Neuropsychology
2003, Vol. 17, No. 4, 658 – 674
Copyright 2003 by the American Psychological Association, Inc.
0894-4105/03/$12.00 DOI: 10.1037/0894-4105.17.4.658
Neural Basis for Verb Processing in Alzheimer’s Disease:
An fMRI Study
Murray Grossman, Phyllis Koenig, Chris DeVita, Guila Glosser, Peachie Moore,
Jim Gee, John Detre, and David Alsop
University of Pennsylvania School of Medicine
Patients with probable Alzheimer’s disease (AD) have difficulty understanding verbs. To
investigate the neural basis for this deficit, the authors used functional magnetic resonance
imaging to examine patterns of neural activation during verb processing in 11 AD patients
compared with 16 healthy seniors. Subjects judged the pleasantness of verbs, including
MOTION verbs and COGNITION verbs. Healthy seniors and AD patients both activated
posterolateral temporal and inferior frontal regions during judgments of verbs. These activations were relatively reduced and somewhat changed in their anatomic distribution in AD
patients compared with healthy seniors, particularly for the subcategory of MOTION verbs,
but AD patients showed minimal activation in association with COGNITION verbs. These
findings imply that poor performance with verbs in AD is due in part to altered activation of
the large-scale neural network that supports verb processing.
Patients with probable Alzheimer’s disease (AD) are
thought to have difficulty understanding single words
(Chertkow & Bub, 1990; Cox, Bayles, & Trosset, 1996;
Grossman et al., 1996; Hodges, Patterson, Graham, & Dawson, 1996; Martin, 1992). Although this deficit has been the
subject of considerable investigation for nouns, the impairment for verbs in AD is less well understood. In this study,
we investigated the neural basis for verb comprehension
difficulty in AD with blood oxygen level-dependent
(BOLD) functional magnetic resonance imaging (fMRI).
Patients with AD appear to have greater difficulty with
verbs than with nouns (Bushell & Martin, 2002; Cappa et
al., 1998; K. M. Robinson, Grossman, White-Devine, &
D’Esposito, 1996; van der Lem et al., 2002; White-Devine
et al., 1996). Although exceptional cases have been described (Parris & Weekes, 2001; G. Robinson, Rossor, &
Cipolotti, 1999), and a recent study involving many axial
verbs (Fung et al., 2001) failed to confirm earlier observations, the verb impairment in AD has been shown with
several different techniques, including confrontation naming, word–picture and word–video matching, and word–
definition matching. The basis for relative difficulty with
verbs in AD is unclear. Some have associated verb deficits
with the loss of sensory–motor feature knowledge, and
particularly with degraded motor–function features of a
verb (Bird, Howard, & Franklin, 2000; Johnson & Hermann, 1995; Parris & Weekes, 2001). However, verb-naming difficulty does not appear to correlate with visual perceptual performance in AD (K. M. Robinson et al., 1996).
Moreover, we have observed greater difficulty in AD patients’ comprehension of COGNITION (we use capitals to
indicate a concept) verbs that are not dependent on sensory–
motor features compared to MOTION verbs (van der Lem
et al., 2002). Verbs are relatively rich in their grammatical
features, and another possibility is that a grammatical deficit
contributes to impaired verb comprehension. However, verb
naming difficulty does not appear to correlate with grammatical comprehension in AD (K. M. Robinson et al.,
1996). In the acquisition of a new verb, moreover, AD
patients were able to learn about some of the grammatical
properties of the new word (e.g., that it is subcategorized
grammatically as a verb), even though they were quite
limited in their ability to acquire the new verb’s meaning or
its thematic relations (e.g., who does what to whom; Grossman, Mickanin, Onishi, Robinson, & D’Esposito, 1997).
Another hypothesis holds that verbs are more difficult than
nouns because verbs generally contain more information
(e.g., meaning, grammatical restrictions, thematic relations)
that must be coordinated for their proper usage. According
to this approach, verb comprehension requires executive
resources that are known to be limited in AD (Baddeley,
Bressi, Della Sella, Logie, & Spinnler, 1991; LaFleche &
Albert, 1995; Patterson, Mack, Geldmacher, & Whitehouse,
1996). However, an unpublished word–picture matching
study of AD patients performed during concurrent administration of a secondary task in our lab failed to support this
hypothesis.
In the present study, we gained additional information
about the status of verb meaning in AD from a different
Murray Grossman, Phyllis Koenig, Chris DeVita, Guila Glosser,
and Peachie Moore, Department of Neurology, University of
Pennsylvania School of Medicine; Jim Gee and David Alsop,
Department of Radiology, University of Pennsylvania School of
Medicine; John Detre, Departments of Neurology and Radiology,
University of Pennsylvania School of Medicine.
Portions of this report were presented at the annual meeting of
the Cognitive Neuroscience Society, New York, April 2003. This
work was supported in part by U.S. Public Health Service Grants
AG15116, AG17586, and NS35867.
Correspondence concerning this article should be addressed to
Murray Grossman, Department of Neurology–3 Gates, University of
Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia,
Pennsylvania 19104-4283. E-mail: [email protected]
658
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VERB PROCESSING IN ALZHEIMER’S DISEASE
perspective— by assessing the neural basis for verb difficulty directly with fMRI. Previous fMRI work in young
healthy adults appears to associate verb comprehension with
recruitment of left posterior temporal cortex, prefrontal cortex, and caudate (Damasio et al., 2001; Grabowski,
Damasio, & Damasio, 1998; Grossman et al., 2002b; Perani
et al., 1999). One interpretation of these observations relates
visual and motor association regions to the respective sensory and motor–function features thought to contribute so
importantly to the meaning of these verbs. For example,
posterior temporal activation has been associated with the
visual motion features related to action and tool use (Bonda,
Petrides, Ostry, & Evans, 1996; de Jong, Shipp, Skidmore,
Frackowiak, & Zeki, 1994; Kourtzi & Kanwisher, 2000;
Patzwahl, Elbert, Zanker, & Altenmuller, 1996; Puce, Allison, Bentin, Gore, & McCarthy, 1998), whereas frontal
brain regions have been associated with the motor features
of verbs (Decety et al., 1994; Gallese, Fadiga, Fogassi, &
Rizzolatti, 1996; Jeannerod, Arbib, Rizzolatti, & Sakata,
1995; Rizzolatti, Fadiga, Matelli, Bettinardi, Paulesu, &
Perani, 1996; Rizzolatti, Fadiga, Matelli, Bettinardi,
Paulesu, Perani, & Fazio, 1996).
There are several reasons to doubt this feature-based
interpretation. For example, the sensory–motor features associated with a particular category do not appear to activate
the same anatomic region as direct probes of the category
itself (Kellenbach, Brett, & Patterson, 2001; Noppeney &
Price, 2002). Another problem is that most previous studies
apparently assumed that all verb categories of knowledge
are comparable, and thus largely limited their stimuli to
MOTION verbs. Two studies investigated COGNITION
verbs as well as MOTION verbs and found considerable
overlap in the activation of left posterolateral temporal and
frontal regions for both verb categories (Grossman et al.,
2002b; Perani et al., 1999). The activation of the same
frontal and temporal brain regions for MOTION verbs as
well as a category of knowledge as impoverished in sensory–
motor features as COGNITION verbs makes it less likely
that these brain regions support the visual motion and action
features associated with MOTION verbs.
