Brain and Language 85 (2003) 211–221
www.elsevier.com/locate/b&l
Neural basis for sentence comprehension deficits in
frontotemporal dementiaq
Ayanna Cooke,a Christian DeVita,a James Gee,b David Alsop,b John Detre,a,b
Willis Chen,a and Murray Grossmana,*
a
Department of Neurology—2 Gibson, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA
b
Department of Radiology, University of Pennsylvania Medical Center, Philadelphia, PA, USA
Accepted 11 September 2002
Abstract
Many patients with frontotemporal dementia (FTD) have impaired sentence comprehension. However, the pattern of comprehension difficulty appears to vary depending on the clinical subgroup. The purpose of this study was to elucidate the neural basis
for these deficits in FTD. We studied patients with two different presentations: Three patients with Progressive Non-Fluent Ahasia
(PNFA), and five non-aphasic patients with a dysexecutive and social impairment (EXEC). The FTD patient subgroups were
compared to a cohort of 11 healthy seniors with intact sentence comprehension. We monitored regional cerebral activity with blood
oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) while subjects read sentences featuring both a
grammatically complex object-relative center-embedded clause and a long linkage between the head noun phrase (NP) and the gap
where the NP is interpreted in the center-embedded clause. Subjects decided whether the agent of the action is a male or a female.
Healthy seniors activated both ventral portions of inferior frontal cortex (vIFC) and dorsal portions of IFC (dIFC) in the left
hemisphere, often associated with grammatical and working memory components of these sentences, respectively. PNFA patients
differed from healthy controls since they have reduced activation of left vIFC, while EXEC patients have less recruitment of left
dIFC. We conclude that FTD subgroups have distinct patterns of sentence comprehension difficulty in part because of selective
interruptions of a large-scale neural network for sentence processing.
Ó 2003 Elsevier Science (USA). All rights reserved.
1. Introduction
Frontotemporal dementia (FTD) is a neurodegenerative condition with progressive language, cognitive, and
behavioral impairments (Grossman, 2002; Snowden,
Neary, & Mann, 1996). Some cases of FTD are linked to
a mutation on chromosome 17 that codes for tau, a microtubule-associated protein, while others show a very
similar pattern of abnormally decreased tau levels in
post-mortem biochemical studies of FTD brains (Foster
et al., 1997; Zhukareva et al., 2001). Clinical-pathologi-
q
This research was supported in part by National Institutes of
Health Grants DC00237, AG17586, NS35867, and AG15116. Portions
of this work were presented at the World AlzheimerÕs Congress,
Washington, DC, July 2000, Academy of Aphasia conference, October
2001, and Society for Neuroscience, November 2001.
*
Corresponding author. Fax: 1-215-349-8464.
E-mail address: [email protected] (M. Grossman).
cal studies involving functional neuroimaging have related this pattern of clinical and biochemical impairment
to neuronal dropout and vacuolar degeneration that
affects frontal and anterior temporal brain regions
(Turner, Kenyon, Trojanowski, Gonatas, & Grossman,
1996). FTD has been sorted into clinical subgroups
(Davis, Price, Moore, Campea, & Grossman, 2001;
Neary et al., 1998; Price, Davis, Moore, Campea, &
Grossman, 2001). One subgroup of FTD patients presents with progressive aphasia. Progressive Non-Fluent
Aphasia (PNFA) patients appear to have effortful
agrammatic speech and grammatical comprehension
difficulty. Other progressive aphasics have Semantic
Dementia (SD), involving a naming deficit and empty
speech with poor single word comprehension. By comparison, another subgroup of FTD patients without
obvious aphasia has an executive disorder that includes
poor working memory (WM), and/or a behavioral
disorder with altered personality and impaired social
0093-934X/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved.
doi:10.1016/S0093-934X(02)00562-X
212
A. Cooke et al. / Brain and Language 85 (2003) 211–221
conduct (abbreviated here as EXEC to avoid confusion
with acronyms similar to FTD). Researchers have begun
to elucidate the neuroanatomic basis for these difficulties
with structural (Chan et al., 2001; Chan, Fox, & Scahill,
2001; DeVita, Lin, Gee, Moore, & Grossman, 2002;
Mummery, Patterson, Price, & Hodges, 2000) and
functional (Grossman et al., 1998; Mummery et al.,
1999) neuroimaging techniques. In the present study, we
report our initial evaluation of the functional neuroanatomy of FTD while patients are performing a sentence comprehension task.
Pick first noted speech difficulty in a patient with
apparent FTD over a century ago (Pick, 1892). Sentence
comprehension difficulty has been documented in FTD
as well (Grossman et al., 1996a; Hodges & Patterson,
1996; Snowden et al., 1996). Our model of sentence
comprehension includes at least two components—core
grammatical processing, and executive resources such as
working memory—and comprehension difficulty in FTD
may be due to a deficit with one or both of these components. Some researchers have described grammatical
impairments in FTD patients (Hodges & Patterson,
1996; Mesulam, 1982; Snowden & Neary, 1994; Snowden, Neary, Mann, Goulding, & Testa, 1992; Turner
et al., 1996; Weintraub, Rubin, & Mesulam, 1990). For
example, PNFA patients have greater difficulty understanding oral sentences containing subordinate clauses
(‘‘The eagle that chased the hawk was fast’’) than
grammatically simple sentences (e.g., ‘‘The fast eagle
chased the large hawk’’) (Grossman et al., 1996b). Their
comprehension impairment was not related to sentence
length. Based on observations such as these, we hypothesized that grammatically impaired PNFA patients
would demonstrate limited recruitment of the neural
substrate for grammatical processes in the large-scale
neural network that supports sentence processing.
Executive impairments such as diminished WM resources also contribute to sentence processing difficulty
(Caplan & Waters, 1999; Just & Carpenter, 1992). Dual
task paradigms in healthy seniors, in which syntactic
processing becomes impaired during concurrent performance of a secondary task (Blackwell & Bates, 1995),
emphasize the role of limited cognitive resources in
sentence comprehension. Another way to assess the
contribution of WM to sentence processing is with a
cross-modal lexical priming paradigm administered to
healthy seniors who have age-related WM limitations
(Zurif, Swinney, Prather, Wingfield, & Brownell, 1995).
In a sentence such as ‘‘½The boyi with black hair who
the girl chased ei was bored,’’ for example, the displaced
noun phrase (NP) ‘‘the boy’’ is retained in WM until its
reactivation at the site of the gap (the gap is indicated by
‘‘e’’, and the linkage between the antecedent NP and the
gap from which it is moved is indicated by the subscript
‘‘i’’). Healthy seniors demonstrated reactivation of the
antecedent noun phrase during object-relative sentences
only when the distance between the antecedent noun
phrase and the gap was decreased to less than seven
words, suggesting an age-related WM limitation during
sentence processing.
A relationship between sentence comprehension difficulty and limited executive functioning has also been
observed in some FTD patients without progressive
aphasia. For example, EXEC patients who were insensitive to grammatical agreement information in an ‘‘online’’ word detection procedure had impaired ‘‘off-line’’
sentence comprehension on a task that required answering a probe question about an orally presented
sentence (Grossman, 2002). Moreover, performance in
the ‘‘off-line’’ comprehension task correlated with a reverse digit span task that requires WM and with a trailmaking task that requires planning. Based on these
observations, we hypothesized that EXEC patients with
a WM impairment but little clinically apparent progressive aphasia would have difficulty recruiting portions of a sentence processing network that are
important for WM-related features of a sentence.
A neural substrate for some aspects of sentence
processing has begun to emerge in neuroimaging activation studies of healthy adults during studies of sentence comprehension. A necessary component of this
large-sale neural network appears to include inferior
frontal cortex (IFC) and posterolateral temporal cortex
(PLTC) of the left hemisphere (Caplan, Alpert, & Waters, 1998; Just, Carpenter, Keller, Eddy, & Thulborn,
1996; Michael, Keller, Carpenter, & Just, 2001; Ni et al.,
2000). The distribution of activation within this sentence
comprehension network appears to depend at least in
part on the grammatical and WM properties of the
sentence material (Cooke et al., 2002; Grossman et al.,
2002a). Left ventral IFC (vIFC) was recruited for object-relative sentences containing a long linkage between
the antecedent NP and the gap where it is interpreted. In
addition, we observed activation in dorsal IFC (dIFC)
and premotor cortex of the left hemisphere. This region
has been associated with WM for letters, possibly a
frontal rehearsal component that helps maintain verbal
information in WM (Awh et al., 1996; Jonides et al.,
1997; Paulesu, Frith, & Frackowiak, 1993; Smith &
Jonides, 1999). This left dIFC region was up-regulated
during an fMRI study of sentence comprehension in
healthy seniors with age-related WM limitations, implying a role for this brain region in WM (Grossman
et al., 2002a).
