wolk a eb memory sys 2010

8/11/2019 Wolk a Eb Memory Sys 2010

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MEMORY SYSTEMSDavid A. Wolk, Andrew E. Budson

ABSTRACT

Converging evidence from patient and neuroimaging studies suggests that memory isa collection of abilities that use different neuroanatomic systems. Neurologic injurymay impair one or more of these memory systems. Episodic memory allows us tomentally travel back in time and relive an episode of our life. Episodic memorydepends on the hippocampus, other medial temporal lobe structures, the limbicsystem, and the frontal lobes, as well as several other brain regions. Semantic memoryprovides our general knowledge about the world and is unconnected to any specificepisode of our life. Although semantic memory likely involves much of the neocortex,the inferolateral temporal lobes (particularly the left) are most important. Proceduralmemory enables us to learn cognitive and behavioral skills and algorithms thatoperate at an automatic, unconscious level. Damage to the basal ganglia, cerebellum,and supplementary motor area often impair procedural memory.

Continuum Lifelong Learning Neurol 2010;16(4):1528.

INTRODUCTION

The ability to remember ones personalpast is a fundamental feature that definesthe human conscious experience. Dis-orders of memory can have devastating

consequences for patients and families.Although numerous medical conditionsmay precipitate memory loss, the agingof our population, with its accordantincreased prevalence of Alzheimer dis-ease (AD) and other neurodegenerativeconditions, has accentuated the needfor the clinician to have a general un-derstanding of normal memory func-tioning and the differential diagnosisassociated with its disruption.

Critical to any discussion of memoryis the concept of a memory system,which can be loosely defined as a brainsystem that supports the maintenanceof information that impacts behaviorafter passage of time from initial ac-quisition.1Although one of the earliest

assertions that human memory is sub-served by several different memory sys-

tems was by the 18th century Frenchphilosopher Maine de Biran, the charac-terization of the famous patient Henry

Molaison (HM; 19262008) pro-vided the experimental support to pop-ularize this conception. HM underwentbilateral medial temporal lobe (MTL)

resections for intractable epilepsy in1953. Unfortunately, the procedure re-sulted in the unintended consequenceof profound amnesia in which he wasunable to acquire new memories of ex-periences or events following the sur-gery. The description of this outcome

firmly established the MTL system asessential to episodic memory and wasdisseminated to the scientific commu-nity in the highly influential 1957 manu-script by Milner and Scoville entitledLoss of Recent Memory after BilateralHippocampal Lesions.2

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Relationship Disclosure: Dr Wolk has received personal compensation for consulting activities with GEHealthcare, Inc.; and Avacat Consulting, LLC. Dr Budson has received personal compensation for speakingengagements with Eisai Inc., Forest Laboratories, Inc., Johnson & Johnson Services, Inc., and Pfizer Inc.Dr Budsons compensation and/or research work has been funded entirely or in part by a grant from agovernmental organization to his university.Unlabeled Use of Products/Investigational Use Disclosure:Drs Wolk and Budson have nothing to disclose.

Copyright # 2010, American Academy of Neurology. All rights reserved.

KEY POINT

A When medial

temporal lobe

structures are

damaged andepisodic

memory is

impaired,

learning can

still occur

through other

memory

systems such as

procedural

memory.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


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It was the sparing of other aspectsof HMs learning and memory, how-

ever, that provided the foundation for

the notion of separable memory sys-tems. For example, his ability to learnnew motor skills, demonstrate the ef-

fects of perceptual priming, and re-

trieve remote pieces of semantic mem-ory suggested that these processes

were not entirely dependent on MTLfunction. Additional dissociations re-

vealed in HM and other patients provideevidence that there are separable mem-

ory systems.Although there is not complete agree-

ment on the best way to categorize thesesystems, almost all accounts involve sep-aration into declarative and nondeclar-ative forms of memory. Declarativemem-ories can be put into words and generally

involve explicit accessor consciousaware-ness of information, whereas nondeclar-ative memories cannot be verbalized and

are instead manifested by changes inbehavior. In the current review, we willdiscuss two forms of declarative memoryepisodic and semanticand one formof nondeclarative memoryprocedural.

Working memory, another form of de-clarative memory, is covered elsewherein this issue, although we have includedit in selected tables and figures for com-parison (Table 1-1). As outlined below,one of the major values of consideringmemory in this manner is that these

systems rely on a dissociable neuroanat-omy, which has variable sensitivity todifferent disease processes and, thus,has localizing and diagnostic implica-tions in the context of impairment.

Continuum Lifelong Learning Neurol 2010;16(4)

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TABLE 1-1 Comparison of Clinically Relevant Memory Systems

MemorySystem Examples Awareness

Length ofStorage

Major AnatomicStructures

Episodicmemory

Remembering a short story,what you had for dinnerlast night, and what youdid on your last birthday

ExplicitDeclarative

Minutesto years

Medial temporal lobe,anterior thalamic nucleus,mamillary body, fornix,prefrontal cortex

Semanticmemory

Knowing who was thefirst US president, the colorof a lion, and how a forkand comb are different

ExplicitDeclarative

Minutes toyears

Inferior lateral temporallobes

Proceduralmemory

Driving a standardtransmission car andlearning the sequence of

numbers on a touch-tonephone without trying

ImplicitNondeclarative

Minutes toyears

Basal ganglia, cerebellum,supplementary motorarea

Workingmemory

Phonologic: keeping a phonenumber in your headbefore dialing

ExplicitDeclarative

Seconds tominutes;informationactivelyrehearsed ormanipulated

Phonologic: prefrontalcortex, Broca area,Wernike area

Spatial: Mentally following aroute, or rotating an object inyour mind

Spatial: prefrontal cortex,visual association areas

Reprinted from Budson AE, Price BH. Memory dysfunction. N Engl J Med 2005;352(7):629699. Copyright # 2005, with permission fromMassachusetts Medical Society. All rights reserved.

KEY POINT

A Memory

impairment may

be seen even if

the medialtemporal lobes

are spared.

Frontal lobes,

inferolateral

temporal lobes,

basal ganglia,

and cerebellum

may all cause

certain kinds of

memory

impairment.

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EPISODIC MEMORY

Definitions

The patient in Case 1-1 had a rela-

tively selective impairment of episodicmemory.

Episodic memory is the memory

system that allows us to remember past

experiences and episodes in our life, or

as Endel Tulving put it, the kind of mem-

ory that allows us to mentally travel

in time.3 Two features differentiate epi-

sodic memory from other memory sys-

tems. (1) Episodic memory involves a

form of consciousness in which theselfis

centralautonoetic or self-knowing con-sciousness according to Tulving. In other

words, it involves remembering ones

own experience of an event. (2) Only

episodic memory is tightly linked to a

sense of time. Indeed, time forms part

of the context by which these events arerepresented, allowing for differentiationof events in the recent past from moreremote events.

Episodic memories may be fraction-ated in a number of different ways,

which often have implications for thenature of an impairment of memoryand the underlying neural substrateinvolved. One such division is the dif-ference between item and associativememory. Whereas item memories are

for individual items without context, as-sociative memories involve the linkingof multiple aspects of an event. For


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Case 1-1A 75-year-old man had decline in his memory over about 1 year. Per his wife, this was manifestedby his repeating questions and forgetting their daily plans. She noted little change in his abilityto perform instrumental activities of daily living, such as driving or handling the finances, buthe did have greater difficulty withremembering details of books or showsthat they had watched together. He

admitted that his memory was poorerand felt a sense of foreboding about thefuture. On examination, he showed verypoor verbal and visual memory, andlimited knowledge of current eventsdespite avidly watching the news.Although he recalled 6/10 words on thethird immediate recall trial of a verbalmemory task, his delayed recall was 0/10,and he only recognized 4/10 items andmade one false alarm. His retention of astory based on initial encoding was very

poor. Nonetheless, he performed inthe normal range on almost all testsof language, executive functioning,attention, and visuospatial ability. Hewas given a diagnosis of amnestic mildcognitive impairment. Note thediminutive hippocampi on his MRI(Figure 1-1).

Comment. This patient has an impairment of episodic memory. A relatively isolatedimpairment of episodic memory is a common feature of early AD given the early neuropathologyin the MTLs with this condition. This patient has a high likelihood of progressing from amnesticmild cognitive impairment to clinical AD.

FIGURE 1-1 MRI coronal T1-weighted image. Notethe relatively disproportionate atrophyof the bilateral hippocampi consistentwith the temporolimbic memory impairmentof this patient.

A Episodic memory

is the type of

memory we

usually mean

when we talk

about memory.

It is memory for

an episode of

ones life.

KEY POINTS

A Episodic memory

impairments

are common

and oftendisrupt the lives

of patients and

their families.



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example, one may remember havingseen a friend earlier in the day and alsothe color of the friends shirt and the

location of the meeting. A commontest of associative memory is to havesubjects study word pairs. At testing,the subject is shown one word in thepair and is asked to recall the second,associated word. A related concept issource memory, which is the ability toremember the specific context from

which a memory came. A commonmemory error is related to this notion,sometimes referred to as reality mon-itoring. An example is when you are

unable to remember whether youactually turned off the stove or justthought about turning it off. Sourcememory is frequently tested in thelaboratory by having subjects study twolists. At testing, they need to decide notonly whether a particular item wasstudied, but remember from which listit came.

A related formulation to the item

versus associative or source memory

distinctions is the difference between

familiarity and recollection,4 a differ-ence that may reflect dissociable under-

lying medial temporal and neocortical

structures. Familiarity is conceptualized

as an acontextual sense of prior en-

counter. An example of an experience of

familiarity is when people see someone

that they are sure they have previously

met but cannot recall how it is that they

know that person (That person is so

familiar to me! Where do I know him

from?). In contrast, recollection is themore detailed retrieval of information

(Oh, thats Bob. I met him at my sis-

ters birthday party last week). Al-

though sometimes recollection occurs

spontaneously, at other times addi-

tional conscious, effortful searching of

ones memory stores is needed.A final important distinction is be-

tween retrograde and anterograde am-nesia. Relative to the time of the braininjury, anterograde amnesia is the in-

ability to form new memories, whereasretrograde amnesia is the loss of pre-

viously acquired memories.

Functional Neuroanatomy ofEpisodic Memory

The MTLand particularly thehippocampusis traditionally thoughtto be the anatomic seat of episodicmemory, as exemplified by the severeamnesia of HM; however, a numberof other neural systems appear to beinvolved. The processes that supportepisodic memory occur from the timethe to-be-remembered event is encoun-

tered (encoding) to the act of remem-bering (retrieval). In between are pro-cesses involved in the maintenance ofthese memories. If the memory is tolast for an extended period of time, anadditional process known asconsolida-tionoccurs. Given the disparate natureof these operations, it is perhaps notsurprising that episodic memory re-quires diverse neural systems for itsproper function and, thus, a variety ofbrain injuries can result in impairedmemory. Historically, it has been diffi-cult to gain traction on the nature ofneural activity associated with thesedifferent stages of memory. The adventof functional neuroimaging techniqueshas allowed for assessment of neuralactivity during memory encoding andretrieval, which has added greatly toour understanding of these processes(Figure 1-2). We will outline a num-ber of critical brain regions associated

with episodic memory function.Medial temporal lobe. Much ofwhat we know about normal episodicmemory function comes from studyingpatients with amnesia resulting fromMTL lesions. The MTL is a complex struc-ture frequently divided into hippocam-pal and extrahippocampal regions.5 The

hippocampalstructures include the den-tate gyrus, cornus ammonis subfields(CA 1, CA2, and CA3), and the postsub-iculum. Extrahippocampal structures


18

KEY POINT

A The hippocampus

and other

medial temporal

lobe structuresare critical for

normal episodic

memory function.

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include the entorhinal, perirhinal, andparahippocampal cortices.

Whereas isolated hippocampal le-sions produce significant amnesia, inclu-sion of surrounding extrahippocampalMTL structures tends to produce evenmore profound memory loss.6 Some

work has suggested that there may be adivision of labor within the MTLs withregard to the nature of their memorystores.68 Hippocampal lesions tend toproduce impairment on tasks of asso-ciative memory, source memory, and re-

collection, with relative sparing of itemmemory and familiarity. However, theadditional involvement of extrahippo-campal MTL regions impairs item mem-ory as well. These and other findings sug-gest that the hippocampus is involvedin the binding of different elements ofa prior study episode. By contrast, theperirhinal cortex and parahippocampusappear critical for the storage of theseindividual elements.An influential modelis that the perirhinal cortex and para-

hippocampus differentially encode ob-ject and spatial elements of an episode,respectively, which are then bound bythe hippocampus (Figure 1-3).8

In addition to significant anterogradeamnesia, patients with MTL injury fre-quently experience retrograde amnesia.Often times, the retrograde amnesia isgreatest for events learned nearest thetime of MTL injury but is spared formore remote episodes. This somewhatparadoxical pattern of memory loss hasbeen labeled as Ribot law9 and may

reflect the changing representation ofmemories over time. One popular ac-count to explain this phenomenon isthe standard consolidation model.10,11

This model argues that when memoriesare initially formed, the MTLlikely, thehippocampusbinds neocortically rep-

resented features of an event. Partialcues that reactivate elements of the epi-sode will also activate related featuresmediated by connections with the hip-pocampus. However, over time, these


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KEY POINT

A An injury to

episodic

memory

typically causes(1) anterograde

amnesia: an

inability to

form new

memories, and

(2) retrograde

amnesia: a loss

of previous

memories.

There are,

however,

always (3) some

preserved

remote

memories.

FIGURE 1-2 Episodic memory. The medial temporal lobes, including the hippocampus andparahippocampus, form the core of the episodic memory system.

Adapted from Budson AE, Price BH. Memory dysfunction. N Engl J Med 2005;352(7):692699.Copyright # 2005, with permission from Massachusetts Medical Society. All rights reserved.



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neocortical representations form theirown associations and the critical roleof the MTL in retrieval may become di-minished or absent, and, thus, an oldermemory may not be affected by MTLpathology.

A number of conditions produce

memory impairment through MTL in-jury. These conditions include AD, de-mentia with Lewy bodies, hippocampalsclerosis, posterior cerebral artery stroke,hypoxic-ischemic injury, and viral and

limbic encephalitis. By far the mostcommon cause of memory loss inolder adults is AD, which is associated

with extensive neuropathology in theMTL. In particular, early neurofibrillarytangle pathology is found in the ento-rhinal cortex layer II neurons, which

form the perforant pathway (the maininput to the hippocampus). Such pa-thology appears to result in a cortico-

hippocampal disconnection,

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perhapspreventing the binding of different neo-cortical elements necessary for effec-tive encoding. Thus, it is not surprisingthat memory loss is an early feature ofthis condition (Case 1-1). As AD prog-resses, all regions of the MTL becomesignificantly involved, further devastat-ing the episodic memory system. Otherfactors that likely contribute to the mem-ory loss include reduced cholinergic in-put due to basal forebrain pathology and

involvement of frontal-subcortical net-works. It has also recently become ap-parent that -amyloid (A), the proteinfragment that forms the hallmark amy-loid plaques of AD, in its soluble formmay inhibit long-term potentiation, acritical cellular mechanism for learningand memory.13

Extended medial temporal mem-

ory system. Several structures with sig-nificant connectivity to the MTL properare critical to episodic memory, as evi-denced by the amnesia associated withtheir injury. Many of these regions werepreviously described by Papez in thecircuit that bears his name.14 Lesions tothe mamillary bodies, bilateral fornices(an efferent pathway from the hippo-campus to the mamillary bodies), andthe anterior thalamic nucleus (whichreceives inputs via the mamillothalamictrack from the mamillary bodies) allproduce episodic memory impairment

thatis difficult to distinguish fromhippo-campally based amnesia (Figure 1-2).6

Additionally, the posterior cingulateand retrosplenial cortex also have denseconnections with the hippocampus andanterior thalamic nucleus, and amnesiaassociated with retrosplenial lesionshave been described.15 Although iso-

lated lesions in these related structuresare uncommon, Korsakoff syndrome rep-resents a classic form of amnesia associ-ated with pathology in the anterior


20

FIGURE 1-3 Functional organization of the medialtemporal lobe system. Neocortical inputregarding the object features (what)

converges in the perirhinal cortex (PRC) and lateral entorhinalarea (LEA), whereas details about the location (where) ofobjects converge in the parahippocampal cortex (PHC) andmedial entorhinal area (MEA). These streams converge inthe hippocampus, which represents items in the context inwhich they were experienced. Reverse projections followthe same pathways back to the parahippocampal andneocortical regions. Back projections to the PHC-MEA maysupport recall or context, whereas back projections to thePRC-LEA may support recall of item associations.

Adapted with permission from Eichenbaum H, Yonelinas AP, Ranganath C.The medial temporal lobe and recognition memory. Annu Rev Neurosci2007;30:123152.

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thalamic nucleus and the mamillarybodies.16

Frontal lobes.While their deficit is

generally more subtle than that seenwith medial temporal lesions, patientswith frontal lobe damage frequentlyexhibit episodic memory impairment.These patients tend to have relativelyselective impairment on memory tasksthat require the linking of different fea-tures of a prior episode. As such, pa-tients with frontal lobe damage tendto have difficulty on tests of associa-tive or source memory,17 memory fortemporal order of presentation,18 and

recollection.4

However, performance isoften normal on tests of item memoryor familiarity. Patients with frontal lobedamage also tend to have more dif-ficulty on memory tasks that requirespontaneously generated encoding orretrieval strategies, but show improve-ment in the context of environmentalsupport. For example, patients withfrontal lobe lesions tend to performmore poorly on a memory test if told tosimply study a list of words rather than

when instructed to perform a specificencoding operation, such as to form amental image of each study item. Thisnotion also applies to different test for-mats, as an unconstrained free recall taskis much more difficult for patients withfrontal lobe lesions than cued recall orrecognition memory.19 On these lattertasks, these patients may show little orno deficit at all. Thus, as a general prin-ciple, prefrontal regions appear to be

involved in different aspects of cognitivecontrol mechanisms that enhance mem-ory encoding and retrieval20 rather thansupporting the retention of information(likely a medial temporal function).

In addition to failure to retrieve in-formation from prior events, patients

with frontal lobe lesions are particularly

susceptible to memory distortions andfalse memories. This is likely related totheir poor memory for contextual orassociative details of a prior episode.21

These patients may conflate details ofvarious events and are susceptible toerrors of reality monitoring reflective of

source memory confusions. In more ex-treme cases, patients may exhibit spon-taneousand sometimes elaborative con-fabulations. Potential contributors to thetendency to confabulate include com-bined MTL and frontal lobe dysfunction(such as is seen in AD, frontotemporaldegeneration, and Korsakoff amnesia),poor selection or focus of the to-be-retrieved memories, impaired monitor-ing and editing of retrieved information,and impaired source monitoring and re-

trieval of temporal contextual details.22

Differences in memory performancebetween conditions that affect the MTLand those that affect the frontal lobescan be conceptualized by analogy. Theepisodic memory system can be thoughtof as a filing system. The frontal lobesare analogous to the file clerk of theepisodic memory system, the MTL (andPapez circuit) to the recent memory filecabinet, and other cortical regions tothe remote memory file cabinet. Thus,if the frontal lobes are damaged, it isdifficultbut not impossibleto getinformation in and out of storage. Ad-ditionally, when the frontal lobes aredamaged, the information stored inmemory may be distorted due to im-proper filing that leads to an inaccuratesource, context, or sequence. If, on theother hand, the MTLs are impaired, itmay be impossible for recent informationto be stored. Older information that has

been consolidated over months to yearsis likely stored in other cortical regionsand will therefore be available for retriev-al even when the MTL or Papez circuit isdamaged. See Table 1-2 for character-istics of memory impairment due tofrontal versus medial temporal injuries.

A number of conditions producememory impairment that is due, atleast in part, to frontal lobe dysfunc-tion. In addition to frontal strokesand mass lesions, other conditions


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KEY POINTS

A Alzheimer

disease is by far

the most

common causeof episodic

memory

impairment.

A Memory

distortions,

false memories,

and confabulation

may occur with

damage to

frontal cortex.

A Think of episodic

memory as afiling system:

The frontal

lobes are the

filing clerk, the

medial temporal

lobes are the

recent memory

file cabinet, and

other cortical

regions are the

older memory

file cabinet.



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associated with a frontally based epi-sodic memory impairment includefrontotemporal degeneration, vasculardementia (particularly when associat-ed with subcortical white matter dis-ease), dementia with Lewy bodies,multiple sclerosis, depression, and headtrauma. Distinguishing between memo-ry impairment due to medial temporalinjury and that associated with frontallobe dysfunction has potential diagnos-tic value. For example, while measuresof free recall and associative memory donot differentiate patients with AD fromthose with subcortical vascular demen-tia, measures of recognition memory

(with patients with AD performingmore poorly) appear to have betterspecificity.23 Although generally moresubtle, healthy age-associated mem-ory loss tends to be qualitatively similarto memory loss due to frontal lobeinjury. This phenomenology is consis-tent with data supporting the relative-

ly selective vulnerability of frontal lobefunction in aging as a result of cortical

volume loss, anterior white matter dis-ruption, and dopaminergic depletion.24

Other regions. Several other re-gions appear to be important substratesfor episodic memory function. Lesionsof the basal forebrain, often due to an-terior communicating artery aneurysm

rupture, produce memory impairment.This region is the main source of cho-linergic input to the MTLs and neocor-tex. Blockade of acetylcholine with themuscarinic antagonist scopolamine pro-duces amnesia in healthy individuals.25

The relative decline in acetylcholine as-sociated with basal forebrain pathologyin AD is the rationale for the use of cho-linesterase inhibitors in this condition.Given a general decline in cholinergic

function with aging, it is not surprisingthat cholinergic blockers, such as sco-polamine, have greater effects on mem-ory and cognition in older than youngadults, which is why anticholinergicmedicines should be avoided in olderindividuals.

Recent work, driven largely by the

functional imaging literature, has sug-

gested that the parietal lobes also par-

ticipate in episodic memory retrieval.

Studies have consistently revealed


22

TABLE 1-2 Memory Deficits With Medial Temporal Lobe VersusFrontal Lobe Lesions

Characteristic Medial TemporalLobe Lesion Frontal Lobe Lesion

Immediate memory Normal to mildly impaired Impaired

Free recall Impaired Impaired

Recognition memoryor cued recall

Impaired Often normal

Source or associativememory (ie, recollection)

Impaired Impaired

Item memory(ie, familiarity)

Impaired Normal

Effects of environmentsupport

Minimal enhancement ofmemory performance

Significant enhancementof memory performance

Tendency for falsememory or confabulation

Variable High

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midline and lateral parietal activations

associated with successful retrieval of

memories.26 While midline structures,

including retrosplenial cortex, have beenimplicated in episodic memory, priorwork had not suggested a role for thelateral parietal cortex. A recent focuson episodic memory in patients withlateral parietal lesions has revealed, per-haps, subtle deficits in this population.

While these patients appear to retrievecontextual details of prior episodes to asimilar extent as controls, they seem tohave greater difficulty doing so spon-

taneously and their memories may be

associated with less confidence or vivid-

ness.27,28A number of potential hypoth-eses have been postulated as to thefunction of the parietal cortex in epi-

sodic memory and are just now begin-ning to be tested experimentally.26

SEMANTIC MEMORY

Definitions

The patient in Case 1-2 had a rela-tively selective impairment of seman-tic memory. Semantic memory definesour knowledge of the world, includinggeneral informationabout objects, peo-ple, historical events, and word mean-

ing.3

Examples of semantic knowledge


23

Case 1-2A 73-year-old man had several years of cognitive decline. Most salient to him was difficultynaming and even recognizing a variety of items that used to be familiar to him. For example,his wife bought a bag of microwave popcorn that he examined at great length, eventually askinghis wife what it was used for. On the way to one of his clinic visits he saw a cement truck andcommented that he had never seen such an unusual truck before. He described marked difficultyin being able to name or even recognize close friendsthey did not look familiar to him. Despitethese issues, he had minimal functional decline and scored 24/30 on the Mini-Mental StateExamination. His wife described his

day-to-day memory as essentiallyunchanged. He spoke fluently onexamination and had reasonablecomprehension of simple words. He hadmarked naming impairment on theBoston Naming Test (14/30 correct), andhe could name only three vegetables in1 minute. He performed average to aboveaverage on tests of executive function,attention, and visuospatial memory.An MRI scan revealed severe bilateralanterior and inferior-lateral temporallobe atrophy. This patient wasfelt to have the early stages of semanticvariant of primary progressive aphasia.Note the significant atrophy in theanterior, inferior, and lateral temporallobe on an MRI scan (Figure 1-4).

Comment. This patient had arelatively selective deficit of semanticmemory, but essentially spared episodicmemory function. This case furtherillustrates the dissociation of these twomemory systems.

