Journal of the International Neuropsychological Society (2006), 12, 132–146.
Copyright © 2006 INS. Published by Cambridge University Press. Printed in the USA.
DOI: 10.10170S135561770606019X

NEUROBEHAVIORAL GRAND ROUNDS

Neural substrates of syntactic mapping treatment:
An f MRI study of two cases

CHRISTINA E. WIERENGA,1,2 LYNN M. MAHER,1,7,8 ANNA BACON MOORE,1,2
KEITH D. WHITE,1,5 KEITH MCGREGOR,1,5 DAVID A. SOLTYSIK,4 KYUNG K. PECK,6
KAUNDINYA S. GOPINATH,4 FLORIS SINGLETARY,1 LESLIE J. GONZALEZ-ROTHI,1,3
RICHARD W. BRIGGS,1,6 and BRUCE CROSSON 1,2
1 Department of Veterans Affairs Rehabilitation Research and Development, Brain Rehabilitation Research Center at the Malcom

Randall VA Medical Center, Gainesville, Florida
2 Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida
3 Department of Neurology, University of Florida, Gainesville, Florida
4 Department of Nuclear and Radiological Engineering, University of Florida, Gainesville, Florida
5 Department of Psychology, University of Florida, Gainesville, Florida
6 Department of Radiology, University of Florida, Gainesville, Florida
7 Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
8 Baylor College of Medicine, Houston, Texas

(Received August 2, 2004; Final Revision October 16, 2005; Accepted October 17, 2005)

Abstract
Two patients (G01, J02) with chronic nonfluent aphasia and sentence production deficits received syntactic mapping
treatment to improve sentence production. The patients had dramatically different outcomes in that improved syntax
production generalized to nontreatment tasks for G01, but not for JO2. To learn how treatment influenced the neural
substrates for syntax production, both patients underwent pre- and posttreatment functional magnetic resonance
imaging (f MRI) of sentence generation. G01 showed more robust activity posttreatment than pretreatment in
Broca’s area; ventral temporal activity decreased slightly from pre- to posttreatment. Comparison of J02’s
pretreatment and posttreatment images revealed little change, although activity was more diffuse pre- than
posttreatment. Findings suggest that for G01, rehabilitation led to engagement of an area (Broca’s area) used
minimally during the pretreatment scan, whereas for J02, rehabilitation may have led to more efficient use of areas
already involved in sentence generation during the pretreatment scan. f MRI findings are discussed in the context of
sentence-production outcome and generalization. (JINS, 2006, 12, 132–146.)
Keywords: Neuroplasticity, Rehabilitation, Aphasia, Functional neuroimaging, Linguistics, Cerebrovascular
accident

1997, 1999; Karbe et al., 1998; Cao et al., 1999; Rosen et al.,
2000; Perani et al., 2003). In at least some cases of rehabilitative intervention, left perilesional regions are mobilized during recovery of nonfluent aphasia (Belin et al., 1996;
Cornelissen et al., 2003), while other reports suggest that
right-hemisphere structures also contribute to language
recovery (Musso et al., 1999; Crosson et al., 2005; Peck
et al., 2004a). The majority of neuroimaging studies investigating language recovery poststroke have focused on word
production or receptive language; unfortunately, little information is available regarding cortical regions mobilized by
rehabilitation of syntax deficits in sentence production.

INTRODUCTION
Emerging functional neuroimaging studies regarding plasticity in aphasia secondary to stroke indicate that good
language recovery most frequently is supported by left perilesional areas, but that patients with significant, persistent
aphasias demonstrate more right-hemisphere activity than
patients with good recovery (Basso et al., 1989; Heiss et al.,

Reprint requests to: Bruce Crosson, Ph.D., Department of Clinical and
Health Psychology, University of Florida Health Science Center, Box
100165, Gainesville, FL 32610-0165. E-mail: bcrosson@phhp.ufl.edu

132

Neural substrates of syntactic mapping treatment
Although there is considerable symptom variability
among nonfluent aphasias, a deficit in thematic role assignment manifested via word-order deficits (i.e., accurate placement of the arguments around the verb) is a frequent form
of syntax impairment (Caramazza & Miceli, 1991). This
deficit is commonly referred to as a mapping deficit
(Schwartz et al., 1980, 1994a). Difficulty mapping thematic roles reflects underlying problems communicating
knowledge of who is doing what to whom. Performance is
often worsened with reversible sentences, that is, ones in
which it is plausible to reverse the actor and the recipient
of the action. Mapping problems may be explained by a
deficit at the early stage of sentence production, during
which the thematic relationship of sentence elements is
established (Garrett, 1980, 1984; Berndt, 1998; Chatterjee
& Maher, 2000). Mapping therapies have been designed to
address assignment of thematic roles in sentences and to
explicitly strengthen the association between thematic roles
and word order (Jones, 1986; Byng, 1988; Byng et al.,
1994; Schwartz et al., 1994b; Chatterjee et al., 1995; Maher
et al., 1995). The effectiveness of this treatment approach
has been variable. In some instances, treatment gains are
specific to treated sentences, with little generalization (Byng
et al., 1994; Schwartz et al., 1994b). It remains unclear
which factors contribute to the relative success or failure
in a given patient, and the mechanisms by which treatment
influences the underlying neural substrates of recovery are
not well understood.
The heterogeneity of syntax deficits (i.e., problems with
word order, thematic role assignment, and morphology)
resulting from various lesion sites suggests that a discrete grammar center in the brain is unlikely. Recent functional neuroimaging studies have implicated Broca’s area
(Brodmann’s Areas 44, 45) in a variety of receptive syntactic functions, including comprehending lexical-semantic
information and syntactic structure (Dapretto & Bookheimer, 1999), processing syntactic ambiguities (Stowe et al.,
1998), detecting syntactic anomalies and errors (Embick
et al., 2000; Ni et al., 2000), and processing syntactically
more complex sentences (Just et al., 1996; Caplan & Waters,
1999; Caplan et al., 2000). Posterior perisylvian regions,
including the superior temporal gyrus, angular gyrus, supramarginal gyrus, and superior parietal lobe, also have been
implicated in syntactic processing (Just et al., 1996; Carpenter et al., 1999; Caplan et al., 2001; Newman et al.,
2001). Studies that have investigated sentence production
have found activity in and around Broca’s area, including
the left anterior Rolandic operculum (Indefrey et al., 2001,
2004; Peck et al., 2004b) as well as in left posterior perisylvian regions (Peck et al., 2004b).
In the current study, two patients with residual nonfluent
aphasia and sentence production deficits (G01 and J02)
received an experimental syntactic mapping treatment to
target thematic role assignment in sentence production (i.e.,
word order). The purpose of the study was to investigate
the neural substrates that support recovery of function following treatment of thematic role assignment. Based on the