Neuroimaging studies have demonstrated the vulnerability of some of these brain structures in FTD,
suggesting a neural basis for FTD patientsÕ sentence
comprehension impairments. Limited left hemisphere
glucose metabolic activity was seen in PET studies of
progressive aphasia patients (Chawluk et al., 1986;
Tyrrell, Warrington, Frackowiak, & Rossor, 1990). A
SPECT correlation study of FTD patients associated
A. Cooke et al. / Brain and Language 85 (2003) 211–221
difficulty understanding sentences containing a grammatically subordinate clause with reduced perfusion of
the lateral superior and inferior portions of the left
frontal lobe and left anterior superior temporal lobe
(Grossman et al., 1998). A perfusion fMRI study
correlated sentence comprehension difficulty with reduced activity in left frontal cortex of FTD patients
(Grossman, Alsop, & Detre, 2001). Difficulty with
resource-related aspects of cognitive processing has been
associated with frontal brain regions as well. Limited
cerebral blood flow activity thus was seen in dorsolateral
prefrontal cortex in FTD patients during a resourcedemanding word production task (Warkentin & Passant, 1997).
In this report, we present BOLD fMRI data from a
study designed to assess the neural basis for sentence
comprehension difficulty in PNFA and EXEC subgroups of FTD. To address comprehension deficits associated with each subgroup, we used sentences
featuring both an object-relative center-embedded
clause and a long linkage between the antecedent NP
and the gap from which the NP has been displaced.
These sentences have reliably produced vIFC and dIFC
activation in the left hemisphere of healthy adults, and
these regions of activation within IFC appear to be related in part to the grammatical and WM components
of this sentence material, respectively. Based on the
findings discussed above, we predicted that PNFA patients would have less activation of left vIFC than
healthy seniors during processing of the grammatical
features of sentences. We also expected that EXEC patients would exhibit relatively decreased recruitment
compared to healthy seniors in the left dIFC-premotor
area associated with verbal WM.
2. Methods
2.1. Subjects
We assessed eight patients with mild FTD diagnosed
according to published criteria (McKhann et al., 2001;
The Lund & Manchester Groups, 1994). Patients were
subgrouped based upon clinical presentation using a
revision (Davis et al., 2001; Price et al., 2001) of Neary et
alÕs clinical diagnostic criteria (Neary et al., 1998). After
conducting a chart review that included a semi-structured medical history and a comprehensive clinical
213
neurological and neurocognitive examination, at least
two independent raters arrived at a consensus subgroup
diagnosis for each patient. Three PNFA patients were
classified based on the insidious onset of nonfluent
spontaneous speech with agrammatism, phonemic paraphasias, and anomia. Five EXEC patients were classified based on the insidious onset of executive
limitations (e.g., poor planning, organization, and
working memory) accompanied by a decline in socialinterpersonal conduct (impairment in regulation of
personal conduct, emotional blunting and loss of insight). Of the five EXEC patients, two did not have alterations of comportment or interpersonal conduct.
Exclusionary criteria included other causes of dementia
(e.g., metabolic, endocrine, vascular, structural, nutritional, infectious, and psychiatric disorders). Mean
( SD) age and education of PNFA and EXEC patients
and 11 healthy seniors are given in Table 1. EXEC
patients [tð14Þ ¼ :138, ns] and PNFA patients
[tð12Þ ¼ 2:09, ns] were age-matched to healthy seniors.
EXEC and PNFA patients were also age-matched to
each other [tð6Þ ¼ 1:61, ns]. EXEC patients and healthy
seniors were education-matched [tð14Þ ¼ 1:15, ns], but
PNFA patients were not as well educated as either
group. All subjects were paid for their participation and
completed an informed consent procedure approved by
the Institutional Review Board at the University of
Pennsylvania.
Table 2 contains representative neuropsychological
measures for FTD patients obtained independently of
subgroup classification, compared to a group of eight
age-matched healthy seniors. The Mini Mental Status
Exam (MMSE) is a brief dementia index scored on a 30point scale (Folstein, Folstein, & McHugh, 1975). The
patients scanned in this experiment were mildly impaired. ‘‘Stroop’’ is a test of inhibitory control (Stroop,
1935). Subjects are given a list of 80 color names arrayed
in five columns on a sheet of paper. Each name is
printed in an ink color that does not correspond to the
named color (e.g., the word ‘‘red’’ printed in a green
color). Subjects are asked to name the color of ink of as
many printed words as possible in 300 s. To perform this
task, subjects must inhibit reading the name of the color
while they report the color of ink. ‘‘Trails B’’ is a test of
task switching and strategic planning (Reitan, 1958).
Subjects are given a paper with 26 letters and numbers
distributed randomly throughout the page. They are
asked to draw a line connecting as many stimuli as
Table 1
Mean (SD) age and education of healthy seniors (SENIOR), Progressive Non-Fluent Aphasic (PNFA) patients and dysexecutive/social (EXEC)
patients
Age (years)
Education (years)
SENIOR (n ¼ 11)
PNFA (n ¼ 3)
EXEC (n ¼ 5)
63.5 (10.8)
17.0 (3.3)
77.0 (2.0)
12.0 (0.0)
64.4 (13.1)
15.2 (1.8)
214
A. Cooke et al. / Brain and Language 85 (2003) 211–221
Table 2
Neuropsychological measures of healthy seniors (SENIOR), Progressive Non-Fluent Aphasics (PNFA) and dysexecutive/social patients (EXEC)
Measure
SENIOR (n ¼ 8)
PNFA (n ¼ 3)
EXEC (n ¼ 5)
MMSE (max ¼ 30)a
Stroop % accuracy
Trails B % accuracy
Tokens (max ¼ 12)
29.6 (.74)
98.6 (2.2)
98 (3.0)
11.3 (.88)
26.3 (3.1)
100 (0)
93.3 (8.3)
7.7 (3.8)
24.4 (4.3)
90.5 (12.4)
78.7 (19.5)
10.5 (2.1)
a
MMSE, Mini Mental Status Exam.
Indicates n ¼ 4.
**
Indicates n ¼ 2.
*
possible in 300 s, with the stipulation that the sequence
alternate between a number and a letter in an ascending
order. EXEC patients were impaired on these measures
relative to PNFA patients. ‘‘Tokens’’ is a test of auditory sentence comprehension (De Renzi & Vignolo,
1962). We used a validated version of this task involving
12 items. Subjects are asked to move colored geometric
shapes arrayed in front of them. To perform this task,
subjects must successfully comprehend the structure of
the oral instructions given by the examiner. PNFA patients performed more poorly than EXEC patients on
this sentence comprehension task.
2.2. Materials
Sentences contained both a grammatically complex
feature (object-relative center-embedded clause) and a
heavy WM load (seven-word long antecedent-gap linkage). These sentences were embedded in the context of
other sentences containing subject-relative constructions
and shorter antecedent-gap linkages. To test our hypotheses, we could not analyze the sentences with object-relative constructions and a short linkage, or
sentences with subject-relative constructions and a long
linkage, because these materials do not fully dissociate
grammatical and WM processes during aging in a uniform manner (Grossman et al., 2002a, 2002b). Using the
same set of sentences to assess both processes also
provided a useful control for other, unanticipated
sources of processing demand, such as the interaction
between these resource-demanding elements of a sentence. Half of each type of sentence had a female as the
agent, the remainder a male. The task for all sentences
was to decide whether a female or male is the agent of
the action in the sentence. Subjects indicated their response by pressing one of two buttons with the thumb of
the left hand or the right hand.
These sentences were presented in a written word-byword manner, allowing us to fully control presentation
rate. This also allowed us to avoid degradation of aural
stimuli due to the loud ( 80 dB) noise level associated
with MRI magnet operation. Moreover, we avoided the
interpretive confound of recruiting primary and secondary auditory cortices for the stimulus modality versus language-sensitive cortices in a left peri-Sylvian
distribution. To equate for duty cycle and the amount of
time needed to process sentences of unequal difficulty,
subjects responded to a sentence as soon as they felt that
they had the correct response, and the next sentence was
initiated by the subjectÕs response. This also minimized
grammatically irrelevant aspects of WM by not requiring subjects to retain their response until the end of
sentence presentation.
In each run of stimulus presentation, longitudinal
magnetization stabilized while subjects were acclimated
to the MRI environment by viewing a blank screen for
20 s and then an asterisk for 40 s. These data were discarded. Eight randomly ordered blocks of sentences
(including two blocks of each type of sentence) were
presented for 40 s each and without a break between
blocks of different sentence types. Subjects were not
informed that blocks of different types of sentences were
being administered. Four runs of sentence stimuli were
presented in total, and the rate of word presentation
alternated across runs at 750 and 500 ms/word for
healthy seniors.1 Data were averaged across rate of
presentation because we did not find a difference in activation patterns for these two presentation rates. For
FTD patients, sentence presentation remained static
across all four runs at either 750 or 1000 ms/word, depending on the patientsÕ ability to maintain performance
during pre-scan testing. Each run also included two
baseline sensory-motor blocks of pseudofont stimuli
designed to resemble the sentence material. The baseline
task probed detection of one of two pseudofont targets
in a sentence-like string of pseudofont ‘‘words,’’ resembling the two-choice probe of the sentences. These were
presented analogously to the true sentences (each
pseudofont word presented sequentially one at a time,
each string containing 13 pseudofont words, identical
presentation rates, the ability to respond as soon as the
target was seen, a response triggered the next string).
The targets were presented at the beginning of each of
these baseline blocks for 1 s. Pauses in performance were
included between runs (every 8 min 20 s).
1
We had initially hoped to assess information processing speed in
this study, but this design feature was subsequently eliminated when it
proved uninformative in healthy seniors and too difficult for FTD
patients.
