Cortico-subcortical organization of language networks in the right hemisphere: An electrostimulation study in left-handers

Neuropsychologia 46 (2008) 3197–3209

Contents lists available at ScienceDirect

Neuropsychologia journal homepage: www.elsevier.com/locate/neuropsychologia

Cortico-subcortical organization of language networks in the right hemisphere: An electrostimulation study in left-handers Hugues Duffau a,b,c,∗ , Marianne Leroy b , Peggy Gatignol c a Department of Neurosurgery, Hôpital Gui de Chauliac, INSERM U678 and CNRS UMR 8189, CHU de Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier Cedex 5, France b UMR-S678 Inserm, UPMC, Hôpital de la Salpêtrière, 47-83 Boulevard de l’hôpital, 75013 Paris, France c Laboratoire de Psychologie et de Neurosciences Cognitives, UMR 8189 (CNRS/Université de Paris V René Descartes), Institut de Psychologie, 71 avenue Edouard Vaillant, 92774 Boulogne Billancourt, France

a r t i c l e

i n f o

Article history: Received 24 February 2008 Received in revised form 22 July 2008 Accepted 22 July 2008 Available online 30 July 2008 Keywords: Left-handers Language Right hemisphere Brain mapping Electrostimulation Connectivity

a b s t r a c t We have studied the configuration of the cortico-subcortical language networks within the right hemisphere (RH) in nine left-handers, being operated on while awake for a cerebral glioma. Intraoperatively, language was mapped using cortico-subcortical electrostimulation, to avoid permanent deficit. In frontal regions, cortical stimulation elicited articulatory disorders (ventral premotor cortex), anomia (dorsal premotor cortex), speech arrest (pars opercularis), and semantic paraphasia (dorsolateral prefrontal cortex). Insular stimulation generated dysarthria, parietal stimulation phonemic paraphasias, and temporal stimulation semantic paraphasias. Subcortically, the superior longitudinal fasciculus (inducing phonological disturbances when stimulated), inferior occipito-frontal fasciculus (eliciting semantic disturbances during stimulation), subcallosal fasciculus (generating control disturbances when stimulated), and common final pathway (inducing articulatory disorders during stimulation) were identified. These cortical and subcortical structures were preserved, avoiding permanent aphasia, despite a transient immediate postoperative language worsening. Both intraoperative results and postsurgical transitory dysphasia support the major role of the RH in language in left-handers, and provide new insights into the anatomo-functional cortico-subcortical organization of the language networks in the RH-suggesting a “mirror” configuration in comparison to the left hemisphere. © 2008 Elsevier Ltd. All rights reserved.

1. Introduction As a consequence of the seminal lesional works of Broca (1861) who discovered that a damage in the left inferior frontal gyrus (IFG) induced a reduced capacity for articulate speech, and Wernicke (1874), who associated speech comprehension with the left superior posterior temporal gyrus, a preeminent role of the left hemisphere (LH) in language processings was inoxerably established. Moreover, Geschwind (1965) summarized the anatomic findings from aphasic patients in a model that outlined regions in the LH, and in particular their connections, that were critical for language. In particular, Geschwind and Levitsky (1968) observed a significant anatomical asymmetry of the planum temporale, which was found to be larger on the left. Consequently, these studies led to the concept of left hemispheric “dominance” or “specialization” for

∗ Corresponding author at: Department of Neurosurgery, Hôpital Gui de Chauliac, INSERM U678 and CNRS UMR 8189, CHU de Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier Cedex 5, France. Tel.: +33 4 67 33 66 12; fax: +33 4 67 33 69 12. E-mail address: [email protected] (H. Duffau). 0028-3932/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2008.07.017

language, and for more than a century, it was believed that the right hemisphere (RH) had little or no potential for processing language. However, using the Wada intracarotid Amytal test, Rasmussen and Milner (1977) showed that in non-right-handed patients, speech was represented in the left cerebral hemisphere in nearly a third of the group, in the right hemisphere in half the group, and bilaterally in the remainder. They also suggested the possibility of a functionally asymmetric participation of the two hemispheres in the language processes of some normal left-handers. Later, Annett (1996) offered a genetic model, the right shift theory, based on the existence of a gene with two alleles, one of which influences the distributions of asymmetries related to language and manual activities by favoring the left hemisphere. Interestingly, in homozygous subjects who do not have this allele, asymmetries are distributed independently and in random fashion, leftwards asymmetries being as frequent as rightward asymmetries. This would explain the fact that right hemispheric specialization for language is far from being systematically associated with left manual preference (Corballis, 1998). More recently, using functional neuroimaging, the notion of inter-individual variability of language lateralization was reinforced (Tzourio-Mazoyer, Josse, Crivello, &

