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Brain Imaging Behav. 2019 December ; 13(6): 1510–1525. doi:10.1007/s11682-019-00118-3.

The utility of lesion classification in predicting language and

treatment outcomes in chronic stroke-induced aphasia
Erin L. Meier, Ph.D.a,1, Jeffrey P. Johnson, Ph.D.a,2, Yue Pan, M.S.a,3, Swathi Kiran, Ph.D.a
aAphasia Research Laboratory, Department of Speech, Language & Hearing Sciences, Sargent
College of Health & Rehabilitation Sciences, Boston University, 635 Commonwealth Avenue,
room 326, Boston, MA 02215
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Abstract
Stroke recovery models can improve prognostication of therapy response in patients with chronic
aphasia, yet quantifying the effect of lesion on recovery is challenging. This study aimed to
evaluate the utility of lesion classification via gray matter (GM)-only versus combined GM plus
white matter (WM) metrics and to determine structural measures associated with aphasia severity,
naming skills, and treatment outcomes. Thirty-four patients with chronic aphasia due to left
hemisphere infarct completed T1-weighted and DTI scans and language assessments prior to
receiving a 12-week naming treatment. GM metrics included the amount of spared tissue within
five cortical masks. WM integrity was indexed by spared tissue and fractional anisotropy (FA)
from four homologous left and right association tracts. Clustering of GM-only and GM+WM
metrics via k-medoids yielded four patient clusters that captured two lesion characteristics, size
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and location. Linear regression models revealed that both GM-only and GM+WM clustering
predicted baseline aphasia severity and naming skills, but only GM+WM clustering predicted
treatment outcomes. Spearman correlations revealed that without controlling for lesion volume,
the majority of left hemisphere metrics were related to language measures. However, adjusting for
lesion volume, no relationships with aphasia severity remained significant. FA from two ventral
left WM tracts was related to naming and treatment success, independent of lesion size. In sum,
lesion volume and GM metrics are sufficient predictors of overall aphasia severity in patients with
chronic stroke, whereas diffusion metrics reflecting WM tract integrity may add predictive power
to language recovery outcomes after rehabilitation.

Keywords
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aphasia; diffusion-weighted imaging; treatment outcomes; lesion size and location

1
Corresponding author (present affiliation and contact information): Erin L. Meier, Neurology Department, Johns Hopkins University,
School of Medicine, 600 N. Wolfe Street, Phipps 546C, Baltimore, MD 21287, Phone: 410-502-6045, emeier5@jhmi.edu.
2Present affiliation: Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, University Drive, Audiology
and Speech Pathology, Pittsburgh, PA 15260
3Present affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, 460 W. 12th Avenue, Columbus,
OH 43210
Ethical approval:
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional
and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards
Informed consent:
Informed consent was obtained from all individual participants included in the study.
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Introduction
Aphasia is one of the most common and long-lasting sequelae of stroke, affecting
approximately 30% of acute stroke survivors and persisting into the chronic post-stroke
stage in 16-31% of these individuals (Engelter et al., 2006; Flowers et al., 2016). Aphasia
typically results in a constellation of language deficits that greatly impair communication
abilities and decrease functional independence (Boehme, Martin-Schild, Marshall, & Lazar,
2016; Tsouli, Kyritsis, Tsagalis, Virvidaki, & Vemmos, 2009). Despite the chronicity of
aphasia, patients can continue to regain lost language skills in the years beyond stroke onset
with targeted language treatment (Brady, Kelly, Godwin, Enderby, & Campbell, 2016).
Nevertheless, variability in language recovery and response to treatment are hallmarks of the
disorder (Code, Torney, Gildea-Howardine, & Willmes, 2010). As such, predictive models
that provide prescriptive treatment recommendations for patients according to demographic,
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stroke and deficit profiles are critical for chronic aphasia care, yet such models do not yet
exist.

A central barrier to accurate recovery prognostication is fully quantifying and incorporating

lesion factors into predictive models (Price, Hope, & Seghier, 2017; Thye & Mirman, 2018).
Historically, lesions in patients with aphasia have been described in terms of focal damage to
anterior (e.g., Broca’s area) and/or posterior (e.g., Wernicke’s area) left hemisphere cortical
gray matter (GM) regions. Such descriptions may be too simplistic given that infarct occurs
along vascular territories—which involve many structures—rather than anatomical
boundaries (Charidimou et al., 2014). For example, beyond cortical involvement, frank
damage to or disconnection of white matter (WM) association pathways is common in
stroke aphasia and has been associated with a variety of linguistic deficits in patients (e.g.,
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Basilakos et al., 2014; Bonilha et al., 2017; Bonilha, Rorden, & Fridriksson, 2014; Breier,
Hasan, Zhang, Men, & Papanicolaou, 2008; Del Gaizo et al., 2017; Geva, Correia, &
Warburton, 2015; Gleichgerrcht et al., 2015; Griffis, Nenert, Allendorfer, & Szaflarski,
2017; Han et al., 2013, 2016; Harvey & Schnur, 2015; Harvey, Wei, Ellmore, Hamilton, &
Schnur, 2013; Ivanova et al., 2016; Kummerer et al., 2013; Marchina et al., 2011; Marebwa
et al., 2017; McKinnon et al., 2018; Rolheiser, Stamatakis, & Tyler, 2011; Rosso et al.,
2015; Wilson et al., 2011). Given that language processing requires a network of
interconnected brain regions, it has been suggested that WM integrity or combined GM and
WM integrity may better predict aphasia recovery outcomes than GM metrics alone
(Bonilha et al., 2014; Del Gaizo et al., 2017; Han et al., 2016; Marebwa et al., 2017;
McKinnon et al., 2018; Mirman, Zhang, Wang, Coslett, & Schwartz, 2015; Naeser &
Palumbo, 1994; Wilson et al., 2011; Xing et al., 2018). For example, Yourganov, Smith,
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Fridriksson, and Rorden (2015) found that a novel parcellation of the brain that considered
spared tissue of both GM and WM outperformed GM-only parcellations in the prediction of
aphasia syndromes in 98 patients. With regards to specific linguistic skills, Bonilha, Rorden,
& Fridriksson (2014) found that even after controlling for cortical damage to left inferior
frontal gyrus, pars triangularis (LIFGtri), structural disconnect of LIFGtri was independently
associated with naming abilities in patients with chronic aphasia. Similarly, Xing et al.
(2018) found that after accounting for demographic variables and overall left hemisphere
lesion volume, naming skills in 45 patients with chronic aphasia were related to the integrity

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of 13 left intra-hemispheric white matter connections but were not associated with the extent
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of lesion in cortical nodes.

In addition to the aforementioned cross-sectional studies, modern computational models that

utilize multimodal imaging datasets to link brain structure and language profiles show
promise for improving prognostication of chronic aphasia recovery over time (Price et al.,
2010). However, such models have not been utilized to predict response to evidence-based
language treatment. Furthermore, the utility of GM-only versus combined GM plus WM
(GM+WM) integrity metrics for predicting language abilities and—most crucially, treatment
response—in chronic aphasia has not been fully explored. Additionally, most lesion
mapping studies infer how damage results in impairment but the reverse inference—how the
integrity of intact tissue relates to language function—can provide additional insights into
the recovery capacity of patients in the chronic post-stroke stage (Charidimou et al., 2014;
Price, Seghier, & Leff, 2010).
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Therefore, the primary goals of the present investigation were to use multimodal structural
metrics and clustering analyses to generate data-driven lesion classification schema and to
subsequently compare the utility of GM-only versus combined GM+WM integrity metrics in
predicting aphasia severity, naming abilities and response to naming treatment for word
retrieval deficits (i.e., anomia) in chronic stroke patients. Anomia was selected as the deficit
targeted in therapy because it is the most common impairment in chronic aphasia, is
ubiquitous across aphasia subtypes and greatly affects the ability to participate in everyday
conversation (Goodglass & Wingfield, 1997). We hypothesized that size and location would
be the primary characteristics of patients’ lesions captured by k-medoids clustering, and that
patients with similar lesions per these two dimensions would cluster together. We
additionally predicted that combined GM+WM lesion classification would better predict
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language abilities than GM-only clusters. The second aim was to determine specific left and
right hemisphere metrics that are associated with language outcomes. We predicted that the
integrity of bilateral WM association tracts would relate to language outcomes independent
of lesion volume whereas GM regions of interest (ROIs) would not.

