Brain Imaging and Behavior

https://doi.org/10.1007/s11682-021-00457-0

ORIGINAL RESEARCH

Multivariate machine learning‐based language mapping in glioma

patients based on lesion topography
Nan Zhang 1,2 & Binke Yuan 3,4,5 & Jing Yan 6 & Jingliang Cheng 6 & Junfeng Lu 2 & Jinsong Wu 2,7

Received: 15 June 2019 / Revised: 11 December 2020 / Accepted: 21 January 2021

# The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021

Abstract
Diffusive and progressive tumor infiltration within language-related areas of the brain induces functional reorganization.
However, the macrostructural basis of subsequent language deficits is less clear. To address this issue, lesion topography data
from 137 preoperative patients with left cerebral language-network gliomas (81 low-grade gliomas and 56 high-grade gliomas),
were adopted for multivariate machine-learning-based lesion-language mapping analysis. We found that tumor location in the left
posterior middle temporal gyrus—a bottleneck where both dorsal and ventral language pathways travel—predicted deficits of
spontaneous speech (cluster size = 1356 mm3, false discovery rate corrected P < 0.05) and naming scores (cluster size = 1491
mm3, false discovery rate corrected P < 0.05) in the high-grade glioma group. In contrast, no significant lesion-language mapping
results were observed in the low-grade glioma group, suggesting a large functional reorganization. These findings suggest that in
patients with gliomas, the macrostructural plasticity mechanisms that modulate brain-behavior relationships depend on glioma
grade.

Keywords Low‐grade glioma . High‐grade glioma . Structural MRI . Language . Machine learning

Introduction

Neuroplasticity is an intrinsic adaptive mechanism for remod-

Nan Zhang, Binke Yuan and Jing Yan contributed equally to this work. eling functional systems after cerebral lesion (Payne and
Lomber 2001). When functional reorganization is sufficient,
* Junfeng Lu cognitive function is preserved. However when insufficient,
junfeng_lu@fudan.edu.cn especially in patients with lesions involving eloquent brain
areas, the results can be multiple cognitive deficits (Corbetta
1
Department of Neurosurgery, The First Affiliated Hospital of USTC, et al. 2015; Warren et al. 2014). Unlike acute cerebral lesion
Division of Life Sciences and Medicine, University of Science and with subsequent postlesional plasticity—such as occurs after
Technology of China, Anhui Hefei, China
traumatic brain injury or stroke—the growth of diffuse and
2
Glioma Surgery Division, Neurologic Surgery Department, Huashan progressive glioma is often accompanied with a good deal of
Hospital, Fudan University, Shanghai, China
functional reorganization (Almairac et al. 2015; Desmurget
3
Institute for Brain Research and Rehabilitation, South China Normal et al. 2007; Herbet et al. 2014, 2016). Exploring the pattern
University, Guangzhou, China
of functional reorganization in the brain following tumor
4
Key Laboratory of Brain, Cognition and Education Sciences (South growth not only broadens our understanding of the brain’s
China Normal University), Ministry of Education,
capacity to reorganize itself, it also provides essential infor-
Guangzhou, China
5
mation for functional surgical neuro-oncology (Duffau 2005;
Center for Language and Brain, Shenzhen Institute of Neuroscience,
Duffau et al. 2014; Weng et al. 2018; Wu et al. 2015; Yuan
Shenzhen, China
6
et al. 2020; Zhang et al. 2018). The majority of current imag-
Department of MRI , The First Affiliated Hospital of Zhengzhou
ing studies focus on the functional alterations, such as spon-
University , Zhengzhou, China
7
taneous or task-induced activity changes (Benzagmout et al.
Institute of Brain-Intelligence Technology , Zhangjiang Lab,
2007; Deverdun et al. 2019; Duffau 2005; Hart et al. 2019;
Shanghai, China

