HOW TO UNDERSTAND IT Pract Neurol 2007; 7: 42–47
Memory
dysfunction in
neurological
practice
Andrew E Budson, Bruce H Price
A E Budson
Geriatric Research Educational
Clinical Center, Edith Nourse
Rogers Memorial Veterans
Hospital, Bedford, MA; Boston
University Alzheimer’s Disease
Center, Boston University, Boston,
MA; Division of Cognitive and
Behavioral Neurology, Department
of Neurology, Brigham and
Women’s Hospital, Boston, MA;
Harvard Medical School, Boston,
MA, USA
B H Price
Department of Neurology, McLean
Hospital, Belmont, MA and Harvard
Medical School, Boston, MA, USA
Correspondence to:
Dr A E Budson
Building 62, Room B30, Edith
Nourse Rogers Memorial Veterans
Hospital, 200 Springs Road,
Bedford, MA 01730, USA;
abudson@bu.edu
42 Practical Neurology
C
omplaints of impaired memory are
among the most common symptoms
reported to neurologists. Moreover,
impairment of memory is one of the
most disabling aspects of many neurological
disorders, including neurodegenerative diseases,
strokes, tumours, head trauma,
hypoxia, cardiac surgery, malnutrition, attention
deficit disorder, depression, anxiety,
medication adverse effects, and just normal
aging. This memory loss often impairs the
patient’s daily activities, profoundly affecting
not just them but also their families.
Memory research that began with neuropsychological
studies of patients with focal
brain lesions now includes new methods such
as positron emission tomography, functional
MRI, and event-related potentials which have
all provided a more refined and improved
classification system. Instead of conceptualising
memory as ‘‘short-term’’ versus ‘‘longterm’’,
we now think of memory as a
collection of mental abilities that use
different systems within the brain. A memory
system is a way that the brain processes
information in order to make it available for
use at a later time. Some systems are
associated with conscious awareness (explicit)
and can be consciously recalled (declarative),
whereas others are typically unconscious
(non-declarative) and are instead expressed
by a change in behaviour (implicit).
Here we will describe the four systems that
are of clinical relevance: episodic memory,
semantic memory, procedural memory, and
working memory (table 1). Additional details
may be found in Budson and Price1
and the
other references listed below.2–6
TABLE 1 Selected memory systems
Memory System Examples Awareness
Length of
storage
Main anatomical
structures
Episodic memory Remembering a short story,
what you had for dinner
last night, and what you
did on your last birthday
Explicit Minutes to
years
Medial temporal lobes,
anterior thalamic nucleus,
mamillary body, fornix,
prefrontal cortex
Semantic memory Knowing who was the first
President of the US, the
colour of a lion, and how a
fork and comb are different
Declarative
Explicit
Minutes to
years
Inferior lateral temporal
lobes
Procedural memory Driving a standard
transmission car (explicit),
and learning the sequence
of numbers on a touch-tone
phone without trying (implicit)
Declarative
Implicit
Minutes to
years
Basal ganglia, cerebellum,
supplementary motor area
Working memory Phonological: keeping a phone
number ‘‘in your head’’ before
dialing
Spatial: mentally following a
route, or rotating an object in
your mind
Non-declarative
Explicit
Declarative
Seconds to
minutes;
information
actively
rehearsed or
manipulated
Phonological: prefrontal
cortex, Broca’s area,
Wernike’s area
Spatial: prefrontal cortex,
visual association areas
Episodic memory is the explicit and declarative
memory system that we all use to recall our
personal experience
43Budson, Price
www.practical-neurology.com
EPISODIC MEMORY
Episodic memory is the explicit and declarative
memory system that we all use to recall
our personal experience, framed in our own
context, such as remembering a short story or
what we had for dinner last night. Episodic
memory loss follows a predictable pattern
known as Ribot’s law: recently acquired
memories are more vulnerable to loss than
longer established ones. This memory system
depends on the medial temporal lobes
(including the hippocampus, entorhinal and
perirhinal cortex). Other critical structures
(some of which are associated with a circuit
described by Papez in 1937) include the basal
forebrain with the medial septum and the
diagonal band of Broca’s area, the retrosplenial
cortex, the mammillothalamic tract,
and the anterior nucleus of the thalamus. A
lesion in any one of these structures may
cause the impairment that is characteristic of
dysfunction of the episodic memory system
(fig 1).
The frontal lobes are also important for
certain aspects of episodic memory, including
the registration, acquisition, or encoding
(learning) of information, retrieval of information
without contextual and other cues,
recalling the source of information, and
assessing the temporal sequence and recency
of events. The left medial temporal and
frontal lobes are most involved when learning
words, whereas the right medial temporal and
frontal lobes are most involved when learning
visual scenes. Distortions of memories, and
false memories, may occur due to frontal lobe
dysfunction, such as when information
becomes associated with the wrong context,
or specific details are incorrect.
One way to think about how the frontal
and medial temporal lobes work together is by
an oversimplified but useful analogy:
N the frontal lobes are the ‘‘file clerks’’ of
the episodic memory system
N the medial temporal lobes are the ‘‘recent
memory file cabinet’’
N other cortical regions are the ‘‘remote
memory file cabinet’’.
So if the frontal lobes are impaired, it is
difficult, though not impossible, to get
information in and out of storage. And the
information may be distorted due to ‘‘improper
filing’’ leading to inaccurate context or
sequence. If the medial temporal lobes are
damaged, it will be difficult or impossible for
recent information to be retained. Older
information that has been ‘‘consolidated’’
over months to years is thought to be stored
in other cortical regions, and will therefore be
available even when the medial temporal
lobes are damaged.
Alzheimer’s disease is the most common
disorder that disrupts episodic memory. Recent
research suggests that these patients suffer
from memory distortions and false memories in
addition to their failure to remember information.
Other common disorders that disrupt
episodic memory are listed in table 2.
If a patient presents with an inability to
remember recent information and experiences,
a disorder of episodic memory should
be suspected. The evaluation should include a
detailed history, with emphasis on the time
course of the memory disorder. For example:
N degenerative diseases such as Alzheimer’s
start insidiously and progressively worsen
N vascular dementia and other multifocal
disorders such as multiple sclerosis tend
to start suddenly and progress in a
stepwise manner
N static disorders such as strokes and
traumatic brain injuries are typically
maximal at onset, improve, and are then
stable
N transient disorders of episodic memory
include those attributable to a concussion,
a seizure, and transient global amnesia.
Prefrontal
cortex
Thalamocingulate
tract
Cingulate gyrus
Anterior thalamic
nucleus
Thalamus
Fornix
Mammillothalamic tract
Mammillary body
Amygdala
Hippocampal
formation
Parahippocampal
gyrus
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. (From
Budson AE, Price BH. Memory
dysfunction. N Engl J Med
2005;352:692–9. Copyright
Massachusetts Medical Society. All
rights reserved.)
44 Practical Neurology
Interviewing a family member or other
informant is usually necessary because the
patient will invariably not remember important
aspects of their history. Any history of
other cognitive deficits should also be elicited,
such as attention, language, and visuospatial
skills. Medical and neurological examination
should be performed to look for signs of
neurodegenerative disorders, focal neurological
injury, and systemic illness.
There are many cognitive tests that can be
used to assess a patient’s episodic memory
function. But the relationships between a
patient’s cognitive functions, test performance,
and their ‘‘real life’’ activities are
often complex. Test performance is rarely
pathognomonic of a specific disorder. And no
single test is capable of evaluating all aspects
of memory. Factors confounding test interpretation
include aphasia, dyslexia, low intellectual
function, alterations in mood and
motivation, confusion or delirium, psychosis,
and medication adverse effects. Cognitive
testing can be performed in the office by
asking the patient to remember a short story
or several words, or by using tests such as the
Mini-Mental State Examination, Blessed
Dementia Scale, and others.1
The accompanying
supplementary appendix available at http://
www.nejm.org or http://www.thebrainlab.org
provides additional guidance about how to
use such tests in clinical practice. Formal
neuropsychological testing is necessary in
complex cases. Depending on the differential
diagnosis, appropriate laboratory and imaging
studies are then carried out.
SEMANTIC MEMORY
Semantic memory is the explicit and declarative
memory system that underpins our
general store of conceptual and factual
knowledge such as the colour of a lion, or
the first President of the United States. It is
not related to any ‘‘specific’’ memory. Indeed,
in its broadest sense, semantic memory
includes all our knowledge that is not related
to a specific episodic memory, and thus can
be kept in many cortical areas. Visual images,
for example, are stored in or nearby visual
association areas. A more restrictive view of
semantic memory, justified in the light of the
naming and categorisation tasks by which it
is usually measured, suggests that it depends
on the inferolateral temporal lobes (fig 2).