Materials and Methods

Participants
Thirty-four individuals (24 males; mean age=61.91±10.84 years) with chronic stroke-
induced aphasia (i.e., ≥ six months post-onset; mean time post-onset=61.18±86.49 months)
due to left hemisphere ischemic infarct participated in the study. The primary eligibility
requirement was presence of anomia. Exclusionary criteria included contraindications for
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MRI; active medical conditions that precluded study participation; history of neurological
disease other than stroke; and history of multiple left hemisphere infarcts. All participants
were premorbidly proficient in English and had normal or corrected-to-normal vision and
hearing. Demographic and neurological case histories were obtained from medical records
and study-specific questionnaires. Study protocols were executed in accordance with the
institutional review boards of Boston University, Massachusetts General Hospital and
Northwestern University. As needed, additional verbal and written explanations were

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utilized to ensure patient understanding of study protocols prior to obtaining their written
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informed consent.

Upon entering the study, all participants were administered the Western Aphasia Battery-
Revised (WAB-R; Kertesz, 2006) and the Boston Naming Test (BNT; Kaplan, Goodglass,
Weintraub, Segal, & van Loon-Vervoorn, 2001) to obtain measures of overall aphasia
severity (per WAB-R Aphasia Quotient [AQ]) and naming impairment, respectively. A 180-
item study-specific confrontation naming probe was utilized to supplement the BNT as a
baseline measure of anomia, to determine treatment assignment and to measure therapy
gains from the pre- to post-treatment time points.

Treatment Protocol
This study was conducted as part of a multi-site project (http://cnlr.northwestern.edu/)
investigating the neurobiology of language recovery in patients with chronic aphasia. The
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study design was quasi-experimental as participants were pseudo-randomly assigned to enter

either a treatment or a no-treatment/natural history branch of the study. Ultimately, 30
participants received modified semantic feature analysis-based treatment for anomia (Boyle,
2010; Kiran & Thompson, 2003) for four hours per week for up to 12 weeks or until
criterion (i.e., ≥ 90% accuracy on trained items on two consecutive weekly probes) was met.
Patients were trained on 36 items, split between two semantic categories (i.e., birds,
vegetables, clothing or furniture). Category assignment was pseudo-counterbalanced across
patients so that categories were assigned to patients who correctly named, on average, <
75% of within-category items across three pre-treatment naming probes. Sessions targeted
training items via auditory and written feature judgment tasks, naming attempts before and
after feature review, and generative naming tasks. Treatment success was determined by
calculating the proportion of potential maximal gain (PMG) (Lambon Ralph, Snell,
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Fillingham, Conroy, & Sage, 2010) for each trained category using the following formula:
AVG PostT x Score − AVG PreT x Score
n trained items − AVG PreT x Score
, where AVG PreTx and AVG PostTx denote the averaged
accuracy on trained items at pre-treatment and post-treatment, respectively. Averaged PMG
across categories captured the degree to which patients’ naming of trained items improved
secondary to therapy while accounting for their pre-treatment abilities. Alternative measures
have been used in single-subject research designs to index treatment gains (e.g., Beeson &
Robey, 2006; Howard, Best, & Nickels, 2015); we report individual scores for three such
effect size measures in the Supplementary Materials. The full results of this treatment study
are also reported in Gilmore, Meier, Johnson, and Kiran (2018).

MR Data Acquisition and Preprocessing

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Patients underwent MR imaging on either a Siemens 3T Trio Tim at the Athinoula A.

Martinos Center in Charlestown, MA or a 3T Siemens Prisma Fit at the Center for
Translational Imaging in Chicago, IL. Participants completed T1-weighted sagittal imaging
(TR/TE = 2300/2.91ms, T1 = 900ms, flip angle = 9°, FOV = 256×256mm, slice thickness =
1mm3, 176 sagittal slices) and a high resolution whole-brain DTI sequence (TR/TE =
900/92ms, T1 = 900ms, flip angle = 90°, FOV = 230×230mm, slice thickness =

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1.98×1.98×2mm voxels, 70 interleaved slices with 60 gradient and 10 b0 volumes, b value =

1500 s/mm2).
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Research assistants blinded to patients’ behavioral scores drew lesion maps slice-by-slice on
T1 structural images using MRIcron (www.mccauslandcenter.sc.edu/crnl/mricron/).
Frankly-damaged tissue was included while other structural abnormalities (e.g., enlarged
ventricles due to ventricular dilation) were excluded from the manual lesion dissections.
Spatial normalization of the T1-weighted images and lesion maps (in which lesioned voxels
were preserved) to MNI space was performed in SPM12. Normalized lesion maps were
filtered at 50%, and the volume of each map was calculated using in-house Matlab scripts.

Preprocessing of the DTI data was performed using a bespoke pipeline optimized for stroke
data. First, diffusion images were denoised using principle components, and a b0 reference
image was created from the mean of the non-diffusion weighted scans. The T1 structural
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image was skull-stripped and enantiomorphic warping of the intact right hemisphere into the
damaged left hemisphere was performed. The modified T1 image was normalized to the
mni_icbm152_T1_2009 template via nonlinear warping, and a pseudo-T2 image (created by
inverting the T1 image contrast) was rigidly aligned to the b0 reference image. Next, the
distortion field was calculated and eddy current distortion correction was performed. The
affine matrix was applied to the b-vector file to yield rotated b-vectors. Eddy current
corrected parameters were concatenated with the b0 distortion field and applied to the
diffusion scans. Finally, the diffusion tensor was calculated using the nonlinear weighted
positive definite tensor-fitting algorithm from Camino (http://camino.cs.ucl.ac.uk/) and then
warped to MNI space to yield normalized scalar maps. For the current investigation,
normalized fractional anisotropy (FA) maps were used to address study aims given that FA is
the most commonly used scalar in both healthy and patient DTI studies to reflect integrity of
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white matter tract microstructure (Geva, Correia, & Warburton, 2011; O’Donnell & Westin,
2011).

Calculation of Spared GM ROIs and WM Tracts

Large GM ROI masks were generated by combining ROIs from the Automated Anatomical
Labeling (AAL) atlas (Tzourio-Mazoyer et al., 2002) that aligned with major anatomical
boundaries of the lateral surface of the brain (see Table 1). As shown in Figure 1A, this
procedure yielded six large ROIs: dorsolateral prefrontal cortex (DLPFC), inferior frontal
(iFrontal), anterior and posterior temporal (aTemporal and pTemporal, respectively), parietal
and occipital masks. The rationale for using large GM ROIs (as opposed to individual AAL
ROIs) was three-fold: the ratio of participants to GM metrics was maximized in aim 1
analyses; the number of multiple comparison corrections in aim 2 analyses was minimized;
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and a comparable number of GM and WM structures were interrogated (see below).

To determine the integrity of canonical WM pathways implicated in lexical-semantics and

naming, we extracted tract masks from the Johns Hopkins University White Matter
Tractography atlas (Wakana, Jiang, Nagae-Poetscher, van Zijl, & Mori, 2004) that
corresponded to the bilateral arcuate (AF), inferior fronto-occipital (IFOF), inferior
longitudinal (ILF) and uncinate (UF) fasciculi (Figure 1B). Tract masks were thresholded
with a probability value of 0.20, binarized and resampled to the resolution and dimensions of

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the FA maps. To ensure optimal image alignment, all lesion maps and WM tract masks were
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warped to the mni_icbm152_T1_2009 template via a 12-parameter affine transformation.

To determine the amount of spared GM and WM tissue, non-lesioned voxels were retained
from the intersection of ROI and tract masks and each patient’s normalized lesion map. The
number of spared voxels from each subject-specific ROI mask (excluding the occipital mask
since it was mostly spared in the sample) and subject-specific tract mask were extracted and
used in subsequent analyses (Figure 1C). Subject-specific tract masks were also multiplied
by each patient’s FA map on a voxel by voxel basis. To decrease the potential for partial
volume effects, only voxels with FA values ≥ 0.20 were averaged to yield mean FA (FAmean)
per tract mask.

Statistical Analysis
Statistical analyses were performed in R (R Core Team, 2017). For aim 1, we conducted two
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k-medoids cluster analyses using the ‘cluster’ package (Maechler, Rousseeuw, Struyf,
Hubert, & Hornik, 2018) and Partitioning Around Medoids (PAM) algorithm to determine
how patients clustered according to (1) GM-only metrics (i.e., number of spared voxels in
the DLPFC, iFrontal, aTemporal, pTemporal and Parietal masks) versus (2) combined GM
+WM metrics (i.e., number of spared voxels in GM masks plus spared voxels in and FA
extracted from the left AF, IFOF, ILF and UF masks). Like k-means, k-medoids partitions a
dataset into a set of k maximally-dissimilar groups (in this case patient subgroups) but is less
sensitive than k-means to outliers and noise in the data (Kaufman & Rousseeuw, 1990).
Cluster assignment was based on the Manhattan distance between the center of each cluster
and other patient data points. Within the Manhattan distance formula, pairwise
dissimilarities between data points are based on absolute distance (as opposed to the squared
error distance); thus, cluster assignment is less influenced by outliers than when other
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distance formulas (e.g., Euclidean distances) are applied. Elbow plots were used to specify
the number of clusters, and cluster assignments of individual participants from the two
analyses (i.e., GM-only and GM+WM clustering) were obtained.

Given our hypothesis that overall lesion size would be reflected in the clustering results, we
first performed linear regressions predicting total lesion volume from GM-only and GM
+WM cluster membership. Next, to test whether clustering also captured lesion location,
lesion subtraction plots (i.e., the pure subtraction of overlaid lesion maps of patients in one
cluster from overlaid lesion maps of another cluster) were generated and visualized in
MRIcron. Finally, linear regression models were constructed to predict aphasia severity (per
WAB-R AQ), baseline naming skills (per BNT total correct [BNTtotal]) and naming
treatment outcomes (per PMG) from the categorical predictors of either GM-only or
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combined GM+WM clusters. These predictors were dummy-coded so that cluster 1 was set
as the reference group in both types of analyses. The ‘gvlma’ package in R (Pena & Slate,
2014) was used to check model assumptions.

For aim 2, Spearman correlations between each behavioral metric (i.e., AQ, BNTtotal and
PMG) and each left hemisphere structural metric (i.e., number of spared voxels in each left
hemisphere mask and FA extracted from left WM tract masks) were conducted. The same
analyses were then run as partial correlations controlling for lesion size. To assess the

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potential of right hemisphere structural compensation, correlations were also conducted

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between each language measure and FA extracted from the right WM tract masks, with and
without controlling for left hemisphere lesion volume. These analyses were conducted to
better understand the specific brain structures that may be most relevant for predicting
different language outcomes. All correlations were corrected for multiple tests according to
the false discovery rate (FDR; Benjamini & Hochberg, 1995).

To support our findings regarding pre-treatment structural correlates of naming therapy

gains, we replicated all treatment-related statistical analyses for both aims by replacing PMG
with effect sizes calculated according to recommendations from Beeson and Robey (2006).
These results are reported in the Supplementary Materials. The dataset generated and
analyzed during the current study is available in the OSF repository (DOI 10.17605/OSF.IO/
3EG4X).
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Results
As shown in Table 2, patients ranged in their overall aphasia severity with a mean ± SD
WAB-R AQ of 62.25 ± 24.60 out of 100. Variability in baseline naming skills was observed,
with a mean of 24.76 ± 20.19 out of 60 items named correctly on the BNT and an average of
32.72 ± 25.13% of correctly-named items on the study-specific probe. As stated previously,
the full treatment results are available elsewhere (Gilmore et al., 2018). In brief, patients
benefitted from therapy such that patients achieved, on average, approximately 43% of their
potential naming gain following therapy. As illustrated by Figure 2 and shown in Table 2,
total lesion volume also varied across the group, suggesting that a variety of lesion and
language deficit profiles were represented in the sample.

Table 3 summarizes descriptive statistics regarding the amount of spared tissue in left
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hemisphere masks and FA in bilateral tract masks. On average, the most damaged GM and
WM structures were the iFrontal ROI and left AF and UF whereas the most spared regions
and tracts were DLPFC and the left IFOF and ILF. As expected, FA was significantly lower
in the left compared to the right hemisphere association tracts (F(4,60) = 54.210, Pillai’s
trace = 0.828, p < 0.001) (see Table 3).

Aim 1: GM-Only versus GM+WM Clustering

Elbow plots for the GM-only k-medoids analysis indicated that four patient clusters were
most representative of the data. As shown in Figure 3A, the first and second clustering
dimensions captured, respectively, 54.7% and 22.9% of the variance in GM integrity. The
regression predicting lesion volume from cluster membership trended towards significance
(F(1, 32) = 4.116, p = 0.051, R2 = 0.086). As shown in Figure 3B, though, a clear difference
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in lesion volume was observed between patients within clusters 1 and 2. Indeed, cluster
membership predicted lesion volume in a regression including only these patients (F(1, 15) =
54.210, p < 0.001, R2 = 0.769), such that patients in cluster 1 had significantly smaller
lesions than individuals in cluster 2. Given that patients within clusters 1 and 2 maximally
differed along the x-axis, we concluded that the first dimension primarily captured lesion
size. Therefore, we hypothesized that the second dimension reflected lesion location and
would differentiate patients in clusters 3 and 4. As shown in Figure 3C, lesion subtraction

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plots indicated that patients in cluster 3 had primarily ventral lesions whereas patients in
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cluster 4 had primarily dorsal lesions.

Four patient clusters were also retained from the combined GM+WM data. As shown in
Figure 4A, the two primary dimensions captured 46.7% and 18.2% of the variance in
combined GM and WM integrity. Considering the GM-only clustering results, we
hypothesized that the first and second GM+WM dimensions captured lesion size and
location, respectively. Indeed, as shown in Figure 4B, GM+WM cluster membership
predicted total lesion volume (F(1, 31) = 8.145, p = 0.008, R2 = 0.183), where patients in
clusters 1 and 3 had smaller lesions than did patients in clusters 2 and 4. Again, lesion map
subtraction plots of patients in cluster 1 versus cluster 3 (Figure 4C) and patients in cluster 2
versus 4 (Figure 4D) illustrate that patients in clusters 1 and 4 had primarily ventral lesions
whereas patients in clusters 2 and 3 had primarily dorsal lesions. Thus, we established that
the two primary dimensions captured in both the GM-only and GM+WM clusters were
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lesion size and location.

The predictive utility of the GM-only versus GM+WM clusters differed by language
measure. Specifically, both clustering types significantly predicted overall aphasia severity
per WAB-R AQ, yet the predictive power of the GM-only lesion classification (F(3, 29) =
12.260, p < 0.001, R2 = 0.559) was higher than the combined GM+WM clustering (F(3, 29)
= 9.562, p < 0.001, R2 = 0.497). As shown in Figure 5A, within the GM-only predictive
model, patients within cluster 2 (β = −48.432, t = −5.363, p < 0.001), cluster 3 (β =
−29.075, t = −3.428, p = 0.002) and cluster 4 (β = −31.932, t = −4.396, p < 0.001) had
significantly lower WAB-R AQ scores than patients in cluster 1. Within the GM+WM
model, patients in cluster 2 (β = −36.610, t = −4.720, p < 0.001) and cluster 4 (β = −36.940,
t = −3.831, p < 0.001)—but not cluster 3 (β = −11.100, t = −1.225, p = 0.230)—had
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significantly more severe aphasia than patients in cluster 1.

In contrast to the AQ models, GM+WM clustering provided greater explanatory power of

pre-treatment naming skills per BNTtotal (F(3, 29) = 4.653, p = 0.009, R2 = 0.325) than did
the GM-only clusters (F(3, 29) = 3.396, p = 0.031, R2 = 0.260). As shown in Figure 5B,
compared to patients in GM-only cluster 1, patients in cluster 2 (β = −26.533, t = −2.790, p
= 0.009) and cluster 4 (β = −17.533, t = −2.292, p = 0.029) had significantly lower BNTtotal
scores, while patients in cluster 3 trended towards lower BNTtotal scores than patients in
cluster 1 (β = −17.333, t = −1.940, p = 0.062). Within the combined GM+WM model,
patients in cluster 2 (β = −24.933, t = −3.412, p = 0.002) and cluster 4 (β = −24.133, t =
−2.657, p = 0.013) had significantly lower BNTtotal scores than patients in cluster 1, whereas
naming skills between patients in clusters 1 and 3 did not significantly differ (β = −12.500, t
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= −1.465, p = 0.154).