A small number of functional neuroimaging studies of
lexical comprehension in AD have been reported. These
have investigated only nouns. In one study, AD patients
judged the semantic relationship between two presented
words (Saykin et al., 1999). Healthy subjects recruited inferior and middle frontal cortex of the left hemisphere when
judging the association of word pairs that include a semantic
superordinate category and an exemplar from the category.
AD patients showed a behavioral impairment during decisions about these word pairs and, correspondingly, did not
recruit left frontal cortex. AD patients recruited right frontal
cortex to a significantly greater degree than control subjects.
This finding suggests limited activation of a brain region
crucial for making a decision about word meaning, and
up-regulation of an anatomically related brain region during
these decisions. However, the behavioral deficit during the
fMRI study made it difficult to interpret the basis for the
changed activation profile in AD subjects relative to control
subjects (Price & Friston, 1999). Activation changes in AD
thus may have been due to their semantic deficit, or to
relative task performance difficulty in AD patients compared with healthy control subjects. To minimize this confound, a recent study investigated comprehension of noun
categories with a “pleasantness” judgment task that was
performed equally well by AD patients and healthy seniors
(Grossman et al., 2003). This study showed limited left
temporal–parietal activation in AD patients, relative to
healthy seniors, for both ANIMAL and IMPLEMENT categories of knowledge. This brain region contains heteromodal association cortex, where the connectivity pattern
involves reciprocal projections with modality-specific association cortices. Because this change was seen for both
categories of knowledge, we hypothesized that this area
supports a category-neutral process important for processing the meanings of words. We also observed a change in
the anatomic distribution of activation in other regions of
the left hemisphere in AD that contain modality-specific
association cortex and are associated with a specific category of knowledge. For example, left ventral temporal–
occipital activation associated with ANIMALS in healthy
seniors was evident about 20 mm anteriorly in AD patients.
We also observed up-regulation of right hemisphere regions, particularly for IMPLEMENTS. These findings are
consistent with a dual-component model of semantic memory involving both category-specific feature knowledge and
category-neutral processes that integrate these features in
semantic memory for the purpose of developing meaning
representations useful for semantic categorization (Grossman et al., 2003).
In the present study, we investigated the integrity of left
hemisphere regions during AD patients’ verb comprehension. On the basis of changes in recruitment patterns for
nouns in AD patients relative to healthy seniors, we hypothesized that verb comprehension in AD would be associated
with limited activation of heteromodal temporal and frontal
regions in the left hemisphere that have been related to verb
comprehension in healthy young adults. We also expected
to observe changes in the activation of modality-specific
brain regions in AD patients that are not activated in healthy
seniors. If these novel areas of activation are related in part
to compensatory up-regulation that helps AD patients
achieve partial comprehension of verbs, we would expect to
see less activation of novel regions for COGNITION verbs
than for MOTION verbs, reflecting AD patients’ relative
accuracy within these domain of verb knowledge.
Method
Subjects
We studied 16 healthy, right-handed seniors and 11 patients
with mild-to-moderate dementia diagnosed as probable AD by a
board-certified neurologist, according to National Institute for
Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria (McKhann et al., 1984). Other neurologic, psychiatric, and medical
conditions that can interfere with cognitive performance were
ruled out in the AD patients and healthy seniors. None of the
subjects were taking medications with sedating properties that can
660
GROSSMAN ET AL.
impair cognition or that can change blood flow, but the AD
patients were taking a medically acceptable dose of an acetylcholinesterase inhibitor. The control subjects were screened with a
semistructured medical history interview to ensure their physical
and mental health and to eliminate subjects taking centrally acting
medications. Mini- Mental State Examination scores were greater
than 27. Structural images were inspected for disease. The demographic features of the AD patients and the age- and educationmatched healthy seniors are summarized in Table 1. These subjects
and their legal representatives participated in an informed consent
procedure approved by the Institutional Review Board at the
University of Pennsylvania.
Materials
We presented blocks of printed words to subjects that included
citation forms of two categories of verbs: MOTION verbs (e.g.,
CRAWL, WRITE) and COGNITION verbs (e.g., BELIEVE, ENJOY). This was done to avoid unwarranted generalizations about
all verbs that may be relevant only for one subcategory of verbs.
The words were either unambiguously verbs, or if not, a word’s
frequency of occurrence as a verb was at least 5 times its frequency
of occurrence as a noun, according to form class-sensitive frequency measures (Francis & Kucera, 1982). The categories of
verbs were matched for mean frequency (Francis & Kucera, 1982):
cognition ⫽ 16.1; motion ⫽ 13.8, t(118) ⫽ 0.83, ns. A cohort
of 42 native English-speaking undergraduates assessed the words
for familiarity: The meanings of all the words were known to all
students, and all but 11 of the 120 words were judged to be highly
familiar by over 90% of these students (1 MOTION verb was
judged familiar by only 90% of students, 5 COGNITION verbs
and 2 MOTION verbs were judged familiar by only 86% of
students, and 3 COGNITION verbs were judged familiar by only
83% of students).
Subjects were asked to judge the “pleasantness” of each stimulus. We chose this single probe for all words to avoid explicit
categorization of verb subcategories, in which the content of the
word category can influence the nature of the categorization process and thus confound the interpretation of the results. This also
allowed us to minimize contaminating the content associated with
category-specific activations by avoiding foils (stimuli that are not
members of a target category and to which subjects would have
Table 1
Mean (⫾ SD) Demographic Characteristics of
Alzheimer’s Patients and Healthy Seniors
Measure
Age (years)
Education (years)
MMSE (maximum ⫽ 30)
Gender (male/female)
Verb comprehensiona
MOTION verbs
COGNITION verbs
Healthy seniors Alzheimer’s patients
(n ⫽ 16)
(n ⫽ 11)
73.9 (3.6)
13.8 (1.8)
29.7 (0.8)
9/7
95.0 (2.8)
97.3 (2.9)
92.8 (4.8)
73.0 (4.9)
15.3 (2.9)
20.2 (6.1)
8/3
77.3 (15.0)
80.0 (15.1)
74.5 (15.1)
Note. MMSE ⫽ Mini-Mental State Examination.
a
Verb comprehension was assessed with an 80-item multiplechoice paradigm requiring subjects to match one of four verbs with
a brief video clip or a verbal description of an action. Half of the
stimuli were MOTION verbs, and half were COGNITION verbs.
Performance on this protocol was available in 5 of the Alzheimer’s
disease patients participating in this study, and this was compared
with a group of 10 healthy, age- and education-matched seniors.
responded “no” in something like a category membership judgment task). Pleasantness decisions of this sort have been used for
over 30 years to probe deep or semantic knowledge (Warrington &
Weiskrantz, 1968). Moreover, pilot testing indicated that this task
can be performed easily by AD patients, thus minimizing interpretive confounds associated with impaired task performance
(Price & Friston, 1999). Each printed stimulus word was available
for 3 s, followed by a 1-s interstimulus interval, and each 10-word
block lasted 40 s. Subjects indicated their judgment of each word
as pleasant or not by depressing one of two buttons (the “pleasant”
button with the right thumb or the “not pleasant” button with the
left), and response and latency were recorded by the computer
presenting the stimuli. A technical error prevented us from collecting pleasantness judgments and latency data in 1 healthy senior. Words were presented continuously, and blocks were presented in a fixed random order without a break between blocks of
different categories. Subjects were not informed that different
categories of words were being administered.