3198

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209

Mazoyer, 2004), a factor currently known to exert a crucial influence on language processing, and at least partly related to handedness (Josse & Tzourio-Mazoyer, 2004). Indeed, it seems that left-handed subjects present less asymmetrical language lateralization (HundGeorgiadis, Lex, Friederici, & von Cramon, 2002; Pujol, Deus, Losilla, & Capdevila, 1999; Szaflarski et al., 2002; Tzourio, Crivello, Mellet, Nkanga-Ngila, & Mazoyer, 1998). However, despite this new view suggesting a more significant involvement of the RH in language than previously thought (in particular via the calculation of a lateralization index using neurofunctional imaging), very few data are currently available concerning the anatomo-functional organization of the language networks in the RH, especially in left-handers. Recently, a study has used electrocortical stimulation for language mapping in the RH, in six epileptic patients with bilateral language (one left-handed). The results revealed the presence of frontal and/or temporal language areas analogous to the classic language areas of the dominant LH in four of the six patients. Nonetheless, in addition to the fact that the parietal and insular cortices were not mapped, the subcortical anatomo-functional connectivity was not studied, due to the use of subdural electrode array (Jabbour, Hempel, Gates, Zhang, & Risse, 2005). Here, our aim was therefore to study the anatomo-functional cortical organization as well as subcortical connectivity of the whole language network within the RH in left-handers. The goal was nevertheless clearly not to analyze the contribution of the RH versus the LH in language in left-handers (i.e. the “hemispheric dominance”). We used intraoperative direct electrical stimulation to map language, during brain surgery performed in nine lefthanded patients operated on under local anesthesia for low-grade gliomas located in different lobes (frontal, insular, parietal, temporal) within the RH. It is common clinical practice to awaken patients in order to assess the functional role of restricted brain regions, so that the surgeon can maximize the extent of the resection without provoking cognitive impairments (Thiebaut de Schotten et al., 2005), especially aphasia (Duffau et al., 2002; Duffau, Gatignol, et al., 2005). On the basis of the data provided by postoperative MRI, we correlated the intrasurgical functional findings with the anatomical locations of the sites where language disturbances were elicited by stimulations, both at the cortical and subcortical levels, using a technique already reported (Duffau et al., 2002; Duffau, Gatignol, et al., 2005). In this series of left-handed patients, our results provide strong arguments in favor of a pattern of language distribution in the RH quite similar to the configuration classically reported in the LH in right-handers. 2. Patients and methods 2.1. Subjects (Table 1) We retrospectively studied a consecutive series of nine left-handed patients harboring a low-grade glioma within the right hemisphere and who underwent awake surgery in order to identify and preserve the cortical and subcortical struc-

tures essential for language during resection. Intraoperatively, the information was collected in the course of the clinical procedures and not as a planned investigation. Preoperatively, all patients underwent a neurological examination. Language was tested by a speech therapist using the Boston Diagnostic Aphasia Examination (BDAE) (Goodglass & Kaplan, 1972)—French version, adapted by Mazaux and Orgogozo (Mazaux & Orgogozo, 1982). Handedness was assessed using a standardized questionnaire (Edinburgh inventory) (Oldfield, 1971). All patients (two males and seven females, mean of age 34 years) were lefthanded (score using the Ebinburgh test ranged from −70 to −100). Three patients had a familial history of left-handedness. The presenting symptoms were seizures in the nine cases (four generalized, five partial with transient language disturbances), evolving over 3–6 months. At the time of the surgery, all patients had been free of seizures for at least 1 week on antiepileptic medication. The preoperative neurological clinical testing and language examination were normal in all patients. The topography of the tumor was accurately analyzed on a pre-operative MR image (T1-weighted and spoiled-gradient images obtained before and after gadolinium enhancement in the three orthogonal planes, and T2-weighted axial images). The preoperative MRI showed in all cases a T1-weighted hypointense and T2weighted hyperintense right cortico-subcortical lesion, without enhancement after gadolinium injection. Five different groups of tumor locations were found (Figs. 1 and 2): three patients with a lesion within the fronto-mesial structures; one patient with a glioma involving the posterior part of the middle frontal gyrus (Fig. 1A); one patient with a insulo-opercular tumor; two patients with a glioma involving the inferior parietal lobule; and two patients harboring a temporal glioma (Fig. 2A). At the end of this presurgical clinico-radiological evaluation, despite the location of the tumor within the RH but due to the strong left-handedness of the nine patients, we decided to perform an awake surgery in these patients. It is worth noting that left-handedness does not necessarily mean that the RH is “dominant” for language, but that the RH may be involved in language. As a consequence, the aim was to use intraoperative electrical language mapping, in order to objectively check the actual presence (or not) of essential language sites within the RH, and to preserve them if detected, thus minimizing the risk of possible postsurgical permanent aphasia. It is worth noting that Wada testing is not performed in our experience, because it represents an invasive testing which is only able to provide information about language laterality, but not about the exact organization of the functional anatomy of language and its relation to the tumor (i.e. what is the margin between the cortical and subcortical structures essential for the function, and the glioma). This is the reason why, when close relationships between tumor and language areas are suspected (here on the basis of the Edinburgh Inventory), we prefer to systematically perform awake mapping. Indeed, this is a very well tolerated procedure, enabling detection and preservation of language structures (if close to the tumor) with a very high reproducibility—while optimizing the quality of glioma removal, as already demonstrated in our previous reports (Duffau et al., 2002; Duffau, Gatignol, Mandonnet, Capelle, & Taillandier, in press; Duffau, Gatignol, et al., 2005; Duffau, Lopes, et al., 2005).

2.2. Intraoperative mapping All patients underwent awake surgery under local anesthesia so that functional, especially language, cortical and subcortical mapping could be carried out using direct electrