19 the Three Words–Three Shapes 2 Supplementary memory test, the word-list memory test of the motor area Consortium to Establish a Registry for Alzhei- 20 2 mer’s Disease, the Drilled Word Span Test, and Basal ganglia the Seven-Minute Screen.21 In complex cases, a (putamen) formal neuropsychological evaluation should be Prefrontal considered. cortex To aid in distinguishing disorders of episodic Inferolateral memory that are attributable to dysfunction of the temporal lobe frontal lobes from those attributable to dysfunction of the medial temporal lobes, difficulties in the encoding and retrieval of information should be con- Cerebellum trasted with primary failure of storage. When infor- Semantic memory mation cannot be remembered even after encoding Procedural memory has been maximized by multiple rehearsals, and af- Working memory ter retrieval demands have been minimized with the use of a multiple-choice recognition test, a primary Figure 2. Semantic, Procedural, and Working Memories. failure of storage is present. (See the Supplementa- The inferolateral temporal lobes are important in the naming and categoriza- ry Appendix, available with the full text of this arti- tion tasks by which semantic memory is typically assessed. However, in the cle at www.nejm.org, for suggestions on how to use broadest sense, semantic memory may reside in multiple and diverse cortical these tests in clinical practice.) areas that are related to various types of knowledge. The basal ganglia, cerebellum, and supplementary motor area are critical for procedural memory. Laboratory and imaging studies will usually be The prefrontal cortex is active in virtually all working memory tasks. Other cor- indicated, according to the differential diagnosis. tical and subcortical brain regions will also be active, depending on the type Treatment depends on the specific disorder. Cho- and complexity of the working memory task. linesterase inhibitors22 and memantine23 have been approved by the Food and Drug Administration (FDA) to treat Alzheimer’s disease; the former have also been used to treat vascular dementia24 and de- nearby visual-association areas.30 However, a more mentia with Lewy bodies.25 Two recent reviews dis- restrictive view of semantic memory, one that is cuss the effectiveness of these treatments.26,27 justified in light of the naming and categorization tasks by which it is usually measured, localizes se- semantic memory mantic memory to the inferolateral temporal lobes (Fig. 2).31,32 Semantic memory refers to our general store of con- Alzheimer’s disease is the most common clini- ceptual and factual knowledge, such as the color of cal disorder disrupting semantic memory. This a lion or the first president of the United States, that disruption may be attributable to pathology in the is not related to any specific memory. Like episodic inferolateral temporal lobes33 or to pathology in memory, semantic memory is a declarative and ex- frontal cortexes,34 leading to poor activation and re- plicit memory system. Evidence that this memory trieval of semantic information.35 In Alzheimer’s system is different from episodic memory emerges disease, episodic and semantic memory decline in- from neuroimaging studies28 and the fact that pre- dependently of each other, supporting the idea that viously acquired semantic memory is spared in pa- two separate memory systems are impaired in this tients who have severe impairment of the episodic disorder.36 memory system, such as with disruption of the Pa- Other causes of the impairment of semantic pez circuit (e.g., in Korsakoff’s syndrome) or sur- memory include almost any disorder that may dis- gical removal of the medial temporal lobes.29 rupt the inferolateral temporal lobes, such as trau- Since in its broadest sense semantic memory in- matic brain injury, stroke, surgical lesions, enceph- cludes all our knowledge of the world not related to alitis, and tumors (Table 2). Patients with the specific episodic memories, one could argue that temporal variant of frontotemporal dementia, it resides in multiple cortical areas. There is evi- known as semantic dementia, also exhibit deficits dence, for example, that visual images are stored in in all functions of semantic memory, including

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naming and single-word comprehension and im- Table 2. Four Memory Systems and Common Clinical poverished general knowledge. They show relative Disorders That Disrupt Them.* preservation of other components of speech, per- Episodic memory ceptual and nonverbal problem-solving skills, and 37 Alzheimer’s disease episodic memory. Mild cognitive impairment, amnestic type Disorders of semantic memory should be sus- Dementia with Lewy bodies pected when patients have difficulty naming items Encephalitis (most commonly, herpes simplex encephalitis) whose names they previously knew. The evaluation Frontal variant of frontotemporal dementia for disorders of semantic memory should include Korsakoff’s syndrome the same components as the evaluation used for dis- Transient global amnesia orders of episodic memory. The history and cogni- Concussion tive examination should ascertain whether the prob- Traumatic brain injury Seizure lem is solely attributable to a difficulty in recalling Hypoxic–ischemic injury people’s names and other proper nouns, which is Cardiopulmonary bypass common, particularly in healthy older adults, or to Side effects of medication a true loss of semantic information. Patients with Deficiency of vitamin B12 mild dysfunction of semantic memory may show Hypoglycemia Anxiety only reduced generation of words for semantic cat- Temporal-lobe surgery egories (e.g., the number of names of animals that Vascular dementia can be generated in one minute), whereas patients Multiple sclerosis with a more severe impairment of semantic memory Semantic memory typically show a two-way naming deficit (i.e., they Alzheimer’s disease are unable to name an item when it is described and Semantic dementia (temporal variant of frontotemporal are also unable to describe an item when they are dementia) Traumatic brain injury given its name). These more severely affected pa- Encephalitis (most commonly, herpes simplex tients also show impoverished general knowledge. encephalitis) Treatment depends on the specific disorder. Procedural memory Parkinsons’s disease procedural memory Huntington’s disease Progressive supranuclear palsy Procedural memory refers to the ability to learn be- Olivopontocerebellar degeneration havioral and cognitive skills and algorithms that are Depression Obsessive–compulsive disorder used at an automatic, unconscious level. Procedur- al memory is nondeclarative but during acquisition Working memory may be either explicit (such as learning to drive a car Normal aging Vascular dementia with a standard transmission) or implicit (such as Frontal variant of frontotemporal dementia learning the sequence of numbers on a touch-tone Alzheimer’s disease phone without conscious effort). That procedural Dementia with Lewy bodies memory can be spared in patients who have severe Multiple sclerosis deficits of the episodic-memory system, such as pa- Traumatic brain injury Side effects of medication tients with Korsakoff’s syndrome or Alzheimer’s Attention deficit–hyperactivity disorder disease or who have undergone surgical removal of 29,38 Obsessive–compulsive disorder the medial temporal lobes, demonstrates that Schizophrenia procedural memory depends on a memory system Parkinson’s disease that is separate and distinct from the episodic mem- Huntington’s disease Progressive supranuclear palsy ory and semantic memory systems. Cardiopulmonary bypass Research with the use of functional imaging has Deficiency of vitamin B12 shown that brain regions involved in procedural memory, including the supplementary motor area, * Tumors, strokes, hemorrhages, and other focal disease basal ganglia, and cerebellum, become active as a processes may affect these memory systems, depending 39 on the neuroanatomical structures disrupted. new task is being learned (Fig. 2). Corroborating evidence comes from studies of patients with le-

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current concepts sions in the basal ganglia or cerebellum who show has traditionally been divided into components that impairment in learning procedural skills.40 Because process phonologic information (e.g., keeping a the disease process in early Alzheimer’s disease af- phone number “in your head”) or spatial informa- fects cortical and limbic structures while sparing tion (e.g., mentally following a route) and an exec- the basal ganglia and cerebellum, these patients utive system that allocates attentional resources.44 show deficits in episodic memory but normal ac- Numerous studies have shown that working quisition and maintenance of procedural skills. memory uses a network of cortical and subcortical Parkinson’s disease is the most common disor- areas, depending on the particular task.45 However, der affecting procedural memory. Other neurode- virtually all tasks involving working memory require generative diseases that disrupt procedural memory participation of the prefrontal cortex (Fig. 2).5 Typ- include Huntington’s disease and olivopontocere- ically, the network of cortical and subcortical areas bellar degeneration. Patients in the early stages of includes posterior brain regions (e.g., visual-asso- these disorders perform nearly normally on episod- ciation areas) that are linked with prefrontal regions ic memory tests but show an impaired ability to to form a circuit. Studies have shown that phono- learn skills.38,41 Tumors, strokes, hemorrhages, logic working memory tends to involve more re- and other causes of damage to the basal ganglia or gions on the left side of the brain, whereas