A. Cooke et al. / Brain and Language 85 (2003) 211–221
An LCD projector (Epson PowerLite 5000) compatible with high magnetic fields was used to back-project
visual stimuli onto a screen at the magnet bore. The
subject viewed the screen through a system of mirrors
available on the GE head coil. A portable computer
(Macintosh G3) outside the magnet room used PsyScope presentation software (Cohen, MacWhinney,
Flatt, & Provost, 1993) to present stimuli and record
response accuracy.
Subjects were familiarized with the word-by-word
presentation technique and the gender probe prior to
entering the magnet bore, and each subject practiced the
task. We monitored behavioral accuracy and latency
while imaging data were being collected. A technical
error prevented the collection of behavioral data in one
healthy senior, so his behavioral data were obtained
outside of the magnet. One PNFA patient was scanned
for only one and one half of the four runs.
2.3. Imaging data acquisition and statistical analysis
This experiment was carried out at 1.5 T on a GE
Echospeed scanner. We used the standard clinical
quadrature radiofrequency head coil. 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 ¼ 500 ms, TE ¼ 10 ms,
192–256 matrix), T2-weighted axial images (FSE,
TR ¼ 2000, TEeff ¼ 85 ms), and T1-weighted axial images of slices used for fMRI anatomic localization
(TR ¼ 600 ms, TE ¼ 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 3:75 5 mm. The echoplanar acquisitions consisted of 24 contiguous slices in the axial plane covering
the entire brain every 2 s. A separate acquisition lasting
1–2 min was needed for phase maps to correct for dis-
215
tortion in echoplanar images (Alsop, 1995). Raw data
were stored by the MRI computer on DAT tape and
then processed off-line.
Initial data processing was carried out with Interactive Data Language (Research Systems) on a Sun Ultra
60 workstation. Raw image data were reconstructed
using a 2D FFT with a distortion correction to reduce
artifact due to magnetic field inhomogeneities. Individual subject data were then prepared and analyzed statistically with a fixed-effects model using statistical
parametric mapping (SPM99), operating on a MatLab
platform, developed by the Wellcome Department of
Cognitive Neurology (Frackowiak, Friston, Frith, Dolan, & Mazziotta, 1997). Briefly, the images in each
subjectÕs time series were registered to the initial image
in the series. The images were then aligned to a standard
coordinate system (Talairach & Tournaux, 1988). The
data were scaled to equate global perfusion, and spatially smoothed with a 12 mm Gaussian kernel to account for small variations in the location of activation
and subtle variability in gyral anatomy across subjects.
Low-pass temporal filtering was implemented to control
auto-correlation with a first-order auto-regressive
method. The data were analyzed parametrically using t
test comparisons converted to z-scores for each compared voxel. Unless noted otherwise, we tested our hypotheses by examining coordinates significant at
p < :001 uncorrected for multiple comparisons.
3. Results
3.1. Behavioral data
Analysis of variance (ANOVA) with factors comparing group (EXEC, PNFA, control), grammatical
structure (object-relative, subject-relative), and antecedent-gap length (short, long) revealed a significant
group grammatical structure interaction F ð2; 14Þ ¼
8:79, p < :005]. The results are summarized in Table 3.
A planned t test confirmed that PNFA performance was
worse than healthy seniors for object-relative sentences
Table 3
Example sentence material and mean percent (SD) accuracy during sentence comprehension tasks for healthy seniors (SENIOR), Progressive NonFluent Aphasics (PNFA) and dysexecutive/social patients (EXEC)
Sentence type
Subject-relative—
short antecedent-gap
Subject-relative—
long antecedent-gap
Object-relative—
short antecedent-gap
Object-relative—
long antecedent-gap
Stimulus example
½The strange mani in black who ei adored Sue was rather sinister in
appearance
½The cowboyi with the bright gold front tooth who ei rescued Julia
was adventurous
½The flower girli who Andy punched ei in the arm was five years
old
½The devoted boyfriendi who Carla from the doughnut shop loved
ei was very content
Accuracy: % correct (SD)
SENIOR
(n ¼ 11)
PNFA
(n ¼ 3)
EXEC
(n ¼ 5)
94.7 (5)
93.8 (11)
79.4 (24)
91.1 (6)
83.5 (4)
68.4 (26)
88.5 (8)
46.3 (33)
79 (21)
90.8 (5)
50.6 (29)
68.1 (23)
216
A. Cooke et al. / Brain and Language 85 (2003) 211–221
Table 4
Areas of significantly activated by healthy seniors (SENIOR), Progressive Non-Fluent Aphasics (PNFA) and dysexecutive/social patients (EXEC)
during comprehension of sentences with an object-relative construction and a long antecedent-gap linkage in contrast to a pseudofont baseline
Subject group
Coordinates
z-score
Region (Brodmann areas)
X
Y
Z
SENIOR (n ¼ 11)
)48,
)44,
)56,
52,
44,
)4,
16,
24,
12,
)44,
)40,
)72,
)68,
12,
)4
28
)4
)4
24
24
16
4.19
4.47
5.35
4.55
5.16
6.46
3.88
Left ventral inferior frontal (47, 45)
Left premotor-dorsal inferior frontal (6, 44)
Left poserolateral temporal (21, 22)
Right posterolateral temporal (21, 22)
Right inferior parietal (40)
Bilateral occipital (18, 19, 17)
Bilateral striatum
PNFA (n ¼ 3)
)32,
)48,
60,
20,
)12,
8,
)20,
16,
16,
)56,
)20,
24,
)80,
)44,
16,
16,
56
)8
32
32
16
24
4
16
4.15
5.17
5.15
7.50
4.91
6.17
3.28
6.60
Left dorsal inferior frontal (6, 44)
Left posterolateral temporal (21, 37)
Right parietal (1, 40)
Right medial frontal, anterior cingulate (8, 32)
Left occipital, posterior cingulate (17, 18, 31)
Right posterior cingulate (23)
Left striatum
Right striatum
EXEC (n ¼ 5)
)52,
56,
52,
12,
20,
)32,
)12,
)60,
20
0
16
4
3.50
3.44
3.64
4.88
Left inferior frontal (45, 47)
Right posterolateral temporal (21, 22)
Right inferior parietal (40)
Bilateral occipital, posterior cingulate (18, 31)
[tð12Þ ¼ 4:67, p < :001 ], corresponding to their grammatical impairment. A second ANOVA contrasting
EXEC and controls showed a significant group length
interaction effect [F ð1; 14Þ ¼ 5:79, p < :03 ]. A planned t
test showed that EXEC performance was worse than
performance in healthy seniors for WM-demanding long
antecedent-gap sentences [tð14Þ ¼ 3:01, p < :01 ], confirming their relative WM impairment.
3.2. Imaging data
Coordinates corresponding to the peak loci in activated areas are given in Table 4. Fig. 1 shows areas of
recruitment during comprehension of object-relative
sentences with a long antecedent-gap linkage relative to
the baseline task. For background purposes, we show in
Fig. 1, Panel A that healthy seniors recruited left vIFC
and dIFC. They also activated left posterolateral temporal cortex and right temporal-parietal cortex. These
findings are discussed in greater detail elsewhere
(Grossman et al., 2002a). Fig. 1, Panel B shows that
PNFA patients activated left dIFC (BA 6/44), like healthy seniors. However, vIFC activity did not exceed our
statistical threshold. Fig. 1, Panel C shows that EXEC
patients recruited left vIFC (BA 45/47), but they did not
recruit left dIFC to a statistically significant degree.
4. Discussion
PNFA patients are thought to have difficulty processing grammatically complex sentences, while EXEC
patients appear to have WM limitations that contribute
to their sentence comprehension deficit. Analyses of
FTD patientsÕ behavioral performance in the present
study are consistent with these characterizations: PNFA
patients were most impaired at understanding sentences
that contain object-relative clauses, and EXEC patients
encountered their greatest difficulty understanding sentences with a long antecedent noun-gap linkage. Previous fMRI studies of sentence comprehension in healthy
subjects have begun to associate grammatical components of sentence processing with ventral portions of left
IFC and WM components of sentence processing with
dorsal portions of left IFC (Caplan et al., 1998; Cooke
et al., 2002; Just et al., 1996; Kang, Constable, Gore, &
Avrutin, 1999; Michael et al., 2001; Ni et al., 2000).
Based on these observations, we hypothesized different
patterns of left frontal activation during comprehension
of sentences with an object-relative center-embedded
clause and a lengthy antecedent noun-gap linkage in
subgroups of FTD patients. In fact, fMRI activation
patterns showed distinct profiles in FTD patient subgroups consistent with our predictions. PNFA patients
had difficulty recruiting ventral portions of left inferior
frontal cortex most closely associated with grammatical
processing, while EXEC patients were impaired activating dorsal portions of left inferior frontal cortex associated with verbal WM. This may be related to the
selective distribution of the histopathological abnormalities seen in FTD patients with distinct clinical presentations (Grossman, 2002; Harasty, Halliday, Code, &
Brooks, 1996; Lieberman et al., 1998; Turner et al.,
1996). Interruptions within the large-scale neural
A. Cooke et al. / Brain and Language 85 (2003) 211–221
217
Fig. 1. Areas of significant activation during comprehension of sentences with an object relative clause and a long antecedent-gap linkage in
comparison to a pseudofont baseline, illustrated with lateral projections. (A) Healthy seniors (n ¼ 11), (B) progressive-non-fluent aphasics (n ¼ 3), (C)
dysexecutive/social patients (n ¼ 5).
network for sentence processing in FTD patient subgroups, reflecting relative difficulty with grammatical or
WM components of sentences, are consistent with a
model of sentence processing that includes partially
dissociable grammatical and WM components.
