**4. Discussion**

116 Advances in the Biology, Imaging and Therapies for Glioblastoma

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

5C). These results are compatible to our previous findings.

of syntactically complex sentences.

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.

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 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 comprehension.

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 these two critical regions.

Gray or White? – The Contribution of Gray Matter in a Glioma to Language Deficits 119

reshaping might affect the observation of the present study, because the tumor types of the patients were heterogeneous including WHO grade II (n = 10), and III (n = 11), with different biological processes for each tumor. However, it should be noted that the patients with a glioma in either 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 cortical regions due to a lesion in L. F3op/F3t or L. LPMC is entirely different each other, thus leading to the differential patterns of condition-selective deficits. Further functional neuroimaging studies for brain-damaged

Understanding cortical networks for a cognitive process requires knowledge of functional as well as anatomical connections between brain regions. Not only lesion symptom mapping but also functional imaging studies of patients with a well-defined lesion are useful for understanding cortical networks by revealing abnormal activations: overactivity (i.e., regions where patients activate more than normal controls) or underactivity (i.e., regions where patients activate less than normal controls) (Price & Friston, 1999; Price, Crinion , & Friston, 2006). These differential activations can imply a change in cognitive or neuronal implementation. Changes in cognitive implementation occur when a patient uses a different set of cognitive processes either because a new cognitive strategy has been learned, or because of increased demands on normal processing due to a brain damage. Changes in neuronal implementation are mediated by changes in the strength of pre-existing connections. Abnormal activations distant to the lesion location suggest the dysfunctional region has been disconnected from its normal inputs. This disconnection may result in overactivity, due to disinhibition of an inhibitory network, or underactivity, due to a failure to activate a cortical region. These abnormal activations can reveal a duplicate system for a cognitive process, in which the dominant system inhibits the others. Within the duplicate system, the less dominant systems are able to respond when the dominant system is damaged. This duplication of functionality renders a function immune from the effects of focal damage. Functional imaging studies of patients, therefore, have an important role to play in the identification of a duplicate system—the multiplicity of sufficient brain systems for a cognitive function. Further study is required to investigate the language-specific

In this chapter, we have presented a lesion-symptom mapping method that can directly examine the effect of a GM lesion on a cognitive process. As a glioma extends to both gray and white matter, it remains to be elucidated whether the cognitive deficits are due to the glioma in gray or white matter. It is typically supposed that a glioma in GM causes dysfunction of the localized region, whereas a glioma in white matter leads to the disconnection of neural networks. Therefore, the effect of GM lesion should be assessed precisely; for this purpose, our method would be useful. 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 right hemispheric tumors (Hahn et al., 2003). The present study demonstrated the severity of dysfunction, such that a GM lesion in L. F3op/F3t and/or L. LPMC can cause clear deficits

patients are required to clarify real mechanisms of cortical reorganization.

system for the human brain.

**5. Conclusion** 

It has been well known that the left temporal cortex is also engaged during 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 when compared 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). A lesion in L. pSTG/MTG may thus result in the SS-selective deficit. A recent intraoperative electrocorticography study in humans 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 et al., 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 gray or white matter of the left temporal region is sufficient to cause deficits in such a linguistic process. Our lesionsymptom method would be useful for this purpose.

Compared with a cerebrovascular disease such as an infarct or a hemorrhage, a glioma has both advantages and disadvantages in neuropsychological 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 a glioma 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 boundary of 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 patients were at least 21 years old at their start of medication, and had 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 compare the lesion symptom data from our lesion-symptom method 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 et al., 2003), which may be enough time for cortical reorganization. Such a functional reshaping might affect the observation of the present study, because the tumor types of the patients were heterogeneous including WHO grade II (n = 10), and III (n = 11), with different biological processes for each tumor. However, it should be noted that the patients with a glioma in either 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 cortical regions due to a lesion in L. F3op/F3t or L. LPMC is entirely different each other, thus leading to the differential patterns of condition-selective deficits. Further functional neuroimaging studies for brain-damaged patients are required to clarify real mechanisms of cortical reorganization.

Understanding cortical networks for a cognitive process requires knowledge of functional as well as anatomical connections between brain regions. Not only lesion symptom mapping but also functional imaging studies of patients with a well-defined lesion are useful for understanding cortical networks by revealing abnormal activations: overactivity (i.e., regions where patients activate more than normal controls) or underactivity (i.e., regions where patients activate less than normal controls) (Price & Friston, 1999; Price, Crinion , & Friston, 2006). These differential activations can imply a change in cognitive or neuronal implementation. Changes in cognitive implementation occur when a patient uses a different set of cognitive processes either because a new cognitive strategy has been learned, or because of increased demands on normal processing due to a brain damage. Changes in neuronal implementation are mediated by changes in the strength of pre-existing connections. Abnormal activations distant to the lesion location suggest the dysfunctional region has been disconnected from its normal inputs. This disconnection may result in overactivity, due to disinhibition of an inhibitory network, or underactivity, due to a failure to activate a cortical region. These abnormal activations can reveal a duplicate system for a cognitive process, in which the dominant system inhibits the others. Within the duplicate system, the less dominant systems are able to respond when the dominant system is damaged. This duplication of functionality renders a function immune from the effects of focal damage. Functional imaging studies of patients, therefore, have an important role to play in the identification of a duplicate system—the multiplicity of sufficient brain systems for a cognitive function. Further study is required to investigate the language-specific system for the human brain.

## **5. Conclusion**

118 Advances in the Biology, Imaging and Therapies for Glioblastoma

It has been well known that the left temporal cortex is also engaged during 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 when compared 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). A lesion in L. pSTG/MTG may thus result in the SS-selective deficit. A recent intraoperative electrocorticography study in humans 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 et al., 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 gray or white matter of the left temporal region is sufficient to cause deficits in such a linguistic process. Our lesion-

Compared with a cerebrovascular disease such as an infarct or a hemorrhage, a glioma has both advantages and disadvantages in neuropsychological 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 a glioma 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 boundary of 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 patients were at least 21 years old at their start of medication, and had 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 compare the lesion symptom data from our lesion-symptom method with the functional neuroimaging

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 et al., 2003), which may be enough time for cortical reorganization. Such a functional

symptom method would be useful for this purpose.

data from normal controls.

In this chapter, we have presented a lesion-symptom mapping method that can directly examine the effect of a GM lesion on a cognitive process. As a glioma extends to both gray and white matter, it remains to be elucidated whether the cognitive deficits are due to the glioma in gray or white matter. It is typically supposed that a glioma in GM causes dysfunction of the localized region, whereas a glioma in white matter leads to the disconnection of neural networks. Therefore, the effect of GM lesion should be assessed precisely; for this purpose, our method would be useful. 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 right hemispheric tumors (Hahn et al., 2003). The present study demonstrated the severity of dysfunction, such that a GM lesion in L. F3op/F3t and/or L. LPMC can cause clear deficits

Gray or White? – The Contribution of Gray Matter in a Glioma to Language Deficits 121

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#### **6. Acknowledgment**

We thank M. Kawamura for his suggestion regarding neurological issues, N. Komoro for her technical assistance, H. Matsuda for her administrative assistance. This research was supported by a research grant from the Narishige Neuroscience Research Foundation (R. K.) and a Core Research for Evolutional Science and Technology (CREST) grant from the Japan Science and Technology Agency (JST) (K. L. S.).

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**Part 2** 

**Novel Imaging and Diagnostic Modalities** 

