Brain & Language 110 (2009) 71–80

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Brain & Language
journal homepage: www.elsevier.com/locate/b&l

Regular Article

Agrammatic comprehension caused by a glioma in the left frontal cortex
Ryuta Kinno a,b,c, Yoshihiro Muragaki d, Tomokatsu Hori d, Takashi Maruyama d, Mitsuru Kawamura b,c,
Kuniyoshi L. Sakai a,c,*a

Department of Basic Science, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan
Department of Neurology, Showa University School of Medicine, Hatanodai, Tokyo 142-8666, Japanc
CREST, Japan Science and Technology Agency, Kawaguchi-shi 332-0012, Japand
Department of Neurosurgery, Tokyo Women’s Medical University, Kawadacho, Tokyo 162-8666, Japanba r t i c l e

i n f oArticle history:
Accepted 6 May 2009
Available online 2 July 2009
Keywords:
Language
Sentence processing
SyntaxAgrammatism
The frontal cortex
VLSM

a b s t r a c t
It has been known that lesions in the left inferior frontal gyrus (L. IFG) do not always cause Broca’s aphasia, casting doubt upon the speciﬁcity of this region. We have previously devised a picture–sentence
matching task for a functional magnetic resonance imaging (fMRI) study, and observed that both pars triangularis (L. F3t) of L. IFG (extending to pars opercularis (L. F3op)) and the left lateral premotor cortex (L.
LPMC) are selectively involved in syntactic processing. The present study with lesion-symptoms mapping
was conducted to examine whether the function of these regions is indeed critical for syntactic comprehension. Using the same picture–sentence matching task, we examined 21 patients with a glioma in theleft frontal cortex but with no apparent disability in verbal/written communication or intelligence quotient. This task included three main conditions of sentence types: canonical/subject-initial active sentences, non-canonical/subject-initial passive sentences, and non-canonical/object-initial scrambled
sentences. The patients preoperatively underwent a high-resolution 3D-MRI, and voxel-based lesionsymptom mapping was employed for the error rates data. We found that the patients with a lesion in
L. F3op/F3t or L. LPMC showed differential patterns of condition-selective deﬁcits in the comprehensionof sentences. More speciﬁcally, the L. F3op/F3t-damaged patients had more profound deﬁcits in the comprehension of non-canonical sentences, whereas the L. LPMC-damaged patients had more profound deficits in the comprehension of object-initial scrambled sentences. These results establish that a lesion in L.
F3op/F3t or L. LPMC is sufﬁcient to cause agrammatic comprehension.
Ó 2009 Elsevier Inc. All rights reserved.

1. Introduction
Since the ﬁrst report of an aphasic patient by Paul Broca in 1861
(Broca, 1994; Signoret, Castaigne, Lhermitte, Abelanet, & Lavorel,1984), the localization and lateralization of human language havebeen major issues in neurology, neuropsychology, and neurolinguistics. Broca’s aphasia is characterized by non-ﬂuent spontaneous speech with relative sparing of comprehension (Mesulam,
2000; Ingram, 2007), and is generally associated with damage tothe pars opercularis (F3op, Brodmann area (BA) 44) and pars triangularis (F3t, BA 45) of the left inferior frontal gyrus (L. IFG). Some
previous studies, however, have indicated that damage to L. IFG
does not always cause traditional Broca’s aphasia (Mohr et al.,
1978; Kertesz, Harlock, & Coates, 1979), and the left insula has
been proposed to be a crucial region for articulation deﬁcits(Dronkers, 1996). On the other hand, patients with lesions in* Corresponding author. Address: Department of Basic Science, Graduate Schoolof Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo
153-8902, Japan. Fax: +81 3 5454 6261.
E-mail address: sakai@mind.c.u-tokyo.ac.jp (K.L. Sakai).
0093-934X/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.bandl.2009.05.001

L. IFG show relatively good comprehension of single words andsimple sentences, but show trouble understanding sentences withmore complex syntactic structures, such as passive sentences andsentences with object relative clauses (Schwartz, Saffran, & Marin,
1980; Caplan, Baker, & Dehaut, 1985; Grodzinsky, 2000); this aspect of Broca’s aphasia is called agrammatic comprehension(Goodglass & Menn, 1985; Menn & Obler, 1990; Pulvermüller,
1995). However, methodological problems have been raised(Badecker & Caramazza, 1985), and general processes of shortterm memory or decision-making have been proposed to be disrupted in agrammatic comprehension (Just & Carpenter, 1992;
Cupples & Inglis, 1993; Dick et al., 2001). Thus, speciﬁcity or reproducibility for agrammatic comprehension remains unclear andcontroversial. The present lesion study was motivated to examineand establish the presence of agrammatic comprehension.
Despite accumulating results from functional magnetic resonance imaging (fMRI) studies, it has also been far from conclusive
whether L. IFG activation is due to any speciﬁc factors: e.g., syntactic processing (Dapretto & Bookheimer, 1999; Embick, Marantz,
Miyashita, O’Neil, & Sakai, 2000), articulatory rehearsal (Cohenet al., 1997), and short-term memory demands (Fiebach,

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R. Kinno et al. / Brain & Language 110 (2009) 71–80