Several researchers have observed dissociations in
language-related processes involving specific sub-regions
of left frontal cortex in healthy subjects that may help
explain our observations in FTD patient subgroups.
Semantic processing may preferentially activate vIFC
(BA 47/45), while phonological processing may activate
more dorsal portions of IFC (BA 44/45) (Poldrack et al.,
1999). Similarly, anterior aspects of ventrolateral prefrontal cortex (PFC) (BA 45/47) may support access and
maintenance of semantic representations, while posterior aspects of IFC (BA 44/6) may support phonological
access and maintenance (Wagner, Maril, Bjork, & Schacter, 2001). Others have contrasted ventral IFC with
dorsolateral PFC. An fMRI study during Wisconsin
Card Sorting Task performance attributed the maintenance of a contingency set to dorsolateral prefrontal
cortex (BA 46/9), and the shifting of attentional set to
mid-ventrolateral IFC (BA 47/12) (Monchi, Petrides,
Petre, Worsley, & Dagher, 2001). Smith and Jonides
(1999) reviewed functional neuroimaging evidence that
short-term storage of verbal material (i.e., subvocal rehearsal) is supported by ventrolateral IFC (BA 45/47),
BrocaÕs area (BA 44), and left supplementary motor
and premotor areas (BA 6), while active manipulation
of verbal material is supported by dorsolateral PFC.
Petrides and coworkers integrated data from lesioned
monkeys and functional neuroimaging studies in humans to put forth a two-level hypothesis that distinguishes active strategic encoding and long-term memory
retrieval processes supported by mid-ventrolateral IFC
(i.e., BA 45, 47/12) from monitoring and manipulation
processes supported by dorsolateral PFC (Petrides,
1996; Petrides, Alivisatos, & Evans, 1995). Others have
218
A. Cooke et al. / Brain and Language 85 (2003) 211–221
emphasized modality-based functional specialization in
dorsal and ventral frontal regions (Owen, 1997).
Functional distinctions along the dorsal-ventral axis
of inferior frontal cortex in this work honor an anatomic
distinction based on cytoarchitectonic studies of these
areas (Amunts et al., 1999). However, the fMRI results
reported above should be interpreted with caution.
Dorsal and ventral regions of the frontal lobe have been
recruited by a wide variety of cognitive tasks, emphasizing that these regions appear to support multiple
cognitive functions (Duncan & Owen, 2000). Our data
can be directly compared with this literature only cautiously, moreover, because of the linguistically rich nature of the sentence stimuli used in the current study. We
can nevertheless attempt to relate our findings to existing non-linguistic work on frontal executive functions to
examine the hypothesis that some aspects of sentence
processing are an emergent property of phylogenetically
older, non-linguistic processes. The association between
dorsal prefrontal activity and active manipulation of
stimulus material suggested by the process-based ‘‘twolevel’’ hypothesis (Petrides, 1996) and studies of WM
(Smith & Jonides, 1999) is consistent with our view of
left dIFC as a WM resource for sentence processing.
Dorsal (BA 44/45) activation for phonological processing (Poldrack et al., 1999) is not inconsistent with our
results to the extent that the information contained in
long antecedent-gap linkages may be processed phonologically and held transiently in a phonological WM
store (Wagner et al., 2001).
There is less clear overlap, however, between our
observations and the role played by ventral IFC in these
non-linguistic studies. One possibility is that vIFC
contributes to an aspect of our procedure the is related
only indirectly to sentence processing, such as the ordered nature of the word-by-word method of sentence
presentation. Some work in patients with frontal insult
has shown difficulty appreciating order information,
even though the content of the information may be
preserved (Shimamura, Janowsky, & Squire, 1991).
However, functional neuroimaging studies of healthy
young subjects appear to have associated order information with dorsal portions of IFC and with dorsolateral PFC (Cabeza et al., 1997; Marshuetz, Smith,
Jonides, DeGutis, & Chenevert, 2001). Other studies
have associated ventral IFC activation with processing
semantic representations (Demb et al., 1995; ThompsonSchill, DÕEsposito, Aguirre, & Farah, 1997; Wagner,
Desmond, Demb, Glover, & Gabrieli, 1997), although
this approach is not compatible with other work showing selective vIFC activation for specific grammatical
structures despite similar lexical semantic content
(Cooke et al., 2002; Kang et al., 1999; Ni et al., 2000).