Huang et al. 2018; Lu et al. 2017; Sarubbo et al. 2012; Yuan
et al. 2019; Zhang et al. 2018), cognitive-related functional
network reorganization (Fox and King 2018; Ghinda et al.
2018; Yuan et al. 2020; Zhang et al. 2016), or changes in
functional network topological properties (e.g., the small-
worldness) (Aerts et al. 2016). However, the structural
neuroplasticity remains largely unknown.
Several studies investigated the structural changes of the
brain flowing tumor growth. Almairac and colleagues showed
that diffuse low-grade glioma (LGG) within the insula—
which infiltrate slowly (generally taking years)—induced a
marked increase in the gray matter volume of the
contralesional homotopic insula (Almairac et al. 2018). The
structural recruitment of the contralesional homotopic areas is
consistent with other similar findings, including compensato-
ry redistribution of activity in contralesional homotopic areas
in cases of left dominant insular LGG (Duffau et al. 2001) and
left dominant Broca’s or Wernicke’s LGG (Duffau 2012;
Duffau et al. 2014; Picart et al. 2018). Patients with LGGs
that include supratentorial lesions in the language network
can also exhibit overlapping changes in gray matter volume
and functional activity in the cerebellum (Zhang et al. 2018).
These evidences suggest structure/function coupled alter-
ations in the brains of glioma.
A more direct way to investigate the structural
neuroplasticity following glioma growth was to assess the
lesion-symptom relationship, i.e., whether or not the tumor
location determines the severity and domain of cognitive def-
icits (Banerjee et al. 2015; Deverdun et al. 2019; Kinoshita
et al. 2016; Mah et al. 2014; Pisoni et al. 2018, 2019; Sagberg
et al. 2019; Wang et al. 2015; Zhang et al. 2014). The neural
bases of diverse functions have been investigated. However,
the studies focusing on language function are still relatively
scarce. In these limited number of investigations focusing on
language function, limitations have to be addressed: First, the
sample size in each lesion location is small, which is critical
for statistical power (Sperber and Karnath 2017); Second, ma-
jority of existent studies focus on patients with LGGs
(Deverdun et al. 2019), and little attention has been paid to
patients with high-grade glioma (HGG). Tumor grade has
been shown to be a leading predictor of neuroplasticity and
cognitive outcomes (Yuan et al. 2019; Zhang et al. 2018).
However, tumor grade-related differences in lesion-language
relationship remain largely unknown.
In this work, we enrolled a large cohort of patients (81
LGG and 56 HGG) with left-hemispheric gliomas within lan-
guage network areas, and investigated lesion-language rela-
tionship. All patients were scanned with high-resolution 3D-
T1 images, were confirmed not to have any midline shift, and
underwent detailed assessment of language function.
Sufficient numbers of the lesions in the left hemisphere and
the different levels of language impairments within LGG and
HGG groups ensured that we could perform lesion-language
Brain Imaging and Behavior
mapping to identify whether tumor location is critical for lan-
guage impairment in each group. Considering the potential
mislocalization in mass-univariate voxel-based lesion-
symptom mapping (VLSM) (Bates et al. 2003), we adopted
a multivariate machine-learning lesion-symptom mapping
technique (Mah et al. 2014; Rorden et al. 2007; Zhang et al.
2014). We hypothesized that the lesion topography for lan-
guage impairments in the LGG group would have limited
predictive ability because of the large functional reorganiza-
tion that occurs with LGGs. In contrast, we suspected that
damage to the eloquent areas in the HGG group would be
associated with language deficits.
Materials and methods
Participants
Patients were prospectively screened and data was collected at
two centers: (1) Huashan Hospital (from 2011 to 2016) and (2)
the First Affiliated Hospital of Zhengzhou University (from
2014 to 2018). We pooled the data from the two centers be-
cause only lesion masks were used .
Inclusion criteria: (1) Pathologically confirmed glioma
(based on the 2007 WHO classification system) in the left
cerebral cortex (Louis et al. 2007); (2) No chemo and/or radi-
ation treatment history; (3) location of the glioma partially
overlapped or was within language network areas proposed
by Fedorenko et al. (2010) ; (4) age was 18–75 years old; (5)
right-handed, as confirmed by the Edinburgh Handedness
Inventory; (6) no symptoms of motor impairment, as evi-
denced by a grade V on the Medical Research Council
(MRC) Scale for Muscle Strength (Paternostro-Sluga et al.
2008); (7) Chinese Han nationality; (8) no history of brain
operation; (9) more than nine years of education; (10) no mid-
line shift in the structural images, confirmed by the in situ
location of midline brain structures (corpus callosum, septa
pellucidum, third ventricle, hypothalamus, and pineal region);
(11) both structural and functional images covered the whole
brain, especially the whole cerebellum; (12) good cooperation
during the linguistic/cognitive evaluation; (13) no history of
other major neurological or psychiatric disorders; and (14) no
alcohol or drug abuse.
In total, 137 patients met all inclusion criteria and complet-
ed the entire preoperative clinical, language, and imaging data
acquisition. The patients were further grouped based on the
malignancy of brain tumors: 81 patients with grade I (n = 2)
and II (n = 79) brain tumors comprised as LGG group and 56
patients with grade III (n = 28) and IV (n = 28) brain tumors
comprised the HGG group. For the two cases of grade I in
LGG group, one patient was diagnosed as ganglio glioma and
the other patient was diagnosed as neuroepithelial glioma.
Brain Imaging and Behavior
Clinical and neuropsychological examination
All patients underwent comprehensive assessment of Karnofsky
performance status (KPS), language, motor, and Mini-mental
State Examination (MMSE). Language function was assessed
by the Aphasia Battery for Chinese speakers (ABC), which is
the Chinese standardized adaptation of the Western Aphasia
Battery (Gao et al. 1992; Lu et al. 2013; Wu et al. 2015; Yang
et al. 2016; Zhang et al. 2018), and includes spontaneous speech
(SSS ; range, 0–20), comprehension (SCom; range, 0–230), repe-
tition (SRep ; range, 0–100), and naming (SNam ; range, 0–100)
scores. The Aphasia Quotient (AQ) score (range, 0–100) can be
calculated from these items to reflect the global severity:


AQ ¼ SSS þSCom  23þSRep  10þSNam  10  2:
Image acquisition
All images were obtained using Siemens Magnetom Verio
3.0 T MRI scanners (Siemens Medical Solutions, Erlangen,
Germany) at the two centers. For LGGs, high resolution T1-
weighted and T2-weighted fluid-attenuated inversion recov-
ery (T2-FLAIR) images were acquired with the following
parameters: T1-weighted images: axial magnetization-
prepared rapid gradient echo (MPRAGE) sequence, repetition
time (TR) = 1,900 ms; echo time (TE) = 2.93 ms; inversion
time (TI) = 900 ms; flip angle (FA) = 90°; field of view
(FOV) = 250 × 219 mm; matrix size = 256 × 215; slice thick-
ness = 1 mm; voxel size = 1 × 1 × 1 mm3; slice number = 176;
and scanning time = 7 min 47 s. T2-FLAIR: TR = 9,000 ms;
TE = 99 ms; TI = 2500 ms; FA = 150°; FOV = 240 × 214 mm;
matrix size = 256 × 160; slice thickness = 2 mm; voxel size =
0.9 × 1.3 × 2.0 mm3; slice number = 66; and scanning time =
7 min 30 s. For patients with HGGs in Huashan Hospital, only
T1-weighted sequences with contrasts (gadopentetate
dimeglumine) were acquired with the same parameters. For
patients with HGGs in the First Affiliated Hospital of
Zhengzhou University, both pre- and post-contrast T1-weight-
ed images were acquired.
Structural data processing
Lesion mapping For each patient, manual tumor drawing on
the 3D-T1 images was performed based on the contrast-
enhancing tumor areas or the FLAIR hyperintense areas (ne-
crotic areas were included but not peritumoral edema). For
3D-T1 images without glioma enhancement, T2- FLAIR im-
ages were first coregistered to the 3D-T1 images as a visual
reference. After manually tracing the tumor, we created a 3D-
T1 volume without tumor area (set to 0) for each patient. This
procedure was achieved manually using RANO criteria as a
reference (Wen et al. 2010). The accuracy of the manual trac-
ing was further confirmed by a senior neurosurgeon.
DARTEL and lesion mask normalization Each 3D-T1 volume
without tumor area was segmented into gray matter (GM), white
matter (WM), and cerebrospinal fluid (CSF), bone, soft tissue
and air/background using SPM12 (Wellcome Centre for
Human Neuroimaging, https://www.fil.ion.ucl.ac.uk/spm). We
then used DARTEL (Diffeomorphic Anatomical Registration
using Exponentiated Lie algebra) for registration,
normalization, and modulation (Ashburner 2007). It has been
demonstrated that DARTEL achieves a better normalization both
in healthy volunteers (Klein et al. 2009) and in patients with focal
lesion (Ripolles et al. 2012) than other methods. After segmen-
tation, a customized template was generated using the average
tissue probability maps across all patients, and each patient’s
segmented maps were warped into the template. This procedure
was repeated until a best study-specific template (Template_6)
was generated. A high quality DARTEL template was created,
which was free of contrast-enhancing effect (Supplementary
Figure S1). The images were then modulated by the Jacobian
determinants to ensure conservation of regional differences in the
absolute amounts of gray matter (GM). Registered images were
then transformed to Montreal Neurological Institute (MNI)
space. For each patient, the native tumor mask was spatially
normalized to standard MNI space by applying the deformation
field estimated in segmentation. All T1 images and tumor masks
were well normalized judged by visual inspection. All LGG (or
HGG) tumor masks in MNI space were then stacked together
and binarized to construct a tumor overlapping image (Fig. 1a),
in which each voxel was identified as part of the tumor region
from at least one patient.
Multivariate lesion‐language mappings
Multivariate lesion-language using SVR-LSM Due to the in-
herent limitations of univariate voxel-based lesion-behav-
ior mapping (VLSM) analysis (Bates et al. 2003; Mah
et al. 2014), here we adopted multivariate machine
learning-based lesion-symptom mapping, SVR-LSM
(Zhang et al. 2014). Rather than each isolated voxel,
SVR-LSM models the symptom relation to the entire le-
sion map using a nonlinear function, which intrinsically
considers the intervoxel correlations. SVR-LSM has been
shown to produce much higher sensitivity and specificity
for detecting lesion-behavior relationships than can be
achieved via the univariate method (Mah et al. 2014;
Yourganov et al. 2016; Zhang et al. 2014). SVR has been
widely used in imaging-based prediction analysis (Cui
and Gong 2018; Dosenbach et al. 2010; Yuan et al.
2017; Zhang et al. 2014). For a linear model, SVR can
be described as
Y ¼ !T ðXÞ þ b ð1Þ

Fig. 1 Lesion distributions and language performance of the 81 patients
with LGGs and the 56 patients with HGGs. a Lesion-frequency overlaps
of tumor location in MNI space. The color bar represents the number of
where X is the lesion patterns across patients, Y is a
network attribute, ð X Þ is the function transforming the
lesion patterns to higher dimensional feature space, ω =
(ω0, ω1, ω2, …) is the fitting coefficient (weight) in high
dimensional space, and b is the fitting error.
SVR-LSM uses libSVM (Chang and Lin 2011) (http://
www.csie.ntu.edu.tw/~cjlin/libsvm/) with epsilon-SVR
and a non-linear radial basis function (RBF) kernel. We
set gamma as 2 and cost (C) as 30 (i.e., the default pa-
rameters in the SVR-LSM). To ensure sufficient statistical
power (Kimberg et al. 2007; Sperber and Karnath 2017;
Brain Imaging and Behavior
patients with a lesion at a specific voxel. b The distributions of language
scores. SS: spontaneous speech; Com: comprehension. L, left; R, right
Winkler et al. 2014), only voxels lesioned in ≥ 10 patients
were included in the analysis. Each patient’s lesion-data
vector was normalized to have a unit norm that served as
a direct total lesion volume control (hereafter SVR-
LSM + dTLVC). For each language measure, a weight
map (the  -map) assessing the voxel-wise prediction
contribution was created by back-projection. One thou-
sand permutation tests were performed to create a proba-
bility map that inferred the regional lesion-behavior rela-
tionship. Significant results were those clusters of voxels
with uncorrected probability P < 0.001 and a false discov-
ery rate (FDR)-corrected P < 0.05.
Brain Imaging and Behavior

Deterministic tractography Table 1 Demographic information and language scores for the LGG
and HGG groups

For each brain region showed significant prediction in SVR- LGG (n=81) HGG (n=56) χ2 or t P value
LSM analysis, deterministic tractography was performed to ex-
plore the white matter tracks passing through it. The fiber track- Age 38.86±9.57 45.11±14.72 -3 0.003
ing utilized a publicly available group-averaged tractography Sex (M/F) 47/34 34/22 0.31 a 0.76 a
atlas, i.e., HCP-1065 atlas (WU-Minn HCP Consortium; - Education 10.79±4.05 10.93±4.43 -0.19 0.85
https://pitt.box.com/shared/static/ Tumor volume (cm3) 82.68±49.27 72.55±48.31 1.07 0.28
wzozvjxxudvyytnzm84ux5h3bx7d8kf9.gz). The HCP-1065 at- WHO grade I/II = 2/79 III/IV = 28/28 - -
las was constructed from 1065 subjects’ diffusion MRI data AQ 95.21±4.86 89.68±10.18 4.25 <0.001
from the Human Connectome Project (2017 Q4, 1200-subject Spontaneous speech 18.86±1.46 17.68±2.65 3.36 0.001
release; multi-shell diffusion scheme, b-values: 1000, 2000, Comprehension 222.25±13.05 210.30±25.91 3.56 <0.001
3000s/mm2; diffusion sampling directions: 90, 90, and 90; in- Repetition 96.72±6.63 93±11.25 2.42 0.017
plane resolution: 1.25 mm). The diffusion data were recon- Naming 94.02±5.51 85.46±13.85 5.03 <0.001
structed in the MNI space using q-space diffeomorphic recon- a
Pearson’s chi-square test
struction (Yeh and Tseng 2011) to obtain the spin distribution
function (Yeh et al. 2010). The analysis was conducted using
diagnosis of aphasia (Fig. 1b). Overall, patients with HGGs
DSI Studio (http://dsi-studio.labsolver.org). For reproducibility
had significantly lower AQ scores (two sample t-test, t
problem in tractography, a combination of fiber tracking
(135) = 4.25, P = 4 × 10− 5), spontaneous speech scores (two
parameters within a working range (anisotropy threshold: 0.5–
sample t-test, t (135) = 3.36, P = 1 × 10− 3), comprehension
0.7; angular threshold: 15–90°; step size: 0.5–1.5 voxel
scores (two sample t-test, t (135) = 3.56, P = 5.3 × 10− 4), rep-
distance) was used. The identified tracks were automatically
etition scores (two sample t-test, t (135) = 2.43, P = 0.017) and
labeled (Yeh 2020). Moreover, automatic fiber tracking was
naming scores (two sample t-test, t (135) = 5.03, P = 1.5 × 10−
also performed when placing no target region. We then quan- 6
) than those with LGGs. The frequency distributions of the
tified the ratio of tracks passing through the target region and
five ABC scores are shown in Fig. 1b.
the total number of tracks of a specific white matter pathway.
To determine whether the language differences between
LGG and HGG groups were due to the age difference or any
The effects of covariates on the lesion‐language
collection site effect, we performed two-sample t-test for each
mappings
language test and added age, sex, education, tumor volume,
and collection site as covariates. After controlling for these
To investigate the reproducibility of the main findings, we
potentially confounding factors, we found that the AQ (t
regressed out patients’ age, sex, education and the imaging
(130) = 3.50, P = 6.26 × 10− 4), spontaneous speech (two sam-
collection site from each language test and reperformed the
ple t-test, t (130) = 2.43, P = 0.016), comprehension (t (130) =
SVR-LSM + dTLVC analyses.
3.19, P = 0.002), and naming (t (130) = 4.27, P = 3.67 × 10− 5)
scores were still significantly lower in the HGG group.
Results
Lesion anatomy
Language deficits in patients with LGGs and HGGs
Tumor locations for both groups were primarily distributed in
We found no significant differences in sex, education, or tu- the left frontal, temporal, insular, and subcortical regions
mor volume between the LGG and HGG groups (Table 1). (Fig. 1a). LGGs were most often in the left insula (N = 32),
The HGG group was significantly older than the LGG group while HGGs were most often in the left superior temporal
(two sample t-test, t (135) = -3, P = 0.003). We also found that gyrus (STG, N = 21).
age showed statistically significant correlations with language
scores for both the LGG and HGG groups (Supplementary Results of lesion‐language mapping by SVR-LSM +
Table S1). Education showed statistically significant correla- dTLVC
tions with language scores in the HGG group. Additionally,
we found no significant correlation between tumor volume No significant results were observed for the LGG group. In
and language scores in either LGG or HGG group (rs < 0.15). contrast, HGG tumor damage (Fig. 2a) in the left posterior
Regarding the five ABC scores, about 21 % (17/81) of middle temporal gyrus (pMTG) was associated with deficits
those with LGGs and 50 % (28/56) of those with HGGs had in spontaneous speech (cluster size = 1356 mm 3, FDR-
AQ scores less than 93.8—which is the clinical criterion for a corrected, P < 0.05) and naming (cluster size = 1491 mm3,

