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dissertation entitled

RELATIONSHIPS BETWEEN MRI-OBSERVED
PLAQUE AND MEMORY FUNCTIONING
IN MULTIPLE SCLEROSIS

presented by

GREGG ASHLEY MARTIN

has been accepted towards fulfillment
of the requirements for

Ph.D. Psychology

degree in

 

 

 

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Bertram P. Karon

5/7/91
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RELATIONSHIPS BETWEEN MRI-OBSERVED PLAQUE
AND MEMORY FUNCTIONING IN MULTIPLE SCLEROSIS

BY

Gregg Ashley Martin

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY

Department of Psychology
1991

ABSTRACT

RELATIONSHIPS BETWEEN MRI-OBSERVED PLAQUE
AND MEMORY FUNCTIONING IN MULTIPLE SCLEROSIS

BY
Gregg Ashley Martin

Memory deficits are fairly common in MS, but like motor
and sensory impairments, relatively little is know about the
the pathological processes responsible for the marked inter-
and intra-patient variations in functioning. Magnetic
resonance imaging (MRI) provides the first reliable method
of observing MS plaque in vivo, but reports of the
relationship between MRI-visualized lesion burden and
impairment have been disappointing. However, these
generally negative findings may have resulted from
insensitive MRI and deficit measures, especially in studies
of memory. This investigation compared several MRI indices
to identify which lesion burden markers are most predictive
of memory dysfunction. Forty-one clinically-definite MS
patients of varying disease and demographic characteristics
were administered the Wechsler Memory Scale - Revised and
California Verbal Learning Test. MRI's were scored for
whole brain, cerebral, and uni-hemisphere lesion area as
well as corpus collosal (CC) and periventricular
involvement. Correlations between lesion burden and memory
measures were relatively small, but comparable to those
reported previously. Contrary to prediction, cerebral
lesion area was not more sensitive to memory test
performance than the other lesion burden indices excepting

CC lesion area. The absolute and relative degree of

Gregg Ashley Martin
association between lesion and memory appeared similar
across primary versus secondary and verbal versus visual
memory measures, disease course and duration, and one
estimate of premorbid cognitive functioning. The failure of
cerebral lesion area to outperform other plaque measures is
attributed partly to a possible nonlinear relationship
between function and acute plaque fluctuation. MRI
insensitivity to histological-level changes, lesion
dissemination characteristics, diffferences between direct
versus representational lesion indices, and restriction of
memory test performance range also are offered as factors

contributing to the results.

In memory of Dane Francis Martin
and

to my parents for their love

ii

ACKNOWLEDGMENTS

My heartfelt appreciation goes to Al Aniskiewicz for
graciously assisting my growth as a clinician, scientist,
and roadtripper. I thank Lauren Harris for his
scholarliness, conscientiousness, and painful efforts to
keep me moving past an intuitive approach to spelling and
grammar. I also thank Bertrom Karon for his willingness to
go beyond literal requirements. Lastly, my gratitude to G.

Anne Bogat for her support, dedication, and friendship.

iii

TABLE OF CONTENTS

LIST OF TABLES. . . . . . . . . . . . . .

LIST OF FIGURES . . . . . . . . . . .

INTRODUCTION. . . . . . . . . . . . .
General Description of MS. . . . . . .
General Description of Memory. . . . .
Functional Aspects. . . . . . . . .
Pathoanatomical Aspects . . . . .
Memory Functioning in MS . . . . . . .
Introduction. . . . . . . . . . .
Primary Memory . . . . . . . .

Secondary Memory . . . . . .
Comparative Functioning. . .
Predictors of Disturbance. .
Pathoanatomical Relationships to
Memory Disturbance . . . . . . . . .
Introduction. . . . . . . . . . . .
MRI Physics . . . . . . . . . . . .
MS Applications . . . . . . . . .
Motor and Sensory Functioning. .
Cognitive and Memory Functioning

Summary and Rationale. . . . . . . .
METHOD. . . . . . . . . . . . . .
Subjects . . . . . . . . . . . .
Procedure. . . . . . . . .
Tests and Measures . . . . . .
Magnetic Resonance Imaging. .
Signa Cursor. . . . . . .

Wechsler Memory Scale — Revised .
California Verbal Learning Test . .
Hypotheses . . . . . . . . . . . . . .

RESULTS 0 O O O O O O O O O O O 0

Preliminary Analyses . . .
Memory Test Performance
MRI Lesion Measures . .

Primary Analyses . . . . .
Hypothesis 1. . . . . .
Hypothesis 2. . . . . .
Hypothesis 3. . . . . .
Hypothesis 4. . . .

Supplemental Analyses. .

iv

Page
vi

vii

114
117

117
117
122
127
127
127
132
133
141

Page

DISCUSSION. . . . . . . . . . . . . . . . . . . . 149
Relative and Absolute Values of
Lesion Measures. . . . . . . . . . . . . 150
Cerebral Lesion Area. . . . . . . . 150
Total Brain Lesion Area . . . . . 153
Corpus Collosal Involvement . . . 154
Periventricular Involvement . . . . . . . 156
Uni-Hemisphere Lesion Area. . . . . . . 158
MRI-Observed Lesion:
Necessary or Sufficient? . . . . . . . . . . . 160
Supplemental Analyses. . . . . . . . . . . . . 161
Aspects of Memory . . . . . . . . . . . . 162
Verbal versus Visual Memory. . . . . . . 162
Deficit Severity . . . . . . . . . 163
Primary versus Secondary Memory. . . . . 164
Aspects of Predictor Variables. . . . . . . 166
Illness Duration . . . . . . . . . . . . 166
Illness Course . . . . . . . . . . . . 166
Premorbid Cognitive Functioning. . . . . 167
Comments Concerning Study
Reliability and Validity . . . . . . . . . . . 167
APPENDIX A. . . . . . . . . . . . . . . . . . . . 172
REFERENCES. . . . . . . . . . . . . . . . . . . . 173

Table

10

11

12

13

LIST OF TABLES

Distribution of Patient Memory Scores .

Patient vs. Normative Sample Mean
Scores: Preliminary Analyses . . .

Patient vs. Normative Sample Mean
Memory Scores: ANOVA Comparisons . . .

Observed vs. Expected Memory Deficit
Prevalence Rates. . . . . . . . . . . .

Lesion Measure Distributions. . . . . .
Lesion Measure Intercorrelations. . . .
Lesion Measure Correlations with Total
Memory Index: Comparison with Cerebral
Lesion Area . . . . . . . . . . . . .

Lesion Measure Correlations with
WMS-R Indices . . . . . . . . . . . . .

Lesion and CVLT Measure Correlations. .

Illness Length Correlations with
Memory Functioning. . . . . . . . . . .

Memory Functioning Correlations with
Education and WAIS-R IQ . . . . . . .

Lesion Measure Correlations with
WAIS-R IQ O O O O O O O O O O O O O

Lesion and Memory Measure Correlations
With and Without Educations Effects

vi

Page
118

120

121

123

125

126

128

130

131

143

145

146

148

LIST OF FIGURES

Figure Page

1 Frequency and Conditional Probability of
Membersh1p to Median Splits of Cerebral
Lesion Area and Total Memory Index. . . . . 135

2 Frequency and Conditional Probability of
Membership to Median Splits of Cerebral
Lesion Area and WMS-R Verbal Memory Index . 136

3 Frequency and Conditional Probability of
Membership to Median Splits of Cerebral
Lesion Area and WMS-R Visual Memory Index . 137

4 Frequenc and Conditional Probability of
Membersh1p to Median Splits of Cerebral
Lesion Area and WMS-R General Memory Index. 138

5 Frequency and Conditional Probability of
Membersh1p to Median Splits of Cerebral
Lesion Area and WMS-R Attention Memory
Index . . . . . . . . . . . . . . . . . . . 139

6 Frequency and Conditional Probability of

Membersh1p to Median Splits of Cerebral
Lesion Area and WMS-R Delayed Memory Index. 140

vii

INTRODUCTION

Multiple sclerosis (MS) is a chronic neurologic disease
noted for its extremely varied symptoms and course, but also
for its consistently similar pathological changes to CNS
myelin. These changes are characterized by glial plaques
disseminated in time and space. Identification of
etiological and pathogenic factors continues to frustrate
the scientific community; thus, much of what is known about
MS concerns its clinical and pathophysiological features
(Matthews, Acheson, Batchelor, & Weller, 1985).

Physical manisfestations associated with MS are fairly
well-documented, whereas investigations of cognitive
dysfunctions have followed more slowly (Grant, 1986).
Paralleling deficits in motor and sensory functions,
deteriorations in mentation vary widely among patients
although some degree of memory decline is relatively common
(Rao, 1986).

Memory impairments were included in the earliest
descriptions of MS (e.g., Charcot, 1877). Yet, delineation
of all cognition in MS lagged until the mid—1900's with the
advent of modern, empirically-based testing. Until the last
decade, however, the evaluation of memory has not been a
major focus. These later efforts have been primarily
concerned with the description of memory impairments within
the patient population. Very little data exist on the
relationship between pathological changes in the CNS and
memory decline. In great part, this paucity reflects the

l

fact that the field lacked reliable methods for identifying
MS plaque in-vivo until recently. Current breakthroughs in
nuclear magnetic resonance imaging (MRI) may offer the
technology needed for such essential, but neglected,
research.

At this point, a general description of MS would be
useful before proceeding with a review of the literature on

memory functioning in MS.
General Description of MS

MS was identified as a clinical entity through the work
of Jean-Martin Charcot in mid-nineteenth century Paris
(Charcot, 1877). Parceling together earlier, but
incomplete, descriptions by Cruveilhier, and his own
clinical experiences, Charcot identified distinguishing
characteristics needed for accurate course description and
differential diagnosis (Compsten, 1988). More importantly,
Charcot made the fundamental connection between clinical
course and the morphological changes (i.e., plaque-like
lesions) seen at autopsy. By the turn of the century, a
large body of knowledge had been compiled about the course,
clinical features, and pathophysiology of MS (e.g., Meuller,
1904) and much of this data remains accurate by modern
standards (see Brain, 1930; Dejong, 1970; McAlpine, 1955 and
1972 for more detailed treatment).

Current research in the United States suggests that,
aside from traumatic injury, MS is the most common
neurological disorder of people under 60 years of age
(Johnson, Katzman, McGreer, Price, Shooter, & Silberberg,

1979), yet it is relatively rare, with an annual incidence

of less than 5 per 100,000 (Baum & Rothschild, 1981).
Incidence rates are typically higher in women than for men
at a ratio of approximately 1.8 : 1 (Kurtzke, Beebe, &
Norman, 1979). MS rarely appears before adolescence; rates
increase greatly through the early 40's and decrease
markedly after the sixth decade (Visscher, Clark, Detels,
Malmgren, Valdiviezo, & Dudley, 1981). Blacks apppear to
have a lower predilection for MS than whites, although both
races have similar age and geographic distributions
(Acheson, 1985).

An especially enigmatic feature of MS is its lack of
uniform geographical distribution as identified in even the
earliest epidemiological studies (e.g., Steiner, 1938;
Limburg, 1950). A direct and positive relationship between
the distance from the equator and the rate of incidence is
consistently apparent (e.g., Gonzalez-Scarno, Spielman, &
Nathanson, 1986). Furthermore, the "risk factor" associated
with residence appears to be mutable. Acheson (1985)
reviewed a number of epidemiological studies collected
throughout the world. From this, he presented evidence
suggesting that a person migrating to a different latitude
before the age of 15 "acquires" approximately the same
probability of developing the disease as his/her new
neighbors. Moves afte; the age of 15 result in no shift in
the "risk factor" and a person retains approximately the
same probability of acquiring MS as his/her homelanders.
Numerous theories were unsuccesfully applied to explain this
relationship between geography and incidence. Familial and
racial genetics, climate (e.g., amount of sunshine), type of

dwelling, and diet were proposed to act as the "trigger" for

MS -- in conjunction with hypothesized viral agents or other
causal processes.

Other etiological models have faired just as poorly.
Pathogens secondary to primary agents such as cholera
overexertion, congenital disposition (especially through
familial inheritance), primary viral infection, venal
thrombosis, and various exogenous (e.g., heavy metals) and
endogenous toxins (e.g., lypolytic enzymes), all have
enjoyed attention as a possible "cause" of MS but have
received little or no empirical support (Dejong, 1970).

More current models suffer from a similar lack of
confirming evidence. One of the most popular and long-
standing family of theories posits long-latency, viral
infectious agents as responsible for onset of demyelination.
Bolstered by epidemiological data consistent with a viral
etiology, by commonalities with disorders occurring from
microvirii (e.g., poliomyelitis), and by the lack of other
viable theories, viral infection models have remained in the
literature even though no viral agent(s) specific to MS have
been identified. Similarly, hypotheses that MS is an
anaphylactic or auto-immune disorder received support from
years of animal research on EAE (experimental allergic
encephalomyelitis), without the identification of
responsible antigens (Field, 1988). Increased incidence and
prevalence rates found amoung certain ethnic groups (e.g.,
Scandinavians) (Kurtske, 1986) and families (Field, 1984)
have pointed to possible idiopathic mechanisms. In fact,
some polygenic inheritance models using HLA
(histocompatability) sites on the 6th and 14th chromosomes

have drawn support as possible markers of inherent

susceptability to MS (Compston, 1986). Still,
substantiation of responsible pathogenic mechanism(s)
remains frustratingly absent. Investigations of pathogenic
models based on the production and maintenance of healthy
myelin are promising new areas of exploration. Chief among
these are the search for genetic lipid abnormalities and
polyunsaturated fatty-acid involvement to affirm MS as an
abiotrophic disorder (Field, 1988). It is still not clear,
however, that the morphological changes seen in MS result
from a fundamental weakness in the development of myelin.
Poor understanding of the processes responsible for
demyelination has hampered the development of effective
treaments. The number and type of therapies that have been
investigated are surprising and include variations on
immunotherapy, plasmapheresis, anti-bacterial and anti-viral
drugs, diet, and snake venom. Current treatment relies on
exercise and drug regimens, often corticosteroids. These
have had disappointing results at best (see Tourelette,
Baumhefner, Potvin, Potvin, & Poser, 1983, or Matthews, 1985
for more extended reviews). The stunted progress of
effective therapy also is attributable to problems
associated with the high frequency of spontaneous remission
in MS. Clinical trials are exquisitely difficult to
evaluate with such an elevated rate of untreated
improvement. Given the state of present etiological models,
it may be that identification of an effective curative or
even preventative agent will occur before an understanding
of how the agent works -- as has happened in the past with
some frequency (e.g., cholera). Until then, management will

be limited to the secondary care of complications, symptoms,

and signs.

The two most distinguishing characteristics of MS are
symptom dissemination in space and in time (e.g., McAlpine,
Compsten, & Lumsdun, 1955). The extreme variability of
symptom type across patients presumably reflects the fact
that numerous locations in the CNS can host MS plaques.
McAlpine's (1972) review of more recent patient series
provides a list of typical presenting symptoms: weakness of
one or more limbs (40%), optic neuritis (22%), parathesiae
(21%), diplopia (12%), vertigo (5%), and disturbance of
micturation (5%). Increased spinal reflexes, cerebellar
involvement, ataxia, and losses of sensory perception and
sphincter control are commonly seen later in the course
(Poser, Wikstrom, & Bauer, 1979). However, many other
symptoms have been reliably attributed to initial and later
stages of MS: prodromal and paroxymal symptoms, Lhermitte's
sign, dysphagia, tonic seizures, facial mykomia, limb
weakness and spasticity, and muscle wasting (Matthews,
1985). Changes in mentation also occur, including
generalized intellectual deterioration, memory and attention
deficits, and impairments in abstract reasoning and
information processing speed (e.g., Grant, 1986; Hill, 1990;
Peyser, Edwards, Poser, & Filskov, 1980).

Temporal factors also vary widely across patients.
Symptoms and signs can appear and disappear within a short
time (e.g., days) and the latency between bouts can vary
from days to years (Hallpike, 1983). Researchers disagree
about possible course differences: however, most agree that
there are at least benign, relapsing-remitting, and chronic-

progressive subtypes (Matthews, 1985). These categories

reflect the wide range of temporal changes seen in clinical
manifestations, ranging from negligible (constantly
declining or no change) to marked (highly variable patterns
of relapse and remission). Some researchers also include a
malignant (or acute) variety to mark the three (Poser,
Wikstrom, & Bauer, 1979) to 12 percent (Bauer, Firnhaber, &
Winkler, 1965) who die and/or deteriorate significantly
within the fifth year of diagnosis. Difficulties in
gathering accurate diagnosis and relapse data make clinical
course distinctions difficult to validate. In fact,
Hallpike (1983) has argued that MS is an essentially
chronic-progressive disease whose clinical picture is
blurred by the randomness of lesion location and the
severity of its effects on functioning. He suggests that it
is in the later stages of MS that a more consistent pattern
emerges when the effects of lesion dissemination accumulate
and remission frequency and intensity lessen. At this time,
it is not clear whether different course designations
represent actual differences in disease parameters (e.g.,
variations in pathological changes/rates) or that different
courses are merely spurious artifacts of happenstance lesion
distribution as offered by Hallpike.

Disagreements over course notwithstanding, Hallpike
(1983) and others do agree that the "Kurtzke 5-year rule" is
a better indicator of long-term disability prognosis than is
course. Based on Kurtzke, Beebe, Nagler, Kurland, and
Auth's (1970) study using the Kurtzke disability scale
(Kurtzke, 1965), the authors found a highly significant and
positive correlation between ratings at 5 years and those at

10 and 15 years. This relationship between first and later

half—decade disability also compares more favorably than
relapse rate, duration, and initial symptoms in predicting
clinical disability (Matthews, 1985).

Mortality prognosis is more difficult to ascertain
after the first five years (pre-fifth year mortality
reflecting a malignant/acute course) because of the long
interval between diagnosis and death where parcelling out
effects unrelated to MS becomes critical (e.g., aging).
Nevertheless, many surveys indicate that a majority of
patients live 25 to 35 years (e.g., Kurtzke, Beebe, Nagler,
Nefzger, Auth, & Kurland, 1970; Confavreaux, Aimard, &
Devic, 1980) with a range of days to 60 years (Matthews,
1985). Few patients die directly of MS, but rather succumb
to secondary causes such as pneumonia (Leibowitz, Kahana,
Jacobsen, & Alter, 1972).

The diagnosis of MS is difficult owing to the
appearance and disappearance of sometimes subtle and wide-
ranging symptoms. And for any given exacerbation, symptoms
can mimic and be mimicked by many other pathologies. Our
limited understanding of pathogenic and etiologic factors
has hampered the development of laboratory tests with
sufficient sensitivity and specificity to serve as
pathognomonic indicators. Diagnosis was and continues to be
essentially a clinical exercise.

Because of this dependence on clinical acumen,
diagnostic accuracy suffered until empirically-supported
criteria could be developed. Present systems supplement
historical clinical data with paraclinical evidence (e.g.,
evoked responses) and laboratory evidence (e.g., oligoclonal

bands in the cerebrospinal fluid) to delimit categories such

as clinically and laboratory-supported definite, probable,
and possible MS. The most commonly used nosologies are
those by the Schumacher Committee, 1965; McAlpine, 1972;
Rose, Ellison, Myers, and Tourtellote, 1976: McDonald and
Halliday, 1977, and especially the Boston University
Workshop (also known as the Poser criteria) (Poser, Paty,
Scheinberg, et a1., 1983).

The reliability of these systems depends heavily on
the use intended. For example, the Boston University
Workshop system has no "possible" category and uses
comparatively stringent inclusion criteria to insure low
false-positive rates. The cost to this system is an
increased false-negative rate, which may hamper, for
example, studies focusing on early-case detection. Thus,
care must be taken to choose a system appropriate for the
task at hand. Although employment of these systems has
improved diagnostic reliability and validity, they still
rely considerably on clinical judgement and remain
susceptible to inter-rater variation. Until true
pathognomonic tests are developed, however, little can be
done to ameliorate this problem. Finally, recent advances
in radiological imaging (MRI) have outpaced revisions of
some schemas, although a flurry of work is currently
underway to validate MRI techniques for use in diagnostic
systems.

Gross pathological examination of MS-involved CNS finds
lesions throughout, although some sites are more apt to
contain plaque. Periventricular white matter locales are
most common, containing as much as 40% of plaque

distribution confirmed at autopsy (Brownell & Hughes, 1962).

10

White matter, in general, is most likely to be affected,
although cortex and the junction between the two also can
contain plaque (Lumsden, 1970). MS typically appears
symmetrically between the cerebral hemispheres and
distribution between the four major lobes is relatively
similar, although usually with less involvement in the
occipital lobe (Brownell & Huges, 1962). Other common sites
include the cervical spinal cord and optical tracts (Adams,
1983). Most plaques lie in close proximity to venules or
larger veins (Fog, 1965), but the reasons for this
association are not known.

Analyses on a histological level have provided possible
clues about the relationship between pathological and
clinical changes. Microscopic examination indicates that
complete axonal and cell body loss occurs infrequently,
although histological changes in these structures are seen
to some degree in most, but especially chronic cases
(Oppenheimer, 1976). Lesion growth fans out from a locus,
usually sparing some portion of an axon's myelin (Lumsden,
1970). Grossly, much of the myelin within this sphere
appears intact, but on closer examination some signs of
deterioration (e.g., thinning) or outright destruction
(e.g., microglial phagocytosis and complete absence of
myelin) can be seen (Adams, 1983). From this, Adams (1983)
concluded that MS lesion distribution is diffuse rather than
multifocal. An important implication of this distinction is
its impact on functioning and this will be discussed in
greater length below.

Several factors have been used to explain why neuronal

functioning in affected areas is not completely nor

11

irrevocably lost. First, demyelination is a gradual
process wherein only the final-stage, chronic lesions show
total loss of myelin and oligodendroglial cells (Weller,
1985). Some functioning may continue between this and the
earliest stages of degeneration where remission, in turn,
may further delay the final result (Weller, 1985). A
gradual degradation also may allow time for the development
of alternative pathways or compensatory functioning. A
second factor that may explain why functioning continues in
affected areas is the tendency for lesion growth to spread
centrifugally (Lumsden, 1970). Localized structures often
are spared from complete demyelination, presumably resulting
in the preservation of at least limited functioning of the
involved tissues. Third, remyelination is thought to

occur in and around plaques, although its extent and quality
is not completely known (Harrison, McDonald, Ochoa, &
Ohlrich, 1972: Blakemore, 1982). Neural transmission may
exist in active lesions where a suffient number of '
oligodendroglial cells remain to allow remyelination. The
pathophysiological mechanisms responsible for a remission
are not known, but it is probably the case that
remyelination is only a small part of the picture. Review
of exisiting literature by Matthews (1985) suggests that de
novo and early exacerbations are caused as much by edemal
and other acute responses to demyelination as the actual
destruction of myelin. Thus, remission may simply reflect
the ending of the acute response. Continued investigation
is needed, however, as the relationship between
pathophysiology and clinical changes is poorly understood

still.

12

Our relative ignorance about the pathophysiological
mechanisms responsible for deficit is due, in great part, to
our almost total dependence on post-mortem examination.

Full description of patho-clinical relationships, including
the processes responsible for relapse and remission, would
be furthered by dynamic, in-vivo examinations. MRI may
provide the technology necessary for such investigation.

Before moving to a review of the literature on memory
functioning in MS, a brief introduction to memory
terminology, theoretical models, and research methodology is

provided.

General Description of Memory
Functional Aspects

The study of human memory encompasses a wide range of
approaches, with contributions by neuropsychologists,
clinical, cognitive, and experimental psychologists,
linguists, educators, computer science and artificial
intelligence specialists, and neurologists. This
introduction is limited to psychological studies of
"conscious" memory as they relate most directly to memory
research on MS. It excludes attentional mechanisms,
executive functions, and other functions that are recognized
as essential to intact memory processing. Extensive
coverage of these functions and other aspects of memory may
be found in texts on cognition and memory (e.g., Ashcraft,
1989: Reynolds & Flagg, 1983: Squire, 1987: Squire &
Butters, 1984: Tulving & Donaldson, 1972).

Early research on memory was guided by intuitively

important features of memory (e.g., Ebbinghaus, 1885), and

13

modern models often still rely on fairly common sense
distinctions. These include temporary versus more permanent
memory systems, the types of information retained in memory,
and the way in which memories are used. The distinctions
between temporary and permanent systems involve a broad
family of concepts and theories that seek to account for
temporal gradients in information processing. Most models
include at least two tiers beyond the level of the sensory
memory registers: one that accounts for immediate and
conscious processing demands without regard to permanent
information storage and a second system responsible for the
storage and recollection of more long-lasting memories. The
best known memory function models use the terms primary
memory (PM) (James, 1890), short-term memory (STM) (e.g.,
Miller, 1956), and working memory (e.g., Baddeley & Hitch,
1974) to refer to the system that deals with information in
here-and-now. Testable distinctions between the concepts of
PM, STM, working memory, attention, and consciousness are
quite blurry and each has received at least partial support
from over 100 years of empirical study. Even though
controversy exists as freely as agreement (e.g., Cermak,
1982), some synthesis and generalization is possible
regarding theories of temporary memory. Pioneering work by
Miller (1956) and others indicates that the temporary system
is limited in capacity by the amount of information that it
can handle (i.e., seven bits of information plus or minus
two) rather than by a simple decay over time. That is,
information in STM is lost more because of competition with
other material than because of failure to rehearse or other

means of deterioration of the memory trace (Peterson &

14

Peterson, 1959). The limit in capacity may by overcome by
increasing the meaningfulness of the information (e.g.,
semantic coding and personal attributions) and by the
process of "chunking" -- grouping specific bits of material
into larger functional units (e.g., grouping a string of
random digits as the area code and exchange of a phone
number).

The working memory model elaborates the temporary
memory system including the presence of a master, "executive
control system" (ECS) that oversees memory and other
intellectual processes (Baddeley, 1981). Analogous to some
conceptualizations of attention and a variety of executive
functions, the ECS purportedly initiates and allocates
cognitive resources, maintains flow of information to and
from memory stores, and otherwise controls decisions. At
least two "slave" systems serve the ECS by providing
"working space" (hence the term, working memory) for
cognitive tasks. The articulatory rehearsal loop handles
most verbally-mediated tasks and, within its limits, holds
and recycles information for later recall. The "visuo-
spatial scratch pad" parallels the articulatory loop but
only for visual tasks. A primary tenet of the working
memory model is that if the limits of either of the slave
systems are reached (i.e., around six bits of information),
the efficiency of the ECS begins to decrease with attendant
increases in processing time and errors. Although the
working memory model does an admirable job of explaining
data on immediate memory, many questions are left
unanswered, the most puzzling of which may be phrased as

"who watches the watcher?" Baddeley has yet to explain how

15

the ECS makes decisions, for example.

A review on memory functioning and MS requires that we
differentiate between temporary and more durable memory, but
it is not necessary to understand all of the nuances that
distinguish the various models of the temporary memory
system. To make thins simpler, PM will be used for all
future references to the less permanent memory system unless
otherwise specified. This should not be taken to mean that
the PM model is most accurate or preferred.