Critically, GM+WM clustering significantly predicted treatment outcomes as measured by

PMG (F(3, 26) = 3.036, p = 0.047, R2 = 0.260) but the GM-only clusters did not (F(3, 26) =
1.773, p = 0.177, R2 = 0.170) (see Figure 5C). Within the GM+WM model, patients in
cluster 2 (β = −0.376, t = −2.571, p = 0.016) and cluster 4 (β = −0.445, t = −2.483, p =
0.020) had significantly lower treatment outcomes than patients in cluster 1; patients in
clusters 1 and 3 similarly benefitted from naming therapy (β = −0.210, t = −1.174, p =

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0.251). While the predictive utility of these models cannot be directly, statistically compared
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(as would be the case in nested models), the amount of explained variance indicates that the
GM-only model best predicts overall aphasia severity, while baseline naming skills and
naming treatment outcomes are best predicted by combined GM+WM metrics.

Aim 2: Relationships between Structural Metrics and Language Outcomes

As shown in the second column of Table 4, without controlling for lesion volume, significant
positive correlations were found between WAB-R AQ and all left hemisphere GM and WM
metrics (range: r = 0.393 – 0.721, p = 0.024 – < 0.001 after FDR correction). Similarly,
without the lesion volume covariate, significant relationships were found between the
majority of left hemisphere GM and WM metrics and BNTtotal (range: r = 0.39 – 0.53, p =
0.035 – 0.002) (see Table 4, third column) and PMG (range: r = 0.34 – 0.64, p = 0.035 – <
0.001) (Table 4, last column). As the only exceptions, spared voxels in the aTemporal and
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pTemporal masks were not associated with either BNT or PMG, and FAmean in left UF was
not related to PMG. No significant relationships between language measures and right
hemisphere tract FA were found (see the bottom four rows of Table 4).

By contrast, partial correlations controlling for lesion volume revealed no significant

relationships remained between AQ and any integrity metrics from either hemisphere (Table
4, second column). When controlling for lesion volume, relationships between BNTtotal and
FA in the left IFOF (partial r = 0.441, p = 0.046) and FA in the left ILF (partial r = 0.507, p
= 0.025) remained significant (see Figure 6A and Table 4, third column). Similarly, partial
correlations with lesion volume revealed remaining significant associations between PMG
and FA in the left IFOF (partial r = 0.560, p = 0.006) and FA in the left ILF (partial r =
0.658, p < 0.001) (see Figure 6B and Table 4, last column). As shown in the bottom four
rows of Table 4, no significant partial correlations between either BNT or PMG and FA in
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the right WM tracts were found.

Discussion
In the present study, we investigated the predictive power of different types of gray and
white matter integrity metrics for understanding language skills and naming treatment
outcomes in patients with chronic stroke-induced aphasia. One novelty of this study was the
use of multimodal imaging in classifying stroke patients according to structural indices of
the lesioned hemisphere. Via the cluster analyses, we found that 13 separate GM and WM
metrics reflecting the integrity of left hemisphere structures involved in language processing
could be boiled down into simple, clinically-accessible classification schemas. Specifically,
according to the GM-only metrics, patients were classified as having either small, large, or
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medium-sized lesions, the latter which further split into ventral versus dorsal involvement.
Clustering of combined GM+WM measures resulted in four lesion classifications that each
carried information about lesion size and reflected the dorsal/ventral bifurcation of the
middle cerebral artery (i.e., small ventral, large ventral, small dorsal, and large dorsal
lesions). These results reflect a marriage of methods researchers use to index brain damage
after stroke (e.g., percentage of spared/lesioned tissue, DTI measures) and ways in which

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 Meier et al. Page 10

clinicians typically qualify patient lesions (i.e., general estimate of size and gross site of
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damage).

Furthermore, as referenced above, the cluster results also indicated such structural metrics
carry non-dissociable lesion size and location information. Recently, Thye and Mirman
(2018) explicitly set out to determine the relative contribution of lesion size versus location
in predicting overall aphasia severity and various linguistic deficits. In this paper, the authors
found that overall aphasia severity and naming abilities were mainly predicted by lesion size
whereas speech recognition and speech production skills were best predicted by lesion
location. Similarly, in the present study, none of the partial correlations between WAB-R AQ
and integrity metrics were significant; thus, it can be inferred that total lesion volume also
adequately captured overall aphasia severity in our patient sample. This finding aligns with
other studies (see Watila & Balarabe, 2015 for review) and is not surprising given that
receptive and expressive language tasks comprise WAB-R AQ, and lesions in the aphasic
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population span frontal, temporal and parietal regions implicated in these abilities.
Analogous to Thye and Mirman's (2018) lesion location finding, we found that naming
abilities—and naming treatment outcomes—were associated with overall lesion volume, but
we also found that the integrity of specific left hemisphere structures (i.e., ILF and IFOF)
was a critical, independent determinant of these language measures. Subtle differences
between the present findings and Thye and Mirman (2018) may lie in differences in the
neuroimaging methods employed in each study (e.g., a whole-brain versus ROI approach).
Future work should aim to further disentangle the relative impact lesion location and size (as
well as other structural factors) have on stroke recovery in general and response to specific
therapies in particular.

Consistent with our hypotheses, we also found that GM+WM cluster membership was a
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stronger predictor of pre-treatment naming skills and better indicator of the potential to
improve word retrieval abilities after treatment than GM-only clustering. The fact that only
diffusion measures explained additional variance in pre-treatment naming and treatment
outcomes indicates that DTI scalars capture different, critical information about structural
integrity in chronic stroke. In particular, the integrity of the left ILF and IFOF—as reflected
by FA—were related to both pre-treatment naming and treatment outcomes. The importance
of structural connectivity of left temporal regions in the preservation of lexical-semantic and
naming skills in patients with chronic aphasia has been highlighted in recent cross-sectional
studies (Gleichgerrcht et al., 2015; Han et al., 2013; Harvey & Schnur, 2015; Ivanova et al.,
2016; Yourganov, Fridriksson, Rorden, Gleichgerrcht, & Bonilha, 2016). Controlling for
demographic variables and total lesion volume, McKinnon et al. (2018) found that the
integrity of a posterior segment of the left ILF (per axonal water fraction, a diffusion metric
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of axonal density) was associated with semantic paraphasias, independent of overall left
hemisphere damage and the degree of cortical necrosis in regions inferior to the perisylvian
fissure. Our findings cohere with this result, given that spared tissue in the aTemporal and
pTemporal ROIs was not related to baseline naming or treatment outcomes and therefore
would not alter the relationship between these language metrics and left ILF and left IFOF
FA. With regards to treatment outcomes, Bonilha, Gleichgerrcht, Nesland, Rorden, and
Fridriksson (2016) used structural connectome methods and found that temporal lobe
connections were particularly critical for anomia therapy success. In a recent study,

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 Meier et al. Page 11

McKinnon et al. (2017) used diffusion keurtosis imaging and found neuroplastic changes in
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the left ILF of patients who underwent semantic feature-based anomia treatment.

One surprising finding of the current study is that no measure of the left AF remained
significant for any language measure after controlling for overall lesion volume. Damage to
the left AF has often been implicated in naming impairments in patients with aphasia (e.g.,
Geva et al., 2015; Han et al., 2016; Ivanova et al., 2016; Marchina et al., 2011; van Hees et
al., 2014; Wang, Marchina, Norton, Wan, & Schlaug, 2013). However, the lack of left AF
findings may be related to the nature of the anomia therapy, which directly targeted semantic
feature re-learning and therefore relied heavily on ventral stream processes. It therefore
stands to reason that baseline integrity of the left IFOF and left ILF—more than the AF—
would predict a patient’s ability to regain semantic knowledge that results in improved
naming skills.
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Similarly, none of the right hemisphere tract metrics predicted language skills independent
of lesion volume. Researchers have postulated that one mechanism of stroke recovery is
structural and functional compensation by the non-damaged hemisphere. Indeed, Forkel et
al. (2014) found that greater volume of the right AF derived from acute diffusion images
predicted greater degree of recovery from aphasia six months post-stroke onset. Yet, similar
to the present study, they found no significant relationships between FA of right hemisphere
tracts and aphasia recovery (Forkel et al., 2014). It may be that the integrity of right
hemisphere structures is most crucial for recovery of language skills in the acute and
subacute phases of left hemisphere stroke but not as critical by the chronic stage. Our
findings align with this interpretation, given that no significant positive or negative
associations between language measures and right hemisphere metrics were found.
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While the results of the current study are compelling, some limitations must be
acknowledged. First, the variance in naming and treatment outcomes explained by the lesion
classification systems was low, and some p-values approached the 0.05 mark. Although the
present sample represents one of the largest samples of patients in the aphasia treatment
neuroimaging literature, it is possible the cluster analyses suffered from lack of power. Thus,
future studies should endeavor to replicate these findings with a larger sample. Moreover,
given that proximal anatomical regions are often damaged together following stroke
(Charidimou et al., 2014), a primary rationale for creating large GM ROIs was to reduce
noise in the spared tissue calculations, thereby increasing the robustness of subsequent
statistical analyses. Nevertheless, it is possible that some granularity in quantifying cortical
GM damage was lost and that more finegrained cortical metrics would predict language
outcomes independent of overall lesion volume. Along the same vein, the manner in which
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gray matter integrity was measured in the present study did not allow for inclusion of right
hemisphere gray matter metrics. As such, future investigations that include bilateral
measures of GM integrity (e.g., cortical thickness) may improve the predictive power of
brain structure indices.

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Conclusions
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To our knowledge, this is the first investigation to directly compare the prognostic utility of
specific GM and WM measures for predicting naming treatment success in patients with
chronic aphasia. We found that GM-only and GM+WM clustering adequately predicted
overall language impairment (i.e., aphasia and anomia severity) but only the combined GM
+WM classification predicted the potential of benefitting from anomia treatment.
Furthermore, while it may be that overall lesion volume can serve as a proxy for aphasia
severity in chronic patients, diffusion metrics reflecting the integrity of left ventral WM
association pathways are critical predictors of naming abilities and treatment success. These
results, therefore, suggest that the inclusion of diffusion measures of WM pathways into
aphasia recovery models would improve prognostication of treatment response in patients
with chronic aphasia. As neuroimaging techniques advance and large databases of patients
increase in size, future research must endeavor to determine how best to quantify and
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incorporate structural integrity metrics into computational models so that the likelihood of
recovery is maximized for patients with aphasia.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
This work was supported by the National Institutes of Health National Institute on Deafness and Other
Communication Disorders through grants 1P50DC012283 and 1F31DC015940.

We would like to thank the individuals with aphasia who participated in this study for their time and effort. We
additionally express our gratitude to past and present members of the Boston University Aphasia Research
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Laboratory, especially Kushal Kapse, Yansong Geng, Kelly Martin, Maria Dekhtyar, Natalie Gilmore, Brett
McCardel and Mara Nussbaum, for their work on this project. We also acknowledge the work of our collaborators
through the Center for the Neurobiology of Language Recovery, in particular Ajay Kurani and Jennifer Michaud.

Potential conflicts of interest:

This study was funded by the National Institutes of Health (NIH) National Institute on Deafness and Other
Communication Disorders (NIDCD) (grant 1P50DC012283). Dr. Meier received funding on a predoctoral research
grant through the NIH/NIDCD during completion of this work (grant 1F31DC015940). Dr. Meier additionally
recently received a travel fellowship sponsored by the NIH/NIDCD (grant R13 DC017375) to present this work at
the 56th annual meeting of the Academy of Aphasia. At the time of this work, Dr. Johnson and Ms. Pan received a
salary/stipend through NIH/NIDCD grant 1P50DC012283. Dr. Meier, Dr. Johnson and Ms. Pan are now affiliated
with other universities, as indicated by the title page. Dr. Kiran is a scientific consultant for The Learning
Corporation, but there is no overlap between this role and the submitted investigation. The authors have no other
financial or non-financial conflicts of interest.

References
Author Manuscript

Basilakos A, Fillmore PT, Rorden C, Guo D, Bonilha L, & Fridriksson J (2014). Regional white matter
damage predicts speech fluency in chronic post-stroke aphasia. Frontiers in Human Neuroscience, 8
10.3389/fnhum.2014.00845
Beeson PM, & Robey RR (2006). Evaluating single-subject treatment research: lessons learned from
the aphasia literature. Neuropsychology Review, 16(4), 161–169. 10.1007/s11065-006-9013-7
[PubMed: 17151940]

Brain Imaging Behav. Author manuscript; available in PMC 2020 December 01.
 Meier et al. Page 13

Benjamini Y, & Hochberg Y (1995). Controlling the false discovery rate: a practical and powerful
approach to multiple testing. Journal of the Royal Statistical Society.Series B (Methodological),
Author Manuscript

(Journal Article), 289–300.

Boehme AK, Martin-Schild S, Marshall RS, & Lazar RM (2016). Effect of aphasia on acute stroke
outcomes. Neurology, 87(22), 2348–2354. [PubMed: 27765864]
Bonilha L, Gleichgerrcht E, Nesland T, Rorden C, & Fridriksson J (2016). Success of anomia
treatment in aphasia is associated with preserved architecture of global and left temporal lobe
structural networks. Neurorehabilitation and Neural Repair, 30(3), 266–279. [PubMed: 26150147]
Bonilha L, Hillis AE, Hickok G, den Ouden DB, Rorden C, & Fridriksson J (2017). Temporal lobe
networks supporting the comprehension of spoken words. Brain, 140(9), 2370–2380. 10.1093/brain/
awx169 [PubMed: 29050387]
Bonilha L, Rorden C, & Fridriksson J (2014). Assessing the clinical effect of residual cortical
disconnection after ischemic strokes. Stroke, 45(4), 988–993. 10.1161/STROKEAHA.113.004137
[PubMed: 24619391]
Boyle M (2010). Semantic feature analysis treatment for aphasic word retrieval impairments: What’s
in a name? Topics in Stroke Rehabilitation, 17(6), 411–422. 10.1310/tsr1706-411 [PubMed:
Author Manuscript

21239365]
Brady MC, Kelly H, Godwin J, Enderby P, & Campbell P (2016). Speech and language therapy for
aphasia following stroke In The Cochrane Collaboration (Ed.), Cochrane Database of Systematic
Reviews. Chichester, UK: John Wiley & Sons, Ltd 10.1002/14651858.CD000425.pub4
Breier JI, Hasan KM, Zhang W, Men D, & Papanicolaou AC (2008). Language dysfunction after
stroke and damage to white matter tracts evaluated using diffusion tensor imaging. American
Journal of Neuroradiology, 29(3), 483–487. 10.3174/ajnr.A0846 [PubMed: 18039757]
Charidimou A, Kasselimis D, Varkanitsa M, Selai C, Potagas C, & Evdokimidis I (2014). Why Is It
difficult to predict language impairment and outcome in patients with aphasia after stroke? Journal
of Clinical Neurology, 10(2), 75 10.3988/jcn.2014.10.2.75 [PubMed: 24829592]
Code C, Torney A, Gildea-Howardine E, & Willmes K (2010). Outcome of a one-month therapy
intensive for chronic aphasia: Variable individual responses. Seminars in Speech and Language,
31(01), 021–033. 10.1055/s-0029-1244950
Del Gaizo J, Fridriksson J, Yourganov G, Hillis AE, Hickok G, Misic B, … Bonilha L (2017).
Mapping language networks using the structural and dynamic brain connectomes. Eneuro, 4(5),
Author Manuscript

ENEURO.0204-17.2017. 10.1523/ENEURO.0204-17.2017
Engelter ST, Gostynski M, Papa S, Frei M, Born C, Ajdacic-Gross V, … Lyrer PA (2006).
Epidemiology of aphasia attributable to first ischemic stroke: Incidence, severity, fluency, etiology,
and thrombolysis. Stroke, 37(6), 1379–1384. 10.1161/01.STR.0000221815.64093.8c [PubMed:
16690899]
Flowers HL, Skoretz SA, Silver FL, Rochon E, Fang J, Flamand-Roze C, & Martino R (2016).
Poststroke aphasia frequency, recovery, and outcomes: A systematic review and meta-analysis.
Archives of Physical Medicine and Rehabilitation, 97(12), 2188–2201.e8. 10.1016/j.apmr.
2016.03.006 [PubMed: 27063364]
Forkel SJ, Thiebaut de Schotten M, Dell’Acqua F, Kalra L, Murphy DGM, Williams SCR, & Catani M
(2014). Anatomical predictors of aphasia recovery: a tractography study of bilateral perisylvian
language networks. Brain, 137(7), 2027–2039. 10.1093/brain/awu113 [PubMed: 24951631]
Geva S, Correia MM, & Warburton EA (2015). Contributions of bilateral white matter to chronic
aphasia symptoms as assessed by diffusion tensor MRI. Brain and Language, 150, 117–128.
Author Manuscript

10.1016/j.bandl.2015.09.001 [PubMed: 26401977]

Geva S, Correia M, & Warburton EA (2011). Diffusion tensor imaging in the study of language and
aphasia. Aphasiology, 25(5), 543–558. 10.1080/02687038.2010.534803
Gilmore N, Meier EL, Johnson JP, & Kiran S (2018). Typicality-based semantic treatment for anomia
results in multiple levels of generalisation. Neuropsychological Rehabilitation, 1–27.
10.1080/09602011.2018.1499533
Gleichgerrcht E, Kocher M, Nesland T, Rorden C, Fridriksson J, & Bonilha L (2015). Preservation of
structural brain network hubs is associated with less severe post-stroke aphasia. Restorative
Neurology and Neuroscience, 34(1), 19–28. 10.3233/RNN-150511 [PubMed: 26599472]

Brain Imaging Behav. Author manuscript; available in PMC 2020 December 01.
 Meier et al. Page 14

Goodglass H, & Wingfield A (Eds.). (1997). Anomia: neuroanatomical and cognitive correlates. San
Diego: Academic Press.
Author Manuscript

Griffis JC, Nenert R, Allendorfer JB, & Szaflarski JP (2017). Damage to white matter bottlenecks
contributes to language impairments after left hemispheric stroke. Neuroimage: Clinical, 14, 552–
565. 10.1016/j.nicl.2017.02.019 [PubMed: 28337410]
Han Z, Ma Y, Gong G, He Y, Caramazza A, & Bi Y (2013). White matter structural connectivity
underlying semantic processing: evidence from brain damaged patients. Brain, 136(10), 2952–
2965. 10.1093/brain/awt205 [PubMed: 23975453]
Han Z, Ma Y, Gong G, Huang R, Song L, & Bi Y (2016). White matter pathway supporting
phonological encoding in speech production: a multi-modal imaging study of brain damage
patients. Brain Structure and Function, 221(1), 577–589. 10.1007/s00429-014-0926-2 [PubMed:
25359657]
Harvey DY, & Schnur TT (2015). Distinct loci of lexical and semantic access deficits in aphasia:
Evidence from voxel-based lesion-symptom mapping and diffusion tensor imaging. Cortex, 67,
37–58. 10.1016/j.cortex.2015.03.004 [PubMed: 25880795]
Harvey DY, Wei T, Ellmore TM, Hamilton AC, & Schnur TT (2013). Neuropsychological evidence for
Author Manuscript

the functional role of the uncinate fasciculus in semantic control. Neuropsychologia, 51(5), 789–
801. 10.1016/j.neuropsychologia.2013.01.028 [PubMed: 23395830]
Howard D, Best W, & Nickels L (2015). Optimising the design of intervention studies: critiques and
ways forward. Aphasiology, 29(5), 526–562. 10.1080/02687038.2014.985884
Ivanova MV, Isaev DY, Dragoy OV, Akinina YS, Petrushevskiy AG, Fedina ON, … Dronkers NF
(2016). Diffusion-tensor imaging of major white matter tracts and their role in language processing
in aphasia. Cortex, 85, 165–181. 10.1016/j.cortex.2016.04.019 [PubMed: 27289586]
Kaplan E, Goodglass H, Weintraub S, Segal O, & van Loon-Vervoorn A (2001). Boston naming test.
Pro-ed.
Kaufman L, & Rousseeuw PJ (1990). Finding groups in data: an introduction to cluster analysis. New
York: New York : Wiley.
Kertesz A (2006). Western Aphasia Battery (Revised) PsychCorp. San Antonio, Tx, (Journal Article).
Kiran S, & Thompson CK (2003). The role of semantic complexity in treatment of naming deficits:
Training semantic categories in fluent aphasia by controlling exemplar typicality. Journal of
Author Manuscript

Speech Language and Hearing Research, 46(4), 773 10.1044/1092-4388(2003/061)

Kummerer D, Hartwigsen G, Kellmeyer P, Glauche V, Mader I, Kl?ppel S, … Saur D (2013). Damage
to ventral and dorsal language pathways in acute aphasia. Brain, 136(2), 619–629. 10.1093/brain/
aws354 [PubMed: 23378217]
Lambon Ralph MA, Snell C, Fillingham JK, Conroy P, & Sage K (2010). Predicting the outcome of
anomia therapy for people with aphasia post CVA: Both language and cognitive status are key
predictors. Neuropsychological Rehabilitation, 20(2), 289–305. 10.1080/09602010903237875
[PubMed: 20077315]
Maechler M, Rousseeuw P, Struyf AK, Hubert M, & Hornik K (2018). cluster: Cluster Analysis Basics
and Extensions (Version R package version 2.0.7-1).
Marchina S, Zhu LL, Norton A, Zipse L, Wan CY, & Schlaug G (2011). Impairment of speech
production predicted by lesion load of the left arcuate fasciculus. Stroke, 42(8), 2251–2256.
10.1161/STROKEAHA.110.606103 [PubMed: 21719773]
Marebwa BK, Fridriksson J, Yourganov G, Feenaughty L, Rorden C, & Bonilha L (2017). Chronic
post-stroke aphasia severity is determined by fragmentation of residual white matter networks.
Author Manuscript

Scientific Reports, 7(1), 8188 10.1038/s41598-017-07607-9 [PubMed: 28811520]

McKinnon ET, Fridriksson J, Basilakos A, Hickok G, Hillis AE, Spampinato MV, … Bonilha L
(2018). Types of naming errors in chronic post-stroke aphasia are dissociated by dual stream
axonal loss. Scientific Reports, 8(1), 14352 10.1038/s41598-018-32457-4 [PubMed: 30254222]
McKinnon ET, Fridriksson J, Glenn GR, Jensen JH, Helpern JA, Basilakos A, … Bonilha L (2017).
Structural plasticity of the ventral stream and aphasia recovery. Annals of Neurology, 82(1), 147–
151. 10.1002/ana.24983 [PubMed: 28628946]
Mirman D, Zhang Y, Wang Z, Coslett HB, & Schwartz MF (2015). The ins and outs of meaning:
Behavioral and neuroanatomical dissociation of semantically-driven word retrieval and multimodal

Brain Imaging Behav. Author manuscript; available in PMC 2020 December 01.
 Meier et al. Page 15

semantic recognition in aphasia. Neuropsychologia, 76, 208–219. 10.1016/j.neuropsychologia.