FIGURE 1-4 MRI sagittal T1-weighted image. Note thesevere temporal lobe atrophy, whichincludes anterior, inferior, and lateralregions, relative to the rest of the brain.

KEY POINT

A Semantic memory

is memory for

knowledge of

the world whenit is unconnected

with a specific

episode of

ones life.



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aretigers have stripesandPhiladelphiais the largest city in Pennsylvania. Thisform of declarative memory can be dif-

ferentiated from episodic memory be-cause its retrieval is not associated witha sense of self-experience or linked to aparticular spatial and temporal context.For example, remembering watchingPresident Barack Obamas inaugurationspeech on television with ones wifeis an example of an episodic memory

while knowing that he is president is asemantic one. That episodic and seman-tic memory represent different mem-ory systems is supported by the disso-

ciations in impairment associated withdifferent brain lesions. For example, thepatient HM, who had bilateral MTL re-sections, displayed profound amnesia

with relative sparing of previously learnedsemantic information.

Semantic memory impairment is mostfrequently manifested by naming defi-cits. This impaired naming is not miti-gated by the use of phonemic cues, andoften naming errors reflect semantically

related word choices (eg, dogforlion).Different from a pure anomia, however,these patients will also display evidenceof nonverbal impairment, such as match-ingpictures ofitemsinto differentseman-tic categories, and difficulty in providingdefinitions or descriptions of items whenprovided with their names. Categoryfluency, in which patients are asked toname as many items as they can think

of in a particular semantic category (eg,animals), is another bedside test that isoften impaired in those with semanticmemory dysfunction.

Functional Neuroanatomy ofSemantic Memory

While semantic memory is likely repres-ented in a distributed fashion through-out much of the neocortex, the infero-lateral temporal lobes (particularly theleft) are the brain regions whose injury

is most associated with disruption ofsemantic knowledge. Indeed, seman-tic variant of primary progressive apha-sia, the archetypal disease producing arelative pure semantic knowledge im-pairment, is associated with relativelyfocal neurodegeneration in this region(Figure 1-5).

Rare instances of category-specific

semantic deficits have provided addi-tional insight into the neural organiza-

tion of semantic memory. The litera-ture describes a number of patientswith relatively selective impairment ofknowledge of living things (eg, animalsand vegetables) but preserved knowl-

edge of artifacts, such as tools.29 Theopposite dissociation has also beendescribed, strengthening the functionalsegregation of these forms of seman-tic memory. Work has suggested thatthese dissociated representations maybe a reflection of the nature by which


24

FIGURE 1-5 Semantic, procedural, and working memory.The anterior and inferolateral temporallobes are important in the naming and

categorization tasks by which semantic memory is typicallyassessed. However,in the broadest sense, semantic memory mayreside in multiple and diverse cortical areas that are related tovarious types of knowledge. The basal ganglia, cerebellum,and supplementary motor area are critical for proceduralmemory. The prefrontal cortex is active in virtually all workingmemory tasks; other cortical and subcortical brain regions willalso be active, depending on the type and complexity of theworking memory task.

Adapted from Budson AE, Price BH. Memory dysfunction. N Engl J Med2005;352(7):692699. Copyright#2005,with permission from MassachusettsMedical Society. All rights reserved.

KEY POINTS

A Previously

learned semantic

information will

be intact whena patient

experiences an

isolated loss of

episodic memory.

A The inferolateral

temporal lobes

(particularly the

left) are critical

for semantic

memory.

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one experiences these different cate-gories.30 For example, our knowledgeof animals usually is largely related to

the visual modality, while our experi-ence with tools is more related to mo-tor representations.

Semantic memory deficits are mostcommonly seen in patients with AD andare likely a reflection of the pathologyin inferolateral temporal neocortex. Ofcourse, AD is also associated with sig-nificant episodic memory impairment,

which often dominates the initial clini-cal picture. Other conditions associated

with semantic memory impairment in-

clude semantic variant of primary pro-gressive aphasia, herpes encephalitis,trauma, and occasionally stroke.

Overlap Between Semantic andEpisodic Memory

Despite beingconsidered separatemem-orysystems,semanticand episodic mem-ory interact in important ways. Forexample, work from the cognitive psy-chology and functional imaging litera-ture supports the benefit of semanticencoding on subsequent episodic mem-ory of studied items.31,32 Further, se-mantic deficits themselves sometimescorrelate with performance on episodicmemory tasks, presumably by reduc-ing the effectiveness of the encodingprocess.33

The episodic memory system is alsocritical for the formation of new se-mantic memories, as evidenced by theprofound impact of MTL lesions on such

new semantic memory formation. Whilefactlike learning in patients with severebilateral medial temporal injury has beenreported, this appears largely relegatedto fragmented information likely sup-ported by perceptual learning ratherthan true pieces of new semantic infor-mation.34 Even relatively limited hippo-

campal lesions can seriously degrade theacquisition of new semantic knowledge.

Autobiographic memories are an-other area in which episodic and seman-

tic memories overlap. These memoriesof our own personal experiences aregenerally conceived as a type of episodic

memory. More remote autobiographicmemories, however, often become qual-itatively more akin to semantic knowl-edge and are likely supported, in part,by the semantic memory system. Onesimple test is that if, when recalling amemory, you can see yourself in it, thememory is likely semantic rather thanepisodic, since you would not ordinarilysee yourself in a memory.

PROCEDURAL MEMORY

Definitions

Procedural memory is the nondeclar-ative memory system that refers to theability to learn cognitive and behavioralskills and algorithms that operate at anautomatic, unconscious level. Examplesinclude learning to ride a bicycle or playthe piano. Because procedural memoryis spared in patients who have severedeficits of the episodic memory system(such as those who have undergone

surgical removal of the MTLs), it is clearthat the procedural memory system isseparate and distinct from the episodicmemory system.35

Functional Neuroanatomy ofProcedural Memory

Patients with damage to the basal gan-glia or cerebellum show impairment inlearning procedural skills.36 Functionalneuroimaging has found that these

regionsand the supplementary motorareabecome active as a new proce-dural memory task is being learned37

(Figure 1-5). Because the basal ganglia,cerebellum, and supplementary motorarea are relatively spared in early AD,these patients show normal acquisitionand maintenance of their procedural

memory skills, despite their episodicand semantic memory deficits.38

Patients in the early stages of Parkin-son disease show impaired procedural


25

KEY POINTS

A Because

Alzheimer disease

affects the

inferolateraltemporal lobes,

it is the most

common cause of

semantic memory

impairment.

Semantic variant

of primary

progressive

aphasia,

encephalitis,

trauma, and

stroke are other

causes of semantic

memory

impairment.

A Procedural

memory is

memory for

cognitive and

behavioral skills

and algorithms

that are typically

operating

unconsciously

such as riding abicycle.

A Critical brain

regions for

procedural

memory are the

basal ganglia,

cerebellum, and

supplementary

motor area.



12/14

memory while performing nearly nor-mally on episodic memory tests.38 Proce-dural memory is also disrupted by other

causes of damage to the basal gangliaor cerebellum, including Huntingtondisease, olivopontocerebellar degenera-tion, tumors, strokes, and hemorrhages.Patients with major depression mayalso show impairment in proceduralmemory tasks, perhaps because depres-sion involves dysfunction of the basalganglia.39

Disruption of procedural memoryshould be suspected when patientsshow evidence of either the loss of

previously learned skills (comparedwith their baseline) or substantial dif-ficulties in learning new skills. For ex-ample, patients may lose the ability toperform automatic, skilled movements,such as writing, playing a musical in-strument, or swinging a tennis racket.

Although these patients may be able torelearn the fundamentals of these skills,

explicit thinking becomes required fortheir performance. As a result, patients

with damage to the procedural memory

system lose the automatic effortlessnessof simple motor tasks that healthy in-dividuals take for granted. Lastly, it is

worth noting that patients whose epi-sodic memory has been devastated bya static disorder, such as encephalitis,have had successful rehabilitation byusing procedural memory (and othernondeclarative forms of memory) tolearn new skills.40

CONCLUSIONSEvidence from patient studies and morerecent neuroimaging research suggestthat memory is composed of separate

and distinct systems. An understandingof these different memory systems willaid the clinician in the diagnosis andtreatment of the memory disorders oftheir patients.

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26

KEY POINT

A Parkinson disease

is the most

common

disorderdisrupting

procedural

memory.

Huntington

disease, tumors,

strokes, and

hemorrhages

may also disrupt

procedural

memory.

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"MEMORY SYSTEMS

wolk a eb memory sys 2010

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