Group Title: BMC Neuroscience
Title: Imaging short- and long-term training success in chronic aphasia
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Title: Imaging short- and long-term training success in chronic aphasia
Physical Description: Book
Language: English
Creator: Menke, Ricarda
Meinzer, Marcus
Kugel, Harald
Deppe, Michael
Baumgärtner, Annette
Schiffbauer, Hagen
Thomas, Marion
Kramer, Kira
Lohmann, Hubertus
Flöel, Agnes
Knecht, Stefan
Breitenstein, Caterina
Publisher: BMC Neuroscience
Publication Date: 2009
 Notes
Abstract: BACKGROUND:To date, functional imaging studies of treatment-induced recovery from chronic aphasia only assessed short-term treatment effects after intensive language training. In the present study, we show with functional magnetic resonance imaging (fMRI), that different brain regions may be involved in immediate versus long-term success of intensive language training in chronic post-stroke aphasia patients.RESULTS:Eight patients were trained daily for three hours over a period of two weeks in naming of concrete objects. Prior to, immediately after, and eight months after training, patients overtly named trained and untrained objects during event-related fMRI. On average the patients improved from zero (at baseline) to 64.4% correct naming responses immediately after training, and treatment success remained highly stable at follow-up. Regression analyses showed that the degree of short-term treatment success was predicted by increased activity (compared to the pretraining scan) bilaterally in the hippocampal formation, the right precuneus and cingulate gyrus, and bilaterally in the fusiform gyri. A different picture emerged for long-term training success, which was best predicted by activity increases in the right-sided Wernicke's homologue and to a lesser degree in perilesional temporal areas.CONCLUSION:The results show for the first time that treatment-induced language recovery in the chronic stage after stroke is a dynamic process. Initially, brain regions involved in memory encoding, attention, and multimodal integration mediated treatment success. In contrast, long-term treatment success was predicted mainly by activity increases in the so-called 'classical' language regions. The results suggest that besides perilesional and homologue language-associated regions, functional integrity of domain-unspecific memory structures may be a prerequisite for successful (intensive) language interventions.
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Research article


Imaging short- and long-term training success in chronic aphasia
Ricarda Menket1,2, Marcus Meinzer* t1,3, Harald Kugel4, Michael Deppe1,
Annette Baumgartner5, Hagen Schiffbauer4, Marion Thomas', Kira Kramer1,
Hubertus Lohmann', Agnes Floel', Stefan Knecht,6 and
Caterina Breitenstein'


Address: 'Department of Neurology, University of Mfinster, Mfinster, Germany, 2Department of Clinical Neurology, Oxford University, Oxford,
UK, 3Department of Clinical & Health Psychology, University of Florida, Gainesville, USA, 4Department of Clinical Radiology, University of
Minster, Mfinster, Germany, 5Department of Health Sciences, Hochschule Fresenius, University of Applied Sciences, Hamburg, Germany and
6Neurocenter, Schin Klinik, Hamburg, Germany
Email: Ricarda Menke ricarda@fmrib.ox.ac.uk; Marcus Meinzer* mmeinzer@ufl.edu; Harald Kugel kugel@uni-muenster.de;
Michael Deppe deppe@uni-muenster.de; Annette Baumgirtner baumgaertner@hs-fresenius.de; Hagen Schiffbauer Schiffbauer@uni-
muenster.de; Marion Thomas Malo.home@t-online.de; Kira Kramer- kira.kramer@uni-muenster.de; Hubertus Lohmann lohmanH@uni-
muenster.de; Agnes Fl6el floeel@uni-muenster.de; Stefan Knecht knecht@uni-muenster.de; Caterina Breitenstein caterina.breitenstein@uni-
muenster.de
* Corresponding author tEqual contributors



Published: 22 September 2009 Received: 19 May 2009
BMC Neuroscience 2009, 10:118 doi: 10.1 186/1471-2202-10-118 Accepted: 22 September 2009
This article is available from: http://www.biomedcentral.com/1471-2202/10/1 18
2009 Menke et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Abstract
Background: To date, functional imaging studies of treatment-induced recovery from chronic aphasia
only assessed short-term treatment effects after intensive language training. In the present study, we show
with functional magnetic resonance imaging (fMRI), that different brain regions may be involved in
immediate versus long-term success of intensive language training in chronic post-stroke aphasia patients.
Results: Eight patients were trained daily for three hours over a period of two weeks in naming of
concrete objects. Prior to, immediately after, and eight months after training, patients overtly named
trained and untrained objects during event-related fMRI. On average the patients improved from zero (at
baseline) to 64.4% correct naming responses immediately after training, and treatment success remained
highly stable at follow-up. Regression analyses showed that the degree of short-term treatment success
was predicted by increased activity (compared to the pretraining scan) bilaterally in the hippocampal
formation, the right precuneus and cingulate gyrus, and bilaterally in the fusiform gyri. A different picture
emerged for long-term training success, which was best predicted by activity increases in the right-sided
Wernicke's homologue and to a lesser degree in perilesional temporal areas.
Conclusion: The results show for the first time that treatment-induced language recovery in the chronic
stage after stroke is a dynamic process. Initially, brain regions involved in memory encoding, attention, and
multimodal integration mediated treatment success. In contrast, long-term treatment success was
predicted mainly by activity increases in the so-called 'classical' language regions. The results suggest that
besides perilesional and homologue language-associated regions, functional integrity of domain-unspecific
memory structures may be a prerequisite for successful (intensive) language interventions.





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BMC Neuroscience 2009, 10:118


Background
Chronic aphasic symptoms affect approximately 18 per-
cent of stroke patients [ 1]. Language abilities can be signif-
icantly improved in the chronic stage after a stroke when
training is sufficiently intensive with more than five hours
of training per week [2], even when total language train-
ing lasts for merely two weeks [3-6]. Several recent func-
tional brain imaging studies investigated the neural
correlates of spontaneous language recovery in aphasia
patients, showing the importance of perilesional areas for
(covert) language production [7]. Additionally, a domi-
nant right-sided activity pattern was observed for the least
recovered patients in the chronic stage after stroke and has
been interpreted in some studies as a less effective com-
pensatory strategy [8]. Similarly, in a longitudinal study
that followed up patients from the acute to the chronic
stage, an early upregulation of right-hemisphere activity
after stroke was followed by reactivation of left frontal
areas in the chronic stage in well recovered patients [9].
However, right-sided activity patterns can also be func-
tionally relevant, at least for the recovery of language com-
prehension [10].

The few available intensive intervention case studies using
functional imaging (for a recent review see [11]) yielded
highly heterogeneous recovery patterns across individual
patients [12-17], making it difficult to draw general con-
clusions about brain areas required for the success of
intensive interventions. Only three very recent studies
assessed the neural substrates of intensive language train-
ing success at the group level. Raboyeau et al. [18] deter-
mined changes of brain activity measured with positron-
emission-tomography (PET) in ten aphasia patients prior
to and after four weeks of (lexical) training. Better per-
formance after training was correlated with activity
increases in right-sided language (insula) and frontal
attention areas. A training-induced modulation of right
frontal areas was also observed in the recent functional
magnetic resonance (fMRI) study by Richter and col-
leagues [5]. On the other hand, Meinzer et al. [19] found
increased fMRI activity after training selectively in individ-
ually determined perilesional brain areas in eleven
chronic aphasia patients, and only activity increases in
these perilesional (predominantly left frontal) areas corre-
lated with intensive therapy success.

One caveat of intensive intervention neuroimaging stud-
ies to date is that only short-term treatment effects were
assessed. Like other types of declarative memory, the long-
term consolidation of language information may require
different brain areas than the ones participating in initial
learning [20-22]. Evidence for dynamic shifts within neu-
ral networks over time stems from recent language learn-
ing studies with healthy subjects showing that brain
structures involved in general learning, such as the hip-


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pocampus, mediate the initial learning of lexical, seman-
tic, and syntactic knowledge [23-27]. During later stages
of memory consolidation, secondary associative cortices
may be functionally required [22,25].

Here, we aimed to differentiate for the first time brain
regions mediating successful short-term versus successful
long-term therapy success in a group of chronic aphasia
patients. We hypothesized that a network of memory and
attention-related brain regions similar to the one
observed in healthy subjects during word learning [e.g.
[25]] and in aphasia patients immediately after intensive
language therapy [5,18,19] is functionally critical for
immediate treatment success, whereas a subsequent
upregulation of 'classical' language areas mediates long-
term stability of intensive language training.

Methods
Eight patients (3 women; age: 34 to 67 years) with chronic
aphasia and moderate to severe word finding difficulties
anomiaa) were studied. Detailed clinical and demo-
graphic information of the patients are provided in Addi-
tional file 1. Figure 1 shows the lesions of the patients. All
patients suffered from anomia following a single left hem-
isphere ischemic stroke (except P03: hemorrhagic insult).
The local Institutional Review Board had approved the
study, written informed consent was obtained from all
subjects and the study was conducted in accordance with
the Helsinki Declaration.

Prior to training, all patients completed a baseline assess-
ment consisting of a neurological examination, speech
and language tests, and neuropsychological testing. All
patients had relatively preserved cognitive abilities except
for the language domain (see Additional file 2 for details).

Additionally, nine healthy control subjects (matched for
age, sex, and handedness with the patients; 36 to 64 years
old; 3 women) were examined twice within a two-week
time interval on an overt naming task during fMRI to (a)
establish the set of brain regions activated by healthy sub-
jects during our naming task and (b) to control for effects
of repeated testing [28].