Schlesewsky, Lohmann, von Cramon, & Friederici, 2005). We havepreviously reported that both the left dorsal F3op/F3t (L. dF3op/
dF3t) and lateral premotor cortex (L. LPMC) are selectively involved in syntactic judgment of sentences, even when comparedwith high-load verbal short-term memory (Hashimoto & Sakai,2002), indicating the critical role of these left frontal regions insyntactic processing (Sakai, 2005). In our recent fMRI study witha picture–sentence matching task, we further examined the effectof sentence structures strictly controlling general cognitive
demands such as the memory load (Kinno, Kawamura, Shioda, &Sakai, 2008), where a sentence was visually presented with a picture representing an action (Fig. 1; the same task and stimuli wereused in the present study). The participants indicated whether or
not the meaning of each sentence matched the action depictedby the corresponding picture. There were three main conditions
with different sentence types: canonical/subject-initial active sentences (AS) (e.g., ‘‘s-ga h-o oshiteru”, ‘‘s pushes h”), non-canonical/subject-initial passive sentences (PS) (e.g., ‘‘h-ga s-ni
osareru”, ‘‘h is affected by s’s pushing it”; see Kinno et al. (2008)
for ni direct passive form), and non-canonical/object-initial scrambled sentences (SS) (e.g., ‘‘h-o s-ga oshiteru”, ‘‘as for h, s pushesit”; this form is allowed not only in Japanese but in German, Finnish, and other languages). Under these conditions, each sentence
had a transitive verb and two arguments (phrases associated withthe predicate) with different grammatical relations, i.e., which
the subject (S) of a verb (V) is, and which its indirect object (IO)
or direct object (DO) is. Sentence comprehension under each condition also explicitly required analysis of two different thematicroles, i.e., who initiates the action, and who is affected by it. In Japanese syntax, the grammatical relations are ﬁrst marked by casemarkers (nominative, dative, or accusative in the present stimuli;
Fig. 1), which in turn allow the assignment of thematic roles (agent,experiencer, or patient), whereas passiveness is also marked in theverb morphology (-areru). More speciﬁcally, the AS, PS, and SS sentences correspond to S–DO–V (agent and patient), S–IO–V (experiencer and agent), and DO–S–V (patient and agent) types,
respectively. Therefore, these syntactic analyses for the two-argument relationships were critically required in our paradigm. In thefMRI study, we observed that activations in L. dF3t (extending to
L. F3op) and L. LPMC were differentially modulated by these threemain conditions. Because it is essential to correlate activation studies with the detailed analysis of lesion symptoms (Rorden &Karnath, 2004), our next goal was to directly clarify the functionalroles of these two left frontal regions with a lesion-symptom mapping method. Based on the results from the previous neuroimaging
studies, we predicted that the patients with a lesion in L. F3op/F3t
or L. LPMC would show agrammatic comprehension.
We examined patients with a glioma especially in the left frontal cortex. The tumor locations covered the most of the left frontal
regions and thus included L. F3op/F3t and L. LPMC. To examine thepresence of agrammatic comprehension, it is crucial to use a taskthat is sensitive enough to extract syntactic components of linguistic judgment among the tested conditions. If such a task is effective
enough, we expected that even the patients without apparent disabilities in verbal communication or intelligence would show condition-selective agrammatic comprehension. Our paradigm withthree distinct syntactic conditions of AS, PS, and SS would be ideal
for this purpose, because the same set of actions depicted by pictures was used under the main conditions, thus controlling semantic comprehension per se. Moreover, the contrasts among thesethree conditions differentially modiﬁed the activations of L. F3op/
F3t and L. LPMC, with their respective contributions dynamicallyregulated by linguistic requirements (Kinno et al., 2008). To precisely localize the glioma, all patients underwent a high-resolution
3D-MRI on the same day as the task examination. All of theseresults were actually utilized for the preoperative evaluation ofFig. 1. The three main conditions used in the picture–sentence matching task. Eachstimulus consisted of one picture (top) and one sentence (bottom). Pictures
depicting actions consisted of two stick ﬁgures; each stick ﬁgure was distinguishedby one of three ‘‘head” symbols: a circle (s), square (h), or triangle (D). The
participants indicated whether or not the meaning of each sentence matched theaction depicted in the corresponding picture by pressing one of two buttons. (A)Under the active sentence (AS) condition, canonical/subject-initial active sentenceswere presented (‘‘s-ga h-o oshiteru”). Below each example, a word-by-wordtranslation in English is shown. Nom, nominative case; Acc, accusative case; Dat,dative case. (B) Under the passive sentence (PS) condition, non-canonical/subjectinitial passive sentences were presented (‘‘h-ga s-ni osareru”). (C) Under thescrambled sentence (SS) condition, non-canonical/object-initial scrambled sentences were presented (‘‘h-o s-ga oshiteru”). An identical picture set was used
under these three conditions. The sentence stimuli were all grammatical andcommonly used in Japanese.

detailed language function and for planning a resection of glioma,
thereby minimizing the risk of postoperative language deﬁcits(Haglund, Ojemann, & Hochman, 1992). Because neurological data
about the real roles of the left frontal regions in syntactic comprehension have been limited, the present examination would haveboth fundamental and clinical implications, which are useful forpreserving the quality of life (QOL) for each patient.

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R. Kinno et al. / Brain & Language 110 (2009) 71–80

2. Subjects and methods

2.2. Stimuli

2.1. Participants

Each visual stimulus consisted of a picture at the top and a Japanese sentence at the bottom (Fig. 1). The pictures used for AS, PS,
and SS were identical (the number of lines used in each picture,mean ± SD: 14 ± 2.4, n = 6). There was one sentence control (SC)condition with intransitive verbs (e.g., ‘‘h-to D-ga hashitteru”, ‘‘hand D run”) and equally complex pictures (14 ± 2.5, n = 6), whichwere all different from those used under the three main conditions.
Half of the pictures depicted action occurring from left to right, andthe other half depicted action from right to left. In the pictures, theuse of symbols was also counterbalanced for both sides withineach condition.
The sentences describing actions were written in a combinationof the ‘‘hiragana” and ‘‘kanji” writing systems, and all sentence
stimuli were grammatical in Japanese. Each sentence included
two noun phrases and one verb; for example, a noun phrase(h-ga) consisted of a symbol (h) and a hiragana (ga). Two sets ofJapanese verbs (six transitive verbs: pull, push, scold, kick, hit, andcall; and six intransitive verbs: lie, stand, walk, run, tumble, andcry) were used, each of which, including the passive forms, had
either four or ﬁve syllables. Note that the verb ‘‘call” is used only
as a transitive verb in Japanese. There was no signiﬁcant differencein frequency between the two sets of verbs (t (10) = .7, p = .5),
according to the Japanese lexical database (‘‘Nihongo-no Goitokusei” (Lexical Properties of Japanese), Nippon Telegraph and Telephone Corporation Communication Science Laboratories, Tokyo,
Japan, 2003). We prepared eight stimuli for each verb; there were
48 stimuli for each condition.
All stimuli were presented visually in yellow against a dark
background. Each stimulus was presented for 5800 ms followed
by a 200 ms blank interval, which was ample time for the patients(see Table 2). For ﬁxation, a red cross was also shown at the centerof the screen. Stimulus presentation and behavioral data collection
were controlled using the LabVIEW software and interface(National Instruments, Austin, TX, USA).

All patients were native Japanese speakers newly diagnosed ashaving a glioma in the left frontal region, who were scheduled
for surgery at the Department of Neurosurgery of Tokyo Women’s
Medical University. The following conditions comprised the criteria for inclusion of patients in the present study: (i) right-handedness, (ii) no deﬁcits in verbal/written communication or othercognitive abilities reported by the patients or physicians, (iii) no
history of neurological or psychiatric disorders other than glioma
and seizures, (iv) freedom from seizures with or without antiepileptic drug, and (v) no medical problems for MRI acquisition.
Twenty-one patients (Table 1) preoperatively underwent a highresolution MRI scan and performed the picture–sentence matchingtask at the University of Tokyo, Komaba. The laterality quotient(LQ) was also determined by the Edinburgh handedness inventory(Oldﬁeld, 1971). The verbal/non-verbal intelligence quotient (IQ)
was assessed with the Japanese version of the WAIS-III (1997,
2006; Harcourt Assessment, Inc., San Antonio, TX, USA), including
more general and demanding tests than the aphasic tests. All but
one patient underwent amytal testing. Following injection of amytal, the patient counted numbers with both hands raised. As soon
as the contralateral hemiplegia occurred, a picture naming task
was used to determine hemispheric dominance, which was either
left or bilateral. The tumor type and grade were postoperatively
and pathologically diagnosed by the WHO Classiﬁcation of Tumorsof the Nervous System (2000). Using the same paradigm andparameters, we also tested 21 right-handed participants with nohistory of neurological or psychiatric disorders. These age-matchednormal controls included 12 males and 9 females (age: 20–58;
mean: 37 years). Informed consent was obtained from each participant after the nature and possible consequences of the studies
were explained. Approval for the experiments was obtained fromthe institutional review board of the University of Tokyo, Komaba.

Table 1
Characteristics of patients in the present study.
Patient

Verbal/non-verbal IQ

Hemispheric dominanceTumor location

Tumor volume

Tumor type

Tumor grade

L. F3op/F3t-damaged patients
PT1
F
42
90
PT2
M
29
100
PT3
F
38
87
PT4
F
34
75
PT5
M
47
73

GenderAge

LQ

95/10994/100111/116
101/9693/100

Left
Left
Left
Left

L. F2/F3op/F3t/F3O/insula
L. F2/F3op/F3t/insula/striatum
L. F3op/F3t/F3O/insula/striatum
L. F3op/F3t/F3O/insula/striatum
L. F3op/F3t/insula/striatum

74,524
122,535
48,90132,353
18,107

OA
AOA
OD
OD
DA

II
III
II
II
II

L. LPMC-damaged patients
PT6
M
47
PT7
M
36
PT8
M
35
PT9
F
27
PT10
M
36
PT11
M
36

81
88
89
45
89
100

105/102
102/92
97/94
101/95
109/98
84/92

Left
Left
Left
Left
Left
Left

L. F1/F2/SMA/LPMC/F3op
L. F1/SMA/F2/LPMC/F3op
L. F1/SMA/F2/LPMC/F3op
L. F2/LPMC/F3op
L. F2/LPMC/F3op
L. LPMC/F3op/insula

33,13989,17287,331
22,497
17,94831,055

AOA
AA
PNET
DA
AOA
DA

III
III
IV
II
III
II

Other patients
PT12
M
PT13
F
PT14
M
PT15
F
PT16
F
PT17
F
PT18
M
PT19
M
PT20
M
PT21
F

25
62
24
38
29
31
31
49
32
36

100
89
89
100
100
100
100
100
100
100

99/101
98/101
115/97106/11386/88
106/100
97/98
105/100
90/99
84/88

Left
Left
Left
Left
Left
Left
Left
Left
Left
Bilateral

L. F1/SMA
L. F1/F2/SMA
L. F1/F2/SMA/striatum
L. F1/F2/striatum
L. F1/F2/F3t/F3O/striatum
L. F1/F2/F3t
L. F1/F2
L. F3t/F3O/insula/striatum
L. F3O/insula/striatum
L. F3O/striatum

30,86349,285
143,361
151,819
48,90145,381
24,92015,25527,35817,710

OA
AOD
OA
AOA
AOD
DA
AOA
AOA
OA
OA

II
III
II
III
III
II
III
III
II
II

Mean

36

90

99/99

53,925
3

Normalized images were used for determination of tumor location and volume (mm ). IQ, intelligence quotient; LQ, laterality quotient. The determination of tumor types andgrades (I–IV, IV as severest) was based on the WHO Classiﬁcation of Tumors of the Nervous System (2000). Abbreviations used: AA, anaplastic astrocytoma; AOA, anaplastic
oligoastrocytoma; AOD, anaplastic oligodendroglioma; DA, diffuse astrocytoma; OA, oligoastrocytoma; OD, oligodendroglioma; PNET, primitive neuroectodermal tumor.

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R. Kinno et al. / Brain & Language 110 (2009) 71–80

2.3. Tasks
In the picture–sentence matching task (Fig. 1), the participants
read a sentence silently and indicated whether or not the meaningof each sentence matched the action of the corresponding pictureby pressing one of two buttons. For AS, PS, and SS, all mismatchedsentences were made by exchanging two symbols in the original
sentences, e.g., ‘‘h pushes s” instead of ‘‘s pushes h”. For SC, symbol-mismatched and action-mismatched sentences were presented equally often, requiring the sentences to be readcompletely in order for the participants to arrive at a correct
judgment.
In addition to the picture–sentence matching task, we used a visual control task (VC), which required neither word nor sentence
processing, as a baseline condition (Kinno et al., 2008). For VC,
the same sets of pictures used in the picture–sentence matchingtask were presented, together with a string of jumbled letters taken from a single sentence in which the symbols (s, h, or D)and ‘‘kanji” appeared at the same positions in the string as in the
picture–sentence matching task. The participants were asked tojudge whether or not all the symbols in a letter string were thesame as those in the picture, irrespective of the order of the symbols. The participants underwent practice sessions before testing tobecome fully familiarized with the tasks.
A single run of the testing sessions contained 24 ‘‘trial events” ofthe picture–sentence matching task (six times each for AS, PS, SS,
and SC), with variable inter-trial intervals of 6 and 12 s (one andtwo VC, respectively), pseudorandomized within a run. Since
meaningless letter strings were presented throughout VC while
sentences were presented only in the trial events, the participants
could switch from VC to the trial events according to the stimulus
type. The order of AS, PS, SS, and SC was pseudorandomized in eachrun to prevent any condition-speciﬁc strategy. Eight runs were

tested in a day per one participant. Half of the stimuli consistedof matched picture–sentence pairs (24 trials for each condition),and the other half consisted of mismatched pairs (24 trials for eachcondition). All patients underwent the testing sessions inside thescanner while they received three to six fMRI runs, and then they
completed the rest of the eight runs outside the scanner. Because
the number of fMRI runs was limited by the patients’ medical conditions, here we focused on the behavioral data and the anatomical
MRI scans alone. All of the behavioral data from normal controls
were acquired outside the scanner.
2.4. MRI data acquisition and analyses
The MRI scans were conducted on a 1.5 T scanner (Stratis II,
Premium; Hitachi Medical Corporation, Tokyo, Japan), and ahigh-resolution T1-weighted 3D image (repetition time: 30 ms,
acquisition time: 8 ms, ﬂip angle: 60°, ﬁeld of view: 192 
192 mm2, resolution: .75  .75  1 mm3) was acquired for each patient. The location of the glioma was ﬁrst identiﬁed on this MR image, and the glioma boundary was semi-automatically determinedusing MRIcro software (http://www.mricro.com/) (Rorden & Brett,2000). T2-weighted MR images (Department of Neurosurgery ofTokyo Women’s Medical University) and positron-emission
tomography (PET) data (Chubu Medical Center for Prolonged Traumatic Brain Dysfunction, Mino-Kamo-shi, Japan) were also used toassist the precise determination of the boundary. The circumscribed region of the glioma was then used as a blank mask to restrict the estimation of the normalization parameters to thehealthy tissue (cost-function masking; http://www.sph.sc.edu/
comd/rorden/mritut.html) (Brett, Leff, Rorden, & Ashburner,
2001). Individual brain images were then spatially normalized tothe standard brain space as deﬁned by the Montreal Neurological
Institute, which was resampled to 1  1  1 mm3 voxel size using

Table 2Behavioral data under each condition.
Participant

Error rates (%)
AS

RTs (ms)
PS

SS

SC

AS

PS

SS

SC

L. F3op/F3t-damaged patientsPT1
8.3 (4.2)
PT2
27.1 (25.0)
PT3
27.1 (29.2)
PT4
0 (0)
PT5
0 (0)

16.7 (25.0)
39.6 (33.3)
39.6 (29.2)
27.1 (25)
8.3 (8.3)

16.7 (25.0)
54.2 (58.3)
50.0 (54.2)
39.6 (45.8)
8.3 (8.3)

4.2 (4.2)
6.3 (4.2)
8.3 (12.5)
4.2 (4.2)
4.2 (4.2)

3512
2138
3269
3325
3673

3227
2203
3331
2439
3620

3657
2799
3073
2268
3642

2011
1831
2243
2305
3394

L. LPMC-damaged patients
PT6
12.5 (20.8)
PT7
16.7 (20.8)
PT8
14.6 (12.5)
PT9
0 (0)
PT10
27.1 (29.2)
PT11
8.3 (12.5)

12.5 (12.5)
6.3 (8.3)
16.7 (12.5)
0 (0)31.3 (29.2)
8.3 (8.3)

66.7 (70.8)
54.2 (58.3)
54.2 (58.3)
20.8 (16.7)
81.3 (79.1)
54.2 (54.2)

6.3 (4.2)
6.3 (8.3)
4.2 (4.2)
2.1 (0)8.3 (8.3)
0 (0)

4334
2971
2764
4048
2488
2944

4436
3030
3163
4154
2573
2420

4549
3093
3063
4248
2621
2647

2739
2486
2646
2945
1746
2043

Other patients
PT12
PT13
PT14
PT15
PT16
PT17
PT18
PT19
PT20
PT21

0 (0)
6.3 (8.3)
0 (0)
0 (0)
0 (0)
2.1 (0)4.2 (4.2)
14.6 (16.7)0 (0)6.3 (12.5)0 (0)6.3 (8.3)
0 (0)
0 (0)
0 (0)
6.3 (4.2)
14.6 (4.2)
16.7 (12.5)0 (0)6.3 (8.3)0 (0)6.3 (8.3)
0 (0)
0 (0)
0 (0)
4.2 (0)8.3 (12.5)
4.2 (0)0 (0)8.3 (8.3)

3436
3867
1759
2609
3867
3860
2702
3856
3410
2795

3567
4085
1848
2881
4085
3753
3128
4223
3263
2921

3420
3619
1749
2669
3619
4062
3326
4432
3312
2969

2047
3159
1322
2111
3159
2716
2153
2954
2642
2063

0 (0)
8.3 (8.3)
0 (0)
0 (0)
0 (0)
2.1 (4.2)
0 (0)14.6 (16.7)0 (0)6.3 (8.3)

Mean*

8.2 ± 9.7*

11.4 ± 12.9*

26.2 ± 26.3

4.1 ± 3.1

3220 ± 670

3255 ± 716

3278 ± 708

2415 ± 533

Controls

3.4 ± 4.2

3.5 ± 3.8

3.3 ± 4.4

3.2 ± 3.7

2958 ± 727

2998 ± 648

3123 ± 583

2114 ± 608

Error rates and RTs (for correct trials only) are shown as mean ± SD. The consistency between the error rates (%) of all trials (in 48 trials for each condition) and those ofmatched trials in brackets (in 24 trials for each condition) indicates similar errors in both matched and mismatched trials. Asterisks denote signiﬁcant differences between theperformances of the patients and normal controls at p < .05.

R. Kinno et al. / Brain & Language 110 (2009) 71–80

75

statistical parametric mapping SPM2 software (Wellcome Department of Cognitive Neurology, London, UK) (Friston et al., 1995)
on MATLAB (Math Works, Natick, MA, USA).
Using the resulting individually normalized images, we next
employed voxel-based lesion-symptom mapping (VLSM; http://
crl.ucsd.edu/vlsm) to analyse the relationship between glioma
location and the error rates on a voxel-by-voxel basis (Bateset al., 2003). The patients were divided into two groups according to whether they did or did not have a glioma including thatvoxel. The error rates for each condition or the difference in error rates between two conditions (e.g., PS AS) were then compared for these two groups by a t-test, in which the statisticalthreshold was set to p = .05 after correction for multiple comparisons using the false discovery rate (FDR). To minimize the effects of outlier observations, the voxels used in the VLSM
analysis were within the gliomas of at least two patients. Finally,
the result of VLSM was projected onto a standard brain using
MRIcro software.

3. Results
In our paradigm with three main conditions of AS, PS, and SS,
under which two-argument relationships were critically required(see the Introduction), the same set of actions depicted by pictures
was used, thus controlling semantic comprehension per se. In contrast, a different set of pictures were used under the SC condition(e.g., ‘‘h and D run”), which basically required matching between
words (symbols and verbs) and pictures alone, without syntactic
analyses for the two-argument relationships. Thus, the SC condition was syntactically less complex and easier to comprehend thanother conditions. It was therefore mandatory to analyse the threemain conditions and SC separately. Moreover, the analyses also
match with our fMRI study (Kinno et al., 2008), in which SC wasused as a separate control. In Sections 3.1–3.4, we focus on themain conditions of AS, PS, and SS, and the results of SC are presented in Section 3.5.
3.1. Behavioral analyses
The error rates for the patients and the normal controls areshown in Table 2. A repeated-measures analysis of variance (rANOVA) with two factors (group [patients and normal controls]  condition [AS, PS, and SS]) revealed signiﬁcant main effects of group(F(1, 40) = 12, p = .0011) and condition (F(2, 80) = 13, p < .0001),
as well as a signiﬁcant interaction of group by condition(F(2, 80) = 14, p < .0001). The patients showed signiﬁcantly higher
error rates than the normal controls for each of AS, PS, and SS (ttest; AS: t (40) = 2.1, p = .046; PS: t (40) = 2.7, p = .011; SS: t(40) = 3.9, p = .0003). According to paired t-tests on the three main
conditions, the patients’ error rates were signiﬁcantly higher for SS
than for AS and PS (AS: t (20) = 4.2, p = .0005; PS: t (20) = 3.4,
p = .0026), whereas there was no signiﬁcant difference between
AS and PS (t (20) = 1.9, p = .07). However, there was no signiﬁcantdifference among the normal controls’ error rates under the main
conditions (p > .7).
The reaction times (RTs) for the patients and the normal controls are also shown in Table 2. An rANOVA with two factors (group[patients and normal controls]  condition [AS, PS, and SS])
showed that neither a main effect of group (F(1, 40) = 1.3, p = .3)
nor that of condition was signiﬁcant (F(2, 80) = 2.3, p = .1), withno signiﬁcant interaction of group by condition (F(2, 80) = .66,
p = .5). There was no signiﬁcant difference in RTs between thesegroups for each condition (p > .1). According to paired t-tests on
the three main conditions, there was no signiﬁcant difference in
RTs of the patients (p > .4). The normal controls showed signiﬁ-

Fig. 2. Results from VLSM analyses for the three main conditions. (A–C) Brainregions identiﬁed by the VLSM analysis among the left frontal-damaged patients(n = 21) for AS, PS, and SS, respectively. The resultant t-map is projected on the left(L) lateral surface; the threshold was established at t > 2.0 (FDR corrected p < .05).

cantly longer RTs for SS than for AS (t (20) = 2.2, p = .044), whereas
there was no signiﬁcant difference between AS and PS, as well as
between PS and SS (p > .1). Because there was a signiﬁcant main effect of condition regarding the error rates, the error rates were better indicators than RTs for estimating condition-selective effects.
The error rates of the patients for the three main conditions(Table 2) were not signiﬁcantly affected by the picture–sentence
consistency, as indicated by the comparison (paired t-test, p > .1)
between matched (AS: 9.1 ± 10.5%; PS: 11.1 ± 11.2%; SS:
27.0 ± 27.8%) and mismatched trials (AS: 7.3 ± 9.6%; PS:
11.7 ± 15.4%; SS: 25.4 ± 25.4%). It should be noted that these significant errors were observed in spite of the patient’s normal verbal
and non-verbal IQs (Table 1; range: 84–116 within about 1 SD of± 15; one sample t-test for the difference from 100: verbal, t(20) = .56, p = .6 and non-verbal, t (20) = .65, p = .5). According tocorrelation analyses, the large individual differences for the threemain conditions (Table 2; note the larger SDs for the three main
conditions than for SC) could not be attributed to their ages,

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R. Kinno et al. / Brain & Language 110 (2009) 71–80

verbal/non-verbal IQs, or tumor volumes (p > .1). It is thus likelythat the tumor locations affected the actual performance of thethree main conditions.
3.2. VLSM analyses for each sentence condition
To identify any critical regions for the main conditions of AS, PS,
and SS, we ﬁrst conducted VLSM analyses, in which error rates foreach condition were evaluated among the left frontal-damaged patients (n = 21). We found that signiﬁcantly higher error rates for AS
were associated with lesions in L. IFG, including L. dorsal F3op/F3t,
as well as isolated lesions in L. LPMC (Fig. 2A). Moreover, signiﬁcantly higher error rates for PS were associated with lesions in
L. dorsal F3op/F3t, further extending to ventral F3op/F3t (Fig. 2B).
In contrast, signiﬁcantly higher error rates for SS were associatedwith lesions in L. LPMC alone (Fig. 2C). These results indicate thatboth of L. F3op/F3t and L. LPMC are the critical regions for AS, PS,
and SS.
3.3. VLSM analyses for non-canonical sentence conditions
Next we examined which regions were critically involved in thecomprehension of syntactically complex sentences. For this purpose, we conducted VLSM analyses, in which the difference in error
rates between the conditions of non-canonical vs. canonical sentences, i.e., PS AS or SS AS, was evaluated among the left frontal-damaged patients. We found that the signiﬁcantly larger
difference in PS AS was associated with lesions in L. ventral
F3op/F3t (Fig. 3A). Moreover, it is striking to note that L. ventral
F3op/F3t identiﬁed by the present study spatially overlapped with

L. dorsal F3t (extending to ventral F3op) reported by our fMRI
study in PS AS (Kinno et al., 2008). In contrast, we found thatthe signiﬁcantly larger difference in SS AS was associated withlesions in L. LPMC (Fig. 3B), which spatially overlapped with L.
LPMC reported previously by our fMRI study in SS AS (Kinno
et al., 2008). These results indicate that both of L. F3op/F3t and L.
LPMC are critically involved in the comprehension of syntacticallycomplex sentences.
3.4. Condition-selectivity in error rates for L. F3op/F3t- or L. LPMCdamaged patients
We further examined the condition-selectivity in error rates forthe patients, who were divided into three groups based on tumor
locations (Table 1): L. F3op/F3t-damaged patients (n = 5; Fig. 4A),
L. LPMC-damaged patients (n = 6; Fig. 4C), and other patients(n = 10; Fig. 4E). Its criterion was whether or not a glioma of eachpatient overlapped, at least partially on a voxel-by-voxel basis,
with the region identiﬁed by the VLSM analyses in PS AS or
SS AS (red to orange region in Fig. 3A or B). The other patients
had a glioma in either L. F1 or L. F3O, but sparing L. F3op and L.
LPMC (Table 1). One patient of this group (PT19 in Table 2) showednon-selective deﬁcits for all of AS, PS, and SS. When the fMRI
results in PS AS or SS AS (blue region in Fig. 3A or B) were used
to assign the patient groups, the three patient groups of all but one
patient (PT10) were identical to those determined by the VLSM
results; the glioma of this patient overlapped with functionallydetermined L. F3op/F3t and L. LPMC. It is notable that this patient
showed the severest deﬁcits under the three main conditions(Table 2).

Fig. 3. Results from VLSM analyses for non-canonical sentence conditions. (A) Brain regions identiﬁed by the VLSM analysis among the left frontal-damaged patients (n = 21)
in PS AS. The resultant t-map is projected on the left (L) lateral surface. The axial slices demonstrate the spatial overlap between L. F3op/F3t identiﬁed by the present study(red to orange) and that reported by our fMRI study in PS AS (blue) (Kinno et al., 2008). (B) Brain regions identiﬁed by the VLSM analysis in SS AS. The axial slices
demonstrate the spatial overlap between L. LPMC identiﬁed by the present study (red to orange) and that reported by our fMRI study in SS AS (blue) (Kinno et al., 2008).

R. Kinno et al. / Brain & Language 110 (2009) 71–80

77

Fig. 4. Condition-selectivity in error rates for L. F3op/F3t- or L. LPMC-damaged patients. (A, C, and E) The lesion overlap map in the L. F3op/F3t-damaged patients (n = 5), the L.
LPMC-damaged patients (n = 6), and the other patients (n = 10), respectively (Table 1). The color scale denotes the number of patients. (B, D, F, and G) Histograms for the error
rates of the L. F3op/F3t-damaged patient, the L. LPMC-damaged patients, the other patients, and the normal controls (n = 21), respectively. Error bars indicate the SEM, andasterisks denote p < .05.

The error rates of each of the three groups are shown in Fig. 4B,
D, and F; those of the normal controls are shown in Fig. 4G. An
rANOVA with two factors (group [L. F3op/F3t-damaged patients,
L. LPMC-damaged patients, and other patients]  condition [AS,PS, and SS]) revealed signiﬁcant main effects of group(F(2, 18) = 11, p = .0006) and condition (F(2, 36) = 88, p < .0001),
as well as a signiﬁcant interaction of group by condition(F(4, 36) = 39, p < .0001). These results suggest that these threegroups can be characterized by condition-selectivity in error rates.
For the L. F3op/F3t-damaged patients, paired t-tests among
the three main conditions showed that these patients’ error rates
were signiﬁcantly higher for PS and SS than AS (PS vs. AS: t(4) = 4.1, p = .015; SS vs. AS: t (4) = 3.6, p = .023), whereas there
was no signiﬁcant difference between PS and SS (t (4) = 2.4,
p = .08) (Fig. 4B). These results suggest that the L. F3op/F3t-damaged patients had more profound deﬁcits in the comprehensionof non-canonical sentences. For the L. LPMC-damaged patients,on the other hand, paired t-tests showed that these patients’error rates were signiﬁcantly higher for SS than AS and PS (SSvs. AS: t (5) = 8.1, p = .0005; SS vs. PS: t (5) = 8.6, p = .0004),
whereas there was no signiﬁcant difference between AS and PS(t (5) = .039, p = .7) (Fig. 4D). These results suggest that the L.
LPMC-damaged patients had more profound deﬁcits in the comprehension of object-initial scrambled sentences. In contrast, forthe other patients, there was no signiﬁcant difference among thethree main conditions regarding these patients’ error rates(p > .2) (Fig. 4F).

When compared with the normal controls, signiﬁcantly higher
error rates for AS, PS, and SS were observed for the L. F3op/F3tdamaged patients (AS: t (24) = 2.6, p = .014; PS: t (24) = 6.8,
p < .0001; SS: t (24) = 6.6, p < .0001), as well as for the L. LPMCdamaged patients (AS: t (25) = 3.8, p = .0009; PS: t (25) = 3.2,
p = .0036; SS: t (25) = 12, p < .0001). These results suggest that bothof these patient groups had deﬁcits in syntactic analyses for the
two-argument relationships. In contrast, the other patients showedno signiﬁcant difference in error rates under the main conditions
when compared with the normal controls (p > .4). The other
patients’ normal performances indicate that neither medical condition nor the difference in testing condition (inside or outside thescanner) affected the performance. This result is thus complementary with the agrammatic comprehension caused by a glioma in L.
F3op/F3t or L. LPMC, in that the patients with intact L. F3op/F3t and
L. LPMC had normal syntactic comprehension of sentences.
3.5. The analyses of the SC condition
We compared the performance data for SC between all patientsand the normal controls to examine whether or not such basic
comprehension of sentences was affected for the patients. The
patients showed no signiﬁcant difference in error rates for SC whencompared with the normal controls (t (40) = .64, p = .5) (Table 2).
Regarding RTs for SC, there was no signiﬁcant difference between
the patients and normal controls (t (40) = 1.3, p = .2). Moreover,paired t-tests showed that the patients’ error rates were78