Additional work is needed to establish whether one role
of left vIFC in cognition is uniquely related to the interpretation of long-distance grammatical relations in
sentences, or can be reduced in part to a process that
subserves non-grammatical, phylogenetically older cognitive functions.
Regardless of the specific contribution of left vIFC to
sentence interpretation, our work demonstrates one
method for investigating the collaboration between
dorsal and ventral portions of left inferior frontal cortex
during the processing of sentences that involve grammatically structured material that varies in its WM demands. In healthy seniors with age-related WM
limitations, we previously observed increased recruitment of WM-related left dIFC brain regions to help
support sentence comprehension, although left vIFC
activation apparently does not change with age during
sentence comprehension (Grossman et al., 2002a,
2002b). The present study provides additional converging evidence concerning the critical relationship between
grammatical and WM functions during sentence processing that is consistent with this approach. Specifically, we show that FTD patients have selectively
impaired comprehension of sentences when a neural
component contributing to grammatical or WM processes is not contributing effectively to the large-scale
neural network underlying sentence comprehension.
One potential confound associated with this approach is
that FTD patient subgroups and healthy seniors were
not equated for sentence comprehension accuracy. Differences in activation profiles thus could be related directly to the different patterns of comprehension
difficulty that we find, or to the fact that poor sentence
comprehension may also be associated with non-specific
increases in resource-related task difficulty for more
difficult sentences. Our approach nevertheless emphasizes that sentence comprehension should not totally fall
apart during the interruption of the large-scale neural
network that supports this complex real-world activity.
Instead, there should be qualitative changes that yield
subtle deficits with particular aspects of sentence processing. We believe that this converging approach,
involving data from multiple sources, will ultimately
lead to a clearer understanding of brain-behavior
relationships.
While selective differences in left IFC recruitment in
subgroups of FTD patients are consistent with our hypothesis, there are other changes in activation that could
also contribute to some of the observed behavioral
profiles seen in PNFA and EXEC subgroups of FTD
patients. For example, PNFA patients additionally recruited medial frontal regions. This activation may
support components of attention important for selecting
and maintaining sensitivity to specific features of sentences (Benedict et al., 1998; Corbetta, Miezin, Shulman, & Petersen, 1993; Coull, Frith, Frackowiak, &
Grasby, 1996; George et al., 1994), compatible with
PosnerÕs executive component of attention (Posner &
Petersen, 1990), or help control the implementation of
A. Cooke et al. / Brain and Language 85 (2003) 211–221
response selection during task performance (Botvinick,
Braver, Barch, Carter, & Cohen, 2001). For example,
several recent fMRI studies of the Stroop effect suggest
that anterior cingulate cortex is activated in situations
where competition between response choices must be
resolved (Barch et al., 2001; Braver, Barch, Gray,
Molfese, & Snyder, 2001; Carter et al., 1998; MacDonald, Cohen, Stenger, & Carter, 2000). Patterns of activation change such as this may reflect the development
of a conscious, alternate behavioral strategy to support
sentence comprehension. Alternately, this may reflect
neural reorganization that is also observed in stroke
patients (Heiss, Kessler, Thiel, Ghaemi, & Karbe, 1999;
Rosen et al., 2000) and in studies of AlzheimerÕs disease
(Becker et al., 1996; Grady, Furey, Pietrini, Horwitz, &
Rapoport, 2001; Grossman et al., in press; Grossman
et al., submitted; Saykin et al., 1999) that may support
the emergence of alternate processing strategies. Regardless of the specific basis for this change, the increased activation of this medial frontal area in FTD
suggests that changes in patientsÕ activation cannot be
attributed entirely to a global reduction in FTD
recruitment.
Another difference relative to healthy seniors is that
left PLTC was not recruited in a statistically significant
manner in EXEC patients. Similarly, we observed limited right PLTC activation in PNFA patients. We assessed small numbers of patients in this study, and we
cannot rule out that there was insufficient power to
demonstrate PLTC activation in FTD patients. Several
studies of healthy young subjects have demonstrated
activation of right PLTC during comprehension of resource-demanding sentences (Just et al., 1996; Keller,
Carpenter, & Just, 2001). Our work suggests the possibility that this recruitment may be related to a materialspecific form of WM (Cooke et al., 2002; Grossman et
al., 2002a), and thus we cannot rule out that PNFA
patients also have a material-specific WM limitation
during sentence processing. Additional work is needed
to establish the precise contribution of these right
hemisphere regions to sentence processing difficulty in
FTD.
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