2015.02.014 [PubMed: 25681739]
Author Manuscript

Naeser MA, & Palumbo CL (1994). Neuroimaging and language recovery in stroke. Journal of
Clinical Neurophysiology: Official Publication of the American Electroencephalographic Society,
11(2), 150–174. [PubMed: 8051302]
O’Donnell LJ, & Westin C-F (2011). An introduction to diffusion tensor image analysis. Neurosurgery
Clinics of North America, 22(2), 185–196. 10.1016/j.nec.2010.12.004 [PubMed: 21435570]
Pena EA, & Slate EH (2014). gvlma: Global Validation of Linear Models Assumptions (Version R
package version 1.0.0.2). Retrieved from https://CRAN.R-project.org/package=gvlma
Price CJ, Hope TM, & Seghier ML (2017). Ten problems and solutions when predicting individual
outcome from lesion site after stroke. NeuroImage, 145, 200–208. 10.1016/j.neuroimage.
2016.08.006 [PubMed: 27502048]
Price CJ, Seghier ML, & Leff AP (2010). Predicting language outcome and recovery after stroke: the
PLORAS system. Nature Reviews. Neurology, 6(4), 202–210. 10.1038/nrneurol.2010.15
[PubMed: 20212513]
R Core Team. (2017). R: A Language and Environment for Statistical Computing. Vienna, Austria: R
Author Manuscript

Foundation for Statistical Computing Retrieved from https://www.R-project.org/

Rolheiser T, Stamatakis EA, & Tyler LK (2011). Dynamic processing in the human language system:
Synergy between the arcuate fascicle and extreme capsule. Journal of Neuroscience, 31(47),
16949–16957. 10.1523/JNEUROSCI.2725-11.2011 [PubMed: 22114265]
Rosso C, Vargas P, Valabregue R, Arbizu C, Henry-Amar F, Leger A, … Samson Y (2015). Aphasia
severity in chronic stroke patients: A combined disconnection in the dorsal and ventral language
pathways. Neurorehabilitation and Neural Repair, 29(3), 287–295. [PubMed: 25096274]
Thye M, & Mirman D (2018). Relative contributions of lesion location and lesion size to predictions of
varied language deficits in post-stroke aphasia. NeuroImage: Clinical, 20, 1129–1138. 10.1016/
j.nicl.2018.10.017 [PubMed: 30380520]
Tsouli S, Kyritsis AP, Tsagalis G, Virvidaki E, & Vemmos KN (2009). Significance of aphasia after
first-ever acute stroke: Impact on early and late outcomes. Neuroepidemiology, 33(2), 96–102.
10.1159/000222091 [PubMed: 19494550]
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, … Joliot M
Author Manuscript

(2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical

parcellation of the MNI MRI single-subject brain. NeuroImage, 15(1), 273–289. 10.1006/nimg.
2001.0978 [PubMed: 11771995]
van Hees S, McMahon K, Angwin A, de Zubicaray G, Read S, & Copland DA (2014). Changes in
white matter connectivity following therapy for anomia post stroke. Neurorehabilitation and
Neural Repair, 28(4), 325–334. [PubMed: 24297762]
Wakana S, Jiang H, Nagae-Poetscher LM, van Zijl PCM, & Mori S (2004). Fiber tract-based atlas of
human white matter anatomy. Radiology, 230(1), 77–87. 10.1148/radiol.2301021640 [PubMed:
14645885]
Wang J, Marchina S, Norton AC, Wan CY, & Schlaug G (2013). Predicting speech fluency and naming
abilities in aphasic patients. Frontiers in Human Neuroscience, 7 10.3389/fnhum.2013.00831
Watila MM, & Balarabe SA (2015). Factors predicting post-stroke aphasia recovery. Journal of the
Neurological Sciences, 352(1–2), 12–18. 10.1016/j.jns.2015.03.020 [PubMed: 25888529]
Wilson SM, Galantucci S, Tartaglia MC, Rising K, Patterson DK, Henry ML, … Gorno-Tempini ML
(2011). Syntactic processing depends on dorsal language tracts. Neuron, 72(2), 397–403. 10.1016/
Author Manuscript

j.neuron.2011.09.014 [PubMed: 22017996]

Xing S, Mandal A, Lacey EH, Skipper-Kallal LM, Zeng J, & Turkeltaub PE (2018). Behavioral effects
of chronic gray and white matter stroke lesions in a functionally defined connectome for naming.
Neurorehabilitation and Neural Repair, 32(6–7), 613–623. 10.1177/1545968318780351 [PubMed:
29890878]
Yourganov G, Fridriksson J, Rorden C, Gleichgerrcht E, & Bonilha L (2016). Multivariate
connectome-based symptom mapping in post-stroke patients: Networks supporting language and
speech. Journal of Neuroscience, 36(25), 6668–6679. 10.1523/JNEUROSCI.4396-15.2016
[PubMed: 27335399]

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Figure 1.
Anatomical masks. (A) Gray matter (GM) regions of interest (ROIs), including DLPFC
(purple), iFrontal (green), aTemporal (red), pTemporal (navy blue), Parietal (cyan) and
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Occipital (yellow). Numbers denote ROIs in the AAL atlas, listed in Table 1. (B) Bilateral
white matter (WM) tract masks, including—from left to right—the arcuate (in red), inferior
fronto-occipital (in green), inferior longitudinal (in blue) and uncinate (in violet) fasciculi.
(C) From left to right, the normalized T1 image, lesion map, and subject-specific GM and
WM masks shown for a sample patient. Matrices below the masks represent 4×4mm swathes
of tissue as a toy example of the procedure used to calculate spared tissue and fractional
anisotropy (FA) per each subject-specific mask. In the far left and middle matrices, 1 =

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spared and 0 = lesioned voxels in the GM and WM masks, respectively; the font color
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corresponds to the mask from which spared voxels were extracted. The numbers in the third
matrix (at right) reflect FA values per voxel in the same 4×4mm of WM tissue shown in the
middle matrix.
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Figure 2.
Patient lesion data. Lesion overlay and lesion volume mean (denoted by ‒x) in cubic
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centimeters (cc) and distribution for n = 34 patients.

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Figure 3.
GM-only clustering. (A) Results of the k-medoids analysis using GM-only ROI metrics.
P1-34 correspond to single patients, Dim = Dimension. (B) Lesion volume per cluster in
cubic centimeters (cc). (C) Lesion subtraction plots of patients in cluster 3 (in orange) versus
cluster 4 (in green). Brighter colors reflect greater overlap of patients’ lesions.
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Figure 4.
GM+WM clustering. (A) Results of the k-medoids analysis using combined GM and WM
metrics, Dim = Dimension. (B) Lesion volume per cluster in cubic centimeters (cc). (C)
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Lesion subtraction plots of patients in cluster 1 (in yellow) versus cluster 3 (in vermillion).
(D) Lesion subtraction plots of patients in cluster 2 (in blue) versus cluster 4 (in pink).
Brighter colors reflect greater overlap of patients’ lesions.

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Figure 5.
Language measures, including A) aphasia severity per WAB-R AQ, B) naming skills per
BNT total correct and C) treatment gains per (PMG) plotted by GM-only and GM+WM
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clusters. *** p < 0.001, ** p < 0.01, * p < 0.01, n.s. = not significant

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Figure 6.
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Associations between language measures and structural metrics, controlling for lesion
volume, including (A) BNT total correct and fractional anisotropy (FA) in the left inferior
fronto-occipital fasciculus (IFOF) and inferior longitudinal fasciculus (ILF) and (B)
proportion of potential maximal gain (PMG) and FA in the left IFOF and ILF.
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Table 1.

Regions of interest (ROIs) included in large gray matter (GM) masks

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Number in
Figure 1 ROI mask Automated Labeling Atlas (AAL) ROI
1 DLPFC Superior frontal gyrus
2 DLPFC Middle frontal gyrus
3 iFrontal Inferior frontal gyrus (IFG), pars orbitalis
4 iFrontal IFG, pars triangularis
5 iFrontal IFG, pars opercularis
6 iFrontal Insula
7 iFrontal Rolandic operculum
8 iFrontal Precentral gyrus
9 aTemporal Superior temporal pole (TP)
10 aTemporal Anterior superior temporal gyrus (STG)
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11 aTemporal Mid TP
12 aTemporal Anterior middle temporal gyrus (MTG)
13 aTemporal Anterior inferior temporal gyrus (ITG)
14 aTemporal Anterior fusiform gyrus (FUSI)
15 pTemporal Posterior STG
16 pTemporal Posterior MTG
17 pTemporal Posterior ITG
18 pTemporal Posterior FUSI
19 Parietal Postcentral gyrus
20 Parietal Superior parietal lobule
21 Parietal Inferior parietal lobule
22 Parietal Supramarginal gyrus
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23 Parietal Angular gyrus

24 Occipital Superior occipital cortex
25 Occipital Mid occipital cortex
26 Occipital Inferior occipital cortex
27 Occipital Cuneal cortex
28 Occipital Calcarine cortex
29 Occipital Lingual gyrus

DLPFC = dorsolateral prefontal cortex; iFrontal = inferior frontal; aTemporal = anterior temporal; pTemporal = posterior temporal
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Table 2.