Each run included two blocks of each category of verb (four
blocks of verbs in total). Each run also included six blocks of filler
words (nouns), and three baseline blocks (including two blocks of
pronounceable pseudoword stimuli and one block of pseudofont
stimuli) interspersed among the blocks of verb stimuli. Subjects
also made pleasantness judgments of these stimuli. We chose to
use the pseudoword stimuli as a sensory–motor control because the
semantically neutral character of these graphemic sequences allowed us to avoid the interpretive confounds associated with verb
activations relative to a baseline containing meaningful material.
Many studies have shown that nouns are associated with different
distributions of activation depending on the specific content of
these words (Farah & Aguirre, 1999; Joseph, 2001), and our use of
a baseline containing meaningful nouns would have potentially
changed the pattern of activation in a manner that is not related to
verb meaning. We were particularly sensitive to this issue in the
present study because of the possibility of different profiles of
noun comprehension difficulty in AD that may vary depending, in
part, on the specific semantic content of the words. We chose to
use pronounceable pseudowords rather than pseudofont stimuli
because we wanted to control in part for the phonemic and graphemic properties of words. Between-group comparisons were
made relative to the pseudoword baseline rather than with direct
contrasts of verb stimuli because the pseudoword baseline also
allowed us to control in part for potential differences in reading
processes known to be present in some AD patients compared with
healthy seniors (Glosser et al., 2002; Noble, Glosser, & Grossman,
2000). Three runs containing nonrepeated stimuli were presented
in total. Before each run, longitudinal magnetization was allowed
to attain equilibrium while subjects were acclimated to the MRI
environment during a 20-s period of viewing the words Get Ready
on the screen. Images corresponding to this period were discarded.
Brief rest periods (about 1 min) were included between runs.
Our stimulus presentation system (Epson 5000 LCD projector),
compatible with high magnetic fields, back-projected the printed
words onto a screen at the magnet bore. The subject viewed the
screen through a system of mirrors. A portable computer (Macintosh 1400C or G3) outside the magnet room used PsyScope
presentation software (Cohen, MacWhinney, Flatt, & Provost,
1993) to present stimuli and record response accuracy and latency.
Subjects were familiarized with the task prior to entering the
magnet bore, and the task was practiced by each subject.
Imaging Data Acquisition and Statistical Analysis
The experiment was performed at 1.5 T on an Echospeed
scanner (General Electric, Milwaukee, WI) capable of ultrafast
661
VERB PROCESSING IN ALZHEIMER’S DISEASE
imaging. We used a standard clinical quadrature radiofrequency
head coil. Firm foam padding was used to restrict head motion.
Each imaging protocol began with a 10 –15-min acquisition of
5-mm thick adjacent slices for determining regional anatomy,
including sagittal localizer images (TR ⫽ 500 ms, TE ⫽ 10 ms,
192 ⫻ 256 matrix), T2-weighted axial images (FSE, TR ⫽ 2,000
ms, TEeff ⫽ 85 ms), and T1-weighted axial images of slices used
for fMRI anatomic localization (TR ⫽ 600 ms, TE ⫽ 14 ms,
192 ⫻ 256 matrix). Gradient echo echoplanar images were acquired for detection of alterations of blood oxygenation accompanying increased mental activity. All images were acquired with fat
saturation, a rectangular FOV of 20 ⫻ 15 cm, flip angle of 90°, 5
mm slice thickness, an effective TE of 50 ms, and a 64 ⫻ 40
matrix, resulting in a voxel size of 3.75 mm ⫻ 3.75 mm ⫻ 5 mm.
The echoplanar acquisitions consisted of 18 contiguous slices in a
transaxial plane covering most of the brain every 2 s. A separate
acquisition lasting 1–2 min was needed for phase maps to minimize distortion in echoplanar images (Alsop, 1995). Raw data
were stored by the MRI computer on digital audio tape and then
processed offline.
Initial data processing was performed with Interactive Data
Language (Research Systems) on a Sun Ultra 60 workstation. Raw
image data were reconstructed with a two-dimensional fast Fourier
transformation with a distortion correction to minimize artifact
caused by magnetic field inhomogeneities. Individual subject data
were then prepared for a fixed-effects analysis and analyzed statistically by means of statistical parametric mapping (SPM) developed by Wellcome Department of Cognitive Neurology (Frackowiak, Friston, Frith, Dolan, & Mazziotta, 1997). The SPM99
system, operating on a MatLab (MathWorks, 1998; Version 5.2)
platform, combines raw difference images from individual subjects
into a statistical t map. In brief, the images in each subject’s time
series were registered to the initial image in the series. The images
were then aligned to a standard coordinate system (Talairach &
Tournoux, 1988) through the use of the Montreal Neurologic
Institute template (Evans et al., 1993). The data were spatially
smoothed with a 12-mm Gaussian kernel to account for small
variations in the location of activation and subtle interindividual
differences in gyral anatomy across subjects, and low-pass temporal filtering was implemented to control autocorrelation with a
first-order autoregressive method. Global means were normalized
by proportional scaling. The data were analyzed parametrically
with t test comparisons converted to z scores for each compared
voxel. We compared verb–pseudoword contrasts within groups
and then between groups with a Group x Task interaction using
these conditions. To test our hypotheses about relative activation in
healthy seniors and AD patients, we accepted a statistical threshold
of p ⬍ .001 uncorrected for multiple comparisons. Clusters were
larger than 18 adjacent voxels.
Results
Behavioral Observations
As summarized in Table 1, a subset of 5 AD patients had
difficulty on a multiple-choice verb comprehension procedure relative to healthy seniors, t(13) ⫽ 3.75, p ⬍ .002.
These AD patients also had relative difficulty with COGNITION verbs compared with their own performance with
MOTION verbs, t(4) ⫽ 3.77, p ⬍ .02.
Pleasantness judgments and response latencies during
imaging are summarized in Table 2. As can be seen, healthy
seniors and AD patients did not differ in their pleasantness
judgments of VERBS. This was true for MOTION verbs,
Table 2
Mean (⫾ SD) Pleasantness Judgments and Response
Latencies (in Milliseconds) for Judgments in Healthy
Seniors and Alzheimer’s Patients
Judgments
Healthy seniors
(n ⫽ 16)
Alzheimer’s patients
(n ⫽ 11)
Pleasantness judgments (range: 0–100)
VERBS
MOTION verbs
COGNITION verbs
75 (16)
68 (24)
83 (9)
66 (19)
77 (19)
55 (19)
Response latencies
VERBS
MOTION verbs
COGNITION verbs
1,371 (252)
1,414 (291)
1,328 (212)
1,604 (311)
1,688 (339)
1,520 (282)
t(24) ⫽ 1.42, ns, and COGNITION verbs, t(24) ⫽ 1.05, ns.
However, control subjects, t(14) ⫽ 3.24, p ⬍ .01, found
MOTION verbs to be less pleasant on average than COGNITION verbs, whereas AD patients, t(10) ⫽ 3.19, p ⬍ .01,
found COGNITION verbs to be less pleasant on average
than MOTION verbs. The AD patients were marginally
slower than the healthy seniors to respond to VERBS. This
was true for MOTION verbs, t(24) ⫽ 2.21, p ⫽ .04, and
COGNITION verbs, t(24) ⫽ 1.97, p ⫽ .06. Both control
subjects, t(14) ⫽ 1.54, ns, and AD patients, t(10) ⫽ 2.11,
p ⫽ .06, were a little slower to respond to MOTION verbs
than to COGNITION verbs. Pseudowords were judged less
pleasant than real words (controls: 31 ⫾ 35, AD patients:
17 ⫾ 19) to an equal extent in both groups, t(25) ⫽ 1.29, ns,
and these judgments did not differ in latency across groups
(controls: 1,443 ⫾ 312 ms; AD patients: 1,388 ⫾ 483 ms)
to an equal extent in both groups, t(25) ⫽ 0.36, ns.