PM is frequently measured by so-called "attention span"
tests. Subjects are required to repeat verbal (e.g.,
digits) or nonverbal (e.g., tapping blocks) bits of
information, which are presented in rapid fashion so as to
prevent rehearsal or the development of other strategies
that could allow storage and recall from secondary memory.
However, evidence indicates that digit span tests may be an
inadequate measure of PM because the task is well-
automaticized in most subjects (Mack, 1986). Another test,
originally developed by Brown (1958) and Peterson and
Peterson (1959), taps slightly different PM functions than
digit span and minimizes the problem of automaticity through
the use of a dual task paradigm. Subjects are shown a
subspan stimulus (e.g., consonant trigrams), asked to
perform some non-automatic distractor task (e.g., counting
backwards), and finally asked to recall the original
stimulus. This test can provide an estimate of
distractability and ability to divide attention. PM
integrity also can be inferred from the response pattern on
a supraspan immediate recall task. For example, subjects

are asked to recall a list of words (usually 12 or more)

16

immediately after their presentation. (Because the amount
of information to be learned exceeds PM capacity -- the span
of attention -- the term "supraspan" is often used). Words
recalled from near the end of the list are drawn directly
from PM, whereas items recalled early in the list depend on
adequate rehersal for recall from secondary memory (Murdock,
1962). Most clinical memory batteries (e.g. Wechsler Memory
Scale - Revised; Rivermeade Behavioural Memory Test) include
a variant of one of the tasks noted above. MS memory
investigations usually include at least one measure of PM,
although, as will be discussed below, the unfortunate trend
is to rely solely on verbal attention span.

Turning towards a description of durable memory, James'
(1890) term, secondary memory (SM), will be used in
reference to the system(s) responsible for the integration
of information into and from longer lasting storage (also
known as long-term memory). No single, comprehensive, and
accurate model has been developed for SM because of the
extreme complexity and scope of the topic. To make
investigation and theory more manageable, researchers have
explored fundamental components within SM. Before reviewing
these distinctions, it is important to note that a huge
amount of material has been published concerning the way in
which information is stored, recalled, recognized, and
otherwise manipulated for later use. Application to MS
research is limited to the following points. One is that PM
is necessary for intact SM functioning because it is quite
difficult to store information when one cannot adequately
attend to or manipulate material in immediate consciousness.

Secondly, research indicates that some period of time is

17

needed to ensure that information is consolidated from PM to
SM and that the consolidation may be distrupted by ECT, head
trauma, toxic chemicals, surgical resection of cerebral
tissue, and the like (Reynold & Flagg, 1983). A third
point is that research questions on memory and MS tend not
to be theory driven. Rather, investigation is limited to
determining whether or not patients can recall or recognize
information -- not why they fail to remember. More specific
discussion about how SM processing is affected can be found
in Estes (1982), Ashcraft (1989), and Tulving (1983).

The first functional division of SM to be discussed is
that of episodic and semantic memory (e.g., Tulving, 1972).
Episodic memory is an individual's autobiographical and
experiential knowledge with attendant context as to when and
where the information was learned. Examples range from the
obvious, such as the memory of one's first kiss, to the less
apparent such as the recall of a list of words in a memory
experiment. By contrast, semantic memory may be
conceptualized as knowledge per se, including memories for
facts and concepts. Although most semantic memories are
verbally-oriented -- hence the term semantic -- they need
not be so. For example, semantic knowledge of colors or
physical sensations may defy verbal description. Confusion
about this point has led Ashcraft (1989) to suggest that

generic memory be used, as it more adequately conveys the

 

meaning of this type of memory than does semantic memory.
In terms of application to the MS literature, the vast
majority of clinical measures tap what is thought of as
episodic memory: recall and recognition of word lists,

paired words, paragraphs, faces, geometric figures, and

18

abstract designs. No MS investigations have been found that
use tests specific to the semantic memory paradigm, although
intelligence tests measure generic knowledge to some degree.
One of the reasons for this scarcity in the literature is
that older, well-learned, "retrograde", and "remote"
memories (especially semantic, but also episodic) are robust
to loss across many pathologies (cf. dementia).

Having just distinguished episodic from semantic memory, it
is essential to recognize that the two cannot be separated
totally in the real world. Semantic memory is derived from
an accumulation of episodic events, our personal experience
of the world. For example, Wilson (1982) reports that
amnestics have great difficulty adding new semantic
information, which she attributes to their impaired episodic
memory. Conversely, acquisition of episodic memory is
affected by our generic knowledge of the world as
exemplified by Loftus' studies (e.g., 1979) on eyewitness
testimony. The psychoanalytic literature has long
recognized the importance of integrating the two through the
mechanisms of accommodation (i.e., changing our view of the
world to corroborate new experiences) and distortion (i.e.,
changing our recollection of events to meet our view of the
world).

Two other SM distinctions will be discussed briefly
here because, although research on MS has yet to employ
these concepts, application may come soon. A flurry of
interest and experiment has occurred following a paper
reviewing implicit and explicit memory by Schacter and Graf
(1986). Their comments stemmed from many prior observations

that amnestics may show learning on tasks that do not

19

require explicit recollection of the information (e.g.,
forced choice answer format) while not being able to

purposefully, accurately, or explicitly verbalize that

 

knowledge. Schacter (1987) reviews previous discussion and
investigation, including some from the psychoanalytic
literature on the unconscious, that indicates that there can
be a dissociation between what a person can recall overtly
and behavior indicative of learning without conscious
awareness. The concept of implicit memory raises several
interesting questions about how we define and measure human
memory. One is how implicit memory relates to the other
components of primary and secondary memory. For example,
implicit probably involves input from ontogenetically older
memory systems (e.g., the sensory registers) but also from
features of episodic and semantic memory. As Schacter
notes, the implicit - explicit distinction is exciting
because it may be applied to so many different aspects of
memory with both traditional (e.g., attention; semantic and
perceptual priming) and nontraditional topics (e.g., the
effects of affective and social associations, hypnosis, and
altered states of consciousness). Although some believe
that recognition format tests used in MS research tap
implicit memory, no one has used such data to draw
inferences about implicit versus explicit memory functioning
in MS.

A final way in which SM will be distinguished is the
contrast of procedural and declarative memory. Anderson
(e.g., 1976) uses the concept of procedural memory to
represent knowledge of how to do things (e.g., pitching a

baseball). Sometimes referred to as motor memory,

20

procedural memory is not necessarily restricted to overt,
motoric behavior. Cognitive procedures also can be included
such as knowing how to operate a calculator. Declarative
memory refers to knowledge of basic facts and other easily
verbalized information. Even with such a brief
introduction, one can see similarities between procedural
and declarative memory and other SM distinctions noted
above. For example, the act of frying an egg could include
aspects of episodic (e.g., how you cooked today's
breakfast), semantic (e.g., recollection of several cookbook
descriptions), and procedural memory (e.g., doing the act
without conscious awareness). Before rejecting the notion
of procedural memory as unspecific or redundant, one has
only to recall the famous amnestic, H.M., with his intact
procedural memory but devastating anterograde amnesia
(Scoville & Milner, 1957), to recognize the validity of the
concept of procedural memory. As with implicit memory,
little has been done to investigate procedural memory
functioning in MS (cf. Caroll, Gates, and Roldan, 1984).

In addition to the topics reviewed above, many other
areas of research have yet to be applied to MS, especially
in regards to modality differences. Memory for tastes,
smells, tactile stimulation, music, and non-language sounds
(e.g., bird calls) are poorly understood relative to visual
and language systems, primarily because the latter are more
important to human information processing. Investigation of
verbal and nonverbal memory is extensive, however. Springer
and Deutsch (1985) provide a good introduction to
hemispheric organization of function, including memory,

which indicates that parallel memory systems exist based on

21

a verbal - nonverbal distinction. This dissociation also
can be found in clinical (e.g., Lezak, 1983) and cognitive
literatures, including discussion on differences in the
sensory registers, PM, and SM in the latter. MS research
shows a similar interest in differences between verbal and
nonverbal memory.

A brief discussion of a difficult measurement issue
will conclude the introduction to memory functioning and MS.
Mack (1986) reviews the problem of non-orthogonality in
cognitive testing (i.e., tests purportedly measure only one,
orthogonal function but really require multiple functions).
This issue has two particularly important applications:
discriminating verbal from visual and primary from secondary
memories. Regarding the former, it is extremely difficult
to obtain a "clean" (orthogonal) measure of nonverbal memory
with most clinical tests. Tasks such as recognizing faces
or recalling simple geometric designs are frequently used
for this purpose, yet humans show a wonderful capacity to
augment learning of nonverbal stimuli through the use of
verbal strategies. The reverse situation also occurs when
easily visualized words are used in a list learning test.
Subjects are known to employ visual strategies to aid
"verbal" memory performance (Wilson, 1982). When easily
cross-cued tests are used, it is difficult to sort out the
relative contributions of the verbal and visual memory
systems. Researchers must carefully choose tests that
minimize the possibility of cross-modality cuing. For
example, Allen Baddeley is leading recent efforts to improve
nonverbal test designs and his test of memory for pictures

of doors will be available soon (personal communication,

22

1991).

Controlling for the effects of PM to yield a pure
measure of SM is even more difficult than differentiating
verbal versus visual memory. Because every memory task (or
cognitive for that matter) requires at least some PM
processing, one cannot assume that impaired performance on
the test is indicative of SM deficits. Researchers have
several ways in which to control for this measurement
problem. One is to slow the presentation rate of
information to be learned to allow adequate rehearsal time
(i.e. access to SM processing). Another is to estimate the
relative integrity of PM. If it is found to be intact, then
one can safely assume that poor performance on tests of both
PM and SM is due to SM deficit. Unfortunately, many
clinical research protocols do not control for the effects
of PM on tests of SM, thus making it difficult for a
reviewer to determine why subjects' performance was
impaired. One way to separate primary from secondary memory
deficits Egg; hgg is to compare tests that challenge PM to
different degrees. Let us return to an example presented
earlier: an immediate recall (supraspan) list learning
task. It was noted that one could estimate the integrity of
both primary and secondary memory by tracking the pattern of
recall. Words recalled from early in the list are mediated
through rehearsal and reflect SM processing, while items
recalled from list end are straight from PM. Since most
authors report only the total number of words recalled or
the learning curve, a reviewer cannot comment on the
relative contribution of PM and SM processing. Even if word

were reported, we would still have difficulty making

23

assertions about PM and SM because individuals differ in
their reliance on PM and SM processing. We can infer,
though, that the "load" on the SM system for immediate
supraspan recall is relatively greater than that for more
orthogonal PM tasks such as the Brown-Peterson test.
Similarly, a delayed recall task requires more SM processing
than an immediate recall test. This method of estimating SM
integrity in the absence of controls for PM will be used in

the review on MS memory research.

Pathoanatomical Aspects

 

As with the section on memory functioning, introduction
of the anatomical features of human memory will be limited
to what is necessary for a review of the MS literature and
the applications of this study.

Controversy over memory localization is a good starting
point because a review of structures important to memory
should not lead one to infer that memory exists outside of
the context of the entire organism, including the brain.
Centuries of study by localists (e.g., Gall, Broca, and
Hebb) and wholists (e.g., Flourens, Koffka, and Lashley) has
yet to resolve the issue of localization. One reason for
the failure is the problem of level of analysis. While
neurophysiologists' study of synaptic changes easily lends
itself to a discussion of "where", psychologists interest in
behavioral systems does not. In this author's view, the
most reasonable answer to the question of memory
localization is (with apologies to George Orwell):

All brain structures are equal
(but some are more equal than others)

One impetus for the current study is to help identify those

24

anatomical structures most important to predictions of
memory dysfunction in MS.

Several relatively primative neurological systems have
been identified that are associated with some forms of
learning. For example, spinal cord reflex arcs subserve
habituation to the auditory startle reflex (Tischler &
Davis, 1983). The midbrain tectum supports some visual
discrimination tasks as with cortically "blind" patients who
show conditioned learning if this second visual system is
intact (Cohen, 1984). Ontogenetically older neural
substrates also contribute to explicit memory functioning,
but since this role is neither clear nor extensive (Squire,
1991), we will move to anatomical correlates of "higher"
memory functioning.

Outside of primate studies, most of the evidence on
memory localization comes from the clinical literature,
especially the amnesias. The implication of several medial
temporal lobe and diencephalic structures will be reviewed,
as well as the contribution of the cortex and other
subcortical elements.

Identification of distinctive forms of amnesia led to
to the conclusion that portions of both the medial temporal
lobe and diencephalon are involved in memory functioning.
Walsh (1985) does an admirable job of sorting out evidence
for and descriptions of the functional characteristics of
the two types of memory disturbance. It is important to
note that the statements presented below are generalizations
and that controversy exists over the relative and absolute
degree of impairment across several aspects of PM and SM

(e.g., Wilson, 1982). Primary and procedural memory are

25

relatively unimpaired in both temporal lobe and diencephalic
amnesia, but they differ on most other comparisons.
Functional features of medial temoral lobe amnesia (MTLA)
include: intact retrieval of older, declarative memories
(i.e., remote episodic and semantic memories): severe
impairments in acquiring information: and self-awareness of
memory deficits. Walsh notes that the failure to acquire
new information seems due to impaired consolidation, as
evidenced by the loss of some events before dysfunction
onset and by a failure to profit from cuing. If a failure
to learn was attributable to a retrieval deficit alone, cues
would help. By contrast, diencephalic amnestics have a
retrieval impairment and therefore are better able to
recognize or otherwise gain from retrieval cues.
Unfortunately, the retrieval impairment also results in
retrograde amnesia in addition to the anterograde problems.
Another important feature of diencephalic memory disturbance
is the loss of organizational associations to memories,
especially temporal and sequencing cues. It is speculated
that the high frequency of confabulation in diencephalic
amnestics is a consequence of their failure to know "when"
and in "what order" events happen. Finally, diencephalic
patients differ from their MTLA counterparts in that the
former tend to be unaware of their memory impairments (e.g.,
Victor, Adams, & Collins, 1971).

The prevalence of diencephalic amnesia is signifcantly
higher than MTLA, in great part because the former can be
caused by severe alcohol abuse. Any thiamine-depleting
condition (e.g., malnourished women on contraceptive

medication) can cause diencephalic amnesia, as well as acute

26

encephalopathies, truama, thalamic infarct, and neoplasms
(Wilson, 1982). Nevertheless, long-standing alcohol use
remains the single best way of developing Wernicke's disease
with Korsakoff's psychosis, of which diencephalic amnesia is
a feature (see Victor & Adams, 1985: Lezak, 1983: Victor et
al., 1971; and Wilson, 1982 for a taste of the Byzantine
history and nosology of Korsakoff psychosis, Wernicke
disease, Wernicke encephalopathy, Wernicke-Korsakoff
syndrome, and their relationship to diencephalic amnesia).
The most notable cause of MTLA is bilateral surgical
resection for intractable epilepsy (e.g., patient H.M.,
Scoville & Milner, 1957), while cases also have been
reported in association with viral, anoxic, and ischemic
encephalopathies and bilateral posterior cerebral artery
occlusion. Unilateral involvement produces less severe and
modality-specific dysfunction (i.e., left- and right-
hemisphere involvement results in verbal and nonverbal
impairments, respectively) (Squire, 1987). Considerable
disagreement exists over which specific sites are involved
in MTLA. The hippocampus (e.g., Scoville & Milner, 1957) is
the most likely condidate, although others have argued for
the temporal stem (e.g., Whitty & Zangwill, 1977; Horel,
1978). Squire's (1991) extensive review of pertinent
research, including his own recent efforts involving the
systematic ablation of various tissue in the macaque,
concludes that only the hippocampus is critical and that
destruction of the temporal stem, amygdala, uncus, and
fornix is neither necessary nor sufficient to impair SM.
This fine work notwithstanding, debate continues still. It

is clear only that some area of the temporal lobe is

27

important to declarative SM, especially consolidation of
information into long-term storage.

There is even greater disagreement about the specific
lesion sites responsible for diencephalic amnesia. Wilson
(1982) and Squire (1987) concur that current evidence is
insufficient to determine whether the mammillary bodies (of.
Delay & Brion, 1969) and/or pulvinar and dorsomedial nuclei
of the thalamus (cf. Victor et al., 1971) are the key
anatomic feature. Despite the tremendous amount of data
available, the failure to confirm may continue because the
structures in question are quite small and because the most
common etiologies of diencephalic amnesia produce
deterioration across anatomic boundaries. At this juncture,
one can infer only that some aspects of the diencephalon are
involved in memory.

Unfortunately for our attempts to understand memory
impairment in MS, the types of memory deficits and lesion
locations in MS do not correspond to those noted with either
diencephalic or medial temporal lobe amnesia. This point
will be elaborated after further consideration of the data
on memory functioning in MS.

The basal ganglia is a third anatomic region with
hypothesized associations to memory. Before continuing, it
should be noted that the evidence supporting basal ganglia
involvement is almost entirely clinical and that its
functional picture often is grouped with so-called
subcortical dementias whose pathoanatomic correlates include
structures other than the basal ganglia (e.g. thalamus).
Thus, one must be careful not to confuse functional

syndromes with anatomic systems and the pathologies that cut

28

across both anatomic and functional distinctions. The
controversy over and differences between subcortical and
cortical dementia will be discussed later.

Pathological conditions that affect basal ganglia
functioning include Huntington's (HD) and Parkinson's
disease (PD), progressive subnuclear palsy, stroke, tumor,
various encephalopathies, and several inherited metabolic
disorders. HD and PD are most studied and involve the
dopaminergic pathways of the mesencephalon (e.g., caudate,
putamen, globus pallidus, and substantia nigra). Because
these two conditions are significant more for their specific
association to a neurotransmitter rather than to an anatomic
structure, it is hypothesized that changes in memory result
from biochemical abnormalities (Victor & Adams, 1985).
Memory impairment in Huntington's disease is chracterized by
a general retrieval deficit resulting in both anterograde
and retrograde SM memory loss. The retrograde disturbance
is distinguished by its lack of a temporal gradient (cf.
diencephalic amnesia) -- performance on uncued recall of old
memories was equally poor regardless of the relative age of
the memories (Albert, Butter, & Brandt, 1981). Other
aspects of SM and PM appear relatively intact (Cummings,
1990) and the severity of SM impairment generally is less
pronounced in comparison to both medial temporal lobe and
diencephalic amnesia. There is disagreement regarding
memory function similarities between PD and HD, as well as
with the other conditions that affect the basal ganglia.

One reason for the controversy is the presence of other
cognitive deficits, including impaired executive functions

and general slowing of information processing (e.g., Lezak,

29

1983) that hamper identification of specific types of memory
impairments.

Data pertaining to memory and the basal ganglia are of
limited use in studies of MS, despite arguments that there
are similarities in symptom patterns (e.g., Cummings &
Benson, 1984). As will be discussed later, basal ganglia
involvement is a minor pathoanatomic feature in MS and,
therefore, cannot account for all memory dysfunctions.

The cerebral cortex is the last anatomic area that will
be reviewed here and it will be given very brief treatment.
One reason is that the types of memory problems seen in MS
are not comparable to those observed in conditions resulting
in cortical pathological changes. Also, cortical
involvement is a relatively minor feature in MS
pathoanatomy. These issues will be discussed at greater
length following a review of memory functioning in MS and
the role of MRI.

Cortical grey-matter is thought to be important to
many SM and PM functions. A wealth of animal studies (see
revies in Squire, 1987: Squire & Butters, 1984) support the
role of cortex in memory, including evidence of cortical
plasticity as a function of learning. Experiments on human
subjects, while limited for obvious reasons, implicates
cortex as a storage site. For example, electrostimulation
of the cortex evokes powerful, memory-like experiences
(Penfield, 1958). Conditions that affect the cortex often
result in devasting losses to many memory functions,
including procedual, semantic, and primary memory. In fact,
the presence of PM deficits is purported to separate the

cortical (e.g., Alzheimer's and Pick's disease) from the

30

subcortical dementias and amnesias (e.g., Cummings, 1990).
Aside from the dementias, cortically-related memory
impairment may result from head truama, neuroma, exposure to
neurotoxins, hydrocephalus, stroke, anoxia, ischemia, aging,
and numerous infectious agents.

The clinical literature also indicates that localized
areas of the cortex support separate memory functions. For
example, right infratemporal cortex has been associated with
visual memory processes: inferior parietal lobe gray matter
has been linked to memory for spatial location;
somatosensory cortex is implicated in the storage of tactile
patterns: and degradation of Wernicke's and Broca's areas
results in language-specific learning loss (e.g., Walsh,
1987). Because the cortex also seems necessary for all
kinds of information processing tasks, however, modality—
specific memory loss also may reflect the secondary effects
of deficits in other cognitive functions (see Luria, 1966
for a discussion on cortical association areas). Squire
(1987) writes that the evidence for cortical localization
also reflects such factors as cortical plasticity and
equivalency. Thus, localization per se probably occurs only
on the level of specific memories, while memory as an
information processing system depends on the mass action of
combined cortical and subcortical systems. A better
description of the role of cortex with memory also is
hindered by the fact that so many of the pathologies that
attack the cortex also produce subcortical insult.

To conclude this introduction to memory and anatomy, we
will return to previous comments regarding the necessity of

a wholistic view of human memory. In addition to the

31

regions discussed above, learning depends on the limbic
system for motivation, the frontal lobes for executive
functions, and intact language, motor, and sensory systems
for the input and output of information. This wholistic
view seems especially pertinent to MS because much of what
is known about memory anatomy and function is not easily
applied to MS. A certain amount of creativity will be
needed to explain how memory deficits are produced in MS and
what pathoanatomic features are related to those changes.
With this in mind, we will turn to a description of memory

and MS.

Memory Functioning in MS
Introduction

Investigations of memory in MS have lagged behind those
of other cognitive, as well as motor and sensory, functions.
Most studies have been limited to a simple description of
test performance through traditional clinical
neuropsychological methods. Cumulative evidence indicates
that, compared with PM, SM is more likely to be impaired and
to a greater degree. The single most distinctive feature of
MS-related memory impairment is the tremendous variation
between patients. The review presents theoretical and
methodological issues relevant to subsequent predictions of
lesion burden - memory relationships.

Historically, it is difficult to track what was known
about memory in MS because it was not treated separately
from other cognitive processes. Charcot (1877) described
"enfeeblement of memory" as a symptom of MS in his original

series of patients. For approximately the next half-century

32

after Charcot's observations, studies of cognition were
limited to anecdotal, clinical impressions and, in fact,
early authors debated whether mentation (including memory)
actually was affected in MS. Psychometrically-sound
comfirmation of at least occasional memory deterioration,
rudimentary description of its relevant aspects, and the
separation of discrete cognitive processes began only with
the appearance of standarized and empirically-based
assessment methods in the mid-1900's. The overwhelming
majority of these research reports still dealt primarily
with generalized cognitive functioning: memory was a
peripheral concern (Trimble & Grant, 1982). For a more
comprehensive review of this pre-1980 research, see Trimble
and Grant (1982) or Marsh (1980).

Research with a more substantial focus on memory began
with Jambor's (1969) study of 103 chronic MS patients. He
found that MS patients had significant decrements in
performance on learning and recall tasks relative to
psychiatric, muscular dystrophy, and normal control groups.
It would be almost another 10 years before the appearance of
the next study (Beatty & Gange, 1977). Investigations have
followed fairly regularly since then, particularly those
concerned with memory.

Despite the increased activity, research on memory
functioning in MS still lags behind studies of other causes
of memory disturbance. There are several reasons for this.
Memory impairments are not so prominent a feature of MS as
they are in many other conditions. Thus, memory dysfunction
is more easily identifed and studied in, for example, the

dementias than in MS. As a consequence, a more extensive

33

empirical and theoretical base exists with which to fuel
subsequent research on memory impairments in conditions
other than MS. The relative paucity of memory research in
MS also reflects the lower incidence of MS compared to other
conditions producing changes in memory: thus, access to
subject populations is not comparable across pathologies.
Empirical treatment began and has continued in spite of
these hurdles, however, and as is often the case in new
fields of endeavor, initial research focused on description.

The single most apparent aspect of memory functioning
in MS is the marked individual variation within and across
subject populations -- exactly paralleling non-cognitive
symptoms and signs. As a group, patients clearly show
deficits in comparison to normals and other chronically ill
control groups (e.g., head injury, muscular dystrophy) on a
wide range of memory measures. However, the prevalence and
severity of memory disturbances is idiosyncratic. For
example, Rao, Hammeke, McQuillen, Khartri, and Lloyd's
(1984) cluster analysis of 44 chronic progressive MS
subjects showed that one subset (20%) had significant
deficits, a second group (43%) had more moderate
impairments, while the third subset's (36%) performance was
normal on a range of memory measures. The overall rate of
"clinically noticable" memory problems in this sample was 40
percent. Inter- and intra-individual variations in specific
types of memory also are widely reported and will be
reviewed next.

Functional Features
Memory functioning in MS has been examined almost

exclusively from a clinical neuropsychological perspective.

34

Cognitive paradigms have had relatively little play, and
neurobiochemical models, none at all. The focus has been on
aspects of secondary memory capacities, mostly declarative
and episodic, while little data exist on procedural,
semantic, autobiographical, and perceptual memory (cf.
Carrol et al., 1984). Some attempts have been made to tie
in the types of memory disturbances seen in MS with those of
conditions known to produce memory impairment, but most MS
investigations are descriptive only. Before continuing with
the review, some commonly found methodological problems will
be discussed as they bear on the conclusions that are drawn
from the data. First, it is very difficult to compare
findings across studies because of the plethora of tests
used -- over 20 by Fischer's (1988) estimate.
Generalizations also are hampered by inadequate and
confounded test designs such as failure to control for the
effects of modality cross-cuing or PM processing on tests of
SM. Finally, the variable course of MS makes it difficult
to determine the degree and frequency of memory impairments
in the population. No longitudinal studies could be found
that speak to the question whether memory functioning, like
many motor and sensory abilities, fluctuates over time.
Temporal fluctuations could explain many of the discrepant
findings reported in the literature and until course
distinctions are well-identified, all existing research on
memory must be viewed with some caution. With this rather
sobering introduction, we will begin the review of memory

functioning in MS.

35

Primary Memory

Many studies have concluded that PM is not affected in
MS. However, almost all of the data are based on tests of
PM capacity (i.e., digit span) without evaluation of other
PM processes. Inadequate study design also precludes a
reliable estimate of the prevalence and severity of SM
impairments.

The data on verbal PM capacity, as measured by digit
span, are conflicting. Fischer (1988), Lyon-Caen, Jouvent,
Hauser, Chaunu, Benoit, Widlocher, and Lhermitte (1986), and
Huber, Paulson, Shuttleworth, Chakeres, Clapp, Pakalnis,
Weiss, and Rammohan (1987) each reported that mean verbal
digit span scores in MS were significantly below those of
controls. Conversely, Heaton, Nelson, Thompson, Burks, and
Franklin (1985), Jambor (1969), Litvan, Grafman, Vendrell,
Martinez, Junque, Vendrell, and Barraquer-Bordas (1988b),
.Marsh (1980), Rao et al. (1984), and Rao, Leo, and St-Aubin-
Faubert (1989) concluded that verbal digit span was not
significantly different from control subjects. Contrasting
scoring methods may explain, in part, these discrepant
reports. For example, Lyon-Caen et al. (1986) and Huber et
al. (1987) used only the forward score in their analyses,
while all the others used a combined digits forward and
backward score. Fischer's (1988) study used the WMS-R and
its slightly different scoring system from the WMS. Studies
that used the Wechsler Adult Intelligence Scale (WAIS)
(Brainin, Goldenberg, Ahlers, Reisner, Neuhold, & Deecke,
1988; Heaton et al., 1985: Jambor, 1969: Litvan et al.,
1988b: Marsh, 1980) and the WAIS-R (Rao et al., 1989) are

not comparable to those using the WMS (Huber et al., 1987;

36

Lyon-Caen et al., 1986; Rao et al., 1984) or WMS-R (Fischer,
1989) because subject performance is reported in terms of
standard scores with the former, while studies using the
Wechsler memory scales typically reported raw scores. This
prevented a meta-analysis of the data. It was determined
that all MS subject mean scores on the WAIS or WAIS-R were
within one standard score of the subtest mean (i.e., 10),
which suggests no gross disturbances in the patient samples.
And with one exception (Hirschenfang & Benton, 1966), this
finding also was true of pre-1980 studies reviewed by Marsh
(1980).

Only one study could be found that tested non-verbal PM
capacity. Fischer (1988) found no significant differences
between her samples of MS patients and normal controls on
the WMS-R Visual Memory Span substest. Fischer offered the
explanation that, in contrast to the verbal digit span
subtest, visual memory span is not subject to interference
(i.e., telephone numbers). Possible interference effects
notwithstanding, there is no a priori reason to suspect that
non-verbal PM capacity is any more or less susceptible to
impairment than verbal PM limits.

It is not clear whether PM functions other than
capacity are impaired in MS. Callanan, Logsdail, Ron, and
Warrington (1989) reported deficits on verbal and visual
cancellation tasks hypothesized to measures vigalance.
However, these results should be catuiously interpreted
because Callanan et al.'s subjects were not confirmed MS
patients (clinically-probable). Using a visual concellation
task similar to Callanan et al.'s (1989), Franklin, Heaton,

Nelson, Filley, and Seibert (1988) reported a significant

37

increase in task time indicative of PM impairment, but total
number of errors was in the normal range. Two studies using
a Brown-Peterson task reported conflicting results. Beatty,
Goodkin, Monson, Beatty, and Hertzgaard (1988) observed
significantly impaired recall because the authors did not
describe their exact procedure: however, interpretation is
difficult. Grant et al. (1984) also demonstrated
significant performance decrements as interference task
difficulty increased (i.e., 3, 6, 9, and 18 seconds of
counting backwards by "threes") in comparison to controls.
However, no difference between patients and controls was
seen in the 18 second condition -- where interference
effects should have been strongest. Both Litvan et al.
(1988b) and Rao et al. (1989) also failed to find patient
versus control group differences with versions of the Brown-
Peterson similar to that used by Grant et al.

In summary, MS patients do not consistently show
impairments on various measures of PM capacity. These
discordant findings do not appear to be due to differences
in subject characteristics (e.g., age, sex, education, SES)
or disease factors (disease length and physical disability)
because both affirming and disconfirming results have been
reported across these characteristics. Psychotropic
medication (Beatty & Gange, 1977; Fischer, 1988; Grant et
al., 1984) and fatigue effects (van den Burg, van Zomeran,
Minderhoud, Prangs, & Meijer, 1987) were evaluated
specifically and found to be unrelated to test performance.

It is argued strongly that, after the consideration of
the following two issue, the evidence suggesting that PM is

not impaired is questionable. First, the failure to observe

38

PM deficits in some studies may be explained by a reliance
on tests of digit span alone. As noted previously, digit
span is fairly automatized (especially digits forward).
Automatized cognitive tasks do not challenge the PM system
(Mack, 1986) and are, therefore, unreliable as a measure of
PM.

The second issue that may have obscured the
demonstration of PM impairment involves the use of mean
group comparisons as the only method of analysis. If the
prevalence rate of PM deficits is relatively low or the
impairments are not continuously distributed across the
population, then studies employing simple mean group
comparisons seriously underreport deficit prevalence and/or
severity. A few patients with a significantly decreased
test score may not be recognized if the remaining sample
test scores are sufficiently normal to compensate for the
small number of patients with PM impairments Egg if only
mean group scores are analyzed. Let us use a disturbance in
micturation to exemplify the point. Matthews (1985) review
of epidemiological studies reports that changes in
micturation occur as an initial symptom in only 5% of all
clinically-definite MS cases. Let us say that a study
measured micturation as a continuous variable (as attention
span is operationalized) on a sample of 100 clinically-
definite MS patients and 100 normal controls. The authors
would conclude that micturation is not affected in MS if
only the mean scores of the two groups were compared. This
would be a spurious conclusion based solely on the fact that
base prevalence rate of micturation is low. Where one has

an a priori belief that a low prevalence rate may abnormally

39

affect the power of the analysis (as was the case in our
example), one must use alternative comparisons. One example
would be to compare the percentage of subjects in the
experimental and control groups falling below one standard
deviation on the measure. Another is to use a cluster-
analysis or others methods that allow comparisons of
subgroups on the basis of test performance. And in fact,
studies using subgroup analyses were more likely to report
PM impairments (e.g., Beatty et al., 1988: Fischer, 1988;
Rao, Glatt, Hammeke, McQuillen, Khatri, Rhodes, & Pollard,
1985) than those investigations that relied on a single
group (e.g., Marsh, 1980).

Secondary Memory.

 

Before reviewing these data, recall that the tests used
to measure SM also are sensitive to PM deficits. This
problem has not been addressed in the MS literature, in
part, because most researchers believe that MS patients do
not have PM deficits. Given the cautions noted in the
previous section, I believe that this is a dangerous
assumption. This point aside, there is no disagreement
that, in comparison to PM, impairments of SM appear to be
more prevalent, consistent, and severe across all types of
tests as well as patient and disease factors. It is
believed that these conclusions are reliable in spite of the
possible confound of inadequate controls for PM. One reason
why it is believed that the conclusions are reliable is that
impaired performance on supraspan memory tests are so
universally reported. Another factor uses the previously
described method of comparing results across tests that

differentially challenge PM and SM processing. That is, if

40

SM deficits are relatively more frequent or severe than PM
impairments, then MS patients should be particularly prone
to increased task complexity.

The data appear to support this prediction. With the
exception of Heaton et al., (1985), all studies testing some
form of supraspan immediate recall reported deficits by
their MS patients. In the case of Heaton et al., the
authors simply did not report the performance of their
sample on the WMS logical memory and visual reproduction
subtests. Otherwise, impaired patient performance occurred
whether in comparison to normal controls (Beatty & Gange,
1977: Beatty et al., 1988: Fischer, 1988: Grant et al.,
1984: Litvan, Grafman, Vendrell, & Martinez, 1988a; Rao et
al., 1984: Rao et al., 1989: and van den Burg et al., 1987)
or non-MS patient controls (Rao et al., 1984) with verbal
material (Beatty & Gange, 1977: Beatty et al., 1988;
Fischer, 1988: Grant et al., 1984; Litvan et al., 1988a; Rao
et al., 1984: Rao et al., 1989: van den Burg et al., 1987)
or nonverbal information (Beatty et al., 1988: Fischer,
1988: and Rao et al., 1984).

MS patients consistently perform poorly on other
clinical measures that tap both primary and secondary memory
processes. These deficits are found whether the task was
verbally (e.g., Beatty & Grange, 1977) or nonverbally
mediated (e.g., Fischer, 1988): in unaided recall (e.g., van
den Berg et al., 1987), paired (aided) recall (e.g.,
Fischer, 1988) or recognition format (e.g., Beatty et al.,
1988): in single trial (e.g., Beatty & Gange, 1977) or
multi-trial learning (e.g., Franklin et al., 1987): whether

subjects had short (Grant et a1, 1984) or long latency since

41

disease onset (Rao et al., 1984): or whether the patients
had a remitting/relapsing (Heaton et al., 1985) or chronic
progressive course (Branin, Goldenberg, Ahlers, Reisner,
Neuhold, & Deeke, 1988). While studies clearly show
significant intra—sample test performance variability (e.g.,
Fischer, 1988: Rao et al., 1984), the pattern of findings
supports the hypothesis that memory deficits are more
frequently seen and more severe when present as tasks
increase involvement of SM. Thus, impairment is most
significant on tests of delayed recall (e.g., Rao et al.,
1984, 1985, & 1989), less marked with list and paired-
stimuli learning (Brainin et al., 1988; Fischer, 1988; Huber
et al., 1987: Litvan et al., 1988b; Rao et al., 1984), and
least apparent on recognition format (Callanan et al., 1989:
Carroll et al., 1984; Elpern, Gunderson, Kattah, & Kirsch,
1984: Fischer, 1988: Rao et al., 1984: van den Burg et al.,
1987).

Retrieval processes have been proposed as the chief
cause of SM disturbance as evidenced by less pronounced
decrements in recognition versus unaided recall, increased
rates of forgetting (e.g., Rao et al., 1989), and
difficulties recalling even well-learned material (Petersen
& Kokmen, 1989). Beatty et al.'s (1988) interesting study
of retrograde, "remote" memory impairment also implicates
retrieval mechanisms. They reported significant differences
on a sample of 38 chronic progressive MS and 36 age- and
education-matched controls using a test of famous names and
events of the past.

Encoding difficulties also may occur in MS. One way in

which encoding processes are implicated is that recognition

42

test performance may be disturbed, albeit less so than on
unaided recall format tests (Petersen & Kokmen, 1989).
Also, Carrol et al. (1984) observed that MS patients were
less likely to use an encoding strategy in a learning task
than were 22 matched controls. More importantly, even in
those cases where a strategy was used, MS subjects'
performance was significantly poorer than that of controls.
The strongest evidence that SM may be impaired by encoding
deficiencies stems from the fact that flatter than normal
learning curves on multi-trial tests are almost universally
found with both verbally- and nonverbally-mediated material
(e.g., Fischer, 1988: Rao et al., 1984, 1989; van den Burg
et al., 1987).

Our best understanding of primary and secondary memory
in MS is that the prevalence and severity of SM deficits are
relatively greater, but that individual variation is still
high. For example, prevalence rate estimates for PM
deficits range from approximately 20 (severe range) to 40
percent (mild-to-moderate range) (Fischer, 1988).
Conversely, the prevalence of severe SM impairments may be
as high as 40 percent (Beatty et al., 1988; Fischer, 1988)
and 60 (Beatty et al., 1988), while milder deficits can
approach 70 percent (Fischer, 1988). Retrieval is
particularly susceptable to disturbance, although other
processes necessary for intact SM functioning (e.g.,
attention, temporary storage, and encoding) may be affected.
Increased task complexity (quantitatively, qualitatively,
and temporally) may also increase the probability of
disturbance. The findings reviewed above support the view

that the randomness of lesion location places all memory

43

systems at risk. Thus, predicting which MS patients will
have what types of impairments may require knowledge of
lesion-specific variables (e.g, location).

Comparative Functioning

 

The pattern of memory deficits reported in MS does not
appear to be closely related to those seen in other memory
impairment syndromes and conditions. One taxonomy popular
in the neuropsychological literature and applied to MS is
the sub-cortical versus cortical dementia schema (e.g.,
Albert, Feldman, & Willis, 1974). Several authors contest
the view that the cognitive changes seen in MS are
consistent with a sub-cortical dementia (e.g., Cummings &
Benson, 1984; Rao et al., 1986). Proponents point to the
fact that, unlike the cortically demented, MS patients have
relatively intact perceptual memory (e.g., Carrol et al.,
1984) and recognition capacities (e.g. Rao et al., 1984),
show at least some incremental learning, and perform
comparatively well on delayed recall tasks. Also, MS
patients infrequently exhibit signs of aphasia, apraxia,
agnosia, or other symptoms of the cortical dementias
(Olmos-Lau, Ginsber, & Geller, 1977; Rao, 1986). The only
study specifically designed to measure cognitive impairments
crucial to discriminating sub-cortical and cortical dementia
in MS reported evidence supporting the subcortical
hypothesis. Beatty et al. (1988) observed that, with the
exception of anomic deficits (an impairment more typically
seen in cortical dementia), the pattern of memory and other
cognitive impairments best matched those found in sub-
cortical dementia. Finally, the predominant location of

lesion in white matter tracts is supportive of the

44

proposition.

Petersen and Kokmen (1989) protest this
characterization of MS as a subcortical syndrome. Their
disagreement is based primarily on a rejection of the
validity of the sub-cortical/cortical distinction, rather
than whether MS cognitive dysfunctions match that nosology.
Petersen and Kokmen concur with others (e.g., Mack, personal
communication, 1990) that the cortical - subcortical
distinction lacks adequate empirical support on the basis of
both functional and anatomical factors. Petersen and Kokmen
review evidence suggesting that, even in those conditions
archetypal of subcortical (e.g., Parkinson's disease) and
cortical dementia (e.g., Alzheimer's disease), pathological
involvement is located throughout the cerebrum. A mixture
of cortical and sub-cortical plaque is not uncommon in MS.
For example, a grey-matter prevalence rate of 94% has been
reported (Lumsden, 1970). Functional differences in memory
between the subcortical syndrome and MS are reported,
including severity (e.g., Caine, Bamford, Schiffer,
Shoulson, & Levy, 1986) and presence of PM deficits (e.g.,
Fischer, 1988). Overall, the controversial nature of the
subcortical versus cortical dementia classification and
inconsistent empirical evidence argue for extreme caution in
applying the nosology to MS.

The severity and pattern of memory deficits in MS also
is different from both the diencephalic and medial temporal
lobe amnesias. Memory dysfunction clearly is more
pronounced in the amnesias and several qualitative
differences distinguish memory in MS. For example, Rao et

al. (1989) note that diencephalic patients, unlike their MS

45

counterparts, experience almost total loss of encoding
capacities. MTLA patients' recognition memory is severely
impaired, suggestive of increased forgetting rates. Rao et
al. (1989) suggest that MS memory impairments most closely
approximate the pattern of deficits (albeit less severely)
seen in Huntington's Disease (HD) in that retrieval problems
occur in the absence of disturbed encoding and forgetting.

I disagree with Rao et al.'s conclusions on several points.
First, the marked difference in degree of impairment should
not be ignored. Also, Rao et al. believe that, as is the
case in HD, encoding and PM are not affected in MS --
previously presented evidence suggests otherwise. Morover,
and as Rao et al. note, the quantity and quality of SM
retrieval deficits seen in MS also resemble those seen in
closed-head injury and normal aging. Thus, the SM retrieval
problems seen in MS are not specific to HD or other
subcortical dementias. Pathoanatomic differences between MS
and HD (i.e., more restricted lesion location and extent in
the latter) also may preclude comparability.

Controversy notwithstanding, the data do not clearly
support contentions that the memory deficits in MS are
comparable to those seen elsewhere. Given the gross and
histological pathology differences between MS and previously
described conditions, this conclusion is not particularly
surprising. We will return to these structural comparisons
in our discussion of patho-anatomical correlates of memory
functioning because they have important implications for the

use of MRI in evaluating memory changes in MS.

46

Predictors g; Disturbance

 

Researchers have looked towards characteristics of MS
in an attempt to account for differential changes in memory,
but these efforts have been routinely unsuccessful. Only
small or insignificant correlations have been found between
all types of memory functioning and disease length --
whether measured by the latency since symptom onset or
diagnosis (Beatty & Gange, 1977: Fischer, 1988: Grant et
al., 1984: Heaton et al., 1985; Ivnik, 1978; Rao et al.,
1984: Rao et al., 1985: Rao et al., 1989). These findings
are entirely consistent with those for motor and perceptual
disturbance correlations with the same independent
variables. We can, therefore, comfortably infer that the
pathological processes responsible for idiosyncratic changes
in memory are not closely related to the length of time one
has MS.

Disease course also has been examined as an associate
of memory disturbance. Data pertinent to this question,
however, are limited, contradictory, and controversial. For
example, no studies have compared samples that include
either the benign or acute subtypes. This leaves us in the
untenable position of having to draw inferences about patho-
clinical relationships from only the progressive and
remittent courses -- when pathological features specific to
benign and/or acute MS actually may be critical to
understanding patho-clinical relationships. All but three
studies either did not report course distinctions in their
sample (e.g., Jambor, 1969), did not analyze the impact of
course on their dependent variables (e.g., Litvan et al.,

1988), or recruited subjects on the basis of having a

47

similar course, typically chronic-progressive (e.g., Rao et
al., 1985: Franklin et al., 1988). Finally, the three
studies that did examine the possible mediating effects of
course on memory reported discrepant findings. Heaton et
al., (1985) and van den Burg et al. (1987) found that
patients with chronic progressive MS were more likely to
experience memory difficulties and that these deficits are
more severe in comparison to relapsing-remitting MS and
normal control subjects. Conversely, Fischer's (1988)
results suggest that relapsing-progressive patients, a
subset of the relapsing-remitting course, are more
susceptible to severe memory decline than other course
types. Differences between the samples and methodologies of
these studies do not allow reliable comparisons. Equivocal
controls for covariance of age and other possible moderators
between course and memory also make the conclusions of these
studies tenuous. Given the difficulies in making accurate
course determinations, it is not surprising that identifying
course - memory relationships has been difficult. For
example, studying asymptomatic and acutely-affected subjects
presents serious methodological concerns, not the least of
which is ascertaining whether such cases are, in fact,
extreme examples of MS. Delineating the importance of
course on memory may have to await longitudinal designs and
an understanding of whether MS has inherently different
subtypes.

Until recently, disease activity was largely ignored as
another potential predictor of memory functioning. One
reason is that the field lacks a consistent and valid

operational definition of disease activity. Previous to in

48

vivo radiographic techniques, disease activity was inferred
directly from clinical course because most laboratory
techniques (e.g., CSF cell studies) were too insensitive to
pathophysiological activity. That is, MS was deemed to be
"active" when one had an exacerbation or de novo appearance
of a symptom. As will be discussed in the section on MRI,
radiographic investigation indicates that clinical and
pathophysiological activity are not exactly comparable.
Thus, one now must be clear to state whether disease
activity was defined either clinically or radiographically.
In the review below, disease activity is clinically
determined.

In the memory literature, most authors do not comment
on clincial activity state. Of those reporting on activity,
the majority merely sampled to ensure comparability (Beatty,
et al., 1988: Brainin et al., 1988: Heaton et al., 1985:
Litvan et al., 1988b: van den Burg et al., 1987). Fischer
(1988) did analyze whether symptom activity helped account
for placement into one of three memory functioning subtypes.
Eighty-nine percent of the subjects who clustered in the
most impaired group had an active disease state: however,
activity did not differ significantly in the other two (less
impaired) clusters. No other comparisons were made, nor
does Fischer make clear the criteria used for "active/non-
active" status. Lyon-Caen et al. (1986) found no
significant relationship between the degree of memory
impairment and disease activity in their sample of 21
"recent-onset" MS subjects. It is difficult to draw
conclusions from this study also because the authors do not

explain their "acute active", "remission", and "clinically

49

inactive" designations. Also, their sample may have
included some non-MS cases of demyelinating disease, since
10 subjects were only "probable" MS (Poser criteria). Grant
et al. (1984) did find a limited relationship between an
"active" disease state and susceptibility to interference
effects on a Brown-Peterson memory task. However, disease
activity did not predict Wechsler Memory Scale (WMS) scores.
Generalization of their results is problematic given the
lack of explicit inclusion criteria and use of 11 subjects
with only "probable" MS (McDonald system) in their
prospective sample. Finally, Callanan et a1. (1989) found
no relationship between "stable versus relapse" status and
various aspects of memory functioning, although there was a
significant correlation between being in relapse and
decreased intelligence as measured by an IQ deficit score.
Inferences drawn from these findings are limited because
their prospective sample necessitated inclusion of subjects
without confirmed MS. However, Callanan et al. (1989) did
describe their criteria for clinical relapse (Poser et al.,
1983).

In summary, the absence or presence of clinical
exacerbation (of any kind) does not appear to predict memory
test performance. But because of cursory treatment,
frequent use of subject populations only in the early stages
of MS, and inadequately described operationalization of
disease activity, the question is neither answered nor
adequately investigated. One other point requires comment
and that concerns controlling for decreased memory
performance secondary to the effects of clinical relapse

and/or chronic disability. That is, memory can be impaired

50

by the general effects of being sick (e.g., increased
distractibility: decreased effort) regardless of the type of
illness. Therefore, decreased memory test performance
during a period of exacerbation relative to a period of
remittence simply may not be due to the effects of
demyelination per se, but to the general deleterious effects
of disease on memory. Comparison with numerous control
subject population types (e.g. muscular dystrophy) with
general disease sequelae similar to MS suggests that the
memory changes seen in MS are not a secondary phenomenon
(e.g., Jambor, 1969). However, it is not clear how to
control for general illness effects within MS samples. One
would have to find another condition with a relapsing -
remitting course but without primary deficits of memory or
other cognitive features.

Investigators also have explored co-ocurring motor,
perceptual, and psychiatric symptoms as predictors of memory
dysfunction. Changes in memory appear unrelated to the
physical severity of illness as measured by the Kurtzke EDSS
or other global measures of motor and sensory functioning
(e.g., Fischer, 1988: Heaton et al., 1985: Litvan et al.,
1988a: Rao et al., 1984, Rao et al., 1985: Rao et al.,
1989). The two studies that did observe a significant
positive correlation between physical and memory debilities
(van den Burg et al., 1987: Grant et al., 1984) used a more
restricted sample (i.e., subjects less severely physically
disabled or "enrolled in the early phases of disease") than
the samples used in investigations not reporting such a
relationship. Also, it is not clear, theoretically, why

only early/less severe physical symptoms would be

51

significantly related to memory functioning.

Depression also does not appear to predict memory
deficits, although other psychiatric symptoms may.
Depression correlates have been frequently studied and
found not to be related to the presence or severity of
memory dysfunction. For example, Rao et al. (1989) found no
correlation between scores on the Zung Depression scale and
performance on an array of memory tests even though the MS
group was significantly more depressed. Similarly, Zambor's
(1969) well-designed study contrasting MS subjects with and
without anxiety or depression observed that the
anxious/depressed group actually performed better on various
measures of memory than the MS group. Zambor concluded that
the "...cognitive impairment [including memory] of patients
suffering from multiple sclerosis, particularly if present
to a marked degree, is unlikely to be due to concommitant
mood disturbances" (pg. 775). Fischer (1988) found no
significant relationship between the Beck Depression
Inventory (BDI) and degree of memory disturbance as marked
by placement into one of three subgroups based on
performance on the Wechsler Memory Scale — Revised (WMS-R).
Beatty et al.'s (1988) study, alone, reported a significant
correlation between depression (as measured by the BDI) and
memory deficits. It is difficult to resolve these findings
with those reported earlier, especially Fischer's, since
both used the BDI to measure depression.

There has been limited demonstration of a correlation
between memory disturbance and emotional symptoms other than
depression. For example, Rao et al. (1984) found "atypical"

MMPI profiles indicative of emotional disturbance in a

52

subgroup that performed most poorly on a battery of memory
tests. These results are consistent with Lyon-Caen et al.'s
(1986) study, which concluded that "...qualitative mood
abnormalities [i.e., emotional expressiveness, reactivity,
and overall lability] were closely correlated with the
presence of cognitive and memory disturbances: thus, ten of
14 patients with mood abnormalities also exhibited signs of
cognitive impairment" (p. 1139). Overall, there are
insufficient data with which to conclude, reliably, that
non-depressive emotional problems are related to memory
difficulties. Several criticisms of this line of
investigation have been forwarded, including the previously
described issue of sorting out primary from secondary
effects of illness on memory. Also, it is difficult to
imagine that the processes responsible for memory
disturbance are directly related to those for psychiatric
morbidity. There is little evidence to suggest that the
pathophysiological changes responsible for memory deficits
are the same (e.g., lesion location) as those for emotional
distress. Moreover, several variables important to
psychiatric morbidity (e.g., personality structure) are not
particularly relevant to intact memory functioning. Thus,
even if a relationship between memory and psychiatric
symptoms was demonstrated, it is not clear how this
information could be useful in determing the associations
between MS pathology and memory.

To summarize, researchers have looked at the type,
severity, and course of several disease characterisitics in
hopes of understanding variations in MS memory functioning.

The data strongly disconfirm disease length and co-occurring

53

motor/perceptual disturbances as reliable predictors. The
case for disease course and activity and psychiatric
symptomology is less clear, but evidence will now be
presented that suggests that aspects of lesion dissemination
factors (e.g., extent, location, and temporal changes) are
more likely to account for memory dysfunction than are the

factors noted above.
Pathoanatomical Relationships to Memory Disturbance

Introduction.

Relatively little is known about memory functioning in
MS. Linking pathoanatomical with functional memory changes
offers hope in understanding the causes of memory impairment
and its widespread variability. Associating MS pathology
with clinical manifestations regardless of function area is,
however, in its formative stages. For example, the latest
edition of McAlpine's Multiple Sclerosis (1985) commits but
four paragraphs to the topic. This neglect is not
purposeful but, rather, reflects prominent methodological
and substantive issues.

Until quite recently, studies attempting to discern
important patho-clinical features were limited to
correlating past symptomology with postmortem examination
(Charcot, 1877: Dawson, 1916: Namerow & Thompson, 1969), and
these investigators found few consistencies between
pathology and symptomology (Field, 1988). For example, with
the exception of some brain stem and optic tract lesions,
plaque location did not correlate significantly with the
appearance of many sensory and motor deficits (Namerow &

Thompson, 1969). Further, numerous studies have reported

54

the existence of clinically "silent" lesions: sometimes
extensive areas of plaque were found at autopsy without
apparent accompanying symptomology (e.g., Castaigne,
Lhermitte, Escourelle, Hauw, Gray, & Lyon-Caen, 1981: MacKay
& Hirano, 1967: Morariu & Klutzow, 1976).

Poser (1980) and others have turned to environmental
factors in hopes of explaining why structural and functional
changes are frequently inconsistent. Emotional stress,
physical trauma, exercise, and temperature correlate
positively with symptom relapse, exacerbation, and/or de
novo appearance (Matthews, 1985). The natural history of
lesions such as seen in acute versus chronic plaques
(Weller, 1985) and antibody-response effects on neurons (see
Field, 1989) also are thought to mediate the relationship
between structural and clinical changes. The exact
mechanisms for these associations are poorly understood and
several counterarguments to environment-as-mediator models
have been offered. One is that some lesions do immediately
produce observable clinical manifestations: thus,
environmental influences are not always necessary (Hallpike,
1983). Secondly, centrifugal spread of lesions,
remyelination, and other properties of deteriorated
conduction may be more closely tied to the lack of more
consistent patho-clinical changes than are environmental
factors (Rao, 1986).

Others have cited the poor quality of investigations
to explain lower than expected correlations between observed
lesion and functioning. One such argument is that current
methods of clinical assessment may not be sufficiently

sensitive to detect more subtle and/or early-stage symptoms.

55

This criticism is unsurprising given earlier comments about
the difficulties inherent in diagnosing MS, and is
especially less so when one considers that a majority of
studies were retrospective analyses -- correlating symptoms
with autopsy confirmation of plaque extent and location.
Attempting to verify symptoms that frequently date back
scores of years is an insurmountable reliability problem.
One cannot be sure that the pathology observed post—mortem
is equivalent to that of in-vivo lesion. Any differences
between the two could obscure significant clinico-pathology
associations. Simply put, autopsy studies are inadequate to
deal with the task at hand. Aside from these issues of
reliability and validity, no autopsy investigations could be
found that correlated neuropathology with memory
functioning. Thus, in-vivo investigation is both logical
and mandatory.

The scientific community has long awaited the advance
of evaluation tools capable of such in-vivo lesion
assessment. Techniques such as X-ray,
pneumoencephalography, angiography, and radioisotope
scanning (including positron emission tomography -- PET)
were tried soon after they became available. However, these
procedures were deemed useful only in aiding differential
diagnosis because MS lesions usually were not evidenced and
only general signs of atrophy could be reliably gleaned from
these procedures (Ormerod, du Boulay, & McDonald, 1986).

Computerized axial tomography (CT) proved to be
considerably more sensitive and, for the first time, MS
lesions could be non-invasively visualized (Cala &

Mastaglia, 1976) and correlated with clinical symptoms

56

(e.g., Rao et al., 1985). CT-imaged plaque has been
confirmed at autopsy (Wurthrich, Gigli, Wiggli, Muller,
Elke, & Hunig, 1976) and a predilection for lesions in the
periventricular white-matter corroborate post-mortem
examinations (Delouvrier, Tritschler, Desbeldes, Cambier, &
Nahum, 1980). Some inroads were made with CT in
understanding the relationship between lesion and
dysfunction (De Weerd, 1979: Hershey, Gado, & Trotter, 1979:
Rao et al., 1985). For example, Rao et al. (1985) found
that increased ventrical enlargement was associated with
decreased memory and other cognitive capacities. However,
concurrent investigations demonstrated serious limitations
in CT imaging and these problems have prevented CT from
becoming a reliable procedure for studies of MS.

One shortcoming of CT is that ventrical hypertrophy and
cortical hypotrophy are more often detected than specific MS
lesions (Gyldensted, 1976: Jacob & Kinkel, 1976). Such
general measures of pathology lack the specificity needed
for more accurate description of patho-clinical
relationships (Rao et al. 1985). Some individual plaques
can be observed via CT, but their number and size are often
grossly underestimated. For example, Haughton, Williams,
and Eldevik's (1979) study correlating CT sensitivity with
post-mortem examination found that lesions less than 7 mm
are not visualized on CT, and that even larger lesions can
be missed if located near the lateral ventricles -- a
frequent site of plaque. A large proportion of subjects may
not show positive scans with estimates ranging from 65%
(Cala, Mastatglia, & Black, 1978) to 89% (Hershey et al.,
1979) of all probable MS cases, and as high as 75% in

57

clinically definite-MS (Paty, Oger, Kastrukoff, Hashimoto,
Hooge, Eisen, Eisen, Purves, Low, Branddejs, Robertson, &
Li, 1988: Sheldon, Disshathan, Tobias, Sheremata, Soila, &
Viamonte, 1985). Sophisticated enhancing media and delayed—
scanning procedures can bolster CT sensitivity, but these
benefits usually are limited to severe, acute cases and
still fail to adequately account for the entire pathological
picture even in these cases (Matthews, 1985). Other
limitations of CT include a restriction to axial-plane views
and to the fact that CT is particularly insensitive to
lesions in the brainstem and optic tracts -- two frequent
sites of MS plaque (Ormerod et al., 1986). Despite these
shortcomings and in the absence of alternatives, CT would
have continued to be the technique of choice had MRI not
appeared on the scene. The latter's imaging superiority was
readily apparent, however, and soon replaced CT in many
clinical and research settings.

MRI Physics

Some working knowledge of MRI is warranted at this
juncture. More extensive treatment than is provided below
may be found in Elster (1988), Elster, Handel, and Goldman
(1986), Stark and Bradley (1988), and Young (1984).

MRI is based on measurement of electromagnetic features
of particular atomic nuclei. Hydrogen is almost exclusively
used in clinical settings because of its ubiquitousness
within the human body and because its most abundant isotope
has the odd-number of protons or neutrons required by the
process. The subject is placed within a powerful magnetic
field, which aligns the hydrogen nuclei into static parallel

vectors. A second magnetic source then introduces a pulse

58

of energy (radiofrequency pulse or RF) at a certain
frequency (known as the resonance frequency) and at a vector
perpendicular (90 degrees) to the original static field.
Explainable via quantum physics, the beginning and end of
the RF burst results in the absorption and re-emission of
the electromagnetic energy as nuclei change quantum levels.
This process is described as nuclear magnetic resonance.
Movement amoung quantum levels causes detectable changes in
the vectors of the hydrogen nuclei (aligning "in phase" with
the RF pulse vector and perpindicular to the original static
field vector). This, in turn, produces measurable signals
picked up by a receiver coil. Signal characteristics are
determined by the proton density (proportion of protons) of
the tissues involved and two measures of nuclei relaxation,
T1 and T2. The relaxation times represent the interval from
the end of the RF pulse until the absorbed energy is
released and is a function of neighboring nuclei's re-
emission efficiency (T1), while T2 is the relative
robustness towards returning to the original vector (i.e.,
loss of "in-phase" alignment with the RF pulse). For any
given static magnetic field strength, various media (i.e.,
CSF, myelin, and grey matter) have different but relatively
constant T1, and T2 values. For example, the lipids in
myelin are much more efficient in transferring energy in
comparison to CSF and grey matter and, therefore, have
shorter T1 relaxation times. T2 times are more dependent on
the proton density of the medium such that liquids, with
less hydrogen per volume (e.g., CSF), have longer values
than the relatively proton-dense structure of solids such as

white matter and muscle. Scanning parameters are

59

manipulated to provide varying degrees of contrast between
tissue types (including pathological tissue) via differences
in proton density and T1 and T2 times according to the needs
of the user. Different relaxation times and proton
densities are seen in varying shades of grey (from black to
white) as computer programs translate the information from
the receiver coils onto X-ray film.

Aside from physical properties inherent in the
process, operator-controlled variables also determine image
characteristics. These include: pulse sequence, pulse time
intervals, number of signal averages, slice thickness,
matrix size, image plane, "windowing", and field of view.

The pattern of RF pulses used is known by its pulse
sequence. To improve signal quality, typically more than
one RF pulse is applied to the static magnetic field and the
entire process (or sequence) may be repeated. Partial
saturation (PS), inversion recovery (IR), and spin-echo (SE)
are the most common patterns of RF pulse latencies and
sequences used in clinical settings. Spin-echo is the
sequence of choice for MS because it provides information
about tissue T2 values in addition to proton density and T1
values. The former is particularly important since it has
been found to be most sensitive to pathology (Elster et al.,
1987) and IR and PS sequences are not especially geared for
T2 measurements (Stark & Bradley, 1988). The spin-echo
technique starts with a 90 degree RF pulse, which, as
described before, synchronizes the nuclei into a vector
perpendicular to the static field vector. This
synchronization pulse is followed by a pulse of 180 degrees

-- which helps minimize background noise -- and the

60

resulting "echo" signal is then measured. Subsequent
repetitions of the rephasing pulse with its attendent echo
signal (known as multi-echo sequencing) have been found to
improve imaging quality, especially for MS imaging uses.
Other factors, however, limit its usefulness beyond two or
four echoes.

Two pulse time sequences are important to the multi-
echo technique. TE (echo time) is the time between the
synchronizing (90 degree) and the echo signal. TR
(repetition time) marks the latency between the
synchronizing (90 degree) pulses. By varying TE and TR, the
operator takes advantage of proton density and T1 and T2
tissues differences to create contrasts suited for his/her
needs. For example, "long" TE's (i.e., > 75 msec) combined
with "long" TR's (i.e., > 2000 msec) produce a T2-weighted
image, more sensitive to variations in T2 relaxation times
than either T1 or proton density values. Numerous
investigations have shown that such T -weighted, compared to
proton density- and T -weighted image:, are more efficient
in detecting MS lesiogs (e.g., Robertson, Li, Mayo, Genton,
& Paty, 1985: Smith, Weinstein, Modic, Pavlicek, Rogers,
Budd, Bukowski, Purvis, Weick, & Duchesneau, 1985). If the
T weighting is too heavy, however, MS lesions can become
iidistinguishible from the CSF found in the ventricles.
This can be remedied by using a multi-echo series and
specifying long, medium, and short TE's in combination with
a long TR. Comparing this series of progressively lighter
T2-loads allows better contrast between CSF and MS lesion

and, in general, greater ability to visulize more subtle

lesions. Hence, Stark and Bradley (1988) recommend multi-

61

echoes with TE set near 30, 60, and 90 msec and TR values
from between 2000 and 3000 msec for MS scanning purposes.

Multiple signals (i.e., signal averaging) can be used
to derive composite images superior to that produced from
one signal. Marginal utility quickly decreases though
because as the number of signals increases, imaging time
rises exponentially and movement artifacts become more
likely (movements by the patient during imaging can
seriously blur the image). The concern with imaging time is
not misspent, since per hour scanner charges can run as high
as $2,000 and research scanning protocols lasting longer
than 30 minutes are common. Furthermore, the scanning bore
-- where the patient lies during the imaging process -- is
uncomfortably tight for many. Patient comfort and ability
to remain motionless, therefore, decrease as imaging time
increases. Signal averages are determined by the cost-
benefit ratio needs of the operator and are usually set at
two or four.

Manipulation of slice thickness and matrix size also
seriously escalate costs for fairly small increases in
visual quality. Most scanners obtain slices from 2 mm to 10
mm thick. More tissue area can be seen and in better detail
with thin slices but with marked increases in imaging time
and noise-to-signal ratios. Similarly, greater matrix size
increases spatial resolution, but with scanning time and
noise-to-signal ratio increase. Most matrices are 128 x
128, 128 x 256, and 256 x 256 and produce picture elements
(i.e., pixels) ranging from 1.7 to 0.8 mm, respectively.

Unlike CT, MRI can produce images from the axial,

sagittal, and coronal plane with equal facility. Choice of

62

scanning, from one to all planes, depends on the needs and
resources of the operator. A review of research protocols
indicates that axial views are almost universally used,
occasionally complemented by sagittal (especially where
evaluation of the brainstem and spinal cord is critical) and
coronal cuts (e.g., orbital/optic tract assessment). The
reliance on axial projections is a carryover from
radiologists' previous experience with CT, although axial
cuts actually are preferred for many MS applications. For
example, the periventricular regions are especially well-
visualized axially. Compared to other more focally
distributed pathologies, choice of plane is not as critical
for MS. Ideally, MS protocols would include series from all
three planes: however, scanning costs often prevent such
comprehensive coverage.

The size of area to be imaged also is under operator
control and can be manipulated to improve imaging quality.
The field of view is roughly spheroid with a diameter
ranging from 10 to 30 mm (Elster, 1988). For ideal
scanning, the field of view should coincide with the size of
the structure imaged. The only significant restraint is
that the field of view must be at least as large as the
target structure: if not, a "fold-over" artifact will result
(Stark & Bradley, 1988). For most cranial protocols, the
field of view is set near 25 cm (Elster, 1988).

With this introduction, let us turn to applications
of MRI to MS and memory.

Mg Applications
MRI was first used in conjunction with MS by Young,

Hall, Pallis, Legg, Bydder, and Steiner, (1981). They

63

compared both normal and contrast-enhanced CT with MRI scans
on 10 MS patients. In addition to the 19 lesions seen on
CT, 112 other plauqes also were identified by MRI.
Subsequent studies have confirmed MRI's superior sensitivity
to CT for most MS-related imaging (e.g., Gerbarski,
Gabrielsen, Gilman, Knake, Latack, & Aisen, 1985: Lukes,
Crooks, Aminoff, Kaufman, Panitch, Mills, & Norman, 1983:
Paty, Oger, Kastrukoff et al., 1988: Sheldon et al., 1985:
Smith, Weinstein, Modic et al., 1985).

Considerable evidence indicates that the signal-
contrasted areas seen on MRI are, at least in part, MS
plaque. MRI-imaged in-vivo lesions correspond to
histological examination at autopsy (Ormerod, Miller,
McDonald, Boulay, Rudge, Kendall, Moseley, Johnson, Tofts,
Halliday, Bronstein, Scaravilli, Harding, Barnes, & Zilka,
1987), post-mortem MRI scanning (Stewart, Hall, Berry, &
Paty, 1984) and previous autopsy descriptions (e.g.,
Brownell & Hughes, 1962: Fog, 1965) of plaque site, size,
and the like. MRI-imaged lesions also coincide with
previous evidence of MS predelection for certain sites. For
example, most MRI observed plaque is found in the
periventricular regions, centrum semiovale, brain stem, and
cerebellum (Ormerod et al., 1986). Cerebral and corpus
collosal atrophy, ventricle hypertrophy, and spinal cord,
basal ganglia, and some grey-matter involvement also are
seen on MRI (e.g., Elster, 1988: Stark & Bradley, 1988).

The exact nature of the pathological changes seen on
MRI have not been confirmed. MS plaque show as different T1
and T2 relaxation times relative to surrounding tissue: for

example, increased T1 and T2 versus healthy white matter

64

(Stark & Bradely, 1988). Disease activity has been proposed
as responsible for signal differences where general
inflamation, disruption of the blood-brain barrier (BBB),
and increased unbound water from edema mark acute lesions.
Demeylination and gliosis are thought to be responsible for
the signal contrast between chronic plaque and normal tissue
on MRI. Ormerod et al. (1987) present conceptual and
emprirical support for a slightly different model. These
authors hypothesized that the gliosis prominent in chronic
plaques certainly results in direct changes in signal
characteristics. That is, increased plaque T2 values occur
because gliosal tissue contains more water per unit volume
(hence more hydrogen protons) and possibly in a form more
easily imaged (i.e., more dense macromolecular state) than
the normal myelin it replaces. Ormerod et al.'s (1987)
histological examination of post-mortem brains found
positive MRI signal correlates with glial growth. This
finding, in combination with previous evidence of increased
water per unit volume in MS lesions with significant gliosis
(Tourtellote & Parker, 1968), strongly affirms that portion
of their model pertaining to signal characteristics of
gliosis. In contrast to other theories, Ormerod et al. do
not believe that relaxation time differences between chronic
plaque and normal tissue are due directly to the loss of
myelin. This portion of their model is supported by
evidence by Pykett and Rosen (1983) and Bottomley, Hart,
Edelstein, Schenck, Smith, Leue, Mueller, and Redington
(1984) that the number of hydrogen protons in myelin is
proportionately smaller than that in surrounding tissues

such that hydrogen proton loss contributes minimally to MRI

65

signal. Ormerod et al. (1987) do note that changes
secondary to the loss of myelin (i.e., replacement of myelin
by non-gliosal tissue with imaging qualities similar to
gliosis) also may occur, which produce the signal contrast
associated with chronic plaque. Larsson, Frederiksen,
Kjaer, Henriksen, and Olesen's (1988) careful study of MRI
signal characterisitics in MS and normal control subjects
revealed that plague T1 and T2 values vary considerably
between and within subjects -- a finding consistent with
Ormerod et al.'s disease activity hypothesis. However,
neither Ormerod et al. (1987) nor Larsson et al.'s (1988)
could seperate MRI signal into those processes attributable
to gliosis versus possible secondary effects of
demyelination. In summary, gliosis clearly contributes to
MRI signal changes associated with chronic plaque. However,
evidence is lacking as to whether myelin loss per se also
produces MRI signal differences or whether non-gliosal
changes secondary to demyelination also are at work.

In support of the acute lesion portion of the model,
Ormerod et al. (1987) cite experimentally-induced edema-
and glial-producing pathologies (e.g., tin intoxication) in
cats. Acute and chronic plaque relaxation times could be
differentiated presumably on the basis of water content,
macromolecular structure, disrupted BBB, and other intra-
and inter-cellular sequelae known to occur from such insult
(e.g., Barnes, McDonald, Johnson, Tofts, & Landon, 1987).
Based on previous histological evidence of similar tissue
changes associated with active MS lesion (Adams, 1983:
Weller, 1985), Ormerod et al. suggest that these processes

(i.e., water content, macromolecular structure, disrupted

66

BBB) result in the MRI signals observed in acute lesions.
The fact that gadolinium enhancement differentiates active
from inactive lesion, where the enhancement medium is able
to pass the disrupted BBB in active lesions (Grossman,
Gonsalez-Scarano, Atlas, Galetta, & Silverberg, 1986) also
supports the notion that different histo-pathological
processes are at work in producing the similar imaging
(noncontrast) characteristics in acute versus chronic
plaque.

Moving from a description of "what" is imaged to
temporal considerations, changes in lesion size are an
excellent source of information regarding the natural
history of MS. Longitudinal, multi-study MRI investigations
are able to track disease activity through the observation
of lesion flux over the period of a few months. Uhlenbrock,
Seidel, Gehlen, Beyer, Haan, Dickman, Zeit, and Herbe (1988)
imaged 22 MS patients during acute relapse and at two
subsequent times -- four to six weeks and three months after
the initial MRI. Between the first and second and second

and third scannings:

roughly 75% of the lesions did not change size

5 - 7% decreased in size

4 - 10% increased in size

41 lesions disappeared

34 new lesions appeared

These variations in lesion size are indicative of disease
activity: the waxing and waning probably correspond to the
acute changes (e.g., the appearance and disappearance of
edemal-related substances) as noted by Adams (1983).

Subsequent studies by Isaac, Li, Genton, Jardine,

67

Grochowski, Palmer, Kastrukoff, Oger, and Paty (1988),
Kappos, Stadtr, Ratzka, Keil, Schneiderbanger-Grygier,
Heitzer, Poser, and Nadjm (1988), and Willoughby,
Grochowski, Li, Oger, Kastrukoff, and Paty (1989) suggest
that new plaque growth maximizes between one and two months
and gradually fades in signal intensity until plateau after
two to four months. Relatively large, acute plaques
frequently left residual MRI-signal comparable to those of
unvarying and presumably chronic lesions. Smaller lesions
often disappeared entirely, but such evidence certainly does
not rule out the possibility that microscopic changes
remained. Willoughby et al. (1989) observed that acute
lesions tended to arise from "healthy" white-matter tissue.
However, they also appeared from previously stable chronic-
lesion areas. In line with the disease activity model,
these authors suggest that edema, and, possibly, secondary
demyelination effects were responsible for the period of
greatest lesion signal-intensity. Given the similarity of
relaxation times between non-fluxing and the residual
plaques, Willoughby et al. (1989) suggested that:
"...the expanding and contrasting new lesions
are the bas1c or primary les1on 1n MS, that the
characteristic demyelinated plaque is represented by
the small residual area that these lesions shrink
down to, and that the typical collection of scattered
white-matter lesions in chronic MS may represent the
accumulated residua of dozens or more of these active
lesions occurring over many years " (p. 43).
When combined with previously described evidence that
morphological alterations occur on a histological level in
tissue that had been previously described as unaffected upon

gross analysis (e.g., Adams, 1983) longitudinal data

indicate that early-stage and/or more subtle pathological

68

alterations are not always seen via MRI. Also, the
microscopic changes associated with pathological activity
cannot be verified via visual inspection of MRI at this
time. For example, end-stage gliosis appears almost
identically on MRI as resolved, formerly acute lesions. As
a result we can infer progressions in disease activity from
multi-study MRI, but not the pathological changes underlying
such activity.

Longitudinal investigations also have observed that
pathological changes are independent within a given patient.
That is, lesion growth occurs simultaneously with shrinkage
in other plaques, while still other lesions will show no
evidence of change (e.g., Willoughby et al., 1989). This
finding supports the hypothesis that pathogenic factors are
localized: however, proponents of the diffuse pathogenesis
model (e.g., AdamS) can argue otherwise. Visual analyses of
MRI detect only more macro-level changes. Yet, histological
deterioration could occur throughout the CNS in a diffuse
manner (as is hinted at in the preliminary analyses of white
matter relaxation times by Larsson et al., 1988) without
being observed by MRI.

Although strongly suggestive, verification of disease
activity's impact on MRI signal via multi-study designs is
incomplete and hindered by the same methodological issues
noted with single-study MRI. First, no current techniques
exist that can cross-validate acute pathophysiological
effects on MRI signal. Post-mortem examinations, for
example, are unable to track acute changes (Isaac et al.,
1988). Conversely, although lipid loss is measurable at

autopsy (Stewart et al., 1986), lipid loss is not seen

69

easily ig yiyg MRI (Ormerod et al., 1987). Separating
signal attributable to glial growth from non-glial tissue
gains or actual myelin loss remains undemonstrated even with
multi-study designs.

Numerous studies confirm MRI's superiority to CT in
detecting MS plaques and providing diagnostic evidence
complementary to clinical history (e.g., Gerbarski et al.,
1985: Paty et al., 1988). Two exceptions to this
superiority lessen MRI's usefullness in describing lesion -
function associations. One is that, like CT, MRI is
relatively poor at detecting lesions in the optic nerves and
chiasm and to a lesser degree the spinal cord -- all high
predilection areas for MS lesion (Gerbarski et al., 1985:
Sheldon et al., 1985: Stevens, Farlow, Edwards, & Yu, 1986).
Stevens et al. (1986) have suggested that MRI's
insensitivity to these locations may help explain the
frequent failure of attempts to correlate lesion burden with
sensory and motor deficits. Typical measures of functioning
(e.g., Kurtske D88 and EDSS, and clinical history) are
heavily influenced by optic and spinal functioning changes,
whereas the pathology in these regions is frequently missed
by MRI. Spuriously low correlations between lesion and
function will continue unless the over-weighting of sensory
and motor manisfestations on functioning indices is somehow
balanced. Recent advances in scanning parameters and
hardware have improved imaging of the spinal cord,
especially the cervical region (Stark & Bradley, 1988):
however, the possibility of missing plaque in hard-to-image
locales remains frustratingly high.

The second caution regarding over-optimistic use of MRI

70

returns us to the earlier discussion on disease activity and
MRI signal. Non-enhanced MRI is not reliable in visually
discriminating acute versus chronic areas of demyelination
on a single study (non-visual methods may be an exception
and will be discussed below) (Ebers, Paty, & Sears 1984).
And although gadolinium-enhanced (e.g., Grossman et al.,
1986) and serial MRI scans (e.g., Uhlenbrock et al., 1988)
can discern inactive from active plaques, these methods
incur considerable tradeoffs. Gadolinium enhancement is an
invasive procedure with attending increases in time, money,
and subject discomfort and complications. Prospective,
serial scanning also entails considerable additions in study
time and Cost. Thus, the traditional, one-time, cross-
sectional MRI study is more frequently used in spite of its
unselectiveness with respect to disease activity.

This practice may hamper investigation of structural-
functional correlates. If it is determined that different
stages of disease activity produce dissimilar effects on
clinical functioning, then cross-sectional MRI
investigations may be insufficent for describing the
association between pathological and functional alterations.
At the very least, understanding the relationship between
disease activity and functioning will help us draw reliable
inferences from single-study MRI investigations.

Many efforts to describe the relationship between
pathophysiology and functional changes have been insidiously
confounded. Prior to MRI, disease activity was inferred
from the increase in or appearance of clinical
manifestations, in part because laboratory techniques were

unreliable in determining disease activity (e.g.,

71

oligodendroglial bands in the CSF). Symptoms were assumed
to reflect pathophysiological activity: however, this logic
is circular. One cannot determine the relationship between
disease activity and clinical changes if disease activity is
defined merely from evidence of the latter. Fortunately,
three types of MRI investigation provide an indicator of
pathophysiological change independent of clinical
functioning: nonvisual comparisons of relaxation times,
gadolinium-enhanced MRI, and multiple-study MRI. These data
suggest that the relationship between lesion activity and
function is not so clear, nor so strong as was originally
hypothesized.

Ormerod et al. (1987) and Larsson et al. (1988) scanned
a variety of tissues in samples of MS and control patients.
Rather than translating the information to visually-
inspectable X-ray film, they recorded the T1 and T2
relaxation times on computer for statistical comparisons.
Both investigations found that the relaxation times of
plaques differed markedly within subjects and in a pattern
that could predict disease activity. The results also
suggested that the direct analysis of relaxation times is
more sensitive to pathological changes than is visual
inspection and that disease activity can be discerned with a
single (nonenhanced) scan. Most importantly, Larsson et
al.'s (1988) study indicated that significant lesion
activity did not affect functioning. Subjects were chosen
specifically not to have had any clinical episodes in the
previous 12 months. Thus, changes in relaxation time
indicative of pathophysiological activity occurred

independently of alterations in function. Additional

72

confirmation is needed before moving on this important
finding, especially in light of apparently contradictory
results with gadolinium enhancement. Also, because Larson
et al.'s sample did have stable clinical manifestations, one
cannot draw inferences about how different phases of
pathological activity can be associated with unchanging
symptoms.

Of value in a later discussion, Ormerod et al. (1986)
and Larsson et al. (1988) also found that what was though to
be "healthy" (undetectable via visual examination of MRI)
white-matter of MS patients was significantly different from
that of normal controls and in the direction expected if
this white-matter were undergoing early-stage deterioration.
Moreover, relaxation times of "healthy" versus "involved"
tissue overlapped with a wide variation within subjects.
These results tie in nicely with Adams' (1983) assertion
that MS is a diffuse, rather than, multi-focal process. The
implications for memory deficit/lesion relationships will be
addressed below.

Longitudinal investigations also report minimal
correlations between lesion activity and symptoms. Isaac et
al. (1988), Paty et al., (1988), Uhlenbrock et al. (1988),
and Willoughby et al. (1989) observed no correspondence
between lesion changes (over one to six months) and the
appearance of de novo and/or exacerbation of old symptoms.
The consensus of these data, in combination with nonvisual
relaxation time studies, strongly indicates that MRI
observed lesion activity is not significantly associated
with alterations in function.

In contrast to direct relaxation time and longitudinal

73

investigations, gadolinium-enhanced MRI studies provide
stronger support for a relationship between disease activity
and clincial manifestations. For example, Grossman et al.
(1986) observed that lesion enhancement (i.e., active
plaque) occurred in a majority of patients in clinical
relapse. Brorson, Braffman, Grossman, Silberberg, and
Gonzalez-Scarano (1988) found that the number of enhancing
lesions was positively and significantly correlated with
clinically—derived disease activity in a study of 45
clinically definite MS patients. However, both studies also
reported enhancing plaques in patients who were in
remission. Thus, enhancement is not specific with respect
to symptom exacerbation.

In summary, three types of MRI study provide
contradictory evidence that lesion activity is associated
with symptom appearance. A case could be made for a
relationship between new clinical manifestations and acute
plaque processes based on the gadolinium studies. However,
gadolinium study is not consistent with the other two
methods and none of the three sources have disease activity
relationships to stable deficits. Before concluding that
pathophysiological activity is not particularly relevant to
functioning, one must consider the following issues.

First, disease activity effects on functioning need not
be an all-or-none phenomenon but can be viewed as one of
many factors contributing to the appearance of dysfunction.
For example, many would argue that lesion characteristics
(e.g., size and location) and subject factors (e.g., current
level of stress) affects the possibility of symptom

appearance. Secondly, the literature is filled with reports

74

of asymptomatic lesions, presumably both active and inactive
plaque (e.g., Koopsman, Li, Grochowski, Cutler, & Paty,
1989). We do not understand why only some lesions produce
impairments, but for the plaques that do, we may find that
different processes are responsible for functional changes
and disease activity may be involved only in some subset of
those processes. For example, increased glial scarring may
increase blockage of neural transmission in chronic plaque
-- a process that is not associated with acute disease
activity. Also, the edema produced during an active phase
of the disease may prevent communication in only some neural
tracts, those already weakened by previous bouts of
demyelination. Thus, while disease activity may not be
related to all lesion effects on functioning, it may be
related to some. As Ormerod et al. (1987) nicely summarize:
"The failure to identify an abnormality after the
acute development of a symptom may not mean that none
was present earlier or that none will be obvious
later: and the apparent disappearance of a
lesion...need not imply resolution of the pathological
changes with restoration of normal structure." (p.
1612)
Common sense dictates that some aspects of
pathophysiological activity contribute to dysfunction
despite our inability currently to characterise them with
any degree of certainty. Teuber's dictum holds true here: a
lack of evidence for a relationship is not evidence that the
relationship does not exist. All three methods hold great
promise for the future and should be vigorously pursued.
Given the probable lack of one-to-one correspondence
between pathophysiological lesion activity and symptom,

disease activity designations must be made more carefully.

Disease activity may refer to either clinical 9;

75

pathophysiological dynamics. The data suggest that for any
given clinical relapse (acute symptomology), lesions may be
both active (acute) and inactive (chronic). Similarly,
patients in "clinical remission" may have both active and
inactive lesions.

A final comment concerns possible differences between
cross-sectional and longitudinal MRI studies. Lesion -
function studies frequently involve some measurement of the
amount of pathology involved. Given Isaac et al.'s (1988)
and others findings that plague number and size change over
a few months, one might infer that cross-sectional study is
unreliable because it cannot speak to these variations.
That is, single-study MRI may over- or under-estimate total
lesion burden depending on the state of disease activity of
the patient when imaged. A number of factors, however,
argue against such a conclusion. First, prospective studies
have shown that the evolution of plaques is independent
within subjects. Lesions may grow, shrink, appear, and/or
disappear concurrently (Willoughby et al., 1989). Thus,
gains and losses in total lesion volume should balance to
some degree with the aggregate total remaining relatively
stable -- at least for latencies less than one year and
across relatively large areas of the CNS. Preliminary
results support this hypothesis, as the actual amount of
lesion volume change is relatively small. For example,
Isaac et al. (1989) observed seven subjects over six months
and found that total lesion volume (mmz) differed by no more
than 13% for any given subject, a statistically
insignificant difference when compared with total lesion

volume. This figure is comparable to the 14 - 15% lesion

76

volume change observed by Kappos et al. (1988) in 74 MS
subjects scanned five to seven months apart during two
medication trials. Although methodological concerns reduce
the reliability of both studies, their results suggest that
longitudinal and cross-sectional studies will obtain similar
estimates of lesion burden. Finally, this investigation's
hypotheses are based on the premise that lesion burden is

correlated with memory functioning a; any given point lg

 

gimp. Cross-sectional MRI is an appropriate procedure for
testing such a premise. Whether multiple-study measures of
lesion burden are more effective than single-study design in
accounting for variations in functioning is a separate
empirical question.

Motor and Sensory Functioning

 

Reports of the strength of the relationship between
MRI-imaged pathology and motor and sensory symptoms have
varied from negligible (e.g., Crisp, Kleiner, DeFillip,
Greenstein, Liu, & Sommers, 1985: Kiel, Greenspun, &
Grossman, 1988: Kirshner, Tsai, Runge, & Price, 1985) to
significant (Bogousslavsky, Fox, Carey, Vinitski, Bass,
Noseworthy, Ebers, and Barnett, 1986: Edwards, Farlow, &
Stevens, 1986: Jacobs, Kinkel, Polachini, & Kinkel, 1986;
Matias-Guiu, Sanz, Gili, Molins, Bonaventura, & Capdevila,
1986: Sheldon et al., 1985: Stevens et al., 1986).
Inadequacies in study design, MRI insensitivity, poor
measures of lesion burden and functioning, and the presence
of so-called "silent lesions" and "silent areas" have been
posited as responsible for less-than-expected correlations
between lesion burden and functional decline.

Generally, correlations between lesions and symptoms

77

have been weaker where sample size was small (e.g., Kiel et
al., 1988) or possible/probable MS cases were examined
(e.g., Kirshner et al., 1985: Sheldon et al., 1985), while
prediction of clinical symptoms from lesion burden improved
in larger and definite MS samples (e.g., Edwards et al.,
1986: Sheldon et al., 1985: Stevens et al., 1986).
Incomplete, unreliable, or gross indices of impairment also
detract from accurate measurement of lesion - symptom
relationships., For example, self— report is frequently
used but is susceptible to patient and/or interviewer
subjectivity. The Kurtzke DSS/EDSS is perhaps the best
grading system for overall functioning in MS (Matthews,
1985) but as such may lack the sensitivity and flexibility
needed for finer-grained examination. For example, the
Kurtzke scales overweight functions whose structures are not
especially appreciable via MRI.

Weaknesses of MRI scoring systems include neglect of
important information. For example, one frequent index used
is the total number of lesions. This type of measure fails
to account for plaque size or location. Another shortcoming
of MRI indices is that scoring criteria are frequently based
on ease of scoring or general anatomical considerations
rather than classifications important to possible functional
localization. Kirshner et al.'s (1985) system is provided
as an example of a system not functionally-derived. They

grouped subjects' MRI's into one of four grades:

grade 1 - lesions only in periatrial and
supraperiventricular regions

grade 2 - same as grade one but with lesions greater
than 2.5 mm

78

grade 3 = PV and periatrial lesions greater than 5
mm and plaque in four cerebral lobes and
capsular region

grade 4 = PV, cerebral lobe, brainstem, and "more

distant white-matter" lesions

This schema reflects expected MRI differences between
patients rather than ratings of lesion burden features most
likely to discriminate clinical manisfestations.
Conversely, Sheldon et al.'s (1985) laudable design grouped
MRI results into four locations relevant to functional
localization (optic nerves, cerebrum, posterior fossa, and
spinal cord).

Authors have cited limitations in MRI sensitivity not
only in hard to visualize areas but also in locales that are
more easily imaged (e.g., posterior fossa) to explain lower-
than-expected correlations. For example, Sheldon et al.
(1985) reported that none of 34 patients with optic neuritis
showed MRI-confirmed lesion in the optic nerves. Although
improvements in plaque visualization have been reported with
enhancing media, surface coils, and the like, it is apparent
that some lesions will be missed and will cause artifactual
decreases in lesion - function correlations.

There is considerable empirical evidence that small
lesion - function correlations occur because some lesions
simply are asymptomatic. As reported earlier, longitudinal
studies indicate that lesion activity (whether de novo or
reactivation of chronic lesions) does not always result in
clinical manifestations. Asymptomatic plaques also have
been described via autopsy examination (e.g., MacKay &
Hirano, 1967), CT with and without enhancement (e.g., Ebers,

Paty, & Sears, 1984), and most recently with MRI cross-

79

sectionally (e.g., Ormerod et al., 1987). A contrast
between true and false positive concordance rates of
symptoms with lesions was highlighted by Sheldon et al.
(1985). Although 83% of their patients with symptoms
localizable to the brainstem or cerebellum had positive MRI
in those areas, 43% of patients with lesions observed in the
posterior fossa did not have localized deficits. These
results suggest that, although most patients with symptoms
have lesions in relevant structures, the reverse is not
necessarily true. The degree to which this relationship
holds for changes in mentation and memory may be important
to ascertain. One might hypothesize that concordance rates
will be even more discrepant in memory since more variables
are likely to mediate the association between structure and
function with memory than with relatively simpler sensory
and motor neuronal networks.

Sheldon et al.'s (1985) observations about so-called
"silent areas" provide an appropriate transition from the
description of asymptomatic plaque. In trying to explain
their failure to demonstrate stronger lesion - symptom
correlations, they state "...(cerebral) plaques usually
occur in cerebral association areas that tend to be
clinically silent" (p. 953). Although the accuracy of this
statement has not been confirmed, it does raise several
important questions. Association areas may be more robust
to the effects of lesions, or at least result in less easily
measured deficits. This point is extremely important, since
it bears greatly on the degree to which researchers have
adequately measured sensory and motor symptoms. As

discussed by Luria (1966), associative areas are thought to

80

integrate raw data from primary cerebral regions into
workable information for all functional systems.

Destruction of a primary zone is likely to result in a loss
of specific function, while insult to an associative area
would interfere with more general abilities -- the so-called
"higher cortical functions". For example, the loss of the
primary visual zone in the occipital lobe can cause the loss
of any visual sensation, a defict known as "cortical
blindness". On the other hand, lesions in visual
associative areas are thought to result in integrative
perceptual deficits such as the failure to recognize a large
building as a skyscraper or to understand the layout of
chesspieces as a Checkmate scenario. One difficulty with
current research is that the functional measures used are
more sensitive to primary zone than to associative area
impairments. Thus, plaque in "silent areas" (associative
regions) may not actually be asymptomatic but, rather, the
subtle deficits produced by associative area lesions
probably are not being evaluated adequately.

Even if this problem of overreliance on measures of
primary zones were addressed, however, difficulties may
still arise simply because of our relative ignorance of the
ways in which association areas work. That is, even in a
perfectly designed study, wherein all relevant primary and
"higher" cortical functions are adequately measured, it is
quite probable that we may still find "asymptomatic" lesions
because association areas may have more redundant pathways
or alternative ways of processing the information necessary
for intact integrative, generalized functioning.

Finally, "silent" areas and lesions probably reflect

81

factors previously described as contributing to disruption
of neuronal functioning (e.g., patient stress, CNS
plasticity, remyelination, and centrifugal dissemination).
Thus, even if MRI could accurately determine the extent and
location of every plaque and all functional changes were
completely described, we still would not have accounted for
all the variance associated with MRI-observed lesion and
dysfunction relationships. For example, Stevens et al.
(1986) secured the highest correlations between MRI-observed
lesion and symptoms reported to date, yet plaque accounted
for only approximately 20% to 35% of the variance in
sensory-motor functioning. The variance accounted for
dropped further still -- to 15% -- when the authors
attempted to correlate lesion burden with mood and
mentation. This latter finding is highlighted because it
foreshadows the exponential rise in measurement difficulties
encountered when one moves from examining sensory-motor to
higher cortical functions. For example, researchers of
sensory-motor symptoms can be more certain which locales to
score (e.g. cerebellum for gait disturbances) than those who

investigate intelligence, judgment, memory, and the like.

Cognitive and Memory Functioning

Few attempts have been made to evaluate the association
between MRI indices of plaque and memory impairments, and
generally negative findings were reported. However,
numerous methodological problems render their results
inconclusive. As is true in studies of motor and sensory
deficits, these difficulties include inadequate measures of

memory functioning and lesion burden, improper matches

82

between the two, and small sample size. Where these
concerns have been addressed, preliminary evidence suggests
that some of the individual variation in memory function may
be predicted by MRI-confirmed lesion burden.

Seven studies have been published to date that include
some attempt to measure the degree of relationship between
MRI-imaged lesion burden and memory functioning. Three
investigations did not examine memory separately from other
cognitive functions, making it difficult to incorporate
their findings. Given the relatively small number of
studies, it is possible to briefly describe each as a means
of illuminating pertinent measurement issues, conclusions
that can be drawn from the data, and the basis for the
current study's hypotheses. The descriptions appear in the
chronological order in which they were published.

Huber et al. (1987) administered the Kurtzke EDSS,
Mini-Mental Status Examination (MMSE), and brief measures of
language, praxis, and visual-spatial perception to 32
clincially-definite MS patients (Poser criteria) and 12
normal controls. The digit span and word—pairs learning
tests from the WMS were used as measures of memory. Proton-
, T1-, and T2-weighted MRI scans were obtained, although the
authors were not clear which planes were scored -- only
saggital cuts were mentioned. The films were scored for
four indices of MS pathology extent: 1) quantity of lesions
(i.e., total area of all observed plaque) 2) general
parenchymal atrophy (i.e., global rating on a scale from one
to five based on appearance of gyri, sulci, ventricles,
cisterns, and "parenchymal atrophy") 3) corpus collosal

atrophy (i.e., global rating from one to five for CC atrophy

83

and number of lesions), and 4) PV involvement (i.e., global
rating from one to five for percentage of lateral ventricle
encasement). Patients were placed in one of three
functioning groups with those labeled "demented" scoring at
least two standard deviations below controls on at least
three of the cognitive measures: "moderate" patients
performed poorly on any two measures: and the "minimal"
group had below normal functioning on one or none of the
tests. The authors found that the three dementia groups
significantly differed only on the CC index of plaque,
although the other three measures showed trends in the
predicted direction.

The Huber study is notable for its well-considered MRI
scoring system, using group comparisons to help adjust for
individual variations, and proposing that the corpus
collosum is a more sensitive indicator of global cognitive
functioning than are other indices. Because the authors did
not analyze different types of functioning, however, it is
impossible to draw inferences specific to memory.

Medaer et al. (1987) administered the WAIS, the
Progressive Matrices Test (an analytical reasoning measure),
the Rey Verbal Learning Test (RVLT), the Benton Revised
Visual Retention Test (a measure of visuo-spatial perception
and memory), and a search task purportedly sensitive to
attention and concentration to a number of laboratory-
supported definite MS patients. Thirty-three of these
patients were matched on age, sex, and disease duration for
placement into three groups based on a global rating of
impairment from the cognitive tests. Those in group one

(GI) showed no impairment: GII subjects had "moderate

84

impairment at least in some tests": and GIII were "seriously
impaired with deficts on most tests." The authors also
reported that some WAIS performance subtests were not given
when patients "showed marked visual or motor disability" (p.
87). It is unclear from their description how the MRI data
were obtained or analyzed. As best as can be determined,
T2-weighted images were obtained from an axial plane with
further multi-echo slices made if plaque was discovered.
Each patient was given a global MRI score from zero to five:
0) one lesion only 1) small PV lesions 2) broad PV and
confluent lesions 3) #2 criteria plus peripheral lesions

4) #2 criteria plus enlarged ventricles and 5) #3 criteria
plus enlarged ventricles. The authors did not state whether
the entire brain or, for example, only the cerebral
hemispheres were scored.

At first glance, the results appear to support the
authors' conclusion that MRI measures of pathology predict
global estimates of cognitive functioning. The three groups
differed significantly on the MRI score such that GI
subjects had lower MRI ratings in comparison to subjects in
GII and GIII. However, the GII and GIII contrast was not
significant and there was sufficient overlap between groups
such that some subjects in the GII had greater MRI scores
than those in GIII. These results led the authors to
conclude that "...the interindividual variation in MRI
scores seen within the groups (especially group II)
indicates that an overall MRI score alone is not sufficient
to account for more specific differences in cognitive
functioning " (pg. 88).

Because of serious methodological issues, even this

85

conclusion may be unreliable. It is not clear how group
membership was determined or how the MRI's were evaluated.
Another concern pertains to the apparent lack of functional
considerations in the MRI indices and the use of such
constructs as "small," "broad," and "confluent." Scoring
criteria should reflect the pathological picture in a way
that is functionally relevant if lesion - dysfunction
relationships are to be adequately investigated. The
scoring system also is vulnerable to errors of reliability
as succeeding investigators choose different values for
"small." The inconclusive results also may be attributed to
their use of indirect indices of MS lesion. For example,
parts of Medaer et al.'s grading system depended on
variations in ventricle enlargement. Most would agree that
ventricle hypertrophy is merely reflective of white-matter
plaque in the cerebrum and not a cause of functional changes
per se. It may be that only direct measures of plaque are
significantly associated with changes in cognition.
Additional evidence supporting this hypothesis will be
reviewed below.

In contrast to Medaer et al., Brainin et al. (1988)
employed more direct measures of MS plaque and scored for
locales implicated in the mediation of cognition and memory.
The authors administered the WAIS Information, Similarities,
Picture Completion, and Digit Span subtests and the WMS
Logical Memory and Paired Associative Learning subtests to
20 clinically definite, chronic-progressive MS subjects
(McDonald criteria). T1 and T2-weighted, spin-echo coronal
and saggital MRI scans were scored for "extensive lesions in

the frontal white matter:" thinning and lining of the corpus

86

collosum: and uni- and bi-lateral involvement of the
cingulate gyrus, temporal horns, and "mediotemporal (lobe)
regions". A cluster analysis of combined scores on the WMS
Logical Memory and Paired Associates subtests was performed
to place subjects in severely-, moderately-, or un-impaired
groups. Analyses determined that lateralized plaque in the
medial temporal lobes predicted membership into the memory
functioning groups. Bilateral lesions were associated with
severe impairment and unilateral plaque with moderate
deficits. No pathology was seen in either temporal lobe in
the unimpaired group. Demyelination in other sites did not
differentiate the memory functioning groups. The authors
offered demyelination of hippocampal pathways as the most
likely cause of the observed memory deficits.

The reliability of these provocative findings is
decreased by small sample size and gross quantification of
MRI data. Most problematic, however, is the authors'
inferences regarding localization. Exact lesion sites were
not described, so it is not certain that plague existed in
the hippocampus. Even if MRI confirmed that there were
lesions in hippocampal formations, one must respect Teuber's
(1959) warning of the necessity for double dissociation in
localizing functional deficits: "...double dissociation
requires that symptom A appear in lesions in one structure
but not with those in another, and that symptom B appear
with lesions of the other but not of the one. Whenever such
dissociation is lacking, specificity in the effects of the
lesion has not been demonstrated" (p. 187). In this case,
Brainin et al. have fulfilled only the first half of

Teuber's first statement and this only partially: symptom A

87

(memory deficit) appears in one structure (hippocampus).
The authors do not provide data that memory deficits appear
with lesions in other areas or that lesions in the
hippocampus produced deficits in other functions.

The perils of failure to doubly dissociate also are
exemplified by another finding of the Brainin et al. study.
They reported that four of the five "unilateral" medial
temporal lobe subjects had their lesions in the right rather
than the left hemisphere despite suffering moderate

impairments on verbally-mediated memory measures. Brainin

 

et al. note that unidentified lesions in the 12;; thalamus
may be responsible for the apparently incongruent laterality
of the lesion -- nicely exemplifying the need for Teuber's
caution.

The authors' use of only two verbal subtests from the
WMS as the only estimate of memory functioning also is
highly questionable. Concluding that a person has severe
memory impairments requires more extensive and specific
testing (i.e., nonverbal memory), especially since Brainin
et al. draw parallels to medial temporal lobe amnesia.
Despite the unreliability of their specific findings and
conclusions, Brainin et al.'s study deserves praise on other
points. MRI scores were theoretically and functionally
driven and their results spark interest in examining
temporal lobe plaque involvement in memory functioning.

The third and fourth studies to be reviewed, Litvan et
al. (1988a) and (1988b), concluded that MRI measures were
insensitive to cognitive deficits. Small sample size
seriously limits the reliability of their results and other

measurement issues also may have contributed to negative

88

findings. In the first study (1988a), 16 clinically-
definite MS patients (Poser criteria) were administered the
WMS battery (with 30 minute delayed recall of the Logical
Memory and Paired Associates subtests), a verbal list
learning test (Rey AVLT), and measures of verbal (Paced
Auditory Serial Additions Task and a variation of the
Sternberg Memory Scanning Paradigm) and motor processing
speed (Purdue Pegboard). The authors did not describe MRI
procedures except to report that films were "of variable
quality," and that they were scored for the total number of
lesions and the "degree of PV involvement." Spearman
correlations were insignificant between these two measures
of demyelination and any of the WMS or processing speed
tests.

Very small sample size leaves their study open to
serious sampling error and the inadequate description of
their MRI protocol prevents reproduction. Some conclusions
may be drawn if applied with caution. One is that a simple
count of plaque may be an insensitive index of lesion
burden: it does not consider plaque location or size. Their
study also furthers questions as to whether MRI-observed PV
involvement alone is sufficent to discriminate memory
deficits (e.g., Huber et al., 1987: Medaer et al., 1987).
On a more positive note, the use of the WMS and a verbal
list learning task are an improvement over previous studies
in that there was a much greater sampling of memory
processes. Unfortunately, the WMS has a number of
shortcomings (for review see Herman, 1988: see also Erickson
and Scott, 1977, and Prigatano, 1978).

The second Litvan et al. (1988b) investigation reported

89

slightly different analyses of MRI-imaged plaque and
cognition with the same sample used in the first study. In
addition to the WMS and Rey AVLT, subjects were administered
modified Brown-Peterson tasks to evaluate Baddeley's working
memory verbal articulatory loop. MRI procedures were
described in this article and may be the same ones used in
the previous publication. Six axial, T2-weighted slices
were scored for the number and location of lesions.

Subjects were placed in one of three groups according to the
following schema: 1) "plaques formed PV lines or nodules"
2) the "configuration of plaques was in bands in both horns
of the lateral ventricles" and 3) "PV bands surrounded the
ventricles".

No significant relationships were found between the
cognitive measures and either MRI index -- plaque number or
lesion grades. These findings contribute to previous
evidence that PV ratings (Huber et al., 1987: Medaer et al.,
1987) and a simple numerical count of lesions (Huber et al.,
1987) are not predictive of memory functioning. Litvan et
al. (1988b) acknowledge the probable insensitivity of their
MRI measures, stating that: "...the level of analysis may
have been too gross...", (p. 610). As with its predecessor,
the inferences drawn from the second study are unreliable
because of small sample size.

Franklin et al. (1988) produced the most
methodologically-sound investigation to date, which, not
incidently, demonstrated the strongest relationships
between MRI-imaged plaque and cognitive dysfunction yet
reported. Sixty clinically-definite, chronic-progressive

(Schumacher criteria) MS patients were administered a

9O

cognitive test battery designed by the authors. The
subtests of this Neuropsychological Screening Battery (NSB)
were duplicate or abbreviated forms of well-known
neuropsychological measures. The NSB samples aspects of
visual attention: verbal and visual learning with delayed
recall: visual perception and construction: and a variety of
language capacities. The battery also included two tests
previously identified as especially sensitive to cognitive
impairment across several functions (i.e. Symbol-Digit
Modalities and Trails A & B). Two summary indices were
derived from this battery: a Total score using all tests and
a Pure (cognitive) score which excluded tasks requiring
intact motor functioning (e.g., visuo-spatial construction).
Each patient's T2-weighted, multi-echo, axial and coronal
slice MRI images were scored for bi-, uni- and quad-
hemispheric cerebral locations and weighted lesion size.

Their results clearly indicate that MRI-observed plaque
can account for variations in cognitive functioning,
including memory. For example, the bi-hemispheric lesion
score correlated significantly with both the Total and Pure
cognitive scores (r = .46 and .35 respectively) and every
memory subtest except the nonverbal learning test. The
authors also reported that the bi-, right-, and left-
hemisphere lesion scores accurately predicted those subjects
with unimpaired versus impaired performance on the Pure
(cognitive) subtests.

The authors offer a number of explanations for the
success of their study, especially in comparison to previous
efforts. One factor cited was that the localization formula

limited scoring of pathology to those areas thought to be

91

most directly related to cognitive and memory processing
(i.e., the cerebrum) while specifically excluding plaque in
structures thought to be relatively less pertinent to intact
cognition (i.e., the brainstem and cerebellum). Franklin et
al. also note that their MRI scoring formula provided
estimates of pgpg the number and size of plaque. In
contrast to previous investigations, Franlin et al. employed
a relatively large and homogeneous subject population (with
respect to course) and more fully measured a range of
cognitive capacities. The latter two points warrant further
consideration.

Franklin et al.'s (1988) study suggests that cerebral
lesion area is more sensitive to cognitive disturbance than
other lesion burden measures, including PV and total brain
involvement, total number of lesions, ventricle hypertrophy,
cerebral atrophy, peripheral and confluent lesions, and
frontal white-matter involvement. Direct comparison of
these MRI measures on the same sample could provide
substantial evidence that cerebral lesion area best
documents the plaque burden responsible for cognitive
dysfunction.

Despite Franklin et al.'s success, it should be noted
that only 12% of memory functioning variance was accounted
for by cerebral lesion area. This relatively small
relationship probably reflects previously described factors
that are thought to reduce associations between MRI-observed
pathology and dysfunction (e.g., histological-level
processes). Another factor that may have reduced the
strength their lesion - memory correlations involves the

extent of measurement. Franklin et al.'s battery is

92

admirable in its breadth, lacking only a verbally-mediated
PM task and verbal and nonverbal recognition format tests
for what many would deem to be complete coverage of memory
functioning. However, the NSB is relatively light in the
depth of its coverage as reflected by its 30 to 45 minute
total administration time. Thus, a more detailed battery of
memory tasks may obtain even stronger correlations between
MRI-observed plaque and memory dyfunction.

Callanan et al. (1989) is the most current publication
on MRI-observed plaque and cognitive functioning. As a
substudy of Ormerod et al.'s (1987) project, the authors
compared the cognitive functioning of 48 patients with
clinically isolated lesions typically associated with
initial-stage MS (e.g., neuritis of the optic nerves,
brainstem, and cervical spine). Due to the difficulties
inherent in scanning these areas, a very complex imaging
procedure was used (see Ormerod et al., 1987). MRI films
were scored for a frontal index (lesions in the frontal lobe
and frontal horns of the lateral ventricles), a temporal
score (temporal and parietal lobes and temporal horns of the
lateral ventricles), and periventricular score (all
ventricle regions). A total brain rating (cerebrum,
cerebellum, optic nerves, brainstem, and cervical cord) as
well as subdivisions of the telencephalon (i.e., internal
capsule and basal ganglia) also were compiled.

Memory was evaluated with an auditory and a visual
cancellation task and verbal (word) and visual (faces)
recognition memory tests. Other cognitive abilites were
measured with the National Adult Reading Test, the WAIS, the

Wisconsin Card Sort Test, and an object naming task. Seven

93

function areas were derived from these tests and each
subject received a grade within each and then across all
function areas (summed score) based on the following
criteria:

G0 = score > 50th percentile of control group scores

G1 = 50th 3 score 2 25th control percentile
G2 = 25th 2 score 5th control percentile
G3 = score < 5th percentile of control group scores

In general, the observed correlations were weak and did
not support many of the hypothesized lesion - function
relationships. For example, although the total brain lesion
score did differentiate the most and least cognitively
impaired subjects (G0 versus G3), it did not appear to
distinguish the other impairment groups. In regards to
separate tests, the total brain lesion score correlated
significantly only with the auditory PM measure and the
Wisconsin Card Sort Test. Finally, none of the other lesion
areas (e.g., frontal score) were found to be meaningfully
associated with any of the memory or other cognitive
measures.

Callanan et al.'s inconsistent results may be
explained, in part, by the type of sample used. Subjects
were not definite MS cases, but were people most likely
to be determined to have MS ip the near future. Most
diagnostic criteria require bouts separated by at least six
months before they are considered to have clinically-
definite MS. Callanan's subjects had had only one episode.
Thus, while many will be diagnosed as definite cases, the
sample probably included cases who do not have MS. These

cases aside, it also is not clear what differences exist

94

between early-stage MS patients and those with clinically-
definite MS. One cannot assume that the types of lesions or
dysfunctions are comparable. Another factor that may have
reduced the strength of memory - lesion correlations is the
type and extent of memory testing. MS patients would be
least likely to show performance decrements on recognition

memory tests and PM tasks.

Summary and Rationale

Investigations of MRI-observed lesion burden and memory
only recently have begun and early results are
disappointing. However, several methodological issues make
it difficult to draw reliable conclusions about the strength
or quality of memory - lesion associations. Where at least
some of these issues have been addressed, significant
correlations were observed between memory functioning and
lesion burden (e.g., Brainin et al., 1988: Franklin et al.,
1988).

Small sample size has plagued many investigations,
severely limiting the power of their analyses (Brainin et
al., 1988: Huber et al., 1987: Litvan et al., 1988a: Litvan
et al., 1988b: Medaer et al., 1987). Inadequate measurement
of memory functioning has been another problem. Memory
tests were not matched appropriately with plaque measures
(e.g., Brainin et al., 1989), were questionably normed or
designed (e.g., Huber et al., 1987), or simply were
insufficient to allow reliable conclusions (e.g., Callanan
et al., 1988). Preliminary evidence suggests that sampling
from a wide range of PM and SM functions would increase the

probability of detecting subject differences and maximize

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correlations with lesion burden.

Difficulties with lesion scoring systems also have
hampered attempts to describe pathoanatomical predictors of
memory disturbance. MRI measures have been poorly described
(e.g., Litvan et al., 1988a) and overly gross (e.g., Litvan
et al., 1988b), derived to ease scoring, or discriminate
patients on the basis of anatomy without considering
function (e.g., Medaer et al., 1987). A simple count of the
number of lesions may be insensitive to changes in memory
(e.g., Litvan et al. (1988a), especially in comparison to
measures of lesion area (e.g., Huber et al., 1987).

It is unclear whether localizing the plaque appreciably
adds to the predictive accuracy of lesion burden measures on
memory changes, in part, because development of localization
criteria has been difficult. One issue is that memory is
not particularly localized. Rather, intact memory depends
on a combination of anatomical systems, and poor memory test
performance may result from one of several types of
dysfunctions that, in turn, may be subserved by various
neural networks. Several anatomic regions have been
identified as especially important to memory functioning,
but application to MS is limited. Sclerotic plaque does not
occur in these areas with sufficient frequency to explain
most memory impairments (e.g., Callanan et al., 1989:
Maravilla, 1988). Thus, although a few cases of memory
deficits may be explained by plaque in strategically
important areas -- as Brainin et al. (1988) may have
illuminated -- one may conclude that the majority are not.
Another problem is that the severity and types of memory

impairments seen in MS are not very similar to those seen in

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other memory syndromes. For example, the devastated
antereograde and more moderately impaired retrograde SM
functions seen in the diencephalic and medial temporal lobe
amnesia are not seen frequently in MS (e.g., Rao, et al.,
1989).

In the absence of better guides to determining
localization criteria, it may be useful first to identify
which regions may be excluded from MRI scoring systems.
Inclusion of irrelevant anatomic regions in estimates of
lesion burden may have contributed to the weak associations
between MRI-imaged plaque and memory functioning in previous
studies. Infratentorial structures warrant attention as
exclusion candidate. This hypothesis is based on a best
guess that the memory deficits seen in MS are produced by
accumulated disruptions in the lines of communication
between the various cortical and subcortical structures
responsible for encoding, consolidation, storage, and
retrieval. Since the primary inter-region communication
networks in the brain are the subcortical white-matter
tracts and because most MS lesions are also found there, one
may hypothesize that the lesions most responsible for memory
impairment are located in the cerebrum. Conversely, most
would agree that the spinal cord, brainstem, cerebellum, and
midbrain are not as involved with memory processes as the
cerebrum (e.g., Carlson, 1983). This is not to say that
lesions below the tentorium may not contribute to memory
deficits. For example, the reticular formation subserves
wakefullness and lesions there may disturb PM and, thereby,
encoding of information for storage and recall. Rather, it

is believed that measurement of only those regions most

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directly involved with memory will produce the most
sensitive predictors of dysfunction. Preliminary data
support this hypothesis. Studies using an MRI index that
included scoring of infratentoral lesions tended to observed
weak associations between that score and memory (Callanan et
al., 1989: Litvan et al., 1988a: Litvan, et al., 1988b).
Conversely, those that excluded the spine, brainstem, and
cerebellum from their MRI protocols reported more
significant findings (i.e., Brainin et al., 1988: Franklin
et al., 1988). If the hypothesis that infratentorial
lesions contribute relatively little to the prediction of
memory, then one should see stronger correlations with
cerebral indices than with measures of whole—brain lesion
burden.

Several studies reported using MRI measures that
included scoring of anatomical regions not usually
considered as important to memory and, therefore, are
exclusion candidates (i.e., periventricular and corpus
collosal involvement). MRI evidence suggests that measures
of these areas are not sensitive to cognitive deficit and
any relationship is thought to be due to their
representational nature. That is, prediction of dysfunction
from such "representational" indices occurs because the
pathology measure is reflective of the lesion actually
responsible for the disturbance. Because data pertaining
specifically to memory are sparse, it would be useful to
compare CC and PV involvement and a direct measure of
cerebral lesion in their relationship to memory functioning.

Periventricular involvement as a predictor of cognitive

impairment has not been supported across a wide range of

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criteria: percentage of lateral ventricle encasement or
ventricle hypertrophy (Huber et al., 1987): small, broad,
and/or confluent PV lesions (Medaer et al., 1987): degree of
PV involvement (Litvan et al., 1988a): and periventricular
lines/nodules, encasement of both lateral ventricle horns,
and complete encasement of the lateral ventricles (Litvan et
al., 1988b). Outright rejection of possible associations
between PV and memory changes must be withheld until several
issues are addressed. The most critical problem is that
memory functioning was not the primary focus in these
studies. Small sample size and unclear MRI parameters also
make it difficult to determine whether the localization
criteria (periventricular involvement) alone resulted in the
negative findings.

Outside the MRI literature, there is little evidence,
either positive or negative, that the white-matter tracts
surrounding the ventricles support memory. An exception is
that of Rao and his co-authors (1984, 1985), who have
suggested that the periventricular prefrontal-limbic
pathways serve some memory functions. This hypothesis was
inferred from their work with CT wherein various PV indices
(e.g., degree of hypertrophy) were found to be correlated
with several types of cognitive defict, including memory
(Rao et al., 1984). However, Rao et al. (1985) also note
the possibility that PV hypertrophy predicts dysfunction
merely because it reflects the degree of pathology elsewhere
(i.e., a representational measure). As noted previously,
representational measures may not be as sensitive to
dysfunction as are more direct ones. For example, ratings

of parynchemal atrophy failed to discriminate three levels

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of dementia (Huber et al., 1987), whereas Franklin et al.'s
(1989) gradings of total cerebral lesion area were
significantly correlated with several cognitive tests.
However, evidence specific to memory has not been reported
as to whether direct measures are superior to
representational ones. Given the fairly consistent findings
with MRI, it is hypothesized that a direct measure of
cerebral lesion will better predict memory test performance
than will indices of PV plaque.

Corpus collosal involvement also has been proposed to
be a correlate of cognitive changes in MS. Huber et al.'s
(1987) MRI measure predicted membership to severely-,
moderately-, and minimally-impaired dementia groups.
However, memory deficit measurement was limited to the WMS
Digit Span Forward and Paired-Associative Learning subtests
and group differences on these tests were not given. Thus,
this study cannot speak to the predictive strength of corpus
collosal involvement to memory functioning per se. An
autopsy study of MS also revealed a significant relationship
between CC atrophy and previous history of dementia (Barnard
& Triggs, 1974), but these results also were not specific
to memory. Given that investigations of the corpus collosum
assign little direct role to it in memory processing (e.g.,
Lesak, 1983), Huber et al. (1987) concluded that corpus
collosal involvement is merely a general indicator of the
degree of pathology in other areas of the brain -- exactly
paralleling earlier hypotheses with PV involvement. The
existing data on the corpus collosal plaque suggest that, at
best, it serves as a rough gauge of the degree of lesion

thoughout the brain. It is believed that a direct indicator

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of lesion burden (i.e., cerebral lesion area) will account
for more individual variation in memory functioning than
will representational measures such as those derived from
the corpus collosum.

A final way this study will attempt to improve
localization criteria involves the possibility that lesion
lateralization may predict modality-specific memory
deficits. Brainin et al. (1988) reported a significant
correlations between MRI indices of bi- and uni-lateral
medial temporal lobe regions and combined scores on a
paragraph recall and a paired associative learning test.
Bilateral involvement predicted severely-impaired
performance, lateralized plaque was associated with
moderately-deficient test scores, and normal-range
performance was observed in patients free of medial temporal
lobe involvement. Their results were deemed unreliable for
several reasons, but especially because of small sample
size, the reliance on only two verbal memory measures, and
questionable localization inferences (i.e., five out of six
of the moderately impaired patients reportedly had right-
sided lesion even though memory measures were verbally-
mediated). Franklin et al. (1988) observed significant
correlations between uni-lateral cerebral lesion area and
several measures of verbal and nonverbal, primary and
secondary memory. Unfortunately, specific data pertaining
to potential modality and localization differences were not
reported. No other study has examined the relationship
between uni-hemisphere plaque distributions and verbal and
nonverbal memory. This neglect may reflect the fact that MS

lesion is usually bilaterally distributed (e.g., Lumsden,

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1970). The lack of notable left- and right-sided lesion
differences hampers any lateralized predictions because of
restriction of range. Nevertheless, limited successes by
Franklin et al. and Brainin et al. argue that the topic
deserves further attention. Given the copious amount of
data on hemispheric asymmetry of function (e.g., Springer &
Deutsch, 1985) it is easy to assign the directionality of
predictions. That is, non-verbal memory performance should
correlate more highly with a right- versus a left-
hemisphere lesion score.

The material just presented discusses MRI scoring
factors that are hypothesized to maximize predictions of
individual variation in memory functioning. Similar
discussion is necessary when considering how memory should
be evaluated for such investigations. Few guidelines are
available from existing research because most studies have
sampled memory only as a subset of several cognitive
processes (e.g., Callanan et al., 1989). However, memory
test selection has been treated in rather cavalier fashion
even in investigations that purportedly focus on memory.
One need only return to Brainin et al.'s (1987) attempt to
discern the role of medial temporal lobe involvement--while
using only digit span and paragraph recall tests--to
illustrate this point. Common sense dictates that
successful assessment of brain - behavior relationships
requires a comprehensive evaluation of memory functioning,
including measures of verbal and nonverbal PM and SM.

A subsequent question concerns the way in which test
scores should be compared with lesion burden indices.

Because some of the MRI measures to be used are global with

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respect to localization, it may be useful to compare them
with a summary memory score that reflects the total degree
of impairment across functions. A score such as the WMS
Memory Quotient does not adequately account for orthogonal
functions. The index employed by Franklin et al. (1988),
however, appears to be sufficently comprehensive, while
minimizing sacrifices in specificity. The authors used cut-
off scores for each cognitive test within their battery.
Test performance below one standard deviation was assigned a
"+1", those below two standard deviations a "+2", and the
resulting sum was correlated with MRI scores. A similar
system easily could be developed for memory factors, with
cut-off scores for verbal and nonverbal attention span,
paired associative and list learning, recognition, and
immediate and delayed recall tests.

More specific measures of memory also will be used to
explore the possibility that MRI lesion burden will better
predict SM than PM functioning. Although no MRI studies
have specifically tested this hypothesis, converging lines
of evidence support the proposition. The first
conceptualization stems from the observation that previous
studies' failure to demonstrate significant lesion - memory
relationships may have been due to the fact that memory
functioning appeared intact (e.g., Callanan et al., 1989).
It may be that lesion burden is most predictive at the most
deficient range of functioning. Since most evidence
suggests that SM processes, in comparison to PM, are more
likely to be impaired, it is predicted that MRI scores will
correlate more highly with tests of SM (e.g., delayed
recall) than of PM (e.g., digit span).

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The second source of deductions also depend on the
assumption that SM is more susceptible to impairment than
PM. That is, as memory task complexity increases from PM to
SM processing, both the prevalence and severity of
impairments may increase. At least some of the factors
responsible for this relationship may be associated with
MRI-observed lesion burden. For example, since more
neuronal networks may be tapped with SM than with PM
processing tasks, increasing amounts of plaque would be more
likely to interfere with SM than PM functioning. Therefore,
it is predicted that MRI scores will be correlated more
highly on tests with more demands on the SM than PM systems.

The last group of hypotheses is drawn from Sheldon et
al.'s (1985) analysis of concordance rates in correlating
sensory and motor symptoms with MRI-observed pathology.
Recall that they found that, while a proponderance of
subjects with localizable symptoms (e.g., gait disturbance)
had lesions in the predicted area (e.g., cerebellum) the
reverse relationship was significantly weaker. For example,
a majority of subjects with lesions in the posterior fossa
did 22; present with measurable symptoms. Those patients
with clinically significant changes in function, however,
were very likely to have plaque in the predicted area. The
authors ascribed these findings to aspects previously
identified as possibly mediating the strength of lesion -
symptom associations. These include but are not limited to
"internal" factors such as: remyelination, the extent of
gliosal changes, the centrifugal pattern of lesion growth,
and the relative importance of the structure to the

function. For example, the deleterious effects to vision of

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a lesion in the optic nerve may be proportionately more
significant than that of plaque in the visual association
cortex. "External" factors may include body temperature,
exercise, and emotional and physical stressors. Comparison
of figures such as obtained by Sheldon et al. (1985) may be
conceptualized as a rough estimate of the proportion of
variance accounted for by these factors.

Despite the potential usefulness of comparing
concordance rates, they have not been obtained with memory
or any other cognitive function. Predictions specific to
memory are inferred directly from Sheldon et al.'s (1985)
pattern of findings. Subjects with significant memory
impairments are predicted to have an increased cerebral
lesion burden, but not all subjects with significant lesion
burden will have notable memory deficits. It is also
predicted that this relationship will hold across separate

memory functions and lesion burden scores.

METHOD

This investigation is part of a larger research
project: therefore, only the methodology relevent to this
particular study will be discussed.

Subjects

Forty-one subjects were recruited through MS support
groups located near a small Midwestern city. Support groups
were contacted and asked to distribute flyers describing the
project and to schedule a guest speaker at an upcoming
meeting of the group. The speaker explained the nature of
the study, asked attendees to participate as subjects, and
answered any resulting questions. Those indicating interest
received follow-up phone calls to schedule a testing
session.

Referrals also were taken from private neurologists:
local neurologists were informed of the aims and referral
needs of the study. These subjects also received a full
description of the project before agreeing to participate.

Diagnostic criteria were based on Poser, Paty,
Scheinberg, et al.'s (1984) research guidelines. Only
subjects with clinically-definite MS were included.
Otherwise, inclusion in the study was by means of
consecutive referrals.

Procedure

Two subjects were scheduled per day. Half the subjects
were assigned randomly to begin with speech and language
testing, the other half started with the other cognitive

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measures. These conditions were reversed after an hour
break for lunch. MRI's were obtained at the Michigan State
University Clinical Center following completion of
neuropsychological testing. Medical histories were taken
after the MRI.

Sessions lasted approximately eight hours, including
two regularly scheduled lO-minute breaks and an hour for
lunch. Additional breaks were taken if requested by the
subject. Because of access to only one imager, one subject
waited approximately 60 minutes before beginning the MRI.

Upon the completion of the testing, subjects were
debriefed, thanked for their participation, and informed
that they would receive personal feedback of their results
when data gathering for the entire project was completed.
Additional questions were handled by the interviewers.

The neuropsychological testing was administered either
by a professor or one of two graduate students in clinical
psychology. All had previous training and experience with
the respective assessment procedures.

Tests and Measures

Magnetic Resonance Imaging (MRI) - The MRI examinations
were performed on a 1.5 Telsa General Electric Signa System.
Three series of sequences were obtained per subject. For
each series, the acquisition matrix was 256 x 128 with a
nexus of 2, while the section thickness was 5 mm and the
distance between slices was 2.5 mm. The first series
obtained was Tl—weighted sagittal-plane images with a TR of
500 ms, and TE of 25 ms taken at the midline and 30 mm left
and right of this position. Sagittal SE sequences with a TR
of 2500 ms and TE's of 30, 60, 90, and 120 ms comprised the

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second series. Finally, T2-weighted, axial SE sequences
with a TR of 2500 ms and TE's of 30, 60, 90, and 120 ms and
compensated for flow effects were obtained.

Signa Cursor - The cursor and accompanying soft-ware
package were developed and sold by Signa. The cursor is a
pen-shaped device with a sensor in its tip that was
developed to aid objective measurement of X-ray film. When
the tip of cursor is drawn around the contour of an image
(e.g., corpus collosum), the visual signal is relayed to the
computer that translates the data into an estimate of the
total area.

Three judges, who were blind to the results of the
neuropsychological tests, scored MRI films according to the
following protocol. All lesion burden indices were derived
from the T2 - weighted axial plane films, with the
exception of the corpus collosum measures. Plaque were
scored for size and location. Lesion size was measured as
its total area in square millimeters. Lesion area was
estimated by multiplying the lesions greatest diameter by
its heighth at the greatest diameter perpendicular to the
first diameter. Because analyses were based on total area
rather than the number of lesions, no attempt was made to
differentiate areas of lesion confluence (i.e., multiple
lesions in close proximity to each other) from single, large
lesion areas with diffuse signal intensity. Lesions were
scored for several locations: medulla, pons, midbrain,
cerebellum, basal ganglia, internal capusule, thalamus,
internal capsule, and the lobes of the cerebrum. Eight

lesion lesion burden indices were developed:

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1. Total Lesion Area (Brain) - all plaque summed
across all slices.

2. Cerebral Lesion Area (Cerebral): all cerebral
plaque

3. Left-Hemisphere Cerebral Lesion Area (Left) - all
left hemisphere cerebral plaque

4. Right-Hemisphere Cerebral Lesion Area (Right) -
all right-hemisphere cerebral plaque

5. Periventricular Involvement (PVinvolve) -
subjective ratings of total plaque area in the PV
regions, ordinally-scaled from one (representing
no involvement) to five (total encasement of the
ventricles by plaque).

6. Periventricular Confluence (PVconflu) - subjective
ratings of the degree of PV confluence, ordinally
scaled from one (representing no confluence) to
three (greatest degree of confluence)

7. Corpus Collosum Lesion Area (CCarea) — all plaque
found in the CC

8. Corpus Collosum Atrophy (CCatrophy) - total area

of the corpus collosum

The following procedure was used to derive the lesion
burden indices. The lesion area for each location was
summed across all slices for each judge. This total was
summed across the three judges and divided by three to
provide the average lesion area. Lesion burden indices were
then computed by summing the average lesion area across
relevant locations. For example, the cerebral lesion area
index (Cerebral) was the sum of the average lesion areas of

the frontal, parietal, temporal, occipital lobes, and the

109
basal ganglia.

The PV ratings were summed across judges and divided by
three to produce an average rating. The average rating was
used in the analyses.

The corpus collosal scores were derived from the T2
weighted sagittal sequences. The corpus collosal lesion
area score (CClesion) for each patient was computed by
summing total lesion area across the three slices. The
total was summed across the three judges and divided by
three. The corpus collosal atrophy score (CCatrophy) was
obtained via cursor measurement of the midline slice. To
aid comparability with the other lesion measures, the
direction of corpus collosal atrophy score was reversed
(from a positive to a negative value) in the correlational
analyses.

Inter-rater reliability coefficients are reported in
Appendix A. One judge's measurements and ratings were
significantly different from those of the other two judges.
The disparity was sufficiently large to seriously affect the
reliability of the measures. Because it was believed that
the discrepancy was not due to the measurement procedures
used, a decision was made to remove all scores and ratings
of the outlying judge. All data reported below are based on

only the two remaining judges.

Wechsler Memory Scale - Revised (WMS-R) (Wechsler,
1988) is an individually administered, clinically-oriented
measure of memory functioning. Thirteen subtests tap
various aspects of episodic primary and secondary memory,
including temporal gradients (recall or recognition within a

few seconds or delayed approximately 30 minutes after

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initial presentation) and input-modality (verbal versus
visually—mediated material). Subtests also differ on
output-modality (oral, drawing, and pointing to desired
responses) and the type and extent of support provided to
the subject in retrieving information. The latter helps
identify what, if any, material is stored and includes
extensive cuing (recognition format), partial cuing (paired-
associative learning paradigm), and no aid (pure recall)
conditions to the subject. The following is a list of the
names and a brief description of each subtest:

1. Information and Orientation - The subtest has
sixteen questions of biographical data (e.g., subject's
mother's first name): orientation (e.g., time and and date):
and information that may help with interpreting the
remaining test data (e.g., handedness and color-blindness).

2. Mental Control - This subtest consists of three
exercises: counting backwards from 20 to one by ones,
reciting the alphabet, and counting forward by three's.

3. Figural Memory - Sets of abstract designs are
presented to the subject. Upon removal, the subject is
asked to point out the designs from sets of distractor
stimuli.

4. Logical Memory I - subjects are read two brief
stories and asked to repeat them immediately after each
presentation.

5. Visual Paired Associates I - six colored squares
are paired with six abstract line drawings and these six
sets of these stimuli are presented to subjects one at a
time. Each line drawing is immediately re-presented to the

subject, who is asked to point to the correct color from a

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board showing all six colors. The task is repeated until
one of two criteria is reached: perfect performance or six
failed trials.

6. Verbal Paired Associates I - eight pairs of words
are presented one pair at a time. The initial word of each
pair is then re-presented and the subject is asked to recall
its pair. Four pairs are deemed "easy" owing to the clear
semantic association between words (e.g., fruit - apple) and
the remaining four pairs are deemed "hard" (e.g., crush -
dark). As with the Visual Paired Associates, the task is
repeated until either perfect performance or six trials and
only the first three trials are scored. Summary scores are
also computed for performance on "hard" versus "easy" items.

7. Visual Reproduction I - subjects are shown a simple
geometric design for 10 seconds. Upon its removal, subjects
are asked to draw the figure from memory. There are four
items.

8. Digit Span - subjects must repeat several series of
digits until two trials of the same length are failed. This
task is done both with a forward and reverse condition.

9. Visual Memory Span — subjects must tap series of
squares in the same and reverse order of that presented by
the examiner. For each condition, the number of squares to
be tapped increases until the subject fails two consecutive
series of identical length.

10. Logical Memory II - approximately 30 minutes after
the original subtest, the subject is asked to repeat as much
of each story as possible. If the subject cannot recall
even one aspect of a story, the examiner can privde a brief,

standarized cue.

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11. Visual Paired Associates II - subjects are re-
presented each line drawing and asked to point to the
correct associated color.

12. Verbal Paired Associates II - subjects are re-
presented each initial word and asked to recall its matched
word.

13. Visual Reproduction II - subjects are asked to

draw from memory each of the four geometric designs.

The scale provides normative and reliability data for
five composite indices: General Memory, Verbal Memory,
Visual Memory, Attention/Concentration, and Delayed Recall.
For each index, relevant subtest scores are weighted and
summed to be presented as a normalized standard scores with
a mean of 100 and standard deviation of 15. The indices are
not independent because some subtests are used in more than
one index. For example, the General Memory Index is a
composite of the Verbal and Visual Memory Indices.
Percentile norms are provided for some subtests (Digit Span
and Visual Memory Span forward and backward: immediate and
delayed recall conditions of Logical Memory and Visual
Reproduction). Reliability and validity data may be found

in the manual.

California Verbal Learning Test (CVLT) (Delis, Kramer,

 

Kaplan, & Ober, 1983) - the CVLT is an individually-
administered measure of verbal learning and memory.
Subjects are asked to recall a list of 16 words, four words
from each of four semantic groups (clothing, spices, tools,
and fruits) for five trials. The entire list is re-

presented to the subject after each of the first four

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trials. This is immediately followed by the presentation
and recall of an interference list of 16 words (Trial B),
also consisting of four words for each of four semantic
categories. Subjects then are asked to recall the original
16 words (short delay free recall): and again when cued by
having the four semantic categories provided to them (long-
delay cued recall). Following a delay period, there is
another free (long-delay free recall) and cued (long-delay
cued recall) recall of the original list. Finally, subjects
must recognize the original words from 28 distractor items.
Five types of possible distractors are used: similarity to
actual test items 1) semantically and 2) phonemically: words
from the second list that are semantically 3) similar and 4)
dissimilar to the original items: and 5) a set of words that
has no objective similarity to any previous test items.

The CVLT manual provides normative, reliability, and
validity data for numerous measures of primary and secondary
verbal memory.

A summary memory index was developed (Total Memory
Index - TMI) from the five WMS-R indices and six subtests
from the CVLT: Trial 1, Trial 5, Trial B, short- (SDFR) and
long-delay free recall (LDFR), and recognition memory hit
rate (Recog - total number of correct responses). A
subject's score on each of the five WMS-R and six CVLT
measures was compared to the normative sample mean score,
which is stratified by age and sex. Subject scores within
the normal range were assigned a "0": scores above or below
one standard deviation from the normative sample mean score
were assigned a "+1" or "—1", respectively: scores above or

below two standard deviations were assigned a "+2" or "-2",

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respectively. These scores were summed across subjects to

produce the TMI.
Hypotheses

1. It is hypothesized that the correlation between the

Total Memory Index and Cerebral Lesion Area score will be
significantly greater than that between the Total Memory
Index and each of the following MRI indices of pathology:

Total Lesion Area
- Corpus Collosal Lesion Area
- Corpus Collosal Atrophy

- Periventricular Involvement

PV Confluence

2. It is hypothesized that the Cerebral Lesion Area score,
in comparison to each of the other measures of lesion
burden, will be more significantly correlated to each of
five WMS-R memory indices:

1. Attention/Concentration Memory Index

2. Verbal Memory Index

3. Visual Memory Index

4. General Memory Index

5. Delayed Recall Memory Index

3. It is hypothesized that, in comparison to the Right
Hemisphere Lesion Area score, the Left Hemisphere Lesion
Area score will correlate more highly with the Verbal Memory
Index. Conversely, it is hypothesized that, in comparison
to the Left Hemisphere Lesion Area score, the Right
Hemisphere Lesion Area score will correlate more highly with

the Visual Memory Index.

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4. It is hypothesized that a significant memory deficit
will better predict a large lesion burden than the reverse.
This hypothesis will be operationalized as follows:
subjects' scores on the Total Memory Index, each of the five
WMS-R indices, and Cerebral Lesion Area will be split at the
median. A "high" (< 50th percentile) memory score reflects
significant memory impairment: a "low" (2 50th percentile)
memory score represents those who have relatively intact
memory. Membership in the "high" Cerebral Lesion Area group
indicates a large lesion burden and "low" Cerebral Lesion
Area reflects a low lesion burden. Specific hypotheses are
as follows:

a) the probability that a subject has a high TMI score
given a high Cerebral Lesion Area score will be
significantly lower than the probability that subject has a
high Cerebral Lesion Area score given a high TMI score.

b) the probability that a subject has a high WMS-R
Attention Memory Index score given a high Cerebral Lesion
Area score will be significantly lower than the probability
that a subject has a high Cerebral Lesion Area score given a
high WMS-R Attention Index score.

c) the probability that a subject has a high Verbal
Memory Index Score score given a high Cerebral Lesion Area
score will be significantly lower than the probability that
a subject has a high Cerebral Lesion Area score given a high
Verbal Memory Index score.

d) the probability that a subject has a high Visual
Memory Index score given a high Cerebral Lesion Area score
will be significantly lower than the probability that a

subject has a high Cerebral Lesion Area score given a high

116

Verbal Memory Index score.

e) the probability that a subject has a high General
Memory Index score given a high Cerebral Lesion Area score
will be significantly lower than the probability that a
subject has a high Cerebral Lesion Area score given a high
General Memory Index score.

f) the probability that a subject has a high Delayed
Memory Index score given a high Cerebral Lesion Area score
will be significantly lower than the probability that a
subject has a high Cerebral Lesion Area score given a high

Delayed Index Memory score.

RESULTS
A description of preliminary lesion and memory data

will be provided before reviewing the results of the major
analyses. Scores on the WMS-R and CVLT indicate the
presence of significant memory deficits across the sample.
At least some dysfunction has been hypothesized as necessary
for optimal prediction of memory functioning by MRI-observed
lesion. The MRI measures appear to be normally distributed
and are thought to be valid estimates of lesion burden and

its relationship to memory functioning.

Preliminary Analyses
Memory Test Performance

Table 1 shows descriptive statistics of the five WMS-R
indices and six CVLT measure used in subsequent analyses
involving MRI data. Sample score distributions satisfy all
assumptions for normality.

Patient mean scores on these measures were compared to
normative sample means as one method of estimating memory
dysfunction within the patient sample. Normative data were
drawn from the WMS-R and CVLT validation samples (complete
descriptions of the performance of normative samples can be
found in tests respective manuals). All WMS-R Index
normative sample means are 100. CVLT normative means were
derived from age- and sex-matched cohorts for each measure.
Because of how it was developed, the Total Memory Index
normal mean is zero. Because the large number of
comparisons increases the possibility of random positive

117

118

 

 

Table 1

I! . .1 . [E . I I I} 5

Measure M 512 Md Max Min
ma

Verb 94.62 15.89 97 125 58
Visual 102.15 17.12 103 138 63
General 95.59 14.57 97 124 68
Attention 95.95 15.22 96 127 64
Delayed 94.46 15.19 94 131 67
QYLI

Trial 1 7.05 1.70 7 11 3
Trial 5 13.00 2.26 14 16 8
Total 52.79 12.34 56 73 35
Trial B 6.82 2.05 7 13 4
SDFR 10.74 3.08 11 15 3
LDFR 11.15 2.97 11 16 4
Recog 14.56 1.64 15 16 9

 

1191;. N =39. M=mean; 5D=standard deviation; Md=median;
Max = maximum; Min = minimum. WMS-R = Wechsler Memory
Smle - Revised. WMS-R: Verbal = Verbal Memory Index; Visual
= Visual Memory Index; General = General Memory Index;
Attention = Attention/ Concentration Memory Index; Delayed =
Delayed Memory Index. CVLT = California Verbal Learning Test.
CVLT: Total = total number words trials 1-5; SDFR = Short-Delay
Free Recall Trial; IDFR = Long-Delay Free Recall Trial; Recog =
total number words correct on recognition trial.

