**3. Results**

112 Advances in the Biology, Imaging and Therapies for Glioblastoma

The MRI scans were conducted on a 1.5 T scanner (Stratis II, Premium; Hitachi Medical Corporation, Tokyo, Japan), and a high-resolution T1-weighted 3D image (repetition time:

Fig. 3. Schematic representation of methods for making GM images.

**2.4 MRI data acquisition and analyses** 

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., " and ∆ 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 than other conditions. It was therefore mandatory to analyze the three main conditions and SC separately. Moreover, the analyses also match with our fMRI study (Kinno et al., 2008), in which SC was used as a separate control. In the sections 3.1-3.3, we focus on the main conditions of AS, PS, and SS, and the results of SC are presented in the section 3.4.

#### **3.1 Behavioral analyses**

The ERs for the patients and the normal controls are shown in Table 2. A repeated-measures analysis of variance (rANOVA) with two factors (group [patients, normal controls] ×

Gray or White? – The Contribution of Gray Matter in a Glioma to Language Deficits 115

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. F3op/F3t (Fig. 4D). In contrast, we found that the significantly larger difference in SS – AS was associated mostly with lesions in L. LPMC (Fig. 4E). These results are consistent with our previous results (Kinno et al., 2009) with better sensitivity, indicating that both of L.

F3op/F3t and L. LPMC are sufficient to cause agrammatic comprehension.

Fig. 4. Brain regions identified by the VLSM analysis for gray and white matters

2.0 (FDR corrected p < .05).

LPMC (Fig. 5A).

**3.1.2 VLSM analyses for gray matter** 

Brain regions identified by the VLSM analysis for gray and white matters among the left frontal-damaged patients (n = 21) for AS, PS, SS, PS – AS, and SS – AS, respectively. The resultant t-map is projected on the left (L) lateral surface; the threshold was established at t >

We performed the modified VLSM analyses to identify the relateve contribution of gray matter to syntactic processing required for the main conditions of AS, PS, and SS, in which a GM image of each glioma was used. We found that significantly higher error rates for AS were associated with ventral lesions in L. IFG, as well as isolated lesions in L.

condition [AS, PS, SS]) revealed significant main effects of group (F (1, 40) = 16, p = 0.0003) and condition (F (2, 80) = 8.9, p = 0.0003), as well as a significant interaction of group by condition (F (2, 80) = 9.2, p = 0.0003). The patients showed significantly higher error rates than the normal controls for each of AS, PS, and SS (t-test; AS: t (40) = 2.5, p = 0.016; PS: t (40) = 2.9, p = 0.0055; SS: t (40) = 4.1 p = 0.0002). 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) = 3.8, p = 0.0010; PS: t (20) = 2.5, p = 0.021), whereas the difference was marginal between AS and PS (t (20) = 1.9, p = 0.07). However, there was no significant difference among the normal controls' error rates under the main conditions (p > 0.7). The resuls from the normal controls is consistent with our previous results (Kinno et al 2008).

These significant errors were observed in spite of the patient's normal verbal and nonverbal IQs (Table 1; range: 86-113 within 1 SD of ± 15; one sample t-test for the difference from 100: verbal, t (20) =1.2, p = 0.25 and nonverbal, t (20) = 0.51, p = 0.62). According to correlation analyses, the error rates for each condition could not be attributed to their ages, verbal / nonverbal IQs, or tumor volumes and GM ratio (all, p > 0.1). These results corresponded with our previous findings (Kinno et al., 2009), demonstrating that the tumor locations affected the actual performance of the three main conditions.

The RTs for the patients and the normal controls are also shown in Table 2. An rANOVA with two factors (group [patients, normal controls] × condition [AS, PS, SS]) showed that neither a main effect of group (F (1, 40) = 2.1, p = 0.2) nor that of condition was significant (F (2, 80) = 2.8, p = 0.1), with no significant interaction of group by condition (F (2, 80) = 0.30, p = 0.7). 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. Therefore, we used error rates as indicators in the following VLSM analyses.


Table 2. Behavioral Data under Each Condition. ERs and RTs (for correct trials only) are shown as mean ± standard deviation.

#### **3.1.1 VLSM analyses for gray and white matters**

To identify any critical regions for the main conditions of AS, PS, and SS, we first conducted VLSM analyses, in which error rates for each 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. 4A). Moreover, significantly higher error rates for PS were associated with lesions in L. dorsal F3op/F3t, further extending to ventral F3op/F3t (Fig. 3B). In contrast, significantly higher error rates for SS were associated with lesions in L. LPMC and ventral IFG (Fig. 3C). These results indicate that both of L. F3op/F3t and L. LPMC are the critical regions for AS, PS, and SS.

Next we examined which regions were critically involved in the comprehension of syntactically complex sentences. For this purpose, we conducted VLSM analyses, in which the difference in error rates between the conditions of noncanonical vs. canonical sentences,

condition [AS, PS, SS]) revealed significant main effects of group (F (1, 40) = 16, p = 0.0003) and condition (F (2, 80) = 8.9, p = 0.0003), as well as a significant interaction of group by condition (F (2, 80) = 9.2, p = 0.0003). The patients showed significantly higher error rates than the normal controls for each of AS, PS, and SS (t-test; AS: t (40) = 2.5, p = 0.016; PS: t (40) = 2.9, p = 0.0055; SS: t (40) = 4.1 p = 0.0002). 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) = 3.8, p = 0.0010; PS: t (20) = 2.5, p = 0.021), whereas the difference was marginal between AS and PS (t (20) = 1.9, p = 0.07). However, there was no significant difference among the normal controls' error rates under the main conditions (p > 0.7). The resuls from

These significant errors were observed in spite of the patient's normal verbal and nonverbal IQs (Table 1; range: 86-113 within 1 SD of ± 15; one sample t-test for the difference from 100: verbal, t (20) =1.2, p = 0.25 and nonverbal, t (20) = 0.51, p = 0.62). According to correlation analyses, the error rates for each condition could not be attributed to their ages, verbal / nonverbal IQs, or tumor volumes and GM ratio (all, p > 0.1). These results corresponded with our previous findings (Kinno et al., 2009), demonstrating that the tumor locations

The RTs for the patients and the normal controls are also shown in Table 2. An rANOVA with two factors (group [patients, normal controls] × condition [AS, PS, SS]) showed that neither a main effect of group (F (1, 40) = 2.1, p = 0.2) nor that of condition was significant (F (2, 80) = 2.8, p = 0.1), with no significant interaction of group by condition (F (2, 80) = 0.30, p = 0.7). 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 normal controls is consistent with our previous results (Kinno et al 2008).

Therefore, we used error rates as indicators in the following VLSM analyses.

AS PS SS SC AS PS SS SC

controls 1.8 ± 2.6 2.1 ± 2.4 2.4 ± 2.6 1.8 ± 1.4 3334 ± 470 3524 ± 466 3599 ± 405 2712± 535 Patients 8.1 ± 7.4 12 ± 12 22 ± 21 2.4 ± 2.3 3372 ± 423 3476 ± 453 3499 ± 455 2760± 298 Table 2. Behavioral Data under Each Condition. ERs and RTs (for correct trials only) are

To identify any critical regions for the main conditions of AS, PS, and SS, we first conducted VLSM analyses, in which error rates for each 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. 4A). Moreover, significantly higher error rates for PS were associated with lesions in L. dorsal F3op/F3t, further extending to ventral F3op/F3t (Fig. 3B). In contrast, significantly higher error rates for SS were associated with lesions in L. LPMC and ventral IFG (Fig. 3C). These results indicate that both of L. F3op/F3t and L. LPMC are the critical

Next we examined which regions were critically involved in the comprehension of syntactically complex sentences. For this purpose, we conducted VLSM analyses, in which the difference in error rates between the conditions of noncanonical vs. canonical sentences,

affected the actual performance of the three main conditions.

Participant Error Rate (%) RT (ms)

**3.1.1 VLSM analyses for gray and white matters** 

shown as mean ± standard deviation.

regions for AS, PS, and SS.