Imaging Observations
Table 3 summarizes the coordinates of the peak loci and
the Brodmann areas associated with activation in healthy
subjects and AD patients for verb categories compared with
the pseudoword baseline. The activated clusters for healthy
seniors are illustrated in Figure 1. Figure 1A shows that
judgments of VERBS minus the pseudoword baseline recruited left posterolateral temporal–parietal, right inferior
frontal–anterior temporal–insula, and bilateral cingulate–
striatal regions in healthy seniors. We also observed right
anteromedial prefrontal activation. Figure 1B shows that
MOTION verbs activated left posterolateral temporal-parietal cortex. Figure 1C shows that COGNITION verbs recruited left posterolateral temporal–parietal cortex, right
inferior frontal–anterior temporal–insula regions, and bilateral anteromedial prefrontal cortex. Direct contrasts of motion verb and cognition verb categories are also provided in
Table 3. These are discussed in another report examining
healthy seniors relative to younger adults.
In AD patients, as summarized in Table 3 and shown in
Figure 2A, judgments of VERBS minus the pseudoword
baseline revealed activation of left posterolateral temporal
662
GROSSMAN ET AL.
Table 3
Locus of Peak Activation and Cluster Size During Pleasantness Judgments of MOTION Verbs and COGNITION Verbs
in Healthy Seniors and Alzheimer’s Disease Patients
x
y
z
Activation
extent
(no. of voxels)
⫺44
8
32
20
40
⫺40
⫺16
36
⫺20
⫺16
⫺12
⫺24
⫺36
32
4
⫺16
⫺36
⫺36
44
8
⫺4
40
⫺64
⫺8
44
⫺4
⫺4
28
44
44
0
0
⫺16
4
40
24
549
44
685a
685a
43
284
271
89
133
189
103
69
5.47
3.66
4.40
4.13
3.88
4.31
4.08
3.64
4.05
3.54
3.51
3.30
.0001
.0005
.0001
.0001
.0001
.0001
.0001
.0001
.0001
.0005
.0005
.0005
⫺48
⫺24
20
24
⫺32
⫺48
⫺12
32
8
⫺8
8
4
16
⫺4
⫺8
292
120
18
41
316
3.69
3.74
4.10
4.56
4.05
.0001
.0001
.0001
.0001
.0001
Coordinates
Contrast
Activation locus (Brodmann area)
z
p
Healthy seniors
VERBS minus baseline
MOTION minus baseline
COGNITION minus baseline
MOTION minus COGNITION
COGNITION minus MOTION
Left posterolateral temporal-parietal (40)
Right anteromedial prefrontal (32)
Right inferior frontal–anterior temporal-insula
Bilateral cingulate–striatum (24)
Left posterolateral temporal–parietal (40)
Left posterolateral temporal–parietal (40)
Bilateral anteromedial prefrontal (32)
Right inferior frontal–anterior temporal-insula
Left parahippocampus
Left anterior prefrontal (10)
Left superior parietal-occipital (19)
Left striatum
Alzheimer’s patients
VERBS minus baseline
MOTION minus baseline
COGNITION minus baseline
MOTION minus COGNITION
COGNITION minus MOTION
a
Left posterolateral temporal (22)
Left striatum
Right anteromedial prefrontal (32)
Right anterior temporal (38)
Left striatum
No significant activations
The peaks of these regions were part of the same, larger cluster.
cortex. Figure 2B shows that MOTION verbs recruited the
left striatum. For COGNITION verbs minus the pseudoword baseline, Figure 2C shows that right anteromedial
prefrontal cortex was activated in AD patients. Table 3 also
shows that the subtraction of MOTION verbs minus COGNITION verbs demonstrated differential activation of striatum and anterior temporal cortex. There were no areas
showing significantly greater activation for COGNITION
verbs than MOTION verbs in AD patients.
We directly contrasted activation associated with each
verb category in AD patients and healthy seniors. Table 4
summarizes the coordinates of the peak loci and the Brodmann areas associated with these activation contrasts in
healthy subjects and AD patients for verb categories compared with the pseudoword baseline. The clusters where AD
patients have less activation than healthy seniors are illustrated in Figure 3. Figure 3A shows that, during judgments
of VERBS minus pseudowords, AD patients had less activation than healthy seniors in the sulcal depths of left
posterolateral temporal–parietal cortex, right medial and
lateral temporal regions, left inferior frontal cortex, and
right striatum. By comparison, Figure 4 shows areas where
AD patients have greater activation than healthy seniors.
Figure 4A shows that AD patients had greater activation
than healthy seniors in left lateral mid-temporal cortex for
VERBS, implying a change in the anatomic distribution of
temporal activation in AD patients inferiorly, anteriorly, and
superficially in comparison to healthy seniors for the same
materials.
We also examined direct contrasts of activation patterns
in healthy seniors and AD patients for each category of
verbs. Figure 3B shows that, during judgments of MOTION
verbs minus pseudowords, AD patients had less activation
of right temporal cortex than healthy seniors. By comparison, Figure 4B shows that AD patients had greater activation than healthy seniors in the left striatum and left inferior
frontal cortex during motion verb judgments. For COGNITION verbs, Figure 3C shows that AD patients had significantly less activation of the right striatum and the left
striatum– cingulate region than healthy seniors. However,
there were no areas where AD patients had greater activation than healthy seniors had for COGNITION verbs.
Discussion
Patients with AD appear to have difficulty with verbs on
several kinds of behavioral tasks such as naming and word–
picture matching (Bushell & Martin, 2002; Cappa et al.,
1998; K. M. Robinson et al., 1996; van der Lem et al., 2002;
White-Devine et al., 1996), although this is not a universal
finding (Fung et al., 2001; Parris & Weekes, 2001; G.
Robinson et al., 1999). In the present study, we demonstrated differences in brain activation patterns for verbs in
AD patients compared with age-matched healthy seniors.
Healthy seniors activated several brain regions for verbs
that are also recruited in studies of young healthy subjects
(Damasio et al., 2001; Grabowski et al., 1998; Grossman et
al., 2002b; Perani et al., 1999). However, AD patients
appeared to recruit only a portion of the activations seen in
healthy seniors. Direct comparisons showed that some activations in AD patients are less robust statistically than the
activations seen in healthy seniors, whereas other activa-
VERB PROCESSING IN ALZHEIMER’S DISEASE
663
tion profile associated with verb processing and with each
verb subcategory below. By way of anticipation, we argue
that reduced verb comprehension in AD patients is related
in part to their limited neural activation of brain regions
critical to understanding verb meaning. We also speculate
that areas of increased activation in AD patients relative to
healthy seniors represent compensatory changes in the face
Figure 1. Activation of verb categories compared with a pronounceable pseudoword baseline in healthy seniors. A: VERBS
minus baseline. B: MOTION verbs minus baseline. C: COGNITION verbs minus baseline.
tions in AD patients appear to be in an anatomic distribution
that is relatively unactivated in healthy seniors. Moreover,
these changes appeared to depend in part on the specific
verb subcategory being probed: Increased activation in AD
patients relative to healthy seniors was seen for MOTION
verbs, but not COGNITION verbs. We discuss the activa-
Figure 2. Activation of verb categories compared with a pronounceable pseudoword baseline in Alzheimer’s disease patients.