119

findings, multivariate analyses of variance (MANOVA) first
were used on the five WMS-R indices and then the six CVLT
scores. A one-way univariate analysis of variance (ANOVA)
was performed on the TMI. As shown in Table 2, all three
analyses were significant, indicating that (a) some patient
mean scores were significantly below normative sample means,
(b) memory impairment exists within the patient sample, and
(c) further comparison of patient versus normative sample
performance was warranted.

Next, patient and normative sample mean scores for each
of the five WMS-R indices and CVLT measures were compared
with one-way univariate ANOVA's to identify specific areas
of deficient performance. As indicated in Table 3, patient
mean scores generally are lower than normative sample means,
although the difference reaches significance only with the
WMS-R Verbal and Delayed Memory Indices and the CVLT Trial 1
and Short-delay Free Recall measures. Trends in the
predicted direction also were observed with the WMS-R
General and Attention/Concentration Indices and the CVLT
Long-delay Free Recall and Recognition Hits measures.

Comparison of group means provides only some evidence
of memory deficit in the patient sample. Deficit prevalence
rates subsequently were obtained because previous
investigation suggests that analysis of mean scores, alone,
can result in under-identification of sample impairment.
Deficit prevalence rates were analyzed by calculating the
percentage of patients with deficient performance on memory
measures (operationalized as scores one standard deviation
below the normative sample stratified by age and sex) and

comparing this observed prevalence figure with that expected

120

Table 2

 

 

Multivariate Analysis of Variance

 

 

Source Hotellings ’I‘2 E if p
WMS-R .64 4.38 34 .003.
CVLT .87 3.96 32 .003'

 

Univariate Analysis of Variance

 

 

Patient Normal
M M E fit 12
TMI -4.69 0.0 13.69 38 .001'

 

Nate. N =39. TMI = Total Memory Index.

‘ all p-values are one-tailed.

121

Table 3

 

 

 

 

Patient Normal

Measure M M E p
M

Verb 94.62 100 4.48 .04
Visual 102.15 100 .62 NS
General 95.59 100 3.58 .07
Attention 95.95 100 2.76 .10
Delayed 94.46 100 5.19 .03
CELT

Trial 1 7.05 8.0 12.14 .01
Trial 5 13.00 13.0 0.00 NS
Total 52.79 56.0 2.63 NS
Trial B 6.82 7.0 0.30 NS
SDFR 10.74 12.0 6.51 .02
IDFR 11.15 12.0 3.17 .08
Recog 14.56 15.0 2.77 .10

 

1101;, N=39. All p—values are one-tailed.

122

in a normal distribution via a Z-score significance test.
The results provided in Table 4 strongly suggest that memory
impairment is widespread across the patient sample. The
prevalence of impaired performance on all scores and indices
is significantly higher than expected, with the exception of
the WMS-R Visual and General Memory Indices. Using CVLT
Trial 1 scores as an example, 24 patients (62% of the
sample) scored at least one standard deviation below the
normative sample mean for their age and sex. A normal
distribution would have resulted in a prevalence figure of
approximately 16%. The resulting Z-score (7.84) is
significant at p < .00001.

Overall, patient performance on the WMS-R and CVLT is
comparable to previous reports of memory dysfunction in MS
(e.g., Fischer, 1988) and is assumed to be valid for the
purposes of the study. One exception -- the apparent lack
of visual memory impairment -- requires additional comment.
At least some impairment is thought to be a necessary
precondition for maximizing prediction of memory functioning
by lesion burden measures. Because this condition is not
met, subsequent analyses involving visual memory will
receive special attention.

MRI Lesion Measures

 

Some lesion measure distributions were sufficiently
skewed that they violated the assumptions necessary for
parametric statistics. Using the Statistical Package for
the Social Sciences - Personal Computer (SSPS-PC) program
"Examine", two cases were determined to be responsible for
the majority of the distortion. When the two cases were

deleted, lesion score distributions fell within acceptable

123

Table 4

 

 

# below % below expected %

 

 

Measure 1 $12 1 SD below 1 512 Z
MB. .
Verbal 10 26 16 1.70
Visual 6 15 16 0.17
General 8 21 16 0.85
Attention 10 26 16 1.70'
Delayed 11 28 16 2.04'
Trial 1 24 62 16 7.84
Trial 5 18 46 16 5.11'"
Total 13 33 16 2.90"
Trial B 18 46 16 5.11'"
SDFR 2o 51 16 5.96'“
LDFR 19 48 16 5.45'"
Recog 16 41 16 4.26'"
Note. N =39.

' p<.05, one-tailed. " p<.01, one-tailed. p<.001, one-tailed.

124

limits for use of parametic statistics. Table 5 shows the
MRI score distributions with the adjusted sample (N = 39).

Next, Pearson-product moment correlations between each
of the MRI measures were compared to identify possible
relationships important to subsequent analyses involving
memory functioning. Table 6 shows that, with the exception
of the correlation between corpus collosal atrophy
(CCATROPHY) and corpus collosum lesion area (CCLESION), all
correlations are significant at p < .001 (two-tailed).
Relatively high lesion variable intercorrelations were
predicted as an estimate of measurement reliability and
validity. That is, if scoring procedures are reliable and
valid, one should have seen fairly strong correlations
between plaque measure. However, the extremely high
correlations observed in some cases warrant further
attention. Of particular interest are the correlations
between the whole brain (Brain), bi-hemisphere cerebral
(Cerebral), left-hemisphere cerebral (Left), and right-
hemisphere cerebral (Right) lesion area measures. The
almost perfect correlation between the Brain and Cerebrum
indices is due to the paucity of infratentorial lesion:
cerebellar and brain stem plaque was a small fraction (less
than five percent) of total lesion area within the brain.
This could reflect sampling error or poor visualization of
the infratentorium by the MRI. Because of the lack of
difference between the two measures, a decision was made to
drop the total brain score from future analyses.

Overall, preliminary analyses provide sufficient
evidence that the conditions necessary for valid examination

of proposed hypotheses are met. Variable distributions are

125

 

 

Table 5

Measure M SD Md Max Min
CClesion' 97 107 67 418 0
CCatrophy' 480 106 475 715 276
Brain 2585 1834 1826 6080 139
Cerebral' 2525 1791 1792 6066 139
Left‘ 1221 908 974 3363 74
Right' 1304 934 995 3086 61
PVinvolveb 2.4 1.3 2.0 5.0 1.0
PVconflu‘ 2.1 0.8 2.0 3.0 1.0

 

Nate, N=39. CClesion = corpus collosal lesion area. CCatrophy =
total corpus collosal area. Brain = brain lesion area. Cerebral =
cerebral lesion area. Left = left-hemisphere cerebral lesion area.
Right = right-hemisphere cerebral lesion area. PVinvolve =
periventricular involvement ratings. PVconflu = periventricular
confluence ratings.

' units are mmz. ” units are ordinally scaled, 1-5. ‘ units are
ordinally scaled, 1-3.

126

Table6
I . II I l.

 

CC PV PV
atrophy involve conflu Left Right Cerebral Brain

 

 

CClesion .40‘ .58 .49 .69 .77 .75 .75
CCatrophy .70 .65 .70 .53 .63 .63
PV‘mvolve s4 .85 so 35 as
PVconflu .75 .71 .75 .75
Left .89 .97 .97
Right .97 .97
Cerebral .99
Note. N =39.

' p<.01, two-tailed. All others p<.001, two-tailed.

127

within normal limits. Measures of lesion burden and memory
do not appear to be significantly different from previous
studies using similar methodology. We will turn now to the

analyses for the major hypotheses.

Primary Analyses

Hypothesis 1

The first prediction was that the correlation between
the TMI and cerebral lesion area would be greater than that
between the TMI and each of the other measures of lesion
burden. To test the hypothesis, the first step was to
obtain correlations between lesion variables and the TMI.
One-tailed significance levels were used since there was no
empirical or theoretical basis to suggest that memory
performance would improve with increased lesion loads.
Table 7 shows that only cerebral lesion area and ratings of
periventricular confluence were significantly correlated
with the TMI (p < .05, one-tailed). Next, a priori t-tests
for dependent correlations were used to contrast the
correlation between TMI and cerebral lesion area with the
correlation between TMI and the other lesion indices. The
results shown in Table 7 indicate that only the contrast
involving corpus collosal lesion area (CCLESION) was
significant and in the predicted direction [§(36) = 2.04, p
< .05, two-tailed).

Hypothesis g

 

The second prediction was that cerebral lesion area, in
comparison to the other lesion measures, would correlate
most highly with the five WMS-R indices. To test this

hypothesis, the same methodology was used as for Hypothesis

128

 

 

 

Table 7

-'.0!U'1-‘l ‘ -OI‘-_!0l .IJ 0.2. O'uos .H'." -0!!'<.!_01

. l C l l I . 5

Pearson Correlations
CC CC PV PV

Measure lesion atrophy involve conflu Cerebral
TMI -.08 ~20 -.24 -.36° -.30°
Mote, N =39.
' p< .05, one-tailed.

Cerebral Lesion Area vs. Other Lesion Measures:

 

 

Correlations with TMI '

Cerebral vs: difierence t y p
OClesion .22 2.04 36 .05
CCatrophy .10 .73 36 N S
PVinvolve .06 .69 36 NS
PVconflu -.06 -.54 36 NS

 

117.0152. N =39. All t-tests two-tailed.

129

#1 except that a more conservative critical value was used
to control for the larger number of correlations and
comparisons. The correlation matrix of lesion variables
with WMS-R is provided in Table 8. Only three correlations
were statistically significant: Visual Memory with cerebral

lesion area (r = -.50, p < .001, one-tailed), ratings of

periventricular involvement (r -.43, p < .01, one-tailed),

and corpus collosal atrophy (r - .53, p < .001, one-
tailed).

Despite the preponderance of insignificant
correlations, a decision was made to carry through with the
planned comparisons. T-tests for dependent correlations
with a critical value yielding rejection at the p = .01
level (two-tailed) were used to reduce the probability of a
Type I error. Although largely in the predicted direction,
cerebral lesion area appeared more strongly related to
memory functioning only in two instances: versus corpus
collosal lesion area on WMS-R Visual Memory Index [3(36) =
2.73, p < .01] and Delayed Recall [E(36) = 2.95, p < .01].

A similar method was used to investigate whether lesion
measure correlations with the CVLT were more in keeping with
predictions that cerebral lesion area would be more highly
correlated than the other lesion measures with memory
performance. Actual rejection of the null hypothesis (r =
.00) was made at p < .01 to control for the large number of
correlations. Again, one-tailed significance levels were
used since there was no empirical or theoretical basis to
suggest that memory would improve with increased lesion

loads. The correlation matrix of lesion and specific CVLT

measures is shown in Table 9. Generally, the pattern of

130

 

 

 

Table 8
I . II C 1° '1 EMISBI l°

CC CC PV PV
Measure lesion atrophy involve conflu Cerebral
EMS-B
Verbal .15 .10 .01 -.13 .01
Visual -.23 -.53" -.43' -.34 -.50”
General .07 -.15 -.18 -.24 -.18
Attention -.25 -.29 -.23 -.28 -.28
Delayed .08 -.08 -.26 -.20 -.27
N919, N=39.

' p<.01, one-tailed. " p<.001, one-tailed.

131

 

 

 

Table 9
I . 1 C1 II I I I C l .
CC CC PV PV

Measure lesion atrophy involve conflu Cerebral
CYLI

Trial 1 -.03 -.16 -.11 -.37° -.21
Trial 5 -.08 -.20 -.30 -.47° -.33
Total -.01 -.24 -.12 -.37° -.20
Trial B -.12 -.16 -.13 -.30 -.29
SDFR -.14 -32 -.42‘ -.43‘ -.49“
IDFR -.07 -.32 -.35 -.39' -.39‘
Recog .00 .00 -.13 -.21 -.15

11191;, N =39.

' p<.01, one-tailed. " p<.001, one-tailed.

132

results using the CVLT measures was similar to those
observed with the TMI: however, the CVLT measures did
provide more support for the hypothesis. In comparison to
the WMS-R indices, more CVLT correlations reached
significance and, in general, cerebral lesion area
correlations were larger than the other lesion burden
measures. However, t-tests for dependent correlations
showed that cerebral lesion area correlations were
significantly greater than the other lesion measures only in
comparison to corpus collosal lesion area on the CVLT Trial
1 and 5, and Short- and Long-delay Free Recall measures (for
all comparisons p < .01, two-tailed).
Hypothesis 3

It was predicted that left hemisphere cerebral lesion
area would be more highly correlated with the WMS—R Verbal
Memory Index than right hemisphere lesion area. Similarly,
it was predicted that right hemisphere cerebral lesion area
would be more highly correlated with the WMS-R Visual Memory
Index than left hemisphere lesion area. Observed
correlations between left- and right-hemisphere cerebral
lesion area and the Verbal Memory Index were r = .001 and r
= .01, respectively. An a priori t-test for dependent
correlations performed to contrast these correlations was
insignificant [§(36) = .11, p > .50, two-tailed].
Correlations with the Visual Memory Index were r = - .52 for
the right hemisphere and r = -.46 for the left hemisphere
cerebral lesion areas. The difference between the two
correlations was not significant [§(36) = -.33, p > .20,
two-tailed]. Similar analyses were attempted on all WMS-R

Verbal and Visual Memory Index subtests, as well as the six

133

CVLT measures. This was done to reveal whether more
detailed investigation might demonstrate the hypothesized
relationship between lateralized plaque and modality-
specific memory dysfunction. However, only one significant
contrast was observed. CVLT recognition hit rate scores
correlated more highly with right-hemisphere lesion area (r
= -.24) than left-hemisphere lesion area (r = -.06), p(36) =
2.72, p < .05 (two-tailed). Moreover, this relationship was
in the opposite direction of what would be predicted given
normal lateralization of function. That is, the left-
hemisphere measure should have been more highly associated
with a verbal memory measure than the right-hemisphere
score. Finally, preliminary analyses also indicated that
the two cerebral indices also did not differ in terms of
ability to predict memory functioning relative to the other
lesion measures.
Hypothesis 4

The fourth prediction was that subjects with
significant memory deficits would have significant amounts
of cerebral lesion, but that subjects with significant
cerebral lesion would not necessarily have significant
memory deficits. Operationally, the hypothesis states that
the conditional probability of having a "high" amount of
cerebral lesion (i.e., above the sample median) given a
"high" memory deficit (i.e., performance below the median)
would be higher than the conditional probability of a "high"
memory deficit given a "high" degree of cerebral lesion.
This relationship was tested by comparing the conditional
probabilities and by contrasting the observed frequency of

each condition (i.e., high deficit given high lesion: high

134

lesion given high deficit) with the frequency expected if
there were no relationship between cerebral lesion area and
memory performance. These analyses were completed with the
TMI and each of the five WMS-R indices. Figures 1 through 6
(found on pages 135 - 140) provide a visual presentation of
the data including the raw frequencies, the expected and
observed conditional probabilities, and resulting p-values.

As predicted, the conditional probabilities are in the
expected direction for all six memory measures: however,
none of the differences are sufficient to support the
hypothesis. Using the data associated with the TMI as an
example, Figure 1 shows that the probability of having a
memory deficit (i.e., "high deficit"), given a large amount
of cerebral lesion (i.e., "high lesion") is .60.

Conversely, the probability of having a large amount of
lesion, given a low Verbal Memory Index Score, is .67. The
difference between the conditional probabilites, while in
the predicted direction, is relatively small.

Similarly, comparison of the probability that the
observed versus the expected conditional probabilities would
occur randomly across the two conditions did not not support
the hypotheses. Returning to the example of the Total
Memory Index, the bottom half of Figure 1 shows that there
is little difference between the probabilities of the
observed versus expected conditions (i.e., p = .12 versus

.07, respectively) in the two probability statements.

135

Frequency Distribution

Memllefisit
HighLow
lemon High 13|7

 

 

 

 

Conditional Probability
Observed Expected 2
Probability of high deficit
given high lesion: .65 .50 .07
Probability of high lesion
given high deficit: .68 .50 .05

 

Figure 1. Frequency and Conditional Probability of Membership
to Median Splits of Cerebral Lesion Area and Total Memory Index.
(N=39. High = _>_ 50th percentile. Low = < 50th percentile. p =
probability that the difference between the observed and expected
conditional probabilities would occur by chance.)

136

Frequency Distribution
Wet
High Low
lesion High 12 | 8
Low 6 I 13

 

 

 

 

Conditional Probability
Observed Expected 2
Probability of high deficit
given high lesion: .60 .50 .12
Probability of high lesion
given high deficit: .67 .50 .07

 

Figure 2. Frequency and Conditional Probability of Membership
to Median Splits of Cerebral Lesion Area and WMS-R Verbal
Memory Index. (N =39. High = ,1 50th percentile. Low = < 50th
percentile. p = probability that the difference between the
observed and expected conditional probabilities would occur by
chance.)

137

Frequency Distribution

MsanQeflcit

High Low

Lesion High 11 9

 

 

 

 

 

Conditional Probability
Observed Expected 11
Probability of high deficit
given high lesion: .55 .50 .17
Probability of high lesion
given high deficit: .61 .50 .12

 

Figure 3. Frequency and Conditional Probability of Membership
to Median Splits of Cerebral Lesion Area and WMS-R Visual
Memory Index. (N =39. High = _>_ 50th percentile. Low = < 50th
percentile. p = probability that the difference between the
observed and expected conditional probabilities would occur by
chance.)

138

Frequency Distribution

MW
High Low
lesion High 12 8

 

 

 

 

Conditional Probability
Observed Expected [1
Probability of high deficit
given high lesion: .60 .50 .12
Probability of high lesion
given high deficit: .67 .50 .07

 

Figure 4. Frequency and Conditional Probability of Membership
to Median Splits of Cerebral Lesion Area and WMS-R General
Memory Index. (N =39. High = 2, 50th percentile. Low = < 50th
percentile. p = probability that the difference between the
observed and expected conditional probabilities would occur by
chance.)

139

Frequency Distribution

Msmmflefisit
High Low
Lesion High 13 7

 

 

 

 

 

Conditional Probability
Observed Expected 12
Probability of high deficit
given high lesion: .65 .50 .07
Probability of high lesion
given high deficit: .72 .50 .03

 

Figure 5. Frequency and Conditional Probability of Membership
to Median Splits of Cerebral Lesion Area and WMS-R Attention
Memory Index. (N=39. High = _>_ 50th percentile. Low = < 50th
percentile. p = probability that the difference between the
observed and expected conditional probabilities would occur by
chance.)

140

Frequency Distribution

MW
High Low
Lem High 12 I 8

 

 

 

 

Conditional Probability
Observed Expected 2
Probability of high deficit
given high lesion: .60 .50 .12
Probability of high lesion
given high deficit: .63 .50 .09

 

Figure 6. Frequency and Conditional Probability of Membership
to Median Splits of Cerebral lesion Area and WMS-R Delayed
Memory Index. (N =39. High = 2_ 50th percentile. Low = < 50th
percentile. p = probability that the difference between the
observed and expected conditional probabilities would occur by
chance.)

141

Supplementary Analyses

The lower than expected correlations between many
lesion and memory measures led to a search for possible
mediator variables. Three disease factors (course type,
illness duration, and number of years since diagnosis) and
three patient characteristics (handedness, education, and
IQ) were evaluated.

Three course-types were represented in the sample --
chronic-progressive, relapsing-remitting, and benign -- and
evaluated first by a univariate ANOVA with TMI as the
dependent variable. This analysis failed to reveal any
apparent difference between course types [F(2, 36) = .51, p
> .60]. Next, a MANOVA was performed to test whether there
were any course differences across the five WMS-R indices.
The resulting Hoetellings T2 value was insignificant (F(5,
34) = .24, p > .40]: therefore subsequent ANOVAs with each
WMS-R index were not obtained. Finally, Pearson product-
moment correlations between lesion burden measures and the
TMI and WMS—R indices were compared with second-order,
partial correlations between the same variables (i.e., the
correlation between lesion burden and memory measures with
the effects of course partialed out). Little or no
difference was observed between the zero- and second-order
correlations, again suggesting that course does not mediate
the relationship between lesion burden and memory.

Since illness duration and years since diagnosis are
continuously distributed variables, analysis of variance was
not the appropriate statistical method for evaluating their
impact on lesion burden - memory relationships. Instead,

zero-order correlations were obtained between the two

142

temporal disease measures and the six memory (i.e., the TMI
and five WMS-R indices) and five lesion burden variables.
As observed in Table 10, only one reached significance even
using a very liberal critical value for post-hoc analyses.
The more generous critical value was used to minimize the
possibility of failing to reject a false null hypothesis
(Type II error). The Verbal Memory Index was significantly
correlated with years since diagnosis (r = -.35, p < .05,
two-tailed). However, when patient age subsequently was
partialled out of both temporal disease variables, all
correlations between memory and the two measures of disease
duration fell to less than .10 -- an insignificant level of
correlation.

One final attempt was made to estimate the degree to
which disease characteristics may mediate the relationship
between lesion variables and the TMI and WMS-R indices.
Disease characterisitics were held constant through second—
order partial correlations. The resulting partial
correlations between lesion and memory measures then were
compared to original zero-order correlations between lesion
and memory indices. There were no significant differences
between the zero-order and partial correlations with the TMI
or WMS-R indices, suggesting that these disease
characteristics do not mediate the relationship between
memory and lesion burden.

A similar methodology was used to examine the possible
mediating effects of IQ and education on lesion burden
correlations with memory dysfunction. Zero-order
correlations were obtained between the TMI and WMS-R indices

and education (in years) and IQ (WAIS-R Full Scale, Verbal,

143

 

 

 

Table 10

Illness Years Since
Measure Duration Diagnosis
M .504 -.15
flMS—R
Verbal -.21 -.35 '
Visual -.05 .00
General -.20 -.30
Attention -.03 I -.12
Delayed --09 '20
My}; N =39.

' p<.05, two-tailed.

144

and Performance IQ scores). As shown in Table 11, both IQ
and education are highly and positively correlated with the
TMI and WMS-R indices. A subsequent step would be to obtain
partial correlations--correlations between lesion burden and
memory performance while controlling for IQ and education.

Before proceeding, however, an attempt was made to
determine whether the cognitive capacities tested on the
WAIS-R were affected by MS. If so, WAIS-R IQ scores cannot
be used in the proposed partial correlations because IQ
would be confounded with lesion burden. This question was
tested by obtaining correlations between WAIS-R IQ scores
and the five lesion measures (Table 12). One—tailed
significance levels were used because previously reviewed
data clearly indicates that intelligence test performance
does not increase with increased lesion load. Converesely,
large negative correlations would indicate that performance
on the WAIS-R decreases as lesion load increases -- evidence
that cognitive impairment resulted from MS and that WAIS-R
scores would not be a valid measure of premorbid cognitive
functioning. This appears to be the case, as the
correlations generally are large and negative, especially
those associated with FIQ and P10. These findings
necessitated that the WAIS—R be dropped as a way of
determining the relationship between lesion burden and
memory deficit while controlling for the effects of
premorbid cognitive functioning.

On the other hand, it was believed that education would
not be confounded with lesion burden since most subjects had
completed their education before onset of MS. And, in fact,

correlations between lesion variables and years of education

145

Table 11

 

 

 

 

 

WAIS-R
Years of
Measure FIQ VIQ PIQ Education
IMI .69" .66" .52" .35
M
Verbal .32 .45. .08 .35
Visual .65" .40 .69" .02
General .52" .53" .35 .34
Attention .66" .58" .54" .14
Delayed .62" .47' .56" .25

 

Note. N =39. FIQ = WAIS-R Full Scale IQ; VIQ = WAIS-R
Verbal Scale IQ; PIQ = WAIS-R Performance Scale IQ.

° p<.01, two-tailed. " p _<_.001, two-tailed.

146

 

 

 

 

Table 12
I . H C l. 'IIMEISBIQ

WAIS-R
Measure FIQ VIQ PIQ
CClesion -.16 .02 -.30
CCatrophy -.39' -.18 -.49"
PVinvolve -.27 -.08 -.38°
PVconflu -.35 -.21 -.39°
Cerebral -.36' -. 13 -.49"
Mote, N =39.

' p<.01, one-tailed. " p<.001, one-tailed.

 

147

were insignificant (g = .03, -.13, -.20, -.07, and .01 for
CCLESION, CCATROPHY, PVINVOLVE, PVCONFLU, and CEREBRAL,
respectively) using a very liberal critical value (p < .05,
two-tailed). Although recognizing that years of education
is only a rough estimate of premorbid cognitive capacities,
it was used to obtain an estimate of the relationship
between memory performance and lesion burden while
controlling for premorbid cognitive ability. These partial
correlations are found in Table 13 with the original zero-
order correlations in parentheses. Visual inspection

shows almost no difference between the zero-order and
partial correlations. These findings suggest that education
and possibly premorbid intellectual capacity do not mediate
the relationship between lesion burden and memory

functioning.

Table 13

148

 

 

 

CC CC PV PV
Measure lesion atrophy involve conflu Cerebral
M -.09 -.16 -.23 -.31' -.32'
(~08) (~20) (-24) ( -36‘) ( -30')
flMS-R
Verbal .15 -.16 .04 -.05 .00
( .15) ( .10) ( .01) (-.13) ( .01)
Visual -.23 -.53°” -.43" -.34' -.50'"
(~23) 053'") (--43") 634') 650'")
General .07 -.11 -.16 -.18 -.20
( .04) (-.15) (-.18) (-.24) (-.18)
Attention -.26 -.28 -.23 -.27 -.28
(-25) (-29) (--23) (48) 628)
Delayed .03 -.05 -.25 -. 15 -.28
( .08) (--08) (-26) (-20) (-27)

 

11919. N =39. All parentheses indicate zero-order correlations
between lesion and memory measures. All others are the partial
correlation between lesion and memory measures with the effects of

education held constant.

' p<.05, one-tailed. .. p<.01, one-tailed. p<.001, one-tailed.

DISCUSSION

The main thesis of the study, that cerebral lesion
area would be associated more strongly with memory test
performance than other measures of MS lesion burden,
received little support. Several issues are offered to
explain these findings, including the role of acute versus
chronic lesion flux. Lower than expected correlations
between cerebral lesion area and memory may due, in part, to
a nonlinear relationship between acute lesion area and
functioning. It is suggested that, as lesion size increases
during relapse, the strength of the relationship to
functioning decreases proportionately. Because chronic
lesion area is not thought to ebb and flow over time, it is
suggested that chronic lesion extent may be more linearly
related to and more predictive of memory disturbance than
acute plaque. Some practical difficulties in measuring
lesion dissemination are proposed as responsible for the
failure of hypotheses relating to infra- versus
supratentorial plaque and left versus right hemisphere
lesion. Finally, variables that may mediate the
relationship between lesion - memory relationships are
discussed. Although several potential factors were
evaluated in this study, it is not clear that features such
as disease course or premorbid functioning of the patient
are not involved with lesion burden and memory deficit

associations.

149

150

Relative and Absolute Values of Lesion Measures
Cerebral Lesion Area

Cerebral lesion area was not clearly more sensitive to
memory functioning than other MRI indices of lesion burden.
In its relationship to several measures of memory, cerebral
lesion area was comparable to ratings of periventricular
confluence, inconclusively superior to corpus collosal
atrophy and ratings of periventricular involvement, and
clearly superior to corpus collosal lesion area. One
implication of these findings is that total lesion area may
be quite similar to representational indices in its
sensitivity to memory disturbances in MS. This author had
attributed, in part, Franklin et al.'s (1988) successful
investigation to their use of more direct, as opposed to
representational, measures of lesion burden. This position
does not appear to be tenable, at least in the specific case
of single-study cerebral lesion area. A model is offered
that may help explain the current study's findings as well
as previous failures to demonstrate a significant
correlation between lesion area and cognitive functioning
(e.g., Callanan et al., 1989: Huber et al., 1987).