Anomia treatment
For the intensive anomia training, 50 concrete object
names were individually selected for each patient
('trained objects'). Each trained object name had been
named incorrectly at least twice during three baseline runs
comprising a standardized set of 344 objects [29] (one
correct run during baseline and post assessments was con-
sidered a random performance fluctuation). Patients
received three hours of computer-assisted naming therapy
per day over a period of two weeks. Each of the 50 trained
objects occurred with a high repetition rate on each train-


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Figure I
Lesions. Series of axial TI images showing the extents of left hemisphere lesions for the eight patients




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BMC Neuroscience 2009, 10:118


ing day (up to 32 presentations) to promote stable long-
term memory consolidation. Previously, it has been
shown that this training approach is highly effective to
improve word-retrieval in chronic aphasia patients [29].
Patients received three hours of daily computer-assisted
naming treatment over a period of two weeks. The train-
ing comprised an associative language learning procedure
that aimed at strengthening semantic associations
between target words (object pictures) and auditory and
graphemic cues to facilitate word-retrieval and followed
the method of'vanishing cues' [30] with five difficulty lev-
els. At the first level, a picture of an object in combination
with its spoken and written word form was presented, and
the patient was asked to repeat the object name. Each
training block comprised 200 object pictures (50 objects
times 4 different object tokens). Training blocks on level
1 were repeated until the patient scored >80% correct
responses. At the second difficulty level, cues were
reduced so that the object picture was only cued with the
first two phonemes and the first two graphemes (instead
of the entire object name). At the third level, phonological
and graphemic cues were reduced to the first phoneme. At
level four, only the first grapheme was presented as a cue.
Object naming without phonological or graphemic cues
was required at the fifth level ('free naming'). Whenever
performance was lower than 80 percent correct on levels
two to five, a training block of level one was interspersed
to provide patients with the complete visual and auditory
target word forms. Patients were not provided online feed-
back during a block (except when perseverative naming
errors occurred), but were informed about their overall
scores after each training block. The computer-assisted
training was supervised by an experienced speech and lan-
guage therapist, who also scored each patient's response
with yes or no using a keyboard connected to a PC. The
language therapist was not involved in the assessment of
primary and secondary outcome measures or in data anal-
ysis.

A separate set of 30 object names matched for several lin-
guistic parameters (name agreement, word frequency,
word-length, semantic categories, visual complexity of the
pictures) served as a control set for the post assessments
(immediately and eight months post training). During the
post assessments, the 50 trained and 30 untrained objects
were presented thrice outside the scanner.

Performance for a respective object name was classified as
correct when at least two of the three runs were correct
(i.e., perfect productions). By definition, the baselines for
trained and untrained object names were zero percent cor-
rect (one or less correct runs out of three for each of the
object names).


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MRI protocol
MRI data were acquired in a 3 Tesla whole body scanner
(Philips Intera T30) with nominal gradient strength 30
mT/m and maximal slew rate 150 mT/m/ms. A circularly
polarized transmit/receive birdcage head coil with a HF
reflecting screen at the cranial end was used for spin exci-
tation and resonance signal acquisition. Functional
images were acquired using a T2* weighted single shot
echo-planar (EPI) sequence (whole brain coverage, 36
transversal slices orientated parallel to the AC-PC line,
slice thickness 3.6 mm without gap, FOV 230 mm, recon-
struction matrix 64 x 64, in-plane resolution 3.6 x 3.6
mm2, i.e. isotropic voxels with 3.6 mm edge length, TE =
40 ms, TR = 3000 ms, flip angle = 900). A high-resolution
Tl-weighted anatomical image was acquired for anatomi-
cal identification and coregistration into the Talairach
space.

fMRI task
The object-naming task comprised the visual presentation
of photos of concrete objects during fMRI. Patients
attended three identical fMRI sessions: The first was prior
to the training (pre), the second directly after the training
postal) and the third eight months after completion of
training (post2). Please note that patient P06 did not
attend the 'two weeks'-appointment due to health prob-
lems unrelated to the study. The 'eight months'-assess-
ment for P08 could not be conducted due to a required
scanner hardware upgrade after his initial training.

During each fMRI session, the participants had to overtly
name the same 90 individually selected objects (Figure
2A). Thirty of the 90 objects had been consistently cor-
rectly named during the multiple baseline assessments.
Half of the 60 incorrectly named objects at baseline were
trained during the intensive therapy (a subset of the total
50 trained object names). The remaining 30 of the incor-
rectly named objects at baseline served as an untrained
control set. Object names of the three different categories
were matched for various linguistic criteria and were pre-
sented in random order during each of the three sessions
(but fixed order for the three sessions per patient). Prior to
scanning, the naming task was trained with all patients
(using different objects) outside the scanner.

Naming performance was assessed during the respective
fMRI session by means of a special MR dual-channel com-
munication system, equipped with software to subtract
gradient noise from the patient microphone channel (MR
Confon GmbH, http://www.mr-confon.de). Control sub-
jects also overtly named ninety visually presented objects
during fMRI that were selected from our standardized set
of 344 object pictures, based on a name agreement of> 80
percent in a different sample of healthy adults [29].



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A 9U ODjects
3 different object categories
matched for various linguistic criteria


,,known" ,,not known"
30 objects 60 objects

correctly named during the baseline performance =
multiple baseline assessment 0% correct namings

no training induced changes
expected ,,trained" ,,untrained"
30 objects 30 objects

intensively and control set for
repetitively trained therapy-unrelated effects

training induced possible changes
changes expected due to unspecific
B training effects
ISI=10 s ISI=15s ISI=13 s ISI=14s ISI=9 s
..-->--- 9- -" 9-> -'.
stimulus: 5 s stimulus: 5 s stimulus: 5 s stimulus: 5 s

Figure 2
Study design. Flowcharts A: explaining the different object categories used during fMRI and B: illustrating the fMRI paradigm.
ISI = Interstimulus interval


Images were projected using the stimulation software
Presentation* onto a screen fixed at the rear opening of the
MR bore, which could be seen by the participant via a mir-
ror fixed on the top of the head coil. Each of the 90 objects
was presented for 5 s, followed by variable inter-stimulus
intervals (ISI; 8-16 s, mean 12 s, Figure 2B). Subjects were
instructed to overtly name the shown object during the 5
s presentation interval.

We used an event-related design proposed by Birn et al.
[31] for fMRI studies involving overt verbal responses.
Comparing different designs and analysis strategies, opti-
mal detection of BOLD signal changes without significant
motion artefacts were found for minimum stimulus dura-
tions (SD) of 5 s and average ISIs of at least 10 s.

fMRI data analysis
Imaging data were analysed with SPM2 http/x4
www.fil.ion.ucl.ac.uk/spm. Scans of each individual were
corrected for slice timing and then realigned to the first
session image. The functional images were first co-regis-
tered to the individual high-resolution anatomical scan.


Then, the anatomical image was used to determine the
parameters for the spatial normalization process [32].
During normalization, cost-function masking was per-
formed to prevent distortion of the image due to the
lesion [33]. The mask excluded the lesioned area and
highly extended (ex vacuo dilated) ventricles. The result-
ing voxel size in standard stereotactic coordinates was 3 x
3 x 3 mm3. The normalized images were spatially
smoothed using an isotropic Gaussian kernel (FWHM 9
mm).

Data were analysed in the context of the general linear
model, using the canonical hemodynamic response func-
tion (hrf) to model responses during the five seconds of
overt object naming for each experimental condition. To
account for movement artefacts, the estimated realign-
ment parameters were entered in the design matrix as user
specified regressors. Anatomical localization of activated
brain regions was determined using the Talairach Demon
[341.




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Planned contrasts-of-interest were calculated for each
individual subject (first level analysis). These included the
individual activity changes from pre to post training
(postl-pre) or the comparison of the baseline scan with
the third scan eight months after the training (post2-pre)
for each object type separately (i.e., 30 trained objects, 30
untrained objects, 30 objects named correctly during the
baseline assessment). To detect areas with the greatest
short- or long-term fMRI activity changes, which linearly
correlated with behavioral improvement, we performed
two linear regression analyses (second level analysis).
Dependent variable was the individual activity change
from pre to post training (postl-pre, post2-pre), respec-
tively. The respective individual training success for
trained items posti or post2) served as behavioral
regressor.

Technical difficulties, which could not be resolved by the
fMRI microphone manufacturer, precluded the recording
of the speech samples during scanning for later off-line
analysis with application of a software filter to extract the
speech signal from the scanner noise. Online assessment
of patient's word production was not reliably possible
because of the scanner background noise. Sound quality
was, however, good enough to determine that all patients
complied with task instructions and tried to name the
objects presented during scanning.

Thus, we decided to use the patients' performance outside
of the scanner on the matched set of items (here, each
object was presented three times) as behavioral regres-
sors. Even though intra-scanner scores are considered to
be the most appropriate measure of performance for lan-
guage production tasks [35], our extra-scanner measure
assessed on the same day provides an appropriate esti-
mate of the patients' performance. Furthermore multiple
baseline assessments (here 3 runs per object name) repre-
sent a far more reliable performance measure in patients
with aphasia with inherent performance fluctuations [36].

To ensure that the results are specific for overt naming of
the trained objects and not due to therapy-unrelated activ-
ity changes over time (e.g., effects of repeated exposure,
increased motor activity), we used the results of the
respective regression analyses for the matched set of
untrained objects as exclusive masks (i.e., areas correlated
with unspecific activity changes were 'masked out'). The
behavioral regressor here was the performance improve-
ment of each patient from pretraining to post or post2,
respectively. Thus, this analysis allows assessing which
areas are specifically related to training-induced improved
word-retrieval in the patient group.

To determine the brain activity pattern during overt pic-
ture naming in the nine healthy subjects, we performed a


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one sample t-test using the individual fMRI activation pat-
terns during overt object naming (first fMRI session only).
The nine healthy control subjects showed overt naming
related activity in brain regions mediating the core proc-
esses of picture naming [37] [for details of the activity pat-
terns of the healthy adults see Additional file 2].
Unspecific effects of repeated assessments were quantified
by comparisons between sessions (Session 1 > Session 2
and vice versa) using paired t-tests. Activity patterns of the
healthy controls at the first session as well as of the
patients at each of the three assessments are presented in
additional file 2.

Maximally activated voxels within significant clusters (p <
0.05) are reported at a voxel threshold of p < 0.05 and a
minimum cluster size of 10 voxels if not otherwise stated.
At least one voxel within a given cluster had to addition-
ally survive a single-voxel statistical threshold of p < 0.001
(Z-score > 3.00) for the patients because of the known
stronger activations seen in chronic stroke patients com-
pared to healthy controls in fMRI studies [38]. Please
note, for the present data analyses we applied a statistical
threshold that does not correct for multiple comparisons,
which protects against detection of false positives. Still,
unlike simple t-tests, the regression analyses we used
require close (linear) relationships between brain activity
patterns and behavioral performance. Additionally, we
exclusively masked the results with those of a parallel set
of untrained object names to control for treatment- unre-
lated effects. This greatly reduces the risk to obtain false
positives. Moreover, the substantial correlations between
behavioral performance and activity changes within
detected clusters (see results) were clearly not outlier-
driven.

Results
Behavioural results
On average, patients' performance improved during train-
ing, i.e., from zero percent correct naming responses at the
baseline assessment to a mean of 64.4 +/- SD 26.7 percent
correct responses immediately after training (details of
improved naming of trained object names are shown in
Figure 3). Performance for untrained object names also
improved from baseline to immediate post training
assessment, but to a lesser degree (mean of 25.0 +/- 18.5
percent correct) (see Figure 4). This training-unspecific
improvement may be either due to the repeated presenta-
tions of untrained objects over the course of the three
assessments or an improved general word retrieval strat-
egy after training. Behavioural improvement (as com-
pared to the baseline) for the trained objects was
significantly greater for trained as compared to untrained
object names (Object name set x Session: F(2,14) = 19.30,
0.001, Greenhouse- Geisser corrected). This was verified in
posthoc analyses for both the immediate as well as the 8-


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Training success for trained objects


20
10
0


Baseline
Performance
-I7 = 0%
P01 P02 P03 P04 P05 P06 P07 P08
subject id


Figure 3
Behavioural results for trained object names. Training success for trained object names after two weeks (black) and after
eight months (grey) for the eight patients. Please note that patient P06 did not attend the 'two weeks'-appointment due to
health problems unrelated to the study. The 'eight months'-assessment for P08 could not be conducted due to a required scan-
ner hardware upgrade after his initial training




Training success for untrained objects


P01 P02 P03 P04 P05 P06
subject id


I -Baseline
Performance

P7 P=0%
P07 P08


Figure 4
Behavioural results for untrained object names. Behavioural changes in naming performance for untrained object names
after two weeks (black) and after eight months (grey) for the eight patients. Please note that patient P06 did not attend the
'two weeks'-appointment due to health problems. The 'eight months'-assessment for P08 could not be conducted due to a
required scanner hardware upgrade after his initial training



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7 80
70
60
0
E 50
a 40
2 30
8 20

10







BMC Neuroscience 2009, 10:118


month follow-up assessments (both F(2,14) > 25.56,
both p < 0.001, Greenhouse-Geisser corrected). The effect
size for short-term success (based on the mean difference
between trained and untrained object names) amounted
to Cohen's d = 1.7, which is a large treatment effect. Per-
formance remained highly stable at the eight months post
training assessment (see Figure 3). Analysis of the error
distributions revealed that semantic paraphasias were the
most common error type at both the baseline and the two
post assessments for all patients (main effects of error
type: all F(5,30/5,35) > 3.40, p < 0.01), and training
resulted in a comparable improvement for all error types
(see Additional file 2).

fMRI results aphasia patients
Greater short-term treatment success was related to
increased activity (see Additional file 3a) bilaterally in the
parahippocampi (Figure 5A + B; left parahippocampus:
r(5) = .98, p = .0002; right parahippocampus: r(5) = .96,
p = .0006) and in the left hippocampus (Figure 5C; r(5) =
.93, p = .002). Please note, removing the data of the
patient who suffered from global aphasia and did not
benefit from the training (P08) did not substantially affect
the significant correlations [left parahippocampal gyms:
r(4) = .88, p = .019; right parahippocampal gyrus: r(4) =
.84, p = .034, left hippocampus: r(4) = .84, p = .033].
Additionally, activity increases in the right parietal cortex
(precuneus, BA 7), the right cingulate gyrus (BA 31), and
bilaterally in the occipital lobes (BAs 19/37) were corre-
lated with behavioral improvement. There were no brain
regions for which decreases of activity correlated with treat-
ment success immediately after the training (see Addi-
tional file 2b).

Long-term success for trained object names (see Additional
file 2c and 2d) was associated with the degree of activity
increase in the right-sided Wernicke's homologue (BAs 21/
22; Figure 6; r(5) = .98, p < .0001). Additionally, increased
left perilesional middle and superior temporal areas (BA
21; x/y/z: -51/3/-12; r(5) = .80, p = .03) activities were
associated with training success at a less stringent correc-
tion level (Z = 2.17). Greater long-term treatment success
was also related to stronger activity decreases, suggestive of
greater automation, in left supplementary motor areas
(BA 6), right inferior parietal (BA 40) regions, the right
fusiform gyrus (BA 19), and the right caudate nucleus.

In healthy control subjects, the comparison between the
two fMRI sessions revealed no increases of brain activity
('Session2 > Sessionl'), even at an uncorrected threshold
of p < 0.05. Only activity decreases in the right inferior
parietal lobe were observed from the first to the second
assessment (BA 40; p < 0.005 voxel threshold, p < 0.05
cluster threshold).


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Discussion
The present fMRI study determined for the first time both
short- and long-term correlates of successful treatment-
induced language recovery in chronic aphasia. We here
show that success of an intensive language training in
chronic aphasia patients depends both on immediate
activity changes in visual, attention-, and memory-related
brain structures as well as on slowly evolving activity
changes (over the course of eight months) in right lan-
guage homologue areas of the middle temporal lobe (and
to a lesser extent in perilesional temporal areas). This lon-
gitudinal study thus demonstrates that even in the chronic
stage after a stroke, language reorganization is a highly
dynamic process, comparable to the time course of lan-
guage or motor recovery in the acute stage after stroke
[9,38].

Short-term treatment success
Patients behaviourally improved from zero percent cor-
rect naming responses at pre-training to a mean of 64.4
percent immediately after training, which amounts to a
very large treatment effect compared to previous studies
with chronic aphasia patients [39]. This demonstrates that
an intensive behavioral training based on associative
learning principles, coupled with a high stimulus repeti-
tion rate, can be highly effective in chronic aphasia.

Immediate treatment success from baseline to immedi-
ately after training was best predicted by an fMRI activity
increase in brain structures orchestrating memory encod-
ing (left hippocampus, bilateral parahippocampi) [21]. It
may seem surprising at first, that memory-related areas are
predominantly involved in the initial recovery of overt
picture naming. However, an association between aphasia
therapy outcome and the functional integrity of memory-
related brain structures has been noted previously. Acute
aphasia patients 'with lesions to temporobasal regions
showed less improvement during therapy and less total
recovery, but a similar amount of spontaneous recovery
than patients without such lesions' [40] (p. 684). The
authors interpreted this finding as evidence for a discon-
nection of the hippocampus and perisylvian language
areas in patients with poor (intensive) training outcomes,
which should be targeted in future studies using diffusion-
tensor imaging. Furthermore, several recent functional
imaging studies in healthy subjects have shown that the
(left) hippocampus contributes to initial language learn-
ing, i.e., the acquisition of lexical [25], semantic [26], and
syntactic [27] knowledge, and left hippocampal activity
during vocabulary learning was an excellent predictor of
vocabulary efficiency post training [25]. The convergence
of findings in aphasia patients and healthy subjects points
to comparable neural mechanisms during language acqui-
sition in neurologically intact adult subjects and post-
stroke language recovery [38]. Thus, in the future, a mini-


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BMC Neuroscience 2009, 10:118


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http://www. biomedcentral.com/1471-2202/10/118


left parahippocampal gyrus


r = 0.98
p = 0.0002


20 40 60 80


left hippocampus


r = 0.93
p = 0.002


40 60
short-term training success (%)


Figure 5
Results of the regression analysis for trained items immediately after training. Positive correlation between short-
term training success and 'post I pre' training activity changes for trained object names in memory related structures (A) the
left parahippocampal gyrus (B) the right parahippocampal gyrus and (C) the left hippocampus for the group of aphasia patients
[Note: signal change refers to the peak voxel within significant clusters]





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20 40 60 80


right parahippocampal gyrus





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http://www. biomedcentral.com/1471-2202/10/118


a
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50 60 70 80
long-term training success (%)


Figure 6
Results of the regression analysis for the follow-up assessment. Positive correlation between long-term training success
and 'post2 pre' training activity changes for trained object names in the right middle temporal gyrus for the group of aphasia
patients (signal change refers to the peak voxel within significant clusters)


ature treatment session with functional imaging as part of
the baseline assessment may allow to determine the func-
tional integrity of the language encoding neural network
in order to predict the likelihood of subsequent treatment
success.

Additionally, a right parahippocampal activity increase
from pre to post training was a good correlate of language
recovery in our patients. This presumably reflects the fact
that language re-learning is more laborious in aphasia as
compared to language learning in healthy subjects and
may thus require the joint effort of both hemispheres. The
right parahippocampus may also mediate the functional
recruitment of right-sided homologue language regions
following left hemisphere damage [23,24].

We also observed increased activity immediately after
training in the right-sided precuneus and cingulate gyrus
and bilaterally in the posterior fusiform gyri in patients
with good naming recovery. This in line with previous
functional imaging studies on treatment induced recovery
of language functions in chronic aphasia [11] and these
areas are known to mediate attention and initial cross-
modal integration of visual, phonological, and semantic
information [41].

A lack of treatment-induced hippocampal activity modu-
lation in prior aphasia intervention neuroimaging studies
may be due to the smaller extent of treatment induced lan-
guage recovery in chronic aphasia (e.g. [5,18,19]). A vis-
ual inspection of our fMRI data revealed that activity


increases in the left hippocampus only occurred for the
four patients who scored 75 percent correct naming
responses and higher immediately after training. This
implies that activity increases in the hippocampal forma-
tion are only observed in patients with very high treat-
ment gains. A different explanation might be that our
findings can be explained by the training paradigm we
used in this study that strongly relies on associative mem-
ory performance and requires the hippocampus. This
issue has to be clarified in future group studies employing
different types of language training paradigms (e.g.,
[17,42]).

Long-term treatment success
The major novel aspect of the present study was the iden-
tification of brain structures mediating the long-term
retention (after eight months) of the training outcome.
Behaviourally, patients' naming performance remained
highly stable throughout the eight months follow-up
period (correlation between short- and long-term training
successes: r = 0.76, p < 0.05). The long-term treatment suc-
cess, however, was mediated by different brain structures
than those involved in short-term language recovery.
Greater treatment success in the long run was predomi-
nantly related to an activity increase in language regions of
right temporal lobe (i.e., the right-sided Wernicke's
homologue; BAs 21,22) when lowering the statistical
threshold to account for the reduced statistical power in
perilesional brain areas [43] in perilesional middle tem-
poral areas. The predominance of increased functional
activity in right-temporal areas might be explained by the


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right middle temporal gyrus





6


5 3


r = 0.98
p < 0.0001


BMC Neuroscience 2009, 10:118







BMC Neuroscience 2009, 10:118


large cortical-subcortical lesions in our patient sample
and the large intersubject variance in terms of lesion loca-
tion and extent. There is evidence from other studies with
more limited and homogenous lesions [e.g., [19,44,45]]
that better recovery is mainly associated with activity in
spared left perilesional areas. On the other hand, middle
and superior temporal lobe regions in both hemispheres
are known to be important for the reliable retrieval of lex-
ical-semantic knowledge in healthy subjects [37,44,45].
Thus, when lesions are large and the residual linguistic
deficit is substantial (as was the case in most of our partic-
ipants), right temporal regions may contribute to effective
functional compensation. Furthermore, in acute aphasic
patients, the degree of spontaneous language recovery over
the course of one year depended on regional cerebral
blood flow increases bilaterally in the temporal lobes
[46,47]. The activity increase in our patients can thus be
interpreted as reflecting strengthened neural connections
between the semantic representations of the objects and
their respective word forms as a result of the intensive
anomia training. Therefore, language areas in the tempo-
ral lobe of both hemispheres seem to subserve long-term
language therapy success. At the eight months post assess-
ment, negative correlations with training success were
found for the right inferior parietal cortex (BA 40), right
occipital areas (BA 19) and for right motor related areas
(BA 6, caudate nucleus), possibly related to greater auto-
mation, similar to the decreased activity found in healthy
controls subjects after repeated testing.

Limitations of the current study
The current study aimed to investigate the neural corre-
lates of immediate versus long-term successes of intensive
naming training in chronic aphasia patients. The results
can therefore not be directly generalized to other types of
language training (non-intensive) or other types of apha-
sic symptoms (e.g., patients with predominantly phono-
logical paraphasias). Future studies may also consider
obtaining complimentary information from different
imaging techniques that have a better temporal resolu-
tion. For example, Laganaro et al. [48] used electroen-
cephalography (EEG) and provided evidence for distinct
abnormalities in the time-course of evoked potentials for
different types of anomia.

Furthermore, the core problem in our patients was the
linking of semantic information with a particular word
form (see Additional file 2). DeLeon et al. [49] reported
that the degree of lexical-semantic impairment correlated
with hypoperfusion in left BA 22 in the acute stage after
ischemic stroke. The slowly evolving activity changes in
the superior and middle temporal lobes as a result of our
training may thus be specific for the successful recovery of
lexical access and not for other production processes
involved in picture naming (e.g., syllabification or pho-


http://www. biomedcentral.com/1471-2202/10/118



netic/articulatory preparation). This might also be an
explanation for the fact that we did not find activity
increases in right or left (inferior) frontal (IFG) brain areas
that have been linked to improved word-retrieval in pre-
vious treatment studies assessing overt language produc-
tion (for review see [ 11 ]). In particular, left inferior frontal
activity during picture naming has been linked to effortful
word retrieval [50], while highly overlearned materials
(like the items in our study) do not necessarily elicit activ-
ity in this brain area [28]. In line with these previous find-
ings, in our own study, (right) IFG activity was only found
during the first imaging session but not immediately after
the intensive treatment period (see additional file 2 for
details of activity patterns elicited by trained pictures at
the pre-training assessment).

Conclusion
Our findings suggest that different brain regions are
required for initial learning versus long-term consolida-
tion induced by intensive training in chronic aphasia. For
initial learning, activity increases bilaterally in brain
regions involved in memory, attention, and multimodal
integration predicted treatment success. The long-term
treatment success, however, was particularly mediated by
activity increases in the right-sided Wernicke's homologue
and left temporal language areas, suggesting bilateral
recruitment of 'normal' task-related areas during the con-
solidation process. The results show that language recov-
ery induced by intensive training is a dynamic, slowly
evolving process involving both hemispheres requiring
both classical language areas and domain-unspecific
attention and memory brain structures even in the
chronic stage after stroke.

Authors' contributions
RM and MM contributed equally to the study (shared first
authorship). RM, MM, HK, MD, AB, HS, MT, KK, HL, AF,
SK and CB contributed to the design of the study. RM,
MM, HK, HS, KK and CB collected the imaging data. HL
conducted the neuropsychological testing. RM, KK and
MT administered the treatment. RM, MM, HK, MD and CB
analyzed the fMRI data. RM, MM and CB drafted the man-
uscript. All authors were involved in revising the initial
draft and approved the final version.

Additional material


Additional file 1
Patient Information. Demographic and clinical information and lan-
guage test results for the eight aphasia patients
Click here for file
[http://www.biomedcentral.com/content/supplementary/1471-
2202-10-118-S1.DOC]


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BMC Neuroscience 2009, 10:118


Additional file 2
Supporting information. Provides additional supportive information
regarding patient characteristics, neuropsychological testing and func-
tional imaging analyses and results
Click here for file
[http://www.biomedcentral.com/content/supplementary/1471 -
2202-10-118-S2.DOC]

Additional file 3
Brain activity changes immediately after training and at the follow-
up assessment. Brain activity changes in the patients and healthy con-
trols: Brain areas showing a) positive and b) negative correlations between
short-term training success and 'post1-pre' training activity changes for
trained object names (masked with the respective results for untrained
object names). Brain areas showing c) positive and d) negative correla-
tions between long-term training success and 'post2-pre' training activity
changes for trained object names (masked with the respective results for
untrained object names). The corresponding results for the control group
(Sessionl versus Sesssion2) are displayed in italic font
Click here for file
[http://www.biomedcentral.com/content/supplementary/1471-
2202-10-118-S3.DOC]




Acknowledgements
We thank all patients and healthy volunteers for their participation in the
study. This work was supported by the BMBF-Research Consortium:
Dopaminergic learning enhancement (01 GWO520), the Volkswagen Stif-
tung (Az.: 1/80 708), a Marie Curie Research and Training Network: Lan-
guage and Brain funded by the European Commission (MRTN-CT-2004-
512141), the BMBF-Competence Network Mednet Atrial Fibrillation, Inter-
disciplinary Center for Clinical Research (Floe 3-004-008), the Neuromed-
ical Foundation Muenster, Germany, and the German Foundation for
Science (DFG, ME 3161/2-I and Fl 379/4-1). All authors declare that they
have no competing financial or other conflicts of interest.

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