A: VERBS minus baseline. B: MOTION verbs minus baseline. C:
COGNITION verbs minus baseline.
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Table 4
Locus and Extent of Peak Activations for Direct Contrasts of Healthy Seniors and Alzheimer’s Patients During
Pleasantness Judgments of MOTION Verbs and COGNITION Verbs in Comparison With a
Pronounceable Pseudoword Baseline
Coordinates
Contrast
Activation locus (Brodmann area)
x
y
z
Activation
extent
(no. of voxels)
z
p
114
97
843a
843a
71
229
75
3.18
3.45
5.04
4.92
3.04
4.12
4.11
.001
.001
.0001
.0001
.001
.0001
.0001
58
74
3.25
3.05
.001
.001
Alzheimer’s patients with less activation than healthy seniors
VERBS
MOTION
COGNITION
Left posterolateral temporal-parietal (22)
Left inferior frontal (45)
Right temporal (21)
Right striatum
Right midlateral temporal (22)
Left cingulate-striatum (24)
Right striatum
⫺28
⫺32
40
28
36
⫺28
28
⫺56
32
⫺40
16
⫺36
⫺12
12
16
16
0
4
8
24
0
Alzheimer’s patients with greater activation than healthy seniors
VERBS
MOTION
a
Left lateral midtemporal (21)
Left inferior frontal-striatum (45)
⫺40
⫺20
⫺28
⫺12
⫺8
4
The peaks of these regions were part of the same, larger cluster.
of a neurodegenerative disease that allow these patients to
achieve partial comprehension of MOTION verbs.
Activation Patterns Associated With Verbs in
Healthy Seniors
Healthy seniors activated left posterolateral temporal cortex during presentation of VERBS in comparison with a
pronounceable pseudoword baseline. This distribution of
activation has been seen in previous functional neuroimaging work with a variety of tasks involving verbs in healthy
young subjects. For example, these reports described posterolateral temporal activation in investigations of verb generation (Fiez, Raichle, Balota, Tallal, & Petersen, 1996),
probes of action knowledge associated with object words
and pictures (Martin, Haxby, Lalonde, Wiggs, & Ungerleider, 1995), and lexicality decisions about printed verbs
(Perani et al., 1999). The precise locus of activation was not
identical across these studies; this difference was probably
related to multiple sources of differences involving the tasks
and the imaging techniques. Nevertheless, left posterolateral
temporal cortex has been implicated in lexical–semantic
processing based on structural imaging studies of patients
with insult to this region (Chertkow, Bub, Deaudon, &
Whitehead, 1997; Hart & Gordon, 1990; Hillis et al., 2001),
correlations of performance on semantic tasks with functional neuroimaging studies obtained at rest in AD patients
who have impaired lexical comprehension (Desgranges et
al., 1998; Grossman, White-Devine, et al., 1997), and
positron emission tomography and fMRI activation studies
in which healthy subjects were challenged to understand the
meaning of a noun (Grossman et al., 2002a; Martin, Wiggs,
Ungerleider, & Haxby, 1996; Price, Moore, Humphreys, &
Wise, 1997; Warburton et al., 1996; Whatmough, Chertkow, Murtha, & Hanratty, 2002). We too observed recruitment of left posterolateral temporal–parietal cortex for
VERBS in the present study, extending this basic finding to
a population of healthy senior subjects.
One account attributes this distribution of activation to
the visual motion thought to be an important component of
the knowledge associated with VERBS. Indirect evidence
consistent with this explanation comes from other fMRI
work that associates this posterolateral temporal distribution
of activation with visual motion that is thought to be a
critical feature of IMPLEMENT knowledge (Bonda et al.,
1996; de Jong et al., 1994; Kourtzi & Kanwisher, 2000;
Patzwahl et al., 1996; Puce et al., 1998). However, recent
observations have begun to cast doubt on this sensory–
motor feature approach to interpreting the activation patterns associated with word meaning (Farah & Aguirre,
1999; Grossman et al., 2002a; Joseph, 2001; Kellenbach et
al., 2001; Noppeney & Price, 2002). With respect to
VERBS, it is noteworthy that most studies in fact have used
motion verb stimuli. Cognition verbs are generally impoverished in their sensory–motor features, yet studies involving this verb subcategory also reported activation of the
posterolateral temporal area of the left hemisphere (Grossman et al., 2002b; Perani et al., 1999). Tyler and her
coworkers (Tyler, Russell, Fadili, & Moss, 2001) reported
posterolateral temporal activation for nouns and verbs, regardless of whether they were high imageability or concrete
on the one hand, or low imageability or abstract on the other
hand, in both lexical decision and semantic categorization
tasks. Left posterolateral temporal cortex thus appears to be
associated with the comprehension of VERBS, but this is
unlikely to be due entirely to the sensory–motor features
associated with this class of words, as COGNITION verbs
activating this area are quite impoverished in sensory–motor
features such as visual motion. In the present study, we
confirmed the left posterolateral temporal–parietal distribution of activation for both MOTION verbs and COGNI-
VERB PROCESSING IN ALZHEIMER’S DISEASE
Figure 3. Areas of reduced activation in Alzheimer’s disease
patients in direct contrasts with healthy seniors for verb categories
compared with a pronounceable pseudoword baseline. A: VERBS
minus baseline. B: MOTION verbs minus baseline. C: COGNITION verbs minus baseline.
TION verbs in healthy seniors. This neuroanatomic recruitment profile for COGNITION verbs parallels activation
associated with abstract nouns in healthy subjects (Beauregard et al., 1997; Grossman et al., 2002a; Kiehl et al., 1999;
Perani et al., 1999). An alternate possibility is that the left
posterolateral temporal region helps integrate the complex
665
network of associative knowledge that underlies the meaning of words, including abstract words that are impoverished in sensory–motor features. Some evidence to support
this alternate account comes from recent work examining
the anatomic distribution of activation associated with the
categorization process that is critical to understanding word
meaning. These studies demonstrated left posterolateral
temporal activation during the processes involved in semantic categorization of object descriptions and acquiring the
meaning of a new semantic category (Grossman, Smith, et
al., 2002; Koenig, Smith, DeVita, et al., 2002). Additional
work is needed to determine the specific role that left
posterolateral temporal cortex plays in lexical semantic
comprehension.
Many functional neuroimaging investigations of verb
knowledge also have reported activation in a frontal distribution (Fiez et al., 1996; Martin et al., 1995; Perani et al.,
1999). We too observed activation in frontal cortex for all
VERBS in healthy seniors. One hypothesis associates this
with the motor-action knowledge contributing to MOTION
verbs being used as stimuli in most studies of verb comprehension (Decety et al., 1994; Gallese et al., 1996; Jeannerod
et al., 1995; Rizzolatti, Fadiga, Matelli, Bettinardi, Paulesu,
& Perani, 1996; Rizzolatti, Fadiga, Matelli, Bettinardi,
Paulesu, Perani, & Fazio, 1996). When we examined the
circumstances associated with frontal activation in the
present study, we found that the frontal distribution of
recruitment was associated more strongly with COGNITION verbs than with MOTION verbs. Given the impoverished motor feature component of COGNITION verbs, it
is unlikely that the frontal activation is related to motion
feature knowledge. One alternate possibility is that the
frontal distribution of this activation contributes to the retrieval process associated with a lexical comprehension task
(Demb et al., 1995; Thompson-Schill, D’Esposito, Aguirre,
& Farah, 1997). However, activations related to retrieval are
often located in the left inferior frontal region, and inferior
frontal activation in the present study was localized to the
right hemisphere in healthy seniors. Moreover, the identical
component of our baseline task is likely to have minimized
frontal activation as a result of this process. Previous work
using a variety of techniques in healthy subjects, split-brain
patients, and aphasic patients with conditions like deep
dyslexia have emphasized that lexical representations in the
right hemisphere are likely to be more robust for words that
are richly endowed with concrete features (Coltheart, 1980;
Kounios & Holcomb, 1994; Zaidel, 1978). Although this
may seem at first inconsistent with activation for a class of
verbs impoverished in their sensory–motor features, other
work suggests that words with less precise meaning, such as
abstract verbs denoting cognition may be more dependent
on right hemisphere-based processes (Beeman et al., 1994),
possibly related to the sustained activation needed to process abstract words. Another possibility is that right inferior
frontal activation is related to a lexical retrieval process
(Nyberg, Cabeza, & Tulving, 1996; Tulving, Kapur, Craik,
Moscovitch, & Houle, 1994). This may have been more
evident in healthy seniors than in the young adults from our
previous work (Grossman et al., 2002b), in which we did
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GROSSMAN ET AL.