Alzheimer’s disease is the most common
disorder affecting semantic memory, as it is
for episodic memory. This disruption may be
attributable to pathology in the inferolateral
temporal lobes or to pathology in frontal
cortex, leading to poor activation and retrieval
of semantic information. Supporting the idea
that two separate memory systems are
impaired in this disorder, episodic and
semantic memory decline independently in
Alzheimer’s disease; one system may be
affected first and decline faster than the
TABLE 2 Four memory systems and the common clinical disorders
which disrupt them
Disease
Episodic
memory
Semantic
memory
Procedural
memory
Working
memory
Alzheimer’s disease +++ ++ – ++
Frontotemporal dementia ++ ++ – +++
Semantic dementia + +++ ? –
Lewy body dementia ++ ? ? ++
Stroke and vascular
dementia
+ + + ++
Parkinson’s disease + + +++ ++
Huntington’s disease + + +++ +++
Progressive supranuclear
palsy
+ + ++ +++
Korsakoff syndrome +++ – – ¡
Multiple sclerosis + ¡ ? ++
Transient global amnesia +++ ¡ – –
Hypoxic–ischaemic injury ++ – – ¡
Head trauma + + ¡ ++
Tumours ¡ ¡ ¡ ¡
Depression + ¡ ++ ¡
Anxiety + – – ¡
Obsessive-compulsive
disorder
+ – ++ ++
Attention deficit
hyperactivity disorder
– – ? +
+++, Early and severe impairment; ++, moderate impairment; +, mild
impairment; ¡, occasional impairment or impairment in some studies but not
others; –, no significant impairment; ?, unknown.
Tumours, strokes and other focal disease processes may affect any of these
memory systems depending on the neuroanatomical structures affected.
Semantic memory is the explicit and declarative
memory system that underpins our general store of
conceptual and factual knowledge
45Budson, Price
www.practical-neurology.com
other. Patients with the temporal variant of
frontotemporal dementia (known as semantic
dementia) have deficits in all aspects of
semantic memory. Although articulation,
non-verbal problem-solving skills, and episodic
memory are relatively preserved, most
aspects of language are impaired: semantic
dementia patients have extreme difficulty
naming, comprehending single words, and
their general knowledge is impaired. Other
common disorders that disrupt semantic
memory include almost any pathology that
affects the inferolateral temporal lobes, such
as traumatic brain injury, stroke, surgical
lesions, encephalitis, and tumours (table 2).
Although difficulty recalling people’s
names and other proper nouns is common
(particularly for older people), impairment of
semantic memory should be suspected when
a patient also has difficulty recalling the
names of common items. An evaluation for
semantic memory impairment should include
the same components as the evaluation of
episodic memory disorders, as above. It is
important to distinguish whether the problem
is solely attributable to naming difficulties
(anomia), or is attributable to a true loss of
semantic information. For example, patients
with mild dysfunction of semantic memory
may only show reduced generation of words
to semantic categories, such as the number of
names of animals that can be generated in
one minute. With severe impairment of
semantic memory, however, patients have a
‘‘two-way’’ naming deficit: they are unable to
name an item when it is described, and they
are also unable to describe an item when
given its name.
PROCEDURAL MEMORY
Procedural memory is the ability to learn
behavioural and cognitive skills and algorithms
that operate at an automatic, unconscious
level. Procedural memory is nondeclarative
and generally implicit, such as
learning to ride a bike or the sequence of
numbers on a touch-tone phone without
trying. Brain regions involved in procedural
memory include the supplementary motor
area, basal ganglia and cerebellum (fig 2).
Parkinson’s disease is the most common
disorder affecting procedural memory
(table 2). Other neurological disorders that
affect basal ganglia or cerebellar function also
disrupt procedural memory, such as
Huntington’s disease and olivopontocerebellar
atrophy, in addition to strokes and tumours
affecting these brain structures. Patients with
major depression also have impairment in
procedural memory, perhaps because depression
involves dysfunction of the basal ganglia.
By contrast, because the disease process in
early Alzheimer’s disease affects cortical and
limbic structures while sparing the basal
ganglia and cerebellum, these patients show
normal learning and maintenance of procedural
skills.
Disruption of procedural memory should be
suspected when there is either loss of
previously learned skills or significant difficulty
in learning new skills. Skills that are
commonly affected include writing, playing a
musical instrument, and swinging a tennis
racket. Although these skills may be relearned,
effortful explicit thinking is often required,
such that patients with damage to the
procedural memory system may never
achieve the automatic effortlessness of
simple motor tasks that healthy individuals
take for granted. Evaluation is similar to that
Semantic memory
Prefrontal
cortex
Supplementary
motor area
Basal ganglia
(putamen)
Inferolateral
temporal lobe
Cerebellum
Procedural memory
Working memory
Figure 2
Semantic, procedural, and working
memories. The inferolateral temporal
lobes are important in the naming and
categorisation tasks by which semantic
memory is typically assessed. However,
in the broadest sense, semantic
memory may reside in multiple and
diverse cortical areas that are related to
various types of knowledge. The basal
ganglia, cerebellum, and supplementary
motor area are critical for procedural
memory. The prefrontal cortex is active
in virtually all working memory tasks.
Other cortical and subcortical brain
regions will also be active, depending
on the type and complexity of the
working memory task. (From Budson
AE, Price BH. Memory dysfunction.
N Engl J Med 2005;352:692–9.
Copyright Massachusetts Medical
Society. All rights reserved.)
Procedural memory is the ability to learn
behavioural and cognitive skills and algorithms
that operate at an automatic, unconscious level
46 Practical Neurology
of episodic memory disorders. It is worth
noting that the preserved procedural memory
system has been used to rehabilitate patients
whose episodic memory has been devastated
by disease such as encephalitis.
WORKING MEMORY
Working memory is a combination of the
traditional fields of attention, concentration
and short-term memory. It is the explicit and
declarative memory system that enables us to
temporarily hold and manipulate information
in our consciousness to assist in goaloriented
behaviour. Working memory is often
divided into a central executive system that
allocates attentional resources, and separate
components that process phonological (such
as keeping a phone number in mind) and
spatial (such as mentally following a route)
information. While the prefrontal cortex is the
most invariant brain region involved (fig 2),
working memory also uses a network of
cortical and subcortical areas which differ
depending upon the particular task. A typical
network includes posterior brain regions (such
as visual association areas) that are linked
with prefrontal regions to form a circuit. Leftsided
brain regions are more active during
phonological working memory tasks, whereas
right-sided brain regions are more active
during spatial working memory tasks.
However, regardless of the type of material
being manipulated, as the complexity of
the task increases there is an increase in the
number of brain regions activated in the
prefrontal cortex of both hemispheres.
Since working memory depends on a
network of activity that includes subcortical
structures as well as frontal and parietal
cortical regions, it may be disrupted by many
degenerative and other neurological disorders,
including Alzheimer’s disease, frontotemporal
dementia, vascular dementia,
Parkinson’s disease, multiple sclerosis, head
injuries, tumours, and strokes (table 2).
Impairment of working memory most
commonly presents as an inability to concentrate
or pay attention. Trouble with working
memory may also present as an apparent
problem with episodic memory when information
cannot be learned because it cannot
be ‘‘kept in mind’’ by working memory.
Continuing the filing analogy mentioned
above, if poor working memory impairs the
ability of the episodic memory file clerk to
obtain new information, then it will be
difficult or impossible to get that information
into the episodic memory filing cabinet.
Evaluation is similar to that for episodic
memory disorders.
CONCLUDING COMMENTS
Although once considered a simple concept,
converging and complementary lines of
evidence suggest that memory is composed
of separate and distinct systems. A single
disease process (such as Alzheimer’s disease)
may impair more than one memory system.
Hopefully research leading to improved
understanding of these memory systems will
in turn lead to better treatments for memory
disorders.
ACKNOWLEDGEMENT
This article was reviewed by Adam Zeman,
Exeter, UK.
REFERENCES
1. Budson AE, Price BH. Memory dysfunction.
N Engl J Med 2005;352:692–9.
2. Mesulam M-M. Principles of behavioral and
cognitive neurology, Second edition. New York, NY:
Oxford University Press, Inc, 2000.
3. Schacter DL. The seven sins of memory: how the
mind forgets and remembers. Boston, MA:
Houghton Mifflin, 2001.
4. Schacter DL, Wagner AD, Buckner RL. Memory
systems of 1999. In: Tulving E, Craik FIM, eds. The
Oxford handbook of memory. New York: Oxford
University Press, 2000:627–43.
5. Simons JS, Spiers HJ. Prefrontal and medial
temporal lobe interactions in long-term memory.
Nat Rev Neurosci 2003;4:637–48.
6. Solomon PR, Budson AE. Alzheimer’s disease. Clin
Symp 2003;54:1–40.
Working memory is the explicit and declarative
memory system that enables us to temporarily hold
and manipulate information in our consciousness
47Budson, Price
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