Fig. 2 Multivariate lesion-language results for the HGG group. a Tumor
damage in the left posterior middle temporal gyrus significantly (FDR-
corrected, P < 0.05) predicted deficits in spontaneous speech (SS) and
naming scores. Each map shows the  -values identified by SVR-
LSM + DTLVC and the p-values obtained from 1000 permutation tests.
FDR-corrected, P < 0.05). The volume of overlapped voxels
of the two clusters was 1026 mm3.
Automatic fiber tracking on tractography atlas showed that
five association or projection pathways passed through the
two identified clusters: arcuate fasciculus (the percentage of
tracks passing through a target region and the total tracks of a
specific white matter pathway, spontaneous speech: 46/
1073 = 4.3 %; naming: 71/1073 = 6.6 %), inferior fronto-
occipital fasciculus (spontaneous speech: 303/650 = 46.6 %;
naming: 448/650 = 68.9 %), and inferior longitudinal fascicu-
lus (spontaneous speech: 2029/2574 = 78.8 %; naming:
2236/2574 = 86.9 %), middle longitudinal fasciculus (sponta-
neous speech: 138/142 = 97.2 %; naming: 129/142 = 90.9 %)
and the posterior part of corticostriatal pathway (spontaneous
speech: 126/906 = 13.9 %; naming: 136/906 = 15 %).
After regressing out sex, age, education and imaging cen-
ters from the language scores, no significant results were ob-
served for the LGG group and very similar results were ob-
served for spontaneous speech and naming deficits of HGG
group (Supplementary Figure S2).
Discussion
We performed lesion-language mapping to identify the struc-
tural basis of language deficits in patients with left hemispher-
ic gliomas. Most patients with LGGs (> 80 %) had nearly
normal language function, and their language deficits could
not be predicted by lesion topography. The weak brain-
symptom relationship suggested a good amount of functional
reorganization of the cortex. Patients with HGGs exhibited
Brain Imaging and Behavior
b The left posterior middle temporal gyrus is located in the white matter
confluence of the arcuate fasciculus (AF), inferior fronto-occipital fascic-
ulus (IFOF), inferior longitudinal fasciculus (ILF), middle longitudinal
fasciculus (MdLF) and the posterior part of corticostriatal pathway. L,
left; R, right
more severe language impairments than those with LGGs.
Tumor location in the left posterior middle temporal gyrus
was significantly associated with spontaneous speech and
naming scores in those with HGGs. These findings suggest
different types of structural plasticity underlie different de-
grees of behavioral impairments in cases of LGG and HGG.
To our knowledge, this is the first investigation that has clar-
ified tumor grade-related macrostructural plasticity, based on
a large cohort of patients with glioma within the brain’s lan-
guage network.
The weak brain-symptom relationship in the LGG
group suggests large amounts of functional
reorganization
The negative results from the lesion-language analyses for the
LGG group might have resulted from a great deal of function-
al reorganization. For example, task-based functional MRI
(fMRI) studies have shown that preoperative patients with
LGGs that infiltrated classical Broca’s, Wernicke’s, or insular
areas exhibited a redistribution of compensatory activations in
perilesional, remote ipsilesional, and contralesional
homotopic language-related areas. Further, they showed only
slight dysphasia (Benzagmout et al. 2007; Duffau 2005, 2012;
Duffau et al. 2001; Duffau and Taillandier 2015; Robles et al.
2008; Sarubbo et al. 2012). Similarly, a recent study has
shown no significant difference in fMRI activation levels on
a picture naming task between preoperative patients with left
cerebral LGGs in the language network and control partici-
pants (Deverdun et al. 2019). Structurally, slowly progressive
glioma infiltration usually induces marked structural changes
Brain Imaging and Behavior
(Almairac et al. 2018; Desmurget et al. 2007; Zhang et al.
2018). Moreover, even though both groups of patients in the
current study had tumor damage in the left pMTG, a bottle-
neck where both dorsal and ventral language pathways travel
(Fig. 2), the significant lesion-language association was only
observed in the HGG group. Surgical neuro-oncological stud-
ies have shown that preoperative patients with LGGs that
infiltrate classical Broca’s, Wernicke’s, or insular areas could
be resected without inducing permanent deficits (Duffau
2005, 2012; Lu et al. 2013; Picart et al. 2018). Thus, in cases
of LGG, marked structural and functional changes occur as a
means of compensating for the loss of function caused by
tumor damage. This could explain the absence of cognitive