Figure 4. Areas of increased activation in Alzheimer’s disease patients in direct contrasts with
healthy seniors for verb categories compared with a pronounceable pseudoword baseline. A:
VERBS minus baseline. B: MOTION verbs minus baseline. There was no increased activation in
Alzheimer’s disease patients compared with healthy seniors for COGNITION verbs.
not see right frontal activation using the same paradigm,
because of the relative difficulty associated with lexical
retrieval in older subjects (Albert & Knoefel, 1994; Barresi,
Nicholas, Connor, Obler, & Albert, 2000; Ramsay, Nicholas, Au, Obler, & Albert, 1999). Several studies investigating age-related changes in the encoding and retrieval of
words have reported right frontal activation during retrieval
in young subjects, but bilateral frontal activation in healthy
seniors (Backman et al., 1997; Cabeza et al., 1997; Madden
et al., 1999). Differences between these studies and the
results described in the present report may be due to the
many differences in the nature of the material being retrieved and the tasks and baselines used to investigate
age-related lexical knowledge. Additional work is needed to
VERB PROCESSING IN ALZHEIMER’S DISEASE
assess the basis for right inferior frontal activation for verbs
in healthy seniors.
We also observed anteromedial prefrontal activation for
VERBS in an anatomic distribution that is not typically
associated with motor-action features. One account for this
activation focuses on the affective component of the pleasantness task we used to probe meaning in this study (Simpson, Snyder, Gusnard, & Raichle, 2001). For example,
medial prefrontal activation has been associated with materials that require the integration of cognitive and emotional
attributes (Drevets & Raichle, 1998; Shulman et al., 1997).
We may have observed medial prefrontal activation in
healthy seniors, but not in our previous studies of healthy
young subjects with the same materials, because an agerelated limitation in executive resources may have been less
effective at suppressing the pleasantness component of the
task in healthy seniors while they were considering the
verb’s meaning (Hasher & Zacks, 1988). Anteromedial prefrontal activation was particularly prominent for COGNITION verbs, and we cannot rule out the possibility that the
more pleasant nature of COGNITION verbs somehow activated this brain region in a category-specific manner.
Alternately, the complex network of associations implicated
in the meaning of verbs—particularly abstract word categories such as COGNITION verbs (Gentner, 1981)—may
have recruited this anteromedial prefrontal region to help
support interpretation of the massively interconnected network of associations underlying these words (Braver &
Bongiolatti, 2002; Koechlin, Basso, Pietrini, Panzer, &
Grafman, 1999; Koechlin, Corrado, Pietrini, & Grafman,
2000). We have also seen recruitment of this area in fMRI
studies of semantic categorization (Koenig, Smith, DeVita,
et al., 2002).
We observed striatal and cingulate activation for VERBS
in healthy seniors as well. Since the striatum is an important
component of a frontal–striatal–thalamic loop mediating
motor functions (Alexander, Crutcher, & DeLong, 1990),
we had hypothesized in our previous work with young
adults that this distribution of activation was related to
knowledge of motor features associated with MOTION
verbs (Grossman et al., 2002b). However, the striatum also
contributes to other frontal–striatal–thalamic loops that are
unrelated to motor functioning (Alexander et al., 1990). One
possibility is that the striatum is part of a frontal–striatal–
thalamic loop mediating affective processing. We noted
above that limited inhibitory control in healthy seniors may
have allowed the pleasantness component of our task to play
a greater role in the overall activation pattern seen in the
present study, including recruitment of anteromedial prefrontal cortex. Another possibility is that striatal activation
is part of a different frontal–striatal loop involving the
cingulate that is important in the support of executive resources. Several recent functional neuroimaging studies in
young subjects emphasize the role of the striatum in executive resources such as working memory for nonlinguistic
problem solving (Poldrack, Prabhakaran, Seger, & Gabrieli,
1999; Rypma, Prabhakaran, Desmond, Glover, & Gabrieli,
1999) and understanding complex linguistic stimuli such as
sentences (Cooke et al., 2000). Studies of age-related dif-
667
ferences in sentence comprehension also appear to relate
striatal activation to the working memory resources needed
to understand complex sentences (Grossman, Cooke, et al.,
2002). The cingulate itself has been associated with selective attention, monitoring response selection, and regulating
the implementation of executive resources (Botvinick,
Braver, Barch, Carter, & Cohen, 2001; Botvinick, Nystrom,
Fissell, Carter, & Cohen, 1999; Carter et al., 1998, 2000). In
this context, it is possible that cingulate and striatal activation were due in part to the effort associated with comprehension of a complex lexical category like VERBS. Cingulate recruitment may have been seen in the present report,
but not our previous study of verbs in young subjects
(Grossman et al., 2002b), because of a relative limitation of
age-related executive resources. Against this account is the
finding that MOTION verbs were marginally more difficult
to process than COGNITION verbs because they were
judged somewhat less rapidly, even though there was no
preferential activation of cingulate and striatal regions for
MOTION verbs. Additional work is needed to interpret the
basis for cingulate and striatal activation during verb comprehension in healthy seniors.
Activation Patterns Associated With Verbs in
Alzheimer’s Patients
Consider in this context the activation pattern for VERBS
in AD patients. Like healthy seniors, AD patients activated
left posterolateral temporal cortex during judgments of
VERBS. However, activation of this brain region appeared
to be less robust than in healthy seniors, on the basis of a
direct comparison of activation patterns across these groups
of subjects. It is not simply that AD patients could not
activate this brain region that is so critical to processing the
meanings of individual words. Instead, the peak of activation in AD patients, when directly compared with healthy
seniors (see Table 4 and Figure 4A), was changed in its
anatomic distribution such that it was localized inferiorly by
more than 20 mm, anteriorly by more than 20 mm, and
superficially by more than 10 mm in comparison to the peak
of activation for VERBS in healthy seniors relative to AD
patients (see Table 3 and Figure 3A). Much work with a
variety of techniques has pointed out the critical contribution of left posterolateral temporal cortex to semantic memory (Chertkow et al., 1997; Desgranges et al., 1998; Grossman et al., 1997; Hart & Gordon, 1990; Hillis et al., 2001),
and recruitment changes in this area in the present study are
consistent with the hypothesis that verb comprehension
difficulty in AD is related in part to impairments of left
posterolateral temporal cortex functioning. Our observation
of activation changes in this region during comprehension
of verbs in AD extends our finding of a similar pattern of
change in the anatomic distribution of activation in AD
patients relative to healthy seniors during probes of noun
meaning (Grossman et al., 2003).