The explanation returns us to the discussion on imaging
differences between acute and chronic plaque. Longitudinal
MRI (e.g., Willoughby et al., 1989) and assessment of
nonvisualized relaxation times (e.g., Larsson et al., 1988)
suggested that large changes in plaque size are not closely
associated with changes in the clinical picture. Several
pathophysiological processes associated with acute disease
activity (e.g., edema) are thought to produce rather large

increases in MRI-visualized plaque with correspondingly less

 

151

impact on functioning. On the other hand, chronic gliosis-
ridden plaque may disrupt functioning with smaller total
area and considerably less fluctuation in size than acute
lesion (e.g., Willoughby et al., 1989). Because cross-
sectional studies derive total lesion area from a sum of
both acute and chronic plaques, the strength of the
correlation between lesion area and symptom is diluted. A
measure only of acute lesion would be bi-modally distributed
with respect to its association to symptoms. At the lower
end of the lesion area - symptom curve, little dysfunction
is seen. More symptoms appear as lesion area increases but
only to the point where acute lesion area rises
exponentially -- as during an active disease phase. Past
this asymptote, the correlation between lesion area and
symptoms will decline because the large, puffy areas of
confluence seen in acute phases are relatively less
disruptive to functioning. On the other hand, chronic
plaque area would show a fairly straight-forward linear
relationship -- as chronic plaque area increases, more
symptoms would appear and the correlation between the two
would remain largely unchanged. A measure that combines
acute and chronic plaque area would result in a deficit -
lesion curve shaped like the acute lesion area curve: linear
at lower lesion area levels, curvilinear in between (with an
asymptote at the peak of the active phase), and a linear
relationship at the upper end of the curve. The return to a
linear relationship with larger lesion areas reflects the
fact that correlations between lesion area and symptom again
would increase when the combined lesion area curve includes

more chronic plaque relative to acute changes (i.e., the

 

152

acute phase has ended and relatively fewer "blooming"
lesions are seen). The overall relationship of acute lesion
area to functioning would be decreased because middle
portions of the curve would cancel out the linear extremes.
By comparison, a combination lesion area index would have
slightly higher symptom correlations because it includes
measurement of chronic plaque. Conversely, the combination
lesion area index would show less of a consistent
relationship with dysfunction than a measure specific to
chronic plaque.

Returning to the cerebral lesion area measure used in
this study, the borderline significant correlations with
memory test performance may reflect the consistent
relationship with chronic plaque and the blurred association
with acute lesion area. Acute lesion fluctuation would
explain the lower than expected correlation values reported
elsewhere (e.g., Huber et al., 1987) in a similar fashion.
Decreased lesion - symptoms correlations due to acute lesion
area flux also is consistent with investigations reporting
significant lesion area associations with dysfunction (i.e.,
Franklin et al., 1988). Their correlations between cerebral
lesion area grades and several measures of memory ranged
from r = -.28 to -.36: very comparable to those reported in
this study. The only difference between Franklin et al. and
the current study is that the farmer's sample size of 60
allows for lower critical values. Acute lesion fluctuation
effects also could explain the failure to demonstrate
cerebral lesion area superiority to representational
measures of plaque burden.‘ Cerebral lesion area would

appear comparable to representational measures because both

153

are equally reflective of chronic and acute plaque burden.

Future investigations easily could test the acute
lesion area fluctuation hypothesis. It suggests that
estimates of chronic lesion area would be more sensitive to
dysfunction than either an acute or a combined acute-chronic
lesion area measure. Gadolinium-enhanced MRI, longitudinal
MRI, and evaluation of specific MRI relaxation times could
provide such data.

The difference between chronic and acute lesion area
change is not the only factor which may account for
generally low lesion - function correlations. Several
others will be discussed, including the direct versus
representational dichotomy.

Total Brain Lesion Area

Comparison of the relative strength of cerebral versus
whole brain lesion area was not tested adequately. The
prevalence of posterior fossa lesion in this sample was well
below previous reports using similar MRI protocols. It is
not clear whether this finding represents a sampling
artifact, poor judgement on the part of the raters, or a
combination of the two. Distinguishing lesion from normal
brain stem and cerebellar tissue is a difficult task owing
to the dense white—matter and surrounding CSF found in these
areas. This problem is reflected in the lower inter-rater
reliability figures shown in Appendix A. Even if a more
representative sample of brain stem and cerebellar
involvement were observed, however, the ratio of infra- to
supratentorial plaque area still may be so small as to
obscure an understanding of their relative effects on

memory. Lesion area in the brain stem and cerebellum is a

154

small fraction of all brain plaque (Lumsden, 1970). The
issue of proportionality, in addition to problems associated
with acute plaque flux, suggests that lesion area probably
is not the best way of discriminating the relative strength
of cerebral versus noncerebral lesion burden relationships
to cognitive changes.

Corpus Collosal Involvement

 

Comparative analyses of corpus collosal atrophy and
cerebral lesion area were inconclusive. There was no marked
difference between the two measures across WMS-R subtests,
although cerebral lesion area was more highly correlated
with performance on the CVLT and the TMI. Because of
methodological differences, it is difficult to resolve these
results with Huber et al.'s (1987) findings that suggested
that corpus collosal atrophy was superior to cerebral lesion
area in predicting cognitive dysfunction. Huber et al. used
a five-point rating scale of atrophy rather than cursor
tracings yielding total corpus collosal area. Also, their
MRI measures were used to predict membership to one of three
degrees of general cognitive impairment rather than memory
dysfunction. The results of the current study certainly do
not force a reappraisal of Huber et al.'s (1987) conclusion
that cognitive deficit is predicted by corpus collosal
atrophy because it reflects lesion involvement elsewhere.
Research on commissurotomy patients suggests that they
perform within normal limits on most standard tests of
cognition (including memory), but struggle on those tasks
requiring integrated transmission of information between the
hemispheres (e.g., LeDoux, Risse, Springer, Wilson, &

Gazzaniga, 1977: Springer & Deutsch, 1985). Given that

155

corpus collosal atrophy allows at least some
interhemispheric traffic, it is probably the case that
corpus collosal atrophy interferes with intact performance
only on tasks with relatively significant communication
between the hemispheres. If this attribution is correct,
corpus collosal atrophy would be a direct indicator of
clinico-pathology associations only where memory tests
involve heavy interhemispheric transmission of information.
Because neither the WMS-R nor the CVLT appear similar to
tasks known to produce such effects, it would seem that
corpus collosal atrophy sensitivity to WMS-R and CVLT
performance occurs because the atrophy reflects pathology
elsewhere.

The strongest findings of this study were that corpus
collosal lesion area predicts memory functioning rather
poorly, both absolutely and in comparison to cerebral lesion
area and across all memory tasks and patient and disease
factors. No previous reports could be found that used
corpus collosal lesion area as a predictor of any aspect of
cognition. Therefore, it is not clear why there were such
consistent differences between corpus collosal and cerebral
lesion area or collosal atrophy in their sensitivity to
memory impairment. Review of the literature on the corpus
collosum and topics other than MS gave no warning that
atrophy and lesion area would correlate differently with
memory. One possible explanation begins with the assumption
that the WMS-R and CVLT do not require intact corpus
collosal functioning. Given findings that corpus collosal
atrophy is more strongly related to WMS-R and CVLT scores

than corpus collosal lesion area, one can infer that,

 

156

although corpus collosal atrophy is a representational
measure, corpus collosal lesion area is not. If so, then a
measure that is specific to pathology in the corpus collosum
only -- such as lesion area -- would not be expected to
correlate highly with performance on the WMS-R or CVLT.

A subsequent step would be to determine why MS plaque
in other areas of the brain is reflected by the degree of CC
atrophy, but not actual corpus collosum lesion. One
possibility returns us to the discussion on imaging of acute
versus chronic lesions and their association to functioning.
While not specifically addressed by Weller (1985) and others
(e.g., Ormerod et al., 1987), their data suggest that the
atrophic changes seen on MRI reflect the permanent loss of
myelin and oligodendroglial cells over a long period of
time. If accurate, an atrophic measure would show more
consistent correlations with symptoms because atrophy is
more reflective of chronic than acute lesion burden, whereas
corpus collosal lesion area includes the measurement
fluctuation problems of acute plaque.

Periventricular Involvement

 

No marked differences were observed between the two
indices of PV involvement and cerebral lesion area their
association to memory. PV confluence was one of only two
measures (with cerebral lesion area) to correlate
significantly with the Total Memory Index, but confluence
ratings did not consistently outperform other MRI measures.
Like the corpus collosum, previous explanations of the
effectiveness of periventricular involvement in predicting
cognitive dysfunction included direct versus

representational conceptualizations. Rao et al. (1984)

157

suggest that demyelination of prefrontal-limbic pathways
running near the ventricles can result in memory loss.
Thus, ratings of PV involvement may directly measure neural
demyelination. Conversely, Huber at al. (1987) write that
PV measures are useful only because they accurately reflect
extent of CNS pathology throughout. These positions are not
mutually exclusive, however. In fact, the relative success
of some PV indices in predicting cognitive deficit may
indicate a combination of both direct and indirect
measurement. This study's methodology, unfortunately, does
not allow one to differentiate between PV involvement as a
specific, representational, or combinatory index of MS
lesion burden.

Regardless of the outcome of the direct versus
representational issue, the lack of consistent differences
between the two PV measures and cerebral lesion area can be
explained through two other factors. One involves the acute
lesion fluctuation model. Because both PV indices included
ratings of acute plaque, one would predict generally poor
correlations with memory functioning as well as little
dissociation between other measures that include measurement
of acute plaque -- such as cerebral lesion area.

The second factor concerns the high degree of
correlation between the two PV ratings and cerebral lesion
area (Table 6). It is not clear that these three MRI
measures were sufficiently different to make reliable
statements about their relative sensitivity to memory test
performance. Theoretically it may be that PV involvement is
less predictive of memory disturbance than cerebral lesion

area, the close correspondance between these indices of

158

lesion burden makes it difficult to separate them in
practical applications. As will be discussed below, this
relative lack of difference between predictor variables also
explains the failure of lesion laterality predictions.

A last comment about PV lesion is directed towards
problems encountered in objectifying measurement -— a
universal complaint in the MRI literature. Subjective
ratings, alone, were used in this study by default.
Originally, PV lesion area (i.e., plaque having at least
some contact with a ventricle) also was to have been
included in MRI scoring. Inter-rater reliability for this
measure was abysmal, however, and a decision was made to
drop it from the study before the final scoring protocol was
completed. The most troublesome scoring problem was in
differentiating the border between plaque and ventricle.
Unfortunately, MRI parameters that best highlight anatomical
features and MS plaque also result in comparable levels of
brightness between ventricle and lesion. This imaging
difficulty, the question of representational versus direct
measurement, and the acute lesion fluctuation problem
provide more than ample explanation for the consistent
failure to demonstrate significant correlations between
cognitive dysfunction and PV indices.

Uni-hemisphere Lesion Area

The data clearly did not support hypotheses that
lateralized cerebral lesion area differentially correlates
with modality-specific memory functioning. These negative
findings may be attributed to the almost identical lesion
area distribution between the left and right hemispheres

(Table 6), which makes it difficult to predict to any

9'1

159

criterion. Equal hemispheric involvement is a consistent
finding with autopsy (Lumsden, 1970) and MRI study
(Marvilla, 1988) and the resulting restriction of range may
be why the topic has been studied so little in MS. Previous
empirical support for lateralization hypotheses was weak and
only tangentially related to the issue. Brainin et al.
(1988) reported a significant gradation of verbal memory
deficit with medial temporal lobe lesions. Maximum severity
was associated with bi-lateral involvement, uni-lateral
lesion with moderate impairment, and more normal functioning
was observed in subjects without medial temporal lesion area
involvement. However, in four of the five "uni-lateral"
patients, the lesion were on the Eighg side rather than the
left -- the reverse of what would be expected given normal
lateralization of function (e.g., Walsh, 1985). Franklin et
al. (1988) reported significant correlations between uni-
hemisphere cerebral lesion area and verbal and nonverbal
memory tests, but did not publish specific results nor
comment on the relative correlation strengths of left-
versus right-sided plaque. In lieu of data specific to MS,
hypothesized lateralization effects were based on
considerable clinical data indicating that other types of
uni-lateral pathology (e.g., stroke) can result in modality-
specific memory deficits (e.g., Walsh, 1987). The results
published here do not disprove the hypothesis that right
cerebral lesion is responsible more for nonverbal than
verbal memory disturbances. However, the lack of lesion
burden differences between the hemispheres makes
demonstration a practical impossibility.

Other factors also may have contributed to the negative

160

findings. More specific localization of lesion indices,
such as restricting comparisons to temporal lobe
involvement, may have improved correlations with verbal and
nonverbal memory. Unreliable nonverbal memory measurement
may have obscured hypothesized relationships. Despite
several changes from the WMS to improve the reliability and
validity of nonverbal memory tasks, WMS-R Visual Index
subtests have been routinely criticized. The most common
complaint is that subjects use verbal strategies to augment
performance on supposedly nonverbal tasks. A second
potential problem is one of ceiling effects. It is not
clear that the WMS-R visual memory subtests are as difficult
verbal ones and, in fact, the patient sample in this study
performed within normal ranges on visual memory tasks. It
may be that patients did have visual memory deficits but,
because of the ease of the tasks, no impairments were
observed. If true, attempts to demonstrate that increased
lesion burden results in decreased function would be doomed
because of the resulting restriction of range.

MRI-observed Lesion: Necessary g; Sufficient?

It was proposed that MRI-observed cerebral
demyelination may be conceptualized as a necessary but
insufficient condition for memory deficit. Comparisons of
conditional probabilities -- the probability of impairment
given considerable cerebral lesion versus the probability of
significant cerebral lesion given memory impairment -- were
in the predicted direction but were insufficient to support
the hypothesis. Before rejecting either the specific
results or the study technique though, some methodological

issues should be addressed. A primary concern is the choice

 

161

of cut-off scores for inclusion criteria. Because no
previous research could be found to guide such a decision,
median splits were chosen arbitrarily as critical values for
both memory functioning and cerebral lesion area. It may be
that there is a critical range of plaque load, only past
which does memory impairment occur. Use of more discrete
cerebral lesion area groupings (e.g., quartiles) would
greatly enhance the identification of any naturally
occurring critical value. Unfortunately, investigations of
this nature would require a relatively large sample to
ensure sufficient cell size for each memory and lesion
burden measure grouping. The second issue that may have
resulted in a serious reduction in the power of the analyses
is the aforementioned acute lesion flux problem. Future MRI
investigations could exclude acute plaque area from lesion
burden measures to more accurately test the conditional
probability hypotheses.
Supplemental Analyses

The weaker than expected relationships between lesion
burden and memory functioning led to a search for factors
that might have mediated their relationship. However, the
absolute and relative strength of lesion burden - memory
correlations were not markedly different when disease
course, length of illness, and type and degree of memory
deficit were taken into consideration. Premorbid cognitive
capacity, as estimated by years of education, also did not
appear to moderate the relationship between MRI measures and

memory test performance.

 

162

Aspects g; Memogy

Verbal versus visual memory. It does not appear
that lesion burden is differentially sensitive to visual
versus verbal memory functioning. Although MRI measure
correlations with the WMS-R Visual Memory Index were
significantly greater from those with the Verbal Memory
Index, other factors suggest that the results are spurious.

First, strong lesion - memory correlations also were seen on

the CVLT, indicating that poor correlations with MRI indices
were not generalized to all verbal memory impairments.
Secondly, information modality was confounded with deficit
severity. Subjects performed within normal limits on the
WMS-R Visual Memory Index but showed significant impairments
on the WMS-R Verbal Memory Index and other estimates of
verbal memory functioning. Therefore, it may be that lesion
burden best predicts normal-range functioning, rather than
visual memory per se. A third argument against concluding
that the relationship between lesion burden and memory is
stronger with visual than with verbal material, is the lack
of empirical and theoretical support for such an association.
The only other investigation reporting verbal and nonverbal
memory correlations with MRI-observed plaque involvement
(Franklin et al., 1988) observed no appreciable modality
differences. Certainly, no current model of memory
physiology and function would lead one to posit differential
sensitivity to the effects of MS plaque. Returning to the
present study, correlations between lesion measures and the
WMS-R Verbal Memory Index were so weak as to cause one to

question whether this result is due simply to sampling

 

artifact.

163

Deficit severity. Correlations between lesion burden
and memory functioning were not necessarily stronger when
memory was depressed. For example, tests on which the
sample performed best (e.g., WMS-R Visual Memory Index)
yielded the highest and most consistent correlations with
lesion burden. Conversely, the weakest correlations
observed were associated with the WMS-R Verbal Memory Index
-- subtests on which patients performed quite poorly. These
instances are not particularly good examples because,
as noted above, modality is confounded with deficit
severity. However, visual inspection of the correlation
matrices shows that there is no reliable pattern between
lesion burden and degree of deficit on memory measures other
than the Visual and Verbal Memory Indices. Previous
failures to observe consistent associations between memory
and MRI-observed plaque have been ascribed, in part, to a
lack of deficient memory performance in test samples (e.g.,
Callanan et al., 1989). This does not appear to be the case
and, in fact, some support can be marshalled for the
reverse: correlations increase with less impaired levels of
performance. Investigations of cognitive functions other
than memory have reported that predictions from lesion
burden improve with increased test performance levels. For
example, correlations between Franklin et al.'s (1988)
cerebral involvement scores and measures of memory and other
information processing tasks (e.g., Trails A & B: Symbol
Digit Modalities) were largest on tests with more normal-
range than impaired performance distributions. Similarly,
Hill (1991) observed that prediction by lesion burden

measures was superior on information processing tests with

 

164

less, rather than more, impairment. Because neither study
specifically compared normal versus impaired cognitive
performance correlations with MRI scores, their findings
should be considered with caution. One interpretation for
the higher lesion - dysfunction correlations with more
normal performance is purely statistical. It may be that
increased impairment results in a restricted range of
performance, thus making prediction difficult as deficit
severity increases. Whether range restriction is the sole
explanation for the findings involving normal versus
impaired performance, it is clear that the relationship
between lesion - symptom correlations and the severity of
cognitive impairment is not a simple, inverse association.
The lack of deficit severity effects also indicates that
observation of strong correlations between plaque and
dysfunction does not mean, necessarily, that the patient is
experiencing considerable dysfunction. This point is most
important to clinicians and is a clear warning to avoid
predictions about prognosis based solely on MRI.

Primary versus secondary memopy. The strength of the
association between lesion burden and memory functioning was
similar across measures of primary and secondary memory. An
almost identical pattern of correlations was observed
between MRI scores and the WMS-R Attention/Concentration and
Delayed Recall Memory Indices -- the studies' two best
single measures of primary and secondary memory,
respectively. Exploration of possible primary versus
secondary memory differences was based on the hypothesis
that increased deficit severity would result in increased

lesion burden correlations with memory (e.g., Callanan et

165

al., 1989). Because subjects were thought to perform better
on measures of PM than SM (e.g., Rao et al., 1989), it was
believed that lesion burden would be more strongly related
to Delayed Recall performance in comparison to scores on the
subtests of the Attention/Concentration Memory Index. As
discussed above, the deficit severity hypothesis did not
hold up. The failure to demonstrate differential lesion
burden relationships between PM and SM also may be
attributed to the observation that SM was not clearly more
impaired than PM in this sample. For example, group mean
performance on the WMS-R Attention/Concentration and Delayed
Recall was not appreciably different and the prevalence of
impaired performance on the two indices was almost identical
(26% and 28%, respectively).

At least two factors should be addressed, however,
before rejecting the possibility that primary and secondary
memory differ in their association to measures of lesion
burden. First, the relatively small correlations between
lesion burden and memory test performance make it difficult
to tease out more subtle relationships. Even more
problematic is that the memory tests used in this study may
not have differed sufficiently in their PM and SM processing
requirements. A chief short coming of the WMS-R and CVLT is
that it is difficult to parcel out the effects of PM on
later SM processing tasks. Using the prose paragraph
delayed recall task of the WMS-R as an example, failure on
this test may reflect intact SM in the presence of
significant PM deficit. A PM impairment would prevent
adequate storage of the story at input regardless of whether

SM was intact or not. This problem with separating primary

 

 

166

from secondary memory deficit has been detailed previously
and is a difficult obstacle to overcome.
Aspects Q; Predictor Variables

Ilness duration. The absence of a relationship between
illness duration and lesion - memory correlations in this
study is consistent with a similar lack of association
between illness length and lesion - motor/sensory
disturbance correlations (e.g., Kiel et al., 1986) and
prevalence or severity of cognitive (e.g., Grant et al.,
1988: Ivnik, 1978) or noncognitive impairment (e.g.,
Matthews et al., 1985). Whether measured as the latency
since symptom onset or diagnosis, no reliable connection
between illness duration and memory has been reported.
Whatever pathophysiological mechanisms are responsible for
memory impairment in MS, they clearly do not involve a
simple accrual of effects over time.

Illness course. Memory test performance was similar
across three disease courses (benign, chronic-progressive,
and relapsing-remitting) and course type did not appear to
change the strength or quality of the association between
plaque and memory measures. For a number of reasons,
however, these findings should be considered with caution.
First, since no previous study has reported course
relationships to lesion - memory dysfunction correlations,
some replication is necessary. Also, the small sample size
of course groups within this investigation greatly increases
the possibility of sampling error. Finally, considerable
controversy exists concerning course distinctions in memory
functioning (e.g. Fischer, 1988 vs. Heaton et al., 1985) or

pathoanatomical changes inferred from disease activity (e.g.

 

167

Omerod et al., 1987 vs. Grossman et al., 1986). As was
highlighted in the literature review, there have been
strikingly few investigations of course and clinical disease
activity regardless of the research question, but especially
in regards to cognitive disturbance. Future examination of
lesion burden - memory associations should include some
treatment of such factors as course and disease activity.

Premorbid cognitive functioning. Premorbid cognitive
functioning appeared to have almost no relationship to
lesion - memory correlations. Although not previously
investigated, it may be that increased premorbid functioning
"innoculates" the patient's susceptibility to the effects of
MS lesion. These findings argue otherwise, but because only
a very gross measure was used -- years of education -- the
question of possible mediating effects of premorbid

cognition was not addressed adequately here.

Comments Concerning Study Reliability and Validity

The quality of the relationship between memory function
and structure bears some responsiblity for the continuing
difficulty to characterize the association between MRI-
observed lesion burden and deficit. Neural pathways
involved with intact memory processing are thought to be
exponentially more numerous and complex than those
subserving primary sensory and motor function. By all
appearances, memory lacks the one-to-one correspondence
between lesion and function as is observed in the case of
cervical cord or optic nerve plaque and sensory disturbance.
Optimal prediction of memory impairment via MRI will require

scoring methods that parallel the complexity of the neural

 

168

systems subserving memory.

We also have not begun to consider many other
pathoanatomic factors that could change the nature of the
relationship between MRI-observed plaque and memory
function. These include but certainly are not limited to:
neural pathway redundancy, neuronal plasticity of function,
and the speed with which pathologic changes occur. For
example, we cannot assume that two lesions -- identical in
size and location but having a different course -- have the
same functional effects. These issues cause one to question
whether prediction of memory function from such gross
indices as lesion size and lobule location will be anything
approaching precise. It is more likely that successful
investigation will rely on much more fine-grained levels of
analysis. For example, a narrowly defined area of function
(e.g., storage of information pertaining to human faces)
will be matched with measurement of plaque in very
circumscribed locations (e.g., left-hemisphere parieto-
occipital white matter tracts).

It is not clear whether the type of MS sample used in
this study contributed to the results in an unexpected
fashion. The rationale for drawing subjects from support
group membership was to ensure a more random sample of MS
patients than has previously been described. Sampling only
from those who have had contact with clinical services
risked drawing from amoung those patients most likely to
have memory deficits. As expected, the sample drawn in this
investigation included patients both with and without memory
impairments. Given the growing body of evidence that it is

difficult to predict dysfunction via MRI-observed pathology,

169

it may be best to control for factors other than those being
explicitly studied until lesion - symptom relationships are
better understood. For the time being, it may be wise for
experimental samples to include patients with memory deficit
or patients without, but samples should not include both
impaired and unimpaired patients.

A similar sampling strategy may be applied to other
factors potentially mediating memory and plaque
associations. While the patient and disease characteristics
examined in this study did not appear to mediate lesion -
dysfunction correlations, caution seems warranted given the
lack of conclusive evidence to the contrary. Conservatism
also should be shown with regards to other aspects of MS not
addressed specifically in this study. Of those reviewed
from the literature, symptom flux seems a particularly
likely candidate for consideration. Changes in the quality
and quantity of motor and sensory impairment over time and
their relationship to MRI-observed pathology are just being
described (e.g., Grossman et al., 1986). No similar
investigations have been reported with memory and other
cognitive capacities, in part, because of the many
difficulties associated with identifying subtle temporal
changes in higher cortical functioning. Yet, there is no a
priori reason to dismiss the possibility that prediction
from MRI data may be different across de novo versus
exacerbated versus stable cognitive deficits.

MRI protocols and other issues associated with
measurement of lesion burden also must be evaluated further
to determine their impact on studies of lesion - function

relationships. The wide variations in methodology make it

 

170

exceedingly difficult to compare results across studies or
to identify which combination of measurement parameters
best fit any given research question. More objective means
of estimating lesion burden would be greatly beneficial
on all counts. The recent development of the computerized
cursor tracings is promising in this regard, although its
reliability remains questionable (Franklin et al., 1988).
Clinical judgement will never be removed totally from the
situation since motion artifact and other scoring issues
defy complete objectivity. Close communication between
radiologists, neuropsychologists, and neurologists is needed
to develop more reliable scoring criteria and strategies.
Sorting out the relative contribution of acute versus
chronic plaque on functioning seems paramount given the
findings and concerns identified in this study. Single-
study measures of lesion area may be a biased estimate of
disease involvement and confirmation either way is sorely
needed. This issue leads to final comments pertaining to
the strategy of using MRI data in understanding clinical and
pathology changes in MS. The findings of this study add to
a very long list indicating that cross-sectional MRI may not
be sufficiently sensitive to fully identify the patho-
anatomic and -physiological changes resulting in
dysfunction. Previously reveiwed research suggests that
centrifugal spread of plaque, incomplete myelination,
remyelination, impaired neuronal transmission due to edema
versus gliosis, and permanent versus temporary breakdown of
neural substrates are important to changes in function.
Yet, we are unable to comment on such processes using MRI

alone. Even if all the MRI measurement difficulties noted

171

above were properly addressed, it is probably the case that
a more microscopic level of analysis is needed to fully
illucidate the pathological changes responsible for memory

disturbance in MS.

 

 

APPENDIX

 

APPENDIX A

Inter-rater Correlations: MRI Data

 

 

GN GR NR AVE ADJ
Brain Sten .66 .68 .57 .64 .84
Cerebellum .62 .65 .32 .53 .77
Corpus Collosum .16 .78 .02 .32 .57
Basal Ganglia .36 .18 .17 .24 .48
Internal Capsule .27 .79 .09 .38 .65
Right Frontal Lobe .69 .85 .66 .73 .89
Left Frontal Lobe .79 .80 .78 .79 .92
Right Temporal Lobe .60 .91 .55 .68 .87
Left Temporal Lobe .51 .89 .52 .64 .84
Right Parietal Lobe .80 .59 .61 .67 .86
Left Parietal Lobe .65 .61 .48 .58 .81
Total Lesion Area .72 .89 .63 .74 .90
GN = correlations between raters G and N
GR = correlations between raters G and R
NR = correlations between raters N and R

AVE = single raters reliability: average correlation among
three raters

ADJ = composite reliability computed using Spearman-Brown
formula

172

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