R. Kinno et al. / Brain & Language 110 (2009) 71–80

signiﬁcantly lower for SC than for AS, PS, and SS (AS: t (20) = 2.4,
p = .028; PS: t (20) = 3.0, p = .0076; SS: t (20) = 4.1, p = .0006),
whereas the normal controls’ error rates for SC were not signiﬁcantly different from those for the three main conditions (p > .7).
For both the patients and normal controls, RTs were signiﬁcantly
shorter for SC than for the three main conditions (all, p < .0001).
Some patients’ error rates were about 10% for SC, but VLSM
analyses showed that error rates for SC were not signiﬁcantly associated with any lesions in the left frontal regions. An ANOVA with
one factor of group [L. F3op/F3t-damaged patients, L. LPMC-damaged patients, and other patients] showed no signiﬁcant main effect of group (F(2, 18) = 1.0, p = .4). Moreover, each of these threegroups showed no signiﬁcant difference in error rates for SC whencompared with the normal controls (p > .3). These results indicatethat basic comprehension of sentences under the SC condition waspreserved among the patients.

4. Discussion
The present study with the picture–sentence matching task successfully clariﬁed that both of L. F3op/F3t and L. LPMC are the critical regions for AS, PS, and SS (Fig. 2), and that both regions areindeed critically involved in the comprehension of syntacticallycomplex sentences (Fig. 3). It is striking to note that these brain
regions identiﬁed by the present study spatially overlapped withthose reported by our fMRI study (Kinno et al., 2008). The patientswith a lesion in either L. F3op/F3t or L. LPMC had signiﬁcant deﬁcits in syntactic analyses for the two-argument relationships
required for the three main conditions, but without deﬁcits inany factors required for SC. When the patients were divided into
groups based on tumor locations, the L. F3op/F3t-damaged
patients had more profound deﬁcits in the comprehension of
non-canonical sentences for both PS and SS (Fig. 4B), whereas the
L. LPMC-damaged patients had more profound deﬁcits in the comprehension of object-initial scrambled sentences for SS (Fig. 4D).
These differential patterns of condition-selective deﬁcits are indeed consistent with the distinct activation patterns in L. F3op/
F3t or L. LPMC shown by our fMRI study (Kinno et al., 2008). These
results provide direct evidence that L. F3op/F3t and L. LPMC subserve syntactic comprehension.
The condition-selectivity in error rates for the patients with alesion in either L. F3op/F3t or L. LPMC cannot be explained by general disorders of the patients, including visual/memory/motor
impairment, attention disturbance due to drowsiness or dizziness,and perseveration for a particular sentence type. It is natural to assume that the patients with normal verbal IQ would not otherwise
experience or exhibit difﬁculty in language comprehension withsuch simple sentences; however the patients indeed exhibited
clear deﬁcits even for canonical sentences for AS in the present
study. In daily conversation, pragmatic information about word
use resolves syntactic difﬁculty (e.g., ‘‘The ofﬁcer chased the thief”
is more acceptable than ‘‘The thief chased the ofﬁcer.”). The use of
appropriate syntactic judgment tests is thus necessary for a proper
assessment of syntactic comprehension. The present results arealso consistent with another recent fMRI study, in which both
L. dF3t and L. LPMC were selectively activated for the syntactic
comprehension of honoriﬁcation, in which two-argument relationships of either subject honoriﬁcs or object honoriﬁcs were criticallyinvolved (Momo, Sakai, & Sakai, 2008). Further research is required
for understanding both anatomical and functional bases for the differential roles of these two critical regions.
In the present study, the L. F3op/F3t-damaged patients showeddeﬁcits in syntactic analyses for the two-argument relationships
including active, passive, and scrambled sentences. More speciﬁcally, these patients showed more profound deﬁcits in the compre-

hension of non-canonical sentences for PS and SS than that of
canonical sentences for AS (Fig. 4B). It is widely assumed in theoretical as well as in experimental linguistics that not only scrambling but also passivization is a purely syntactic operation. It istrue that different grammatical theories include different ways of
implementing the distinctions between these two types of syntactic operations: e.g., syntactic movement in Government and Binding Theory/Minimalist Program (Chomsky, 1995), type of linking in
Lexical-Functional Grammar (Bresnan, 2001), and structure tomeaning mapping in Role and Reference Grammar (Van Valin, Jr.
& LaPolla, 1997). However, these theories commonly assume a
direct relation between the syntactic operations and the underlying syntactic structures. Our present ﬁndings agree well with theaccount of sentence processing proposed in contemporary linguistics, and thus we conclude that the deﬁcits of the L. F3op/F3t-damaged patients are purely syntactic in nature, i.e., agrammatic
comprehension. Therefore, the critical role of the L. F3op/F3t, suchthat a lesion in this region alone sufﬁciently causes selective deﬁcits in syntactic comprehension, is now established.
The L. LPMC-damaged patients also exhibited deﬁcits in syntactic analyses for the two-argument relationships. More speciﬁcally,
these patients showed more profound deﬁcits in the comprehension of object-initial scrambled sentences for SS than that of subject-initial sentences for AS and PS (Fig. 4D). The ignorance ofcase markers or the persistent semantic analysis regarding the ﬁrst
noun as an agent, irrespective of sentence type, cannot explain theless impaired performance of these patients for AS and PS. One
explanation for this SS-selective impairment is that the buildingof syntactic structures might be unimpaired but that the derivationof the corresponding meaning, i.e., its interpretation, is affected bya glioma in L. LPMC. Along with this line, a linguistic operation at
the syntax-semantic interface has been proposed, such that thefeature of animacy (Grewe et al., 2006) or an argument hierarchy(Bornkessel, Zysset, Friederici, von Cramon, & Schlesewsky, 2005)
is related to this operation. However, the L. LPMC-damaged patients showed signiﬁcantly higher error rates not only for SS but
for AS and PS than the normal controls (Fig. 4D and G), even under
the conditions without scrambling and thus with little load of sucha linguistic operation. Alternatively, we propose that the SS-selectivity is due to difﬁculty in the basic syntactic analysis of structurally more complex sentences (Saito & Fukui, 1998), and that AS and
PS are also under the control of such a general syntactic analysis.
This possibility provides further support for agrammatic comprehension associated with a lesion in L. LPMC.
It has been long believed that not only the left frontal cortex but
the left temporal cortex is also involved in sentence comprehension. In our fMRI study with the same paradigm, we have reported
that a localized activation in the left posterior superior/middle
temporal gyrus (L. pSTG/MTG) was also enhanced for SS whencompared with AS and PS (Kinno et al., 2008). Other fMRI studies
have also reported that this region was activated by contrasting
object-initial vs. subject-initial sentences (Bornkessel et al.,2005), as well as by contrasting sentences with syntactic/semantic
anomaly and normal sentences (Suzuki & Sakai, 2003). It is thus
possible that a lesion in L. pSTG/MTG also results in the SS-selective deﬁcit. A recent intraoperative electrocorticography study inhumans showed bidirectional connectivity between L. IFG and
L. pSTG/MTG (Matsumoto et al., 2004), and additional evidence
for this connectivity has been reported in studies using MRI to
investigate structural connectivity (Catani, Jones, & Ffytche, 2005;
Friederici, Bahlmann, Heim, Schubotz, & Anwander, 2006). Therefore, it is possible that this network subserves syntactic integration, thereby combining multiple linguistic information. Further
lesion studies are required to examine whether or not a lesion in
the left temporal region is sufﬁcient to cause deﬁcits in such a linguistic process.

R. Kinno et al. / Brain & Language 110 (2009) 71–80

Compared with a cerebrovascular disease such as an infarct or ahemorrhage, a glioma has both advantages and disadvantages inneuropsychological and neurolinguistic research. First, it is advantageous that the location of a glioma is basically random in the
cerebrum and not restricted by the cerebrovascular distribution.
Indeed, damage to the middle cerebral artery affects the perisylvian cortex including F3op/F3t, but it spares more dorsal regions
including LPMC. Using the lesion data with a glioma, we successfully showed the functional roles of L. F3op/F3t and L. LPMC.
Second, the precise determination of the location and extent of aglioma is often difﬁcult, because a glioma may induce edemas,
abnormalities by compressing its peripheral region, and inﬁltration. In the present study, we used both T2-weighted MR images
and PET data, which enabled us to determine precise boundaryof lesions including brain edemas and abnormalities of perfusion.
Third, some neural functions may be still preserved within a
glioma, as indicated by cortical stimulation and fMRI studies(Ojemann, Miller, & Silbergeld, 1996; Krainik et al., 2003). It has
been also reported that patients with tumors in the left hemisphere showed less language impairment than their counterparts
with stroke (Anderson, Damasio, & Tranel, 1990). In the present
study, however, we regarded an entire glioma as a lesion, and clear
language deﬁcits were observed despite such residual functions.
Fourth, the onset and time course of a glioma is difﬁcult to determine; a glioma develops gradually without apparent symptoms
such as hemiplegia or dysarthria. In the present study, the patientswere at least 24 years old at their start of medication (Table 1), andhad no prior history of benign or malignant brain tumors, indicating an adult-onset glioma. For evaluating the real function of a cortical region, it is thus important to correlate the lesion symptom
data with the functional neuroimaging data from normal controls.
It has been recently demonstrated that slow-growing lesions
like WHO grade II gliomas, but not high-grade gliomas, may induce
cortical reorganization even before operation (Desmurget, Bonnetblanc, & Duffau, 2007). Moreover, the grade II gliomas undergo
anaplastic transformation over the years, i.e., the progression into
grade III gliomas (Behin, Hoang-Xuan, Carpentier, & Delattre,2003), which may be enough time for cortical reorganization. Sucha functional reshaping might affect the observation of the present
study, because the tumor types of the patients (Table 1) were heterogeneous including WHO grade II (n = 11), III (n = 9), and IV(n = 1) gliomas, with different biological processes for each tumor.
However, it should be noted that the patients with a glioma ineither L. F3op/F3t or L. LPMC showed marked deﬁcits in syntactic
comprehension, which had not been rescued by any functional
reshaping. It is possible that the reorganization of other corticalregions due to a lesion in L. F3op/F3t or L. LPMC is entirely different
each other, thus leading to the differential patterns of conditionselective deﬁcits. This possibility also explains some deviations between the error rate patterns in the present study (Fig. 4B and D)
and the activation patterns in our previous fMRI study (Fig. 5A
and C of Kinno et al., 2008). Further functional neuroimaging studies for brain-damaged patients are required to clarify real mechanisms of cortical reorganization.
While a glioma in the cerebral cortex causes a deﬁcit in cognitive function, the severity and course of such a dysfunction need
to be thoroughly assessed (Wefel, Kayl, & Meyers, 2004). An extensive study of tumors with multiple neuropsychological tests have
conﬁrmed that patients with left hemispheric tumors exhibited
poorer verbal ﬂuency and verbal learning than those with righthemispheric tumors (Hahn et al., 2003). The present study demonstrated the severity of dysfunction, such that a glioma in L. F3op/
F3t and/or L. LPMC can cause deﬁcits in syntactic comprehension
almost at a chance level. Our language task would be thus sensitive
enough and useful for a general assessment of linguistic knowledge. Our ﬁndings further indicate that brain surgery for a glioma

79

in the left frontal cortex requires careful assessment for maintaining syntactic abilities, which are indeed the source of the creative
faculty for producing inﬁnite expressions (Hauser, Chomsky, &Fitch, 2002), and thus for ensuring the best possible QOL for individual patients.

Acknowledgments
We thank the late S.-Y. Kuroda for his helpful discussion,
N. Komoro and N. Saeki for their technical assistance, H. Matsuda
and S. Matsukura for their administrative assistance. This research
was supported by a Core Research for Evolutional Science andTechnology (CREST) grant from the Japan Science and Technology
Agency (JST) and by Grants-in-Aid for Scientiﬁc Research on Priority Areas (‘‘System study on higher-order brain functions”, No.
17022013) and Grants-in-Aid for Scientiﬁc Research (S) (No.
20220005) from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan.

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