133
research reviewed earlier, we developed the following
hypotheses: (1) patients will show an improvement in producing syntactically correct sentences following treatment,
and (2) because treatment emphasizes word order, we expect
to see increased activation in cortical regions associated
with syntax. Specifically, f MRI activity during sentence
production is expected to increase from pre- to posttreatment in the intact perilesional regions of the left inferior
frontal gyrus (including Broca’s area).

METHOD
Research Participants
Two patients (G01, J02) with chronic nonfluent aphasia
received syntactic mapping treatment under two different
conditions as part of a larger study, and underwent f MRI
pre- and posttreatment. Pretreatment assessment suggested
that both G01 and J02 demonstrated aphasia profiles most
consistent with transcortical motor aphasia, with repetition,
naming, and auditory comprehension scores relatively higher
than fluency scores (see Table 1).

Patient G01
G01 was a 72-year-old right-handed woman treated 53
months postonset of a left hemisphere cerebral vascular
accident (CVA). She obtained 12 years of education and
had been a homemaker prior to her stroke. She reportedly
had received 6 months of speech and language therapy following her stroke. An MRI scan revealed a lesion consistent with a proximal occlusion of the left middle cerebral
artery, with damage to the left temporal and parietal lobes,
basal ganglia, thalamus, sensorimotor area, premotor cortex, and centrum semiovale (Figure 1).
In addition to deficits in fluency and word retrieval on
the Western Aphasia Battery (WAB; Kertesz, 1982), results
of the pretreatment Action Naming Test (ANT; Obler &
Albert, unpublished) and Boston Naming Test (BNT; Kaplan
et al., 2000) indicated that G01 had greater difficulty with
verb than noun retrieval (see Table 1). Verb retrieval errors
tended to be the use of nonspecific or “light” verbs (such as
“using a saw” for “sawing”). Performance on the Circles
and Squares Test (Schwartz et al., 1980) revealed auditory

Table 1. Pretreatment language assessment

WAB Aphasia Quotient
Fluency
Naming
Auditory comprehension
Repetition
Boston Naming Test
Action Naming Test
Note. WAB 5 Western Aphasia Battery

G01

J02

81.9
6
8.9
9.85
9.2
52
46

85.6
5.5
8.3
10
10
36
53

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C.E. Wierenga et al.

Fig. 1. T1-weighted axial magnetic resonance images in radiologic space (left is on the right) showing the extent of
left cerebral vascular infarction for G01 and J02.

comprehension of reversible active sentences was quite good
(23024 correct), however, comprehension of passive sentences, particularly when the action was depicted from left
to right, was impaired (16024 correct).
Sentence production in response to reversible action pictures highlighted the difficulty in generating accurate active
and passive sentences. A 90-sentence subset of the pretreatment responses was coded for type of error, and half (45)
of these sentences were coded by a second examiner. Interjudge agreement for presence of error was 100%, and for
type of errors was 83%. Disagreements in error coding
were resolved by consensus. Errors were predominantly

word order errors (e.g., beginning a passive sentence with
the agent or “actor” noun), use of a light verb in place of
the target verb (e.g., “went after” for the target “follow”),
and incorrect verb selection (e.g., “teasing” for “biting”).
Pretreatment performance on the baseline and probe measures revealed a stable deficit in sentence generation (z 5
1.04; p . .05). Analysis of narrative discourse using the
Quantitative Production Analysis (Berndt et al., 2000) and
additional linguistic measures revealed persistent deficits
with word order and morphology, decreased representation of verbs, and reduced syntactic accuracy and
complexity.

Neural substrates of syntactic mapping treatment

Patient J02
J02 was a 58-year-old right-handed man seen 8 months postonset of a left hemisphere CVA. He completed 18 years of
education and prior to his stroke had been employed in law
enforcement. He had received approximately one month of
speech and language therapy following his stroke. An MRI
scan revealed a lesion consistent with a proximal occlusion
of the left middle cerebral artery, with damage to the anterior
temporal lobe, insular region, basal ganglia, and premotor
and sensorimotor cortex (Figure 1). Results of J02’s pretreatment ANT and BNT indicated he had greater difficulty with
noun retrieval than verb retrieval (see Table 1). Predominant
word retrieval errors included no responses, perseverations,
and semantic paraphasias. Performance on the Circles and
Squares test revealed relatively preserved comprehension of
active (19024) and passive (23024) reversible sentences.
Much like G01, J02’s performance on active and passive
sentence generation revealed marked difficulty in generating active and passive sentences. Again, a 90-sentence subset of the pretreatment responses was coded for type of
error, and half (45) were coded by a second examiner. Interjudge agreement for presence of error was 100%, and for
type of errors it was 76%. Disagreements in error coding
were resolved by consensus. The types of errors he produced were predominantly in verb retrieval (e.g., incorrect
or absent verbs), word order (e.g., active syntax for a passive sentence), and morphologic (e.g., omission of functors). Pretreatment performance on the baseline and probe
measures revealed a stable deficit in sentence generation
(z 5 1.24, p . .05). J02’s narrative discourse also revealed
persistent deficits with word order and morphology, marked
decrease in verb use, and reduced syntactic accuracy and
complexity.

Syntactic Mapping Treatment
The syntactic mapping treatment differed from what has
been most often reported in the literature in that the inter-

135
vention focused on sentence production rather than comprehension of thematic roles. Sentence production was paired
with a color and spatially coded mapping template focusing
on thematic role positions (see Figure 2). The patients were
encouraged to use the illustration in the template to guide
the placement of the lexical items in the sentence to accurately reflect the thematic roles. Errors in morphological
endings and article omissions were ignored for scoring purposes, with the exception of the passive morphology for
passive sentence construction (e.g., “was 1 verb 1 by”).
The treatment was administered in two phases. In the
first phase, Errorless Learning Mapping (ELM) utilized constant time delay as an errorless training procedure for sixteen 90-minute sessions, occurring 3– 4 times per week
(Wolery et al., 1992; Maher et al., 2002). This was followed
by a second phase, Errorful Mapping (EFM), which utilized the more traditional approach for the same number
and frequency of sessions. Active sentences were trained
first (8 sessions), followed by passive sentence training (8
sessions) in each of the phases. In ELM, sentence production errors were prevented by providing an immediate model
for repetition of the target sentence. The patient was
instructed to only produce the sentence if he0she was certain it would be correct. Otherwise, the therapist would
provide the model and the patient would repeat the target
sentence. After 80% of the sentences were produced correctly at this stage, then a time-delay between the presentation of the picture and the model was introduced, allowing
the patient increasing independence in producing the sentence. However, if an error was either produced or anticipated, the model for the correct response was provided
yielding a near errorless learning environment. In contrast,
in EFM, the patients first generated their independent
responses to the target, and errors were corrected through a
query approach of the lexical items to fill the respective
thematic roles of agent (actor) and patient (recipient of
action) in the target sentence (Schwartz et al., 1994b). In
both the ELM and EFM phases, the color-coded template of

Fig. 2. Illustration of color and spatially coded mapping template used to train active and passive sentences in both
phases (Errorless Mapping Treatment, Errorful Mapping Treatment) of the intervention.

136
the sentence constituents (and when appropriate the passive
morphology) was present. In the ELM phase, written words
corresponding to the agent, recipient, and verb were placed
in the appropriate locations to “fill in” the map prior to the
response (or after a specified time delay). In EFM, the map
was filled in as the patient produced the lexical items, either
independently or with cues for the therapist. The comparative impact of ELM and EFM has been reported elsewhere
(Maher et al., 2002).
For each participant, a corpus of reversible sentences
was probed to yield three different sets of transitive verbs
that were balanced for word frequency (Kucera & Francis,
1967) for each patient. All of the verbs required only an
agent (actor) and a patient or goal (recipient) to be syntactically correct. Within each set, no two verbs began with the
same initial phoneme. These verbs were paired with high
frequency animate nouns to yield reversible sentences that
were pictured in simple line drawings (see Figure 2). Multiple baselines of active and passive sentence production in
response to the three sets of reversible action pictures were
obtained prior to the initiation of treatment. These same
sentences were probed throughout the two phases of treatment to determine treatment and generalization effects.
Again, errors in morphologic endings and article omissions
were ignored for scoring purposes, with the exception of
the passive morphology for passive sentence construction
(e.g., “was 1 verb 1 by”). Synonyms for the lexical items
(e.g., “lady” for woman; “bashing” for hitting) were scored
as correct. Each response was transcribed and scored offline by the therapist and by a second examiner who was
unfamiliar with the patients for reliability. Interjudge agreement exceeded 90%; disagreements were resolved by a third
examiner.
Following the determination of a stable baseline as indicated by the C-statistic (Tryon, 1982), ELM treatment was
initiated using the first set of pictures, while the other two
sets were not treated but were probed with the same frequency as the treated set. The second set of pictures was
used for training during EFM, and the third set of pictures
was never treated, to allow for a generalization comparison
for both phases of treatment.

Functional Magnetic Imaging Task
G01 and J02 underwent f MRI scanning both pre- and postmapping treatment. A silent sentence generation task alternated with a passive viewing task in a block paradigm. For
the baseline task, patients passively viewed nonsense objects
thought to have minimal semantic representation (Kroll &
Potter, 1984). A similar paradigm has been used for detecting the neural substrates of simple sentence production in
healthy adults (Peck et al., 2004b). The use of perceptual
tasks during baseline states is recommended to interrupt
ongoing neural activity that may involve the same brain
regions activated during linguistic retrieval (Binder et al.,
1999). For the sentence production task, patients were
instructed to silently produce sentences describing events

C.E. Wierenga et al.
depicted in black-and-white line drawings of an action
occurring between two nouns (one actor and one recipient). Because stimuli presented in the scanner were similar
to the items presented during treatment probes, performance of patients in the scanner could be estimated based
on their performance during the treatment-related sentence
generation tasks. Although often erroneous in lexical selection and0or thematic role assignment, even prior to
treatment, G01 produced active sentences containing an
argument structure (characterized by the presence of noun0
verb combinations) 99% of the time, and for J02, 94% of
the active sentences he produced contained an argument
structure, indicating generation of a syntactic frame during
each attempt. Therefore, we are confident that both patients
engaged in syntactic processing during the active blocks
of the paradigm.
Silent sentence production was chosen, despite its drawbacks, to minimize imaging motion artifacts brought about
by extended speech. Although artifacts from overt language production can be averaged away across participants
in group studies of healthy adults, Barch et al. (1999) advised
against individual participant analyses using overt production. Given the variability in lesion size, shape, and location, studies of stroke patients are constrained to withinsubject designs to avoid grossly underestimating perilesional
activity. Such underestimation can result with group averages when perilesional activity for some patients falls within
the lesion territory of other patients. Methods to reduce
motion-related signal change by discarding motion-corrupted
images obtained while speaking (Birn et al., 1999) cannot
easily be applied to overt sentence production in aphasic
patients because of the variable onsets and variable durations of their overt responses. Furthermore, those early
images are crucial for capturing processes related to ordering sentence elements because those must occur prior to
spoken sentence production (Garrett, 1980, 1984; Berndt,
1998). Lastly, comparisons of overt and covert language
production reveal similar patterns of activity regardless of
response modality, with the addition of regions associated
with motor aspects of speech production in overt responding (Palmer et al., 2001; Ackermann & Riecker, 2004; Kan
& Thompson-Schill, 2004).
Each 26.4-second active (silent sentence production) block
contained 3 line drawings, each presented for 8.8 seconds
to allow time for patients to respond. A run comprised 6
active blocks interleaved with 7 passive viewing intervals
that varied in length. Each experimental run began and ended
with a passive viewing block. Passive viewing intervals
were pseudorandomly varied between 17.6 sec (4 images),
22 sec (5 images), and 26.4 sec (6 images) to mitigate low
frequency artifacts (Zarahn et al., 1997). The minimum interval was long enough to allow hemodynamic responses to
return to baseline before the subsequent active block began.
Each run lasted 316.8 sec during which 72 whole-brain
functional images were acquired. Each patient completed 3
runs for 216 images total. Stimuli were projected onto a
translucent screen at the patients’ feet via a Solo 2500 LS

Neural substrates of syntactic mapping treatment
Laptop Computer (Gateway) and an XG-NV7XU LCD Projector (Sharp Electronics) using E-Prime Version 1 software.

Image Acquisition
Images were acquired on a 1.5T GE Signa MR scanner
using a dome-shaped quadrature radio frequency head coil
(MRI Devices). Head motion was minimized using foam
padding. For functional images, 24 contiguous sagittal slices
covering the whole brain were acquired using a gradient
echo 2-shot spiral scan sequence (TE 5 40 ms; TR 5
2200 ms; FA 5 908; FOV 5 180 mm) (Macovski, 1985;
King et al., 1995; Noll et al., 1995). Slice thickness differed
slightly (less than 4%) between sessions to accommodate
slight differences in head angle within the field of view
between sessions (6.0 mm pre- and 6.2 mm posttreatment
for G01; 6.6 mm pre- and 6.4 mm posttreatment for J02). In
a 2-shot spiral sequence, each spiral is acquired during a
separate TR; thus, the total time for acquisition of a single
whole-brain volume of functional images was 4.4 seconds.
For purposes of analysis, data were interpolated to a 128 3
128 matrix. Subsequent to functional images, structural
T1-weighted images were acquired for 124 3 1.3 mm thick
sagittal slices, using a 3D spoiled GRASS volume acquisition (TE 5 7 ms; TR 5 27 ms; NEX 5 1; FOV 5 240 mm;
FA5 458; matrix size 5 256 3 192). Dual-echo T2-weighted
images were also acquired (TE eff 5 34 ms and 85 ms; TR 5
3000 ms; NEX 5 1; FOV 5 240 mm; matrix size 5 256 3
128) using a fast spin echo sequence.

Image Analysis
Functional images were analyzed and overlaid onto structural images with the Analysis of Functional Neuroimaging
(AFNI) program from the Medical College of Wisconsin
(Cox, 1996). To minimize the effects of head motion, time
series images were spatially registered in 3-dimensional
space. Images were visually inspected for gross artifacts
and viewed in a cine loop to detect residual motion. Neither
patient’s data contained enough images with gross artifacts
or uncorrected head motion in pre- or posttreatment scans
to warrant exclusion from the study. To mitigate large vessel effects and other sources of error, voxels where the standard deviation of the signal change exceeded 5% of the
mean signal intensity were set to a value of zero. This threshold was developed in our laboratory for use with the current
instrument and spiral pulse sequences as a convenient way
to eliminate nonbrain voxels and voxels in large veins identified on MR angiograms, while at the same time preserving brain activity outside of major veins. Linear trends were
removed from individual imaging runs by orthogonalization (i.e., detrending) (Birn et al., 2001).
Imaging runs were concatenated into a time series of 216
serial images. Hemodynamic responses for the active task
were deconvolved from the time series on a voxel-by-voxel
basis. Deconvolution was based on a 44-sec or 10-image
lag comprising the active block length (6 images) plus 4

137
images (the shortest baseline interval). Deconvolution estimates the hemodynamic response by empirically determining the optimum shape of waveform matching the data and
finding its goodness-of-fit or R 2 (Ward, 1998). Because the
shape of the hemodynamic response in a given area for a
particular task can vary considerably from one individual
to another (Aguirre et al., 1998), deconvolution analysis
should offer greater sensitivity between patients than methods making a priori assumptions about the shape of the
hemodynamic response.
Signal-to-noise ratios (SNRs) were calculated based on
the method of Weisskoff (1996), using the formula SNR 5
(0.655 3 Sbrain )0Sbackground, with Sbrain being the mean
of the signal in a 5 3 5 region of the periventricular white
matter in a medial slice and Sbackground being the standard deviation in a 5 3 5 region of the signal in the background of the image (i.e., outside the head) in a region free
from motion-related signal change. Although for G01 the
SNRs were similar between sessions (pre: 45.2; post: 46.7),
the SNRs for J02 were 59.7 pretreatment and 48.1 posttreatment. Since the noise structure varied between these scans,
prior to analysis of pre- and posttreatment functional MR
images, images were equated for sensitivity to BOLD
response across sessions on a voxel-by-voxel basis using a
procedure developed in our laboratory. In brief, this procedure uses residual variances from the deconvolution analyses to estimate the noise structures of pre- and posttreatment
images. Different known amounts of signals were added to
those noise structures. Probability density curves were generated for each noise structure at each signal level, showing
the fraction of voxels as a function of R 2 . Detection probability was then used to equate the pretreatment and posttreatment R 2 s for sensitivity. This procedure was applied to
both patients’ images.
After equating for sensitivity, each patient’s pre- and
posttreatment images were spatially coregistered in
3-dimensional space and converted to 1-mm cubic voxels
having the same spatial coordinates for both scans. Activation was defined by statistical thresholds of R 2 ⱖ .30 for
G01 and R 2 ⱖ .40 for J02. To compare amplitude of response
in areas activated in pre- or posttreatment images, a composite image was created such that a voxel would be declared
activated if statistical threshold was met either pre- or posttreatment (or both). A contiguity threshold of volume ⱖ
200 microliters was used to select areas of activity for this
union of pre- and posttreatment scans, so that the possibility of interpreting false positive activity was minimized.
Hemodynamic response waveforms for each voxel in an
area so identified were extracted from pre- and posttreatment deconvolution analyses. Conversion to Talairach coordinate space (Talairach & Tournoux, 1988) was performed
to assist in finding the general regions in which these clusters of activity were located. Because locations of structures vary between individuals and mislocalization could
result from using atlas coordinates alone, clusters were localized by reference to anatomic landmarks, using the atlas as
a guide when necessary. A smaller contiguity threshold (vol-

138
ume . 100 microliters) was adopted for interpretation of
the results of individual scans.
Finally, differences in volume of the active clusters could
be observed by comparing pre- to posttreatment scans. The
likelihood that these differences occurred by chance was
evaluated by testing with binomial statistics whether there
were different proportions of active voxels within a larger
volume containing the pre- and posttreatment active clusters. That is, an active voxel was counted as a success, and
the probability of success was estimated from the average
of pre- and posttreatment counts. There were two caveats
for these calculations. First, voxel counts were based on
acquisition voxels (not 1 mm cubic voxels), because the
former are more nearly independent, an important assumption about binomial trials. Second, there was no ideal way
to determine the size of the larger volume within which the
active clusters were embedded, that is, by analogy, the total
number of binomial trials within which proportions of successes could be evaluated. Therefore, a wide range of volumes were used in the calculations, from the smallest
possible for embedding the clusters (min) to larger than the
whole brain, in steps of 2 3 min, 4 3 min, 10 3 min, 100 3
min, 1,000 3 min, 10,000 3 min, and 1,000,000 3 min. We
accepted as reliably different only those clusters for which,
over the whole range of embedding volumes, p , .01 that
the observed number of active voxels either pre- or posttreatment resulted from the probability of being active, estimated from their average.

RESULTS
Patient G01
Mapping treatment
Outcomes of the intervention are depicted in Figures 3 and
4. Significant change from baseline performance for the
treated set was determined using the C-statistic (Tryon,
1982). Significant change on the untreated set (set U) was
interpreted as a positive generalization effect. Functional
generalization to narrative discourse was evaluated comparing performance on repeated story-retelling samples preand posttreatment. An examination of the treatment effects
for G01 (Figure 3) demonstrates that a significant improvement occurred for treated sentences (Phase 1: z 5 3.45;
Phase 2: z 54.03, p , .01). Separate review of active versus passive sentence production (see Table 2) revealed an
average gain of 56% for treated active sentences and over
66% for treated passive sentences collapsed over the two
phases of treatment. However, G01 did not show significant change on the untreated sentences (Phase 1: z 5 1.26;
Phase 2: z 5 .66, p . .05), with performance on untreated
actives and passives yielding no appreciable change. An
analysis of the types of errors made at the end of treatment
suggests that the failure to generalize accurate production
to the untreated set of sentences is accounted for by a persistent difficulty with verb retrieval. At the conclusion of

C.E. Wierenga et al.
Table 2. Mean percent correct of baselines for active and
passive sentence production pre- and post-Errorless Mapping
Therapy and pre- and post-Errorful Mapping Therapy
Actives
Sentence set

Passives

Pre-TX

Post-TX

Pre-TX

Post-TX

38.75
65.00
23.75
73.75

93.73
73.75
81.25
67.50

30.00
48.75
18.75
56.25

88.75
56.25
85.00
62.50

5.00
6.25
68.75
81.25

97.50
81.25
85.00
72.50

3.75
1.25
70.00
77.50

83.75
77.50
70.00
63.75

G01
Errorless mapping set
Untreated set
Errorful mapping set
Untreated set
J02
Errorless mapping set
Untreated set
Errorful mapping set
Untreated set
Note. TX 5 treatment

treatment, G01 made relatively few errors in word order
(see Figure 4), which was the target of treatment. Despite
this persistent deficit in verb retrieval, G01 did demonstrate
generalization of improved sentence production in narrative discourse, as indicated by increased proportion of wellformed sentences to within normal range of .98, (SD 5 .05)
(Berndt et al., 2000), suggesting that a functional impact of
the intervention was achieved (see Table 3).

Functional magnetic resonance imaging
Volumes of significant activity in various regions are graphed
in Figure 5a. For G01, pretreatment sentence production
resulted in a volume of activity (176 ml) in the left inferior
frontal gyrus including Broca’s area along the diagonal sulcus and within pars opercularis (Brodmann’s Area 44; Figure 6, upper left). Additionally, a large volume of activity
was found in the left posterior middle temporal gyrus, and a
moderately large volume was found in the left inferior tem-

Table 3. Linguistic analyses of narrative discourse
(story retelling) prior to and upon completion
of mapping for G01 and J02

G01 Story Retelling
Proportion of words in sentences
Proportion of sentences that were well-formed
J02 Story Retelling
Proportion of words in sentences
Proportion of sentences that were well-formed

PreTX

PostTX

.91
.71

.98
.97

.89
.56

.83
.60

Note. Results suggest G01evinced a marked increase following therapy in
the proportion of well-formed sentences during story retelling, whereas
J02 did not. TX 5 treatment

Neural substrates of syntactic mapping treatment

139

Fig. 3. Time-series graphs of treatment and generalization response for G01 and J02 during the course of the study.
BL 5 Baseline, TXELM 5 Errorless Mapping Treatment, TXEFM 5 Errorful Mapping Treatment. Numbers indicate
the session.

poral gyrus and the right middle temporal gyrus (Figure 5a). Following treatment, G01 exhibited more robust
activity (1146 ml; p , .01, binomial test) in Broca’s area
and adjacent left inferior frontal cortex, including pars opercularis (Brodmann’s Area 44) along the anterior ascending
ramus and extending medially within pars triangularis
(Brodmann’s Area 45) and pars orbitalis (Brodmann’s Area
47) along the anterior horizontal ramus of the Sylvian fissure (Figure 6, upper right). Posttreatment there was a small
(nonsignificant) decrease in activity in the left inferior temporal gyrus (pre: 307 ml; post: 205 ml). Activity in the
posterior left middle temporal gyrus was also relatively stable in extent from pre- to posttreatment imaging (pre: 879 ml;

post: 832 ml). Thus, treatment effects for syntax generation
by G01 may be attributed to greater recruitment of Broca’s
area (see Figure 5a).
A similar picture emerges when the time courses of activations are examined. Figure 7 shows waveforms recovered by deconvolution averaged over voxels in G01’s frontal
(upper left panel) and temporal (upper right panel) regions
of activation. As expected, the MR signal rises during active
sentence production (first 6 images) and falls during passive viewing (last 4 images). The rise is smaller pre- than
posttreatment frontally but larger pre- than posttreatment
temporally, consistent with changes in the extent of activity
exceeding threshold, as noted earlier.

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C.E. Wierenga et al.

Fig. 4. Change in error distribution for G01 and J02 sentence probes pre- and posttreatment (TX). A ratio of the
frequency of occurrence of each error type over the total number of errors made was used to calculate the proportion
of each error relative to the total sample.

Patient J02
Mapping treatment
J02 (Figure 4) demonstrated significant improvement at the
.01 level for both treated (ELM, z 5 3.39; p , .01) and
untreated (z 5 3.21; p , .01) sentences. Assessment of
Phase 2 intervention could not be made, as there was generalization from the first phase to the sentences for Phase 2,
as well as the untreated sentence set. However, visual inspection of the graph suggests this performance was somewhat
variable, especially during the second phase of treatment.
While J02 demonstrated improvement in untreated sentences, these gains did not appear to impact narrative discourse, as indicated by the lack of improvement in the
proportion of words in sentences or well-formed sentences
during story retelling (Table 3). The variability in sentence
production during treatment, and the lack of generalization
to more functional narrative discourse, suggests improvement in the process of sentence generation specific to the
treatment task (i.e., active or passive sentence production in
response to picture description) rather than to the process of
sentence generation per se. This notion is supported by the

continued heavy distribution of word-order errors, as well
as verb retrieval errors, at the end of treatment (see Figure 4).