Normal

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. F3op/F3t (Fig. 4D). In contrast, we found that the significantly larger difference in SS – AS was associated mostly with lesions in L. LPMC (Fig. 4E). These results are consistent with our previous results (Kinno et al., 2009) with better sensitivity, indicating that both of L. F3op/F3t and L. LPMC are sufficient to cause agrammatic comprehension.

Fig. 4. Brain regions identified by the VLSM analysis for gray and white matters

Brain regions identified by the VLSM analysis for gray and white matters among the left frontal-damaged patients (n = 21) for AS, PS, SS, PS – AS, and SS – AS, 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).

#### **3.1.2 VLSM analyses for gray matter**

We performed the modified VLSM analyses to identify the relateve contribution of gray matter to syntactic processing required for the main conditions of AS, PS, and SS, in which a GM image of each glioma was used. We found that significantly higher error rates for AS were associated with ventral lesions in L. IFG, as well as isolated lesions in L. LPMC (Fig. 5A).

Gray or White? – The Contribution of Gray Matter in a Glioma to Language Deficits 117

We compared the performance data for SC between all patients and 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 when compared with the normal controls (t (40) = 0.87, p = 0.4) (Table 2). Regarding RTs for SC, there was no significant difference between the patients and normal controls (t (40) = 0.36, p = 0.7). Moreover, paired t-tests showed that the patients' error rates were significantly lower for SC than for AS, PS, and SS (AS: t (20) = 3.6, p = 0.020; PS: t (20) = 3.4, p = 0.0029; SS: t (20) = 4.5, p = 0.0002), whereas the normal controls' error rates for SC were not significantly different from those for the three main conditions (p > 0.7). For both the patients and normal controls, RTs were significantly shorter for SC than for the three main conditions (all, p < 0.0001). These results indicate that basic comprehension of sentences under the SC condition was

In this chapter, we have presented the modified VLSM method that can directly examine the effect of a GM lesion on a cognitive process. The present study successfully demonstrates that GM of L. F3op/F3t and L. LPMC are actually essential for AS, PS, and SS (Fig. 5), and that both regions are indeed critically involved in the comprehension of syntactically complex sentences. The patients with a lesion in GM of 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 in any factors required for SC. These results provide crucial evidence that GM of L. F3op/F3t and L. LPMC subserves syntactic

The condition-selectivity in error rates for the patients with a GM lesion 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 with such 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 importance of GM of L. F3op/F3t and L. LPMC has been underpinned by accumulating results from fMRI studies, which demonstrated the selectivity for syntactic processing in L. F3op/F3t and /or L. LPMC (Dapretto & Bookheimer, 1999; Embick et al., 2000; Hashimoto & Sakai, 2002; Bornkessel et al., 2005; Grewe et al., 2006), indicating the critical role of the two left frontal regions on the language network for syntactic processing (Sakai, 2005). Moreover, the present results are consistent with another recent fMRI study, in which both L. dF3t and L. LPMC were selectively activated for the syntactic comprehension of honorication, in which two-argument relationships of either subject honorifics or object honorifics were critically involved (Momo, Sakai, & Sakai, 2008). Further research is required for understanding both anatomical and functional bases for the differential roles of

**3.2 The analyses of the SC condition** 

preserved among the patients.

**4. Discussion** 

comprehension.

these two critical regions.

Fig. 5. Brain regions identified by the VLSM analysis for gray matter.

Moreover, significantly higher error rates for PS were associated with lesions in L. ventral F3op/F3t, further extending to dorsal F3op/F3t (Fig. 5B). In contrast, significantly higher error rates for SS were associated with lesions in L. LPMC (Fig. 5E) and ventral IFG (Fig. 5C). These results are compatible to our previous findings.

Next we examined the effect of gray matter on the comprehension of syntactically complex sentences. We found that the significantly larger difference in PS – AS was associated with lesions in L. F3op/F3t (Fig. 5D). In contrast, we found that the significantly larger difference in SS – AS was associated mostly with lesions in L. LPMC. These results indicate that the gray matter of L. F3op/F3t as well as L. LPMC are critically involved in the comprehension of syntactically complex sentences.