Changed activation in left posterolateral temporal cortex
associated with poor verb comprehension in AD provides an
important beginning in our attempt to understand the basis
for comprehension difficulty in these patients. However,
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GROSSMAN ET AL.
this observation does not provide specific information about
the role played by this brain region in semantic memory.
One possibility is that partial activation of left posterolateral
temporal cortex during verb comprehension in AD may
reflect partial degradation of verb knowledge in these patients, such as difficulty with visual-motion features. However, we have not found a correlation between verb naming
and visual–perceptual functioning in AD (K. M. Robinson
et al., 1996). We discussed above several other problems
with attributing changes in temporal–parietal activation to
visual-motion feature knowledge. Another possibility relates reduced left posterolateral temporal activation to a
deficit in the process of semantic categorization. For example, the interpretation of word meaning requires the integration of feature knowledge that may be represented in a
distributed manner in several cortical regions. The anatomical connectivity pattern of this heteromodal brain area with
multiple sensory–motor association regions (Mesulam, van
Hoesen, Pandya, & Geschwind, 1977; Seltzer & Pandya,
1978) is consistent with this integrative role. Recent fMRI
work directly assessing this integrative function for the
purpose of semantic categorization has demonstrated posterolateral temporal activation as well (Koenig, Smith,
Moore, et al., 2002), and patients with AD are compromised
on these semantic categorization measures (Grossman,
Smith, Koenig, Glosser, Rhee, & Dennis, in press; Koenig,
Smith, Moore, et al., 2002). Regardless of the specific role
in impaired verb comprehension played by partial left posterolateral temporal activation, one possible explanation for
this observation is related to the histopathologic distribution
of disease in AD. Thus, AD patients may have a relatively
greater disease burden in the anatomic area most strongly
activated in healthy seniors, but less disease in the portion of
the left temporal lobe that they did activate. Although this
may have allowed AD patients to activate a portion of the
left posterolateral temporal area contributing to verb comprehension, the relatively reduced area of activation in AD
patients compared with healthy seniors may explain in part
their limited comprehension of verbs.
Several other brain regions were recruited by healthy
seniors, but not AD patients. Limited activation of frontal,
striatal, and right temporal regions in AD thus may contribute to their poor comprehension of VERBS as well. This
conclusion should be viewed cautiously, however, since
these differences may have been due in part to the limited
power associated with a study involving only 11 AD patients. Evidence consistent with this latter possibility comes
from the observation that AD patients showed activation in
some of these regions for subcategories of verbs, such as
recruitment of the striatum for MOTION verbs and anteromedial prefrontal cortex for COGNITION verbs. Additional
work is needed to determine the basis for this limited
activation in AD patients relative to healthy seniors. Regardless of the specific explanation, the observation of increased activation in a portion of the left temporal lobe in
AD patients compared with healthy seniors implies that
areas of limited recruitment in AD are not easily explained
by something like a global, nonspecific reduction in brain
activity in these patients.
Healthy seniors and AD patients both recruited the left
inferior frontal region as well, although this was evident
only in the direct contrasts across groups and not readily
apparent in the activation pattern of each group compared
with the pseudoword baseline. The loci of peak activation
were somewhat different across these two groups of subjects. Left inferior frontal activation in AD patients for
VERBS thus was about 30 mm posterior and 10 mm inferior
to that seen in healthy seniors for MOTION verbs. Because
left inferior frontal cortex is thought to contribute to grammatical processing (Constable et al., 1998; Dapretto &
Bookheimer, 1999; Kang, Constable, Gore, & Avrutin,
1999; Ni et al., 2000), one possibility is that changes in left
inferior frontal integrity in AD, reflected in a changed
anatomic distribution of activation, may reflect AD patients’
limited retrieval of the grammatical properties contributing
to verb comprehension. AD patients do have some difficulty
on measures of grammatical comprehension (Croot,
Hodges, & Patterson, 1999; Kontiola, Laaksonen, Sulkava,
& Erkinjuntti, 1990; Swihart, Panisset, Becker, Beyer, &
Boller, 1989; Tomoeda, Bayles, Boone, & Kaszniak, 1990),
although this appears to be closely related to a working
memory limitation that also contributes to these measures of
grammatical comprehension (Grossman & Rhee, 2001;
Grossman & White-Devine, 1998; Kempler, Almor, Tyler,
Andersen, & MacDonald, 1998; Waters, Caplan, & Rochon,
1995). Moreover, grammatical comprehension does not appear to be correlated with verb naming in AD (K. M.
Robinson et al., 1996). An alternate account focuses on
several studies showing age-related increases in left inferior
frontal activation during the retrieval phase of verbal anterograde memory tasks (Backman et al., 1997; Cabeza et
al., 1997; Madden et al., 1999). Although generalizations
from studies of anterograde memory to studies of semantic
memory must be conducted only with great caution, one
possibility suggested by this work is that differences in left
inferior frontal activation in healthy seniors and AD patients
may reflect differential retrieval efficiency in anterograde
memory compared with semantic memory. This would also
be consistent with imaging observations of healthy adults
suggesting that left inferior frontal cortex contributes to
some aspect of retrieval from semantic memory (Demb et
al., 1995; Thompson-Schill et al., 1997; Wagner, PareBlagoev, Clark, & Poldrack, 2001). The role played by
changes in left inferior frontal activation during verb comprehension in AD requires additional investigation. Regardless of the specific consequences of changed activation in a
left inferior frontal distribution, partial activation of this
region in AD may be related to the histopathologic distribution of their disease, thus allowing these patients to recruit only a portion of the region involved in verb comprehension and consequently limiting their verb comprehension performance.
Direct contrasts with healthy seniors also showed that AD
patients have relatively reduced right temporal activation,
particularly for MOTION verbs. Although we did not observe activation for MOTION verbs in the right hemisphere
in healthy seniors that exceeded our statistical threshold, the
relative reduction of right hemisphere activation during
VERB PROCESSING IN ALZHEIMER’S DISEASE
motion verb judgments in AD may have contributed to AD
patients’ limited comprehension of this verb subcategory.
For example, some workers have emphasized the spatialtemporal properties associated with motion verb knowledge
(Jackendoff, 1983). These features may be represented in
the right hemisphere, and AD patients may be less effective
than healthy seniors at recruiting these particular features of
verbs. This account must be treated cautiously, however,
since we did not observe a relationship between verbnaming difficulty and visual–perceptual processing in our
previous behavioral work with AD patients (K. M. Robinson et al., 1996). On the basis of activation of ventral
temporal cortices in AD patients for MOTION verbs relative to COGNITION verbs, another possibility is that AD
patients are attempting to activate features related to object
form/shape that are more appropriate for noun meaning—
such as the object associated with a motion—than for verb
meaning. Other possibilities include a change in the nature
of the processes associated with understanding complex
categories of words such as MOTION verbs (Beeman et al.,
1994). Additional work is needed to understand the role of
reduced right temporal activation in AD patients’ limited
comprehension of MOTION verbs.
AD patients did activate the left striatum during their
comprehension of MOTION verbs relative to the
pseudoword baseline, although this region was not recruited
to a statistically significant degree for MOTION verbs by
healthy seniors. Indeed, a direct contrast of activation for
MOTION verbs in these subject groups demonstrated that
AD patients had significantly greater striatal recruitment,
accompanied by significantly greater activation of a portion
of left inferior frontal cortex, than was seen in healthy
seniors. The precise role played by the increased inferior
frontal–striatal activation for MOTION verbs in AD is not
clear. One possibility is that up-regulation of these regions
helps support AD patients’ motor-action knowledge. We
suggested above several reasons to doubt this feature-based
account. An alternate possibility is that lexical retrieval is
more difficult for AD patients than it is for healthy seniors.
Confrontation naming difficulty is a well-known characteristic of AD (Bayles, Tomoeda, & Trosset, 1990; Dennis,
Koenig, Moore, Patel, & Grossman, 2002; Hodges et al.,
1996; Huff, Corkin, & Growdon, 1986; Lambon Ralph,
Patterson, & Hodges, 1997; Martin, Brouwers, & Lalonde,
1986; Shuttleworth & Huber, 1988), including difficulty
naming actions with verbs (Cappa et al., 1998; K. M.
Robinson et al., 1996; White-Devine et al., 1996). Thus,
increased frontal–striatal activation may support the need to
meet relatively greater resource demands associated with
lexical retrieval in AD patients compared with healthy
seniors.
We also found that AD patients, like healthy seniors,
activated anteromedial prefrontal cortex during comprehension of COGNITION verbs. However, this activation was
unilateral in AD patients, compared with the bilateral activation in healthy seniors. The reduced activation of this area
in AD patients relative to healthy seniors may contribute to
AD patients’ relatively poor comprehension of COGNITION verbs. Moreover, direct contrasts of these subject
669
groups showed that AD patients have reduced cingulate–
striatal activation for COGNITION verbs in comparison to
healthy seniors for COGNITION verbs, and this also may
play a role in AD patients’ relatively reduced comprehension of COGNITION verbs. Finally, we did not see any
areas of increased activation for COGNITION verbs in AD
patients relative to healthy seniors for COGNITION verbs,
nor any increased activation for COGNITION verbs in AD
patients relative to their own activation for MOTION verbs.
This is unlike judgment of VERBS, in which AD patients
showed relatively greater left lateral temporal activation
than healthy seniors, and unlike judgment of MOTION
verbs, in which AD patients showed relatively increased left
frontal–striatal activation compared with healthy seniors.
The apparent absence of increased activation in AD patients
compared with healthy seniors in any brain region for
COGNITION verbs may also contribute to the relatively
poor comprehension of these words in AD patients compared with healthy seniors, and in comparison to their own
performance with MOTION verbs. Thus, at least three
factors appear to contribute to AD patients’ relative difficulty with COGNITION verbs: reduced activation in an
area activated by both groups, apparent failure to activate an
area that is recruited by healthy seniors, and the absence of
activation in novel brain regions that are not activated by
healthy seniors.
A unique feature of AD patients’ activation profiles was
the absence of areas of increased activation relative to
healthy seniors only for COGNITION verbs, which are
thought to depend on a complex and massively interconnected network that derives knowledge from the associations represented in this network (Gentner, 1981). In a
progressive neurodegenerative condition such as AD, in
which associative networks may be degraded over time
(Gonnerman, Andersen, Devlin, Kempler, & Seidenberg,
1997; Tyler, Moss, Durrant-Peatfield, & Levy, 2000), one
possibility is that comprehension of COGNITION verbs
may not be supportable. Another possibility is that AD
patients may not be able to marshal the processing resources
needed to support interpretation of the complex network
underlying the meanings of COGNITION verbs. For example, healthy seniors may depend in part on anteromedial
prefrontal cortex to help organize knowledge represented in
the complex associative network underlying COGNITION
verbs, and may use cognitive resources supported by cingulate–striatal activation to help them selectively attend to a
category of knowledge like COGNITION verbs that is
relatively difficult to process. However, this mechanism
may be limited in AD patients because they apparently do
not fully recruit anteromedial prefrontal cortex or a cingulate–striatal loop during cognition verb processing. Moreover, unlike the activation seen with MOTION verbs, we
did not see increased activation for COGNITION verbs in
AD patients compared with healthy seniors for COGNITION verbs. Several previous functional neuroimaging assessments of AD in other cognitive domains appeared to
show up-regulation during task performance that was
thought to compensate in part for the AD patients’ reduced
activations (Becker et al., 1996; Grady, Furey, Pietrini,
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GROSSMAN ET AL.
Horwitz, & Rapoport, 2001; Woodard et al., 1998), and we
have seen up-regulation during an fMRI study of noun
comprehension in AD (Grossman et al., 2003). In a similar
way, we speculate that partial activation during processing
of VERBS in general and MOTION verbs in particular may
represent compensatory recruitment that helps AD patients
understand some aspects of verbs. This would be consistent
with AD patients’ relative success understanding MOTION
verbs compared with COGNITION verbs. The potential
contribution of compensatory up-regulation in AD may
parallel functional neuroanatomic observations of reorganization following stroke, in which areas of increased brain
activation have been shown to contribute to recovery of linguistic function in aphasia (Heiss, Kessler, Thiel, Ghaemi,
& Karbe, 1999; Rosen et al., 2000). The biological basis for
this compensatory activation in AD may be the axonal
sprouting and biochemical changes associated with cortical
reorganization that are described in these patients (Geddes
et al., 1985; Kowall & McKee, 1993; Scheibel & Tomiyasu,
1978).
There are several shortcomings associated with this study
that must be kept in mind when considering our results. We
do not have behavioral measures of comprehension accuracy in all of the AD patients we studied. Although we used
a pseudoword baseline to control for reading differences
and other potential sensory–motor differences between subject groups, the pseudoword baseline itself may be associated with activations that limited our ability to identify brain
areas important for word meaning in our subtractions. Subtle differences in cerebral anatomy caused by regional atrophy in AD may have contributed to some of the changes
seen in these patients relative to healthy seniors. Although
the AD patients we examined were mildly demented and
thus had minimal atrophy, the normalization algorithm we
used nevertheless may not have been able to map AD
patients’ brain volumes as accurately as healthy seniors’
brain volumes onto the anatomic template we used to analyze activation. In addition, although our work was intended
to assess cerebral activation patterns associated with verbs,
the examination of subcategories of MOTION verbs and
COGNITION verbs also proved quite informative, but at a
cost of reduced statistical power. The statistical analyses
thus may have been limited because of several effects that
only approached our statistical threshold for significance for
a word subcategory. MOTION verbs showed some activations in AD patients that differed from the activations seen
in healthy seniors, but a similar pattern of selectively greater
activation for COGNITION verbs was not seen. This leaves
open the possibility that COGNITION verbs were more
difficult than MOTION verbs in some nonspecific sense.
With these limitations in mind, our observations suggest
that limited performance on tasks requiring verb knowledge
may be due in part to changes in AD patients’ activation of
the large-scale neural network implicated in the comprehension of verbs. Left posterolateral temporal and inferior frontal regions are partially activated in AD to support verb
comprehension, and the distribution of these activations in
AD patients are changed relative to that of healthy seniors.
We believe that these areas are implicated in processes
important for word meaning such as integrating feature
knowledge distributed throughout modality-specific association cortices. Other brain regions that apparently contribute
to verb processing in healthy seniors are less activated in
AD, although category-specific compensatory up-regulation
for MOTION verbs may allow AD patients to achieve
partial comprehension of MOTION verbs compared with
COGNITION verbs. These category-specific changes may
be related to the neural representation of knowledge specific
to MOTION verbs.
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Received March 25, 2002
Revision received April 9, 2003
Accepted April 10, 2003 䡲