Functional magnetic resonance imaging
FMRI findings for J02 were substantially different than for
G01. In the two largest areas of activity from J02’s pretreatment images, activity from posttreatment images
decreased significantly. This decrease in posttreatment activity was especially evident in the inferior frontal sulcus (pre:
1616 ml, post: 449 ml; p , .01, binomial test) (Figure 5b),
but also happened in the left middle temporal gyrus (pre:
641 ml, post: 140 ml; p , .01, binomial test). Other areas of
activity from pre- or posttreatment images in the left inferior frontal gyrus, right pre-supplemental motor area (preSMA), left SMA, or right middle temporal gyrus did not
meet the contiguity threshold for interpretation.
The time courses of activations for J02 are shown in the
lower panels of Figure 7. The rise is larger pre- than posttreatment both frontally and temporally. Although these
reductions in amplitude are superficially what could be
expected from the lower SNR in the posttreatment scan,

Neural substrates of syntactic mapping treatment

141

Fig. 5. Volumes (in microliters) of Activity Pre- and Post-Syntactic Mapping Treatment. Note: * indicates areas of
significant change between pre- and posttreatment based on the binomial equation ( p , .01). Volumes of significant
activity in microliters (R 2 ⱖ .30 for G01 pre- and posttreatment, R 2 ⱖ .40 for J02 pre- and posttreatment, volume ⱖ
100 microliters) are shown for presyntactic mapping treatment f MRI and postsyntactic mapping treatment f MRI. From
pre- to posttreatment scans for G01, activity increased in the left inferior frontal gyrus including Broca’s area and
remained relatively consistent in inferior temporal regions (a). For J02, activity was predominantly frontally mediated
both pre- and posttreatment, with a decrease in activity along the inferior frontal sulcus and left middle temporal gyrus
from pre- to posttreatment (b). L 5 left, R 5 right, IFG 5 inferior frontal gyrus, IFS 5 inferior frontal sulcus, MTG 5
middle temporal gyrus, ITG 5 inferior temporal gyrus.

there were other brain regions with the inverse relationship
(e.g., right pre-SMA, left SMA), which would be inconsistent with this interpretation. This pattern of decreased activity in major ROIs therefore suggests greater efficiency in
utilizing areas posttreatment that were active during pretreatment imaging.

DISCUSSION
In summary, these two patients with chronic nonfluent aphasia and syntactic language deficits prior to rehabilitation

underwent the same intervention with the same intensity
and methodology. Treatment yielded rather different outcomes, as indicated by both their response to probes during
treatment and generalization to nontreatment tasks. G01 did
not demonstrate generalization from treated to untreated
sentences when both word-finding and syntactic (word order)
errors were considered, but error analysis revealed a decrease
in thematic role assignment errors on treated active and
passive sentences posttreatment. Further, her narrative discourse showed an increase in well-formed sentences,
although she continued to make lexical retrieval errors for

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C.E. Wierenga et al.

Fig. 6. Deconvolved waveforms averaged over voxels within regions of interest in the frontal and temporal lobes.
Regions of interest were identified by means of composite images uniting activations observed pre- and posttreatment.
For G01, Broca’s area and left middle temporal gyrus are depicted. For J02, left inferior frontal sulcus and left middle
temporal gyrus are depicted.

verbs, which accounts for her lack of generalization to the
untreated sentences. On the other hand, J02 showed a rapid
improvement on treated and untreated items, but demonstrated variability in accuracy at the end of treatment. Error
analysis reveals that he continued to make word order errors
and did not show changes in the proportion of well-formed
sentences in narrative discourse from pre- to posttreatment.
In other words, he did not learn procedures for producing
proper thematic role assignment during treatment.
The differences in response to treatment for G01 and
J02 were paralleled by the differences in their functional
neuroimaging results. Pre- versus postmapping treatment
changes in neural activity during sentence generation
showed different patterns in these two patients. For G01,
rehabilitation led to a significant expansion in the extent
of activity in Broca’s area both medially and anteriorly
along the inferior frontal gyrus. In posterior regions, G01

demonstrated a slight reduction of activation in inferior
and lateral temporal cortices from pre- to posttreatment
images, but continued to recruit regions responsible for
the semantic processing of items (Ungerleider & Haxby,
1994; Foundas et al., 1998; Chao et al., 1999; Ishai et al.,
1999) within a sentence, even with improvement in thematic mapping ability. On the other hand, J02 demonstrated little change in the location of activity from pre- to
posttreatment except for a significant reduction in the
volume of activity for the left inferior frontal sulcus from
pre- to posttreatment scans. Recent findings from our laboratory indicate that healthy adults activate a network of
structures including, but not limited to left Broca’s area,
inferior frontal sulcus, angular gyrus, superior temporal
gyrus, and fusiform gyrus during passive-voice sentence
generation. Both of our patients activated only partial syntactic networks compared to healthy adults.

Neural substrates of syntactic mapping treatment

143

Fig. 7. Pre- and Post-Mapping Therapy f MRI Images for G01 and J02 during sentence generation. Frontal activity
during naming for group comparison. Pretreatment images are shown for G01 and J02 on the left side of the figure and
posttreatment images for both patients are shown on the right side of the figure. Images for G01 show changes in
activity in Broca’s area, red 5 R 2 ⱖ .30; yellow 5 R 2 ⱖ .35 for pre- and posttreatment. Prior to the mapping treatment,
G01 showed some activity in this region (BA 44, 45). Posttreatment, activity in Broca’s area increased substantially to
include pars opercularis (BA 44) along the anterior ascending ramus and extended medially within pars triangularis
(BA 45) and pars orbitalis (BA 47) along the anterior horizontal ramus of the Sylvian fissure. Images for J01 show the
left lateral frontal and temporal cortices, red 5 R 2 ⱖ .40; yellow 5 R 2 ⱖ .45 for pre- and posttreatment. His pattern of
activation remained relatively consistent pre- and posttreatment, with a decrease in activity in the left inferior frontal
sulcus and left middle temporal gyrus.

Differences in functional activity reflecting neuroplasticity demonstrated by G01 and J02 shed light on the mechanisms underlying language rehabilitation. The patients’
behavioral performance at the end of treatment informs interpretation of functional activity. For G01, expansion of activity within Broca’s area may reflect increased syntactic
abilities, given that an increase in the intensity and extent
of brain activation in nondemented older adults during learning tasks has been interpreted as reflecting a compensatory
mechanism wherein individuals utilize additional cognitive
resources to bring performance to a normal level (Cabeza
et al., 2002; Reuter-Lorenz, 2002). If this is the case, then
G01’s ability in thematic role assignment may have been
supported by the relative preservation and reengagement of

Broca’s area, since Broca’s area plays a role in connecting
noun phrases to distinct grammatical positions that determine their thematic roles (Zurif et al., 1993; Swinney et al.,
1996; Grodzinsky, 2000). Thus, remobilization of this region
is consistent with G01’s improvement in syntactic production of treated sentences, and may have contributed to her
functional improvement in less constrained sentence production. Generalization of syntax processing posttreatment
is consistent with previous studies of syntax treatment
(Thompson et al., 1997). It also should be noted that treatment did not address word retrieval; therefore, G01’s persistent verb retrieval deficit could be expected.
On the other hand, the decreased activity in lateral frontal regions for J02 corresponding to treatment improvement

144
may reflect an alternative form of neuroplasticity. Given
that a reduction in activity was found to correspond to practice effects in healthy adults (Petersen et al., 1998), the
reduction in activity posttreatment for J02 may reflect
increased efficiency in the use of cortical areas that were
already involved in sentence generation prior to treatment.
Although J02 demonstrated improvement for both treated
and untreated sentences following mapping treatment, the
variability in his performance at the end of treatment suggests that ultimately he did not learn the process of thematic role assignment necessary to produce well-formed
sentences. Instead, his performance suggests that he may
have adopted a strategy in which he learned a syntactic
template that he applied to treatment items, but this strategy
was inadequate for less constrained discourse, accounting
for the lack of generalization to narrative production. Overall, for J02, findings suggest that a failure to recruit new
brain regions may yield restricted results, with limited generalization outside the template of the treatment paradigm.
That being said, it is unclear what mechanisms are responsible for different responses to treatment and apparent differences in brain reorganization. Factors such as education
level, length of time since CVA onset, age of onset, length
of immediate poststroke speech and language therapy, and
gender cannot be ruled out. Even so, a plausible reason for
different neural substrates supporting recovery in these two
patients is that their lesion sites and extents differentially
impacted neural response to treatment. Although J02’s lesion
was a smaller, relatively circumscribed lesion affecting primarily the left sensorimotor and premotor cortex, insular
region, the superior temporal gyrus extending medially, and
the basal ganglia, it is possible that damage to white matter
pathways prevented the communication between anterior
and posterior regions responsible for syntax processing
(Naeser et al., 1989, 1998). In contrast, G01 sustained a
larger lesion involving a greater portion of the left perisylvian cortex, and extending more laterally and posteriorly
than J02’s lesion. Preservation of anterior insular cortex medially and posterior inferior temporal gyrus may have facilitated recovery through a neural network similar to that used
in healthy sentence production, with recruitment of Broca’s
area to participate again in syntactic production (Naeser et al.,
1998). Further research is needed to elucidate mechanisms
that contribute to or hinder rehabilitation success.
In conclusion, the two patients in this study appeared to
benefit from syntactic mapping treatment in different ways.
Likewise, their posttreatment f MRI data reveal different
patterns of activation and suggest that the neural mechanisms of rehabilitative change can differ between participants. The hypotheses generated from these data can act as
the basis for further exploration of the different neural mechanisms of rehabilitative change and their cognitive correlates based on lesion characteristics and treatment response.
Knowledge of these mechanisms will enable development
of conceptually driven rehabilitation strategies based on
physiological principles of recovery to maximize treatment
efficacy.

C.E. Wierenga et al.

ACKNOWLEDGMENTS
This work was supported by NIDCD Grant #P50-DC03888 and
the Department of Veteran Affairs Rehabilitation R&D Center of
Excellence Grant #F2182C. We thank Floris Singletary, Diane
Kendall, Jennifer Swearengin, and Cathy Clayton for their valuable contributions.

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