**2.1 Participants**

108 Advances in the Biology, Imaging and Therapies for Glioblastoma

transitive verb and two arguments (phrases associated with the 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 thematic roles, i.e., who initiates the action, and who is affected by it. In Japanese syntax, the grammatical relations are first marked by case markers (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 the verb 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 the fMRI study, we observed that activations in L. dF3t (extending to L. F3op) and L. LPMC were differentially modulated by these three main conditions. Moreover, we have recently found that a glioma in the opercular and triangular parts of the left inferior frontal gyrus (L. F3op/F3t) or left lateral premotor cortex (L. LPMC) is indeed sufficient to cause agrammatic comprehension that is selective to syntactic decision (Kinno et al., 2009). These findings indicated that our paradigm with three distinct syntactic conditions of AS, PS, and SS would be ideal for appropriately assessing agrammatic comprehension, because the same set of actions depicted by pictures was used under the main conditions, thus controlling semantic comprehension per se. However, it remains to be elucidated whether a cognitive deficit such as agrammatic comprehension is due to the glioma in gray matter (GM) or not, as a glioma extends to both gray and white matter. It is typically supposed that a glioma in a gray matter causes dysfunction of the localized region, whereas a glioma in white matter leads to the disconnection of neural networks. Therefore, a lesion-symptom method, in which brain lesions are precisely divided into gray and white matter, is required to examine the relative contribution of gray matter in a

In this chapter, we firstly propose a modified lesion-symptom method for examining the effect of a GM lesion. Our method is based on the following two methods for processing the structural magnetic resonance imaging (MRI) data and the behavioural data of patients with a glioma: the voxel-based lesion-symptom mapping (VLSM) (Bates et al., 2003) and the "unified segmentation" algorithm (Ashburner & Friston, 2005). The VLSM is a method to analyze the relationship between a lesion location in the structural MRI and behavioural data such as the error rates (ERs) or reaction times (RTs) on a voxel-byvoxel basis. The unified segmentation algorithm is a generative model that combines tissue segmentation, bias correction and spatial normalization in a single unified model. Using our picture-sentence matching task (Fig. 1), we actually applied this new method to real data of patients with a glioma 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 precisely localize the glioma, all patients underwent a high-resolution 3D-MRI on the same day as the task examination. All of these results were actually utilized for the preoperative evaluation of 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, our lesion-symptom method would have both fundamental and clinical implications, which are useful for

glioma to cognitive deficits.

preserving the quality of life (QOL) for each patient.

All patients were native Japanese speakers newly diagnosed as having 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 other cognitive 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 (Fig. 2 and Table 1) preoperatively underwent a highresolution MRI scan and performed the picture-sentence matching task at the University of Tokyo, Komaba. The laterality quotient (LQ) was also determined by the Edinburgh handedness inventory (Oldfield, 1971). The verbal / nonverbal 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 tumour type and grade were postoperatively and pathologically diagnosed by the WHO Classification of Tumours of the Nervous System (2000). Using the same paradigm and parameters, we also tested 21 right-handed participants with no history of neurological or psychiatric disorders. These age-matched normal 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 from the institutional review board of the University of Tokyo, Komaba.


Table 1. Characteristics of Patients

Date are shown as mean ± standard deviation MR images were normalized with SPM8 for determination of tumor location and volume (mm3), as well as the ratio (%) of gray matter (GM) for each tumor. LQ = laterality quotient VIQ = verbal intelligence quotient.

Gray or White? – The Contribution of Gray Matter in a Glioma to Language Deficits 111

canonical / subject-initial active sentences were presented ("∆-ga ○-o hiiteru"). Below each example, a word-by-word translation in English is shown. Nom, nominative case; Acc, accusative case; Dat, dative case. (B) Under the passive sentence (PS) condition, noncanonical / subject-initial passive sentences were presented ("○-ga ∆-ni hikareru"). (C) Under the scrambled sentence (SS) condition, non-canonical / object-initial scrambled sentences were presented ("○-o ∆-ga hiireru"). An identical picture set was used under these three conditions. The sentence stimuli were all grammatical and commonly used in Japanese.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 center of the screen. Stimulus presentation and behavioural data collection were controlled using the LabVIEW software and interface (National Instruments, Austin, TX,

In the picture-sentence matching task (Fig. 1), the participants read a sentence silently and indicated whether or not the meaning of each sentence matched the action of the corresponding picture by pressing one of two buttons. For AS, PS, and SS, all mismatched sentences were made by exchanging two symbols in the original sentences, e.g., " pushes ○" instead of "○ pushes ". For SC, symbol-mismatched and action-mismatched sentences were presented equally often, requiring the sentences to be read completely in order for the

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 matching task were presented, together with a string of jumbled letters taken from a single sentence in which the symbols (○, , or ∆) and "kanji" appeared at the same positions in the string as in the picturesentence matching task. The participants were asked to judge whether or not all the symbols in a letter string were the same as those in the picture, irrespective of the order of the symbols. The participants underwent practice sessions before testing to become fully

A single run of the testing sessions contained 24 "trial events" of the picture-sentence matching task (six times each for AS, PS, SS, and SC), with variable inter-trial intervals of 6 and 12 s (one and two 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 each run to prevent any condition-specific strategy. Eight runs were tested in a day per one participant. Half of the stimuli consisted of matched picture-sentence pairs (24 trials for each condition), and the other half consisted of mismatched pairs (24 trials for each condition). All patients underwent the testing sessions inside the scanner 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 behavioural data and the anatomical MRI scans alone. All of the behavioural data from

USA).

**2.3 Tasks** 

participants to arrive at a correct judgment.

normal controls were acquired outside the scanner.

familiarized with the tasks.

Fig. 2. Lesion overlap map for 21 patients with a glioma in the left frontal cortex