spatial cerebellum may also disrupt procedural memory. working memory tends to involve more regions on Patients with major depression have also been the right side.5 Studies have also shown that more shown to have impairment in procedural memory, difficult tasks involving working memory require perhaps because depression may involve dysfunc- bilateral brain activation, regardless of the nature tion of the basal ganglia (Table 2).42 of the material being manipulated.46 Furthermore, Disruption of procedural memory should be sus- there is an increase in the number of activated brain pected when patients show evidence of either the regions in the prefrontal cortex as the complexity of loss of previously learned skills or substantial im- the task increases.47 pairment in learning new skills. For example, pa- Because working memory depends on a network tients may lose the ability to perform automatic, of activity that includes subcortical structures as skilled movements, such as writing, playing a mu- well as frontal and parietal cortical regions, many sical instrument, or swinging a golf club. Although neurodegenerative diseases impair working-mem- they may be able to relearn the fundamentals of ory tasks. Studies have shown that patients with these skills, explicit thinking is often required for Alzheimer’s, Parkinson’s, or Huntington’s disease their performance. As a result, patients with damage or dementia with Lewy bodies, as well as less com- to the procedural memory system may never achieve mon disorders such as progressive supranuclear the automatic effortlessness of simple motor tasks palsy, may show impaired working memory (Table that healthy people take for granted. 2).48,49 In addition to neurodegenerative diseases, Evaluation of disorders of procedural memory almost any disease process that disrupts the frontal is similar to that of disorders of episodic memory; lobes or their connections to posterior cortical re- treatment of the underlying cause depends on the gions and subcortical structures can interfere with specific disease process. It is worth noting that pa- working memory. Such processes include strokes, tients whose episodic memory has been devastated tumors, head injury, and multiple sclerosis, among by encephalitis, for example, have had success in re- others.50,51 Because phonologic working memory habilitation by using the procedural memory sys- involves the silent rehearsal of verbal information, tem to learn new skills.43 almost any kind of aphasia can also impair it. Al- though the pathophysiology is not well understood, working memory disorders that diminish attentional resources, such as attention deficit–hyperactivity disorder, obses- Working memory is a combination of the tradition- sive–compulsive disorder, schizophrenia, and de- al fields of attention, concentration, and short-term pression, can also impair working memory.52-54 memory. It refers to the ability to temporarily main- A disorder of working memory can present in tain and manipulate information that one needs to several ways. Most commonly, the patient will show keep in mind. Because it requires active and con- an inability to concentrate or pay attention. Diffi- scious participation, working memory is an explicit culty performing a new task involving multistep in- and declarative memory system. Working memory structions may be seen. A disorder of working mem-

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ory may also present as a problem with episodic duced converging and complementary lines of evi- memory. In such cases, the evaluation will show a dence, suggesting that memory is composed of sep- primary failure of encoding, because in order to arate and distinct systems. A single disease process transfer information into episodic memory, the in- (such as Alzheimer’s disease) may impair more than formation must first be “kept in mind” by working one memory system. Improved understanding of memory.5 the types of memory will aid clinicians in the diag- Evaluation of working memory is similar to that nosis and treatment of their patients’ memory dis- of disorders of episodic memory. Treatment de- orders. This knowledge will become increasingly pends on the specific cause; for instance, stimulants important as more specific strategies emerge for have been approved by the FDA to treat attention the treatment of memory dysfunction. deficit–hyperactivity disorder.55,56 Dr. Budson reports having received consultation or lecture fees from Eisai, Forest Pharmaceuticals, Janssen, and Pfizer. We are indebted to Daniel Schacter, David Wolk, Daniel Press, Jef- conclusion frey Joseph, Dorene Rentz, Paul Solomon, and Hyemi Chong for their helpful comments on the manuscript, figures, and supplemen- Traditionally, memory has been viewed as a simple tary appendix. concept. In fact, the use of various methods has pro-

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