deficits and the weak brain-symptom relationship that we ob-
served here.
The macrostructural bases of language impairments
in patient with HGGs
Converging evidence has shown that language processing re-
cruits delocalized but structurally and functionally connected
left lateralized cortico-subcortical areas (Cui et al. 2018;
Duffau et al. 2014; Fedorenko and Thompson-Schill 2014;
Wu et al. 2015; Xu et al. 2016) and damage to these gray
matter (Ramsey et al. 2017; Siegel et al. 2016) or the white-
matter tracts that connect them (Fang et al. 2015; Griffis et al.
2017; Yourganov et al. 2016) highly predict language deficits.
However, our lesion-language mapping analysis showed that
only the posterior MTG (pMTG) is associated with spontane-
ous speech and naming deficits in people with HGGs.
Functional neuroimaging studies have shown that the
left pMTG is consistently activated in phonological, se-
mantic, and sentence tasks (Binder 2017; Vigneau et al.
2006). Diffusion tensor imaging studies have shown that
multiple long-range fiber pathways (Turken and Dronkers
2011), including dorsal (arcuate fasciculus) and ventral
(inferior longitudinal fasciculus, middle longitudinal fas-
ciculus and inferior fronto-occipital fasciculus) language
pathways (Kummerer et al. 2013; Saur et al. 2008) tra-
verse this region (Fig. 2b). Additionally, a functional net-
work study has shown that the left pMTG connects the
left frontoparietal network with the left perisylvian net-
work (Xu et al. 2016). Intraoperative electrocortical stim-
ulation of the left pMTG and its underlying white matter
pathways induces language deficits, which has been
regarded it as a non-resectable area (Duffau et al. 2014;
Ius et al. 2011; Sanai et al. 2008; Wu et al. 2015). Our
results are also highly consistent with findings in patients
with chronic left hemispheric stroke, which showed that
damage to the left pMTG and its traversing fibers tracts
induced multiple language deficits (Corbetta et al. 2015;
Griffis et al. 2017; Ivanova et al. 2016), including com-
prehension (Dronkers et al. 2004; Geva et al. 2012;
Henseler et al. 2014; Pustina et al. 2016; Yourganov
et al. 2016), naming (Baldo et al. 2013; Harvey and
Schnur 2015; Henseler et al. 2014; Pustina et al. 2016;
Yourganov et al. 2016), repetition (Butler et al. 2014;
Henseler et al. 2014; Pustina et al. 2016; Yourganov
et al. 2016), and phonology (Butler et al. 2014), as well
as poor language recovery (Bonilha et al. 2016;
Fridriksson 2010; Ramsey et al. 2017). Taken together,
our findings suggest that damage in the left pMTG caused
by HGGs disrupts the signaling in dorsal and ventral lan-
guage processing streams and the deficits in speech pro-
duction cannot be compensated for due to the rapid glio-
ma infiltration.
Limitations
This study has several limitations. First, the sample sizes of the
two groups were relatively small and cannot fully represent the
entire spectrum of patients. This might also affect the model
accuracy and stability (Cui and Gong 2018; Sperber et al.
2019). A large sample size from more centers is needed to in-
crease representativeness and better test the reliability of the find-
ings to independent datasets. Moreover, to ensure the statistical
power, only voxels lesioned in ≥ 10 patients were considered.
The functional relevance of those voxels lesioned in < 10 patients
or intact brain regions need to be clarified in the future study.
Second, although we speculate that the negative results for
LGGs might have been due to sufficient structural and func-
tional compensation, we did find that 20 % of the LGG groups
had aphasia. There were also aphasia HGG patients whose
tumor spare the left pMTG. The aberrant structural and func-
tional brain patterns for these patients, especially the remote
functional and structural disconnection (Boes et al. 2015;
Foulon et al. 2018), underlying insufficient plasticity must
be clarified in the future study.
Third, lesion-language mapping analysis only account for the
tumor infiltration effect. Gliomas cause symptoms through a
combination of mass effect on the surrounding brain tissue and
direct infiltration of the brain tissue. Thus, longitudinal behaviour
and multimodal neuroimaging data are needed to fully under-
stand the neural mechanisms underlying glioma aphasia.
Conclusions
The present study found that tumor damage in the left pMTG,
which is located in the white matter confluence of dorsal and
ventral language pathways, was significantly associated with
the spontaneous speech and naming deficits exhibited by pa-
tients with HGGs. The negative results for the lesion-language
mapping in the LGG group suggest sufficient functional
compensation.

Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s11682-021-00457-0.
Abbreviations LGG, low-grade glioma; HGG, high-grade glioma;
ABC, Aphasia Battery of Chinese; AQ, aphasia quotient; SS, spon-
taneous speech
Acknowledgements The authors wish to thank Dr. Xiuyi Wang and
Jianfeng Zhang for their advice in drafting the manuscript.
Author contributions Conception and study design (JSW and JLC), data
collection or acquisition (NZ, JFL and JY), statistical analysis (BKY),
interpretation of results (NZ, BKY, JSW and JFL), drafting the manu-
script work or revising it critically for important intellectual content (NZ,
BKY and JFL) and approval of final version to be published and agree-
ment to be accountable for the integrity and accuracy of all aspects of the
work (All authors).
Funding This work was supported by the Shenzhen Double Chain Grant
[2018]256, the Fundamental Research Funds for the Central Universities
(No. WK9110000133), Guangdong Key Basic Research Grant (No.
2018B030332001), Guangdong Pearl River Talents Plan (No.
2016ZT06S220), China Postdoctoral Science Foundation (No.
2018M640825), National Natural Science Foundation of China (No.
81401395, No.82001794), Natural Science Foundation of Anhui
Province (No. 2008085QH380), Shanghai Young Talents in Health
(No. 2017YQ014), Key Program of Medical Science and Technique
Foundation of Henan Province (No. SBGJ202002062), the Joint
Construction Program of Medical Science and Technique
Foundation of Henan Province (No. LHGJ20190156), Research
Projects of Henan Higher Education (No.18A320077), the Scientific
and Technological Research Projects of Henan Province
(No.192102310123). J.S.W is supported by Shanghai Municipal
Science and Technology Major Project (No. 2018SHZDZX03) and ZJ
Lab. The funding agencies took no part in the design or implementation
of the research.
Declarations All processes strictly followed the requirements of the
Declaration of Helsinki. This study was approved and supervised by the
Ethics Committees of Huashan Hospital and First Affiliated Hospital of
Zhengzhou University. Written informed consent was obtained from the
legal guardians of all patients.
Competing financial interests The authors declare no competing finan-
cial interests.
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