Demographic, behavioral and lesion data for all patients

Lesion WAB-R AQ Naming

Meier et al.

ID Sex Handedness Age MPO Education Volume (cc) (/100) BNT (/60) Probe (%) PMG
P1 M R 55 12 16 57.25 87.2 50 58.33 0.89
P2 F L 50 29 16 249.93 25.2 1 0.99 0.00
P3 F R 63 62 16 175.38 52.0 10 17.59 0.36
P4 M R 79 13 16 84.78 74.1 52 67.96 1.00
P5 M R 67 8 18 171.94 30.8 4 6.11 −0.07
P6 M R 49 113 16 298.97 66.6 44 55.97 0.74
P7 M R 55 137 16 181.97 48.0 6 14.07 0.27
P8 F R 71 37 16 11.66 95.2 45 59.07 0.83
P9 F R 53 12 16 76.55 80.4 37 64.81 0.83
P10 M R 78 22 18 32.11 92.1 41 33.70 0.39
P11 M R 68 104 12 186.85 40.0 1 2.78 0.03
P12 M L 42 18 13.5 12.13 92.7 43 56.94 0.98
P13 F R 64 24 13 96.93 64.4 41 40.56 0.77
P14 F R 71 74 12 189.31 87.2 43 56.48 0.28
P15 M R 61 152 16 163.49 74.3 54 52.22 0.98
P16 F R 70 152 16 69.64 78.0 24 48.33 0.76
P17 M R 80 22 18 89.03 28.9 1 7.78 0.22
P18 F R 48 14 16 164.33 13.0 0 0.00 0.42
P19 M R 65 16 18 247.59 11.7 0 0.37 0.06
P20 M R 62 12 16 100.02 65.4 1 7.22 0.11

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P21 M R 60 24 16 172.81 45.2 6 5.19 0.04
P22 M R 69 170 16 183.45 40.4 3 6.85 0.14
P23 F R 76 33 18 184.39 37.5 2 2.22 0.06
P24 F R 64 115 12 127.70 58.0 15 20.56 0.20
P25 M R 62 15 12 76.65 56.0 21 35.74 0.42
P26 M R 49 49 12 87.59 85.5 53 68.61 1.00
P27 M R 81 11 12 51.70 73.8 24 40.56 n/a
P28 M R 49 67 12 317.07 32.3 3 5.00 0.00
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Lesion WAB-R AQ Naming

ID Sex Handedness Age MPO Education Volume (cc) (/100) BNT (/60) Probe (%) PMG
P29 M R 39 18 16 26.22 71.3 36 47.22 0.23
P30 M L 64 13 12 34.15 79.6 41 45.93 0.63
Meier et al.

P31 M L 62 21 16 1.57 91.5 42 74.26 n/a

P32 M R 68 21 13.5 80.28 82.5 33 31.48 n/a
P33 M R 58 23 14 186.52 61.8 10 11.94 0.37
P34 M R 53 467 17 120.82 94.0 55 65.74 n/a
AVG 62.18 61.18 15.09 126.79 62.25 24.76 32.72 0.43
SD 10.89 86.49 2.11 82.13 24.60 20.19 25.13 0.36

M=male; F=female; L=left-handed; R=right-handed; MPO=months post-onset; WAB-R AQ=Western Aphasia Battery-Revised Aphasia Quotient; BNT=Boston Naming Test; PMG=Proportion of potential
maximal gain; AVG=average; SD=standard deviation; cc = cubic centimeters

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Table 3.

Summary of ROI and tract mask results

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FA (mean±SD)
Mask LH %spared (mean±SD) LH RH F(1,63) p-value
DLPFC 93.02±11.20 . . . .
iFrontal 67.77±27.69 . . . .
aTemporal 75.60±19.19 . . . .
pTemporal 78.61±17.76 . . . .
Parietal 77.92±24.25 . . . .
AF 57.11±28.45 0.353±0.052 0.496±0.047 132.86 <0.001
IFOF 74.01±16.35 0.375±0.043 0.409±0.028 14.46 <0.001
ILF 77.70±17.47 0.365±0.048 0.394±0.028 7.709 0.0072
UF 57.84±31.31 0.322±0.037 0.443±0.026 250.02 <0.001
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LH=left hemisphere; RH=right hemisphere; SD=standard deviation; DLPFC = dorsolateral prefontal cortex; iFrontal = inferior frontal; aTemporal
= anterior temporal; pTemporal = posterior temporal; AF = arcuate fasciculus; IFOF = inferior fronto-occipital fasciculus; ILF = inferior
longitudinal fasciculus; UF = uncinate fasciculus
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Table 4.

Correlations between structural metrics and language variables, with and without controlling for total lesion
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volume

Aphasia Severity Naming Skills Treatment Gains

(WAB-R AQ) (BNT Total) (PMG)
Measure Corr. Partial corr. Corr. Partial corr. Corr. Partial corr.

DLPFC (%sp) 0.512** −0.088(n.s.) 0.416* 0.014(n.s.) 0.557** 0.111(n.s.)

iFrontal (%sp) 0.657*** 0.229(n.s.) 0.435* 0.041(n.s.) 0.432* −0.117(n.s.)

aTemporal (%sp) 0.600*** 0.256(n.s.) 0.270(n.s.) −0.113(n.s.) 0.289(n.s.) −0.169(n.s.)

pTemporal (%sp) 0.494** 0.238(n.s.) 0.231(n.s.) −0.036(n.s.) 0.196(n.s.) −0.143(n.s.)

Parietal (%sp) 0.629*** 0.138(n.s.) 0.435* 0.022(n.s.) 0.406* −0.161(n.s.)

Left AF (%sp) 0.721*** 0.371(n.s.) 0.492** 0.144(n.s.) 0.642*** 0.333(n.s.)

Left IFOF (%sp) 0.641*** 0.252(n.s.) 0.507** 0.211(n.s.) 0.638*** 0.370(n.s.)

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Left ILF (%sp) 0.567** 0.243(n.s.) 0.423* 0.155(n.s.) 0.506** 0.211(n.s.)

Left UF (%sp) 0.641*** 0.261(n.s.) 0.392* 0.018(n.s.) 0.454* 0.040(n.s.)

Left AF (FA) 0.518** 0.174(n.s.) 0.384* 0.108(n.s.) 0.502** 0.259(n.s.)

Left IFOF (FA) 0.393* 0.427(n.s.) 0.441* 0.441* 0.513** 0.560**

Left ILF (FA) 0.465** 0.468(n.s.) 0.527** 0.507* 0.624*** 0.658***

Left UF (FA) 0.454** 0.410(n.s.) 0.348* 0.267(n.s.) 0.212(n.s.) 0.117(n.s.)

Right AF (FA) −0.129(n.s.) −0.169(n.s.) −0.123(n.s.) −0.137(n.s.) −0.161(n.s.) −0.234(n.s.)

Right IFOF (FA) 0.186(n.s.) 0.323(n.s.) 0.250(n.s.) 0.332(n.s.) 0.184(n.s.) 0.281(n.s.)
Right ILF (FA) 0.128(n.s.) 0.425(n.s.) 0.166(n.s.) 0.349(n.s.) 0.016(n.s.) 0.202(n.s.)
Right UF (FA) 0.250(n.s.) 0.107(n.s.) 0.301(n.s.) 0.207(n.s.) 0.197(n.s.) 0.005(n.s.)
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WAB-R AQ=Western Aphasia Battery-Revised Aphasia Quotient; BNT=Boston Naming Test; PMG=Proportion of potential maximal gain; Corr. =
Correlation; %sp = percentage of spared mask tissue; FA = fractional anisotropy; DLPFC = dorsolateral prefontal cortex; iFrontal = inferior frontal;
aTemporal = anterior temporal; pTemporal = posterior temporal; AF = arcuate fasciculus; IFOF = inferior fronto-occipital fasciculus; ILF = inferior
longitudinal fasciculus; UF = uncinate fasciculus. An FDR correction via the Benjamini-Hochberg (BH) method was performed to correct for
multiple comparisons; significance levels reflect adjust p-values.
***
p < 0.001
**
p < 0.01
*
p < 0.05, n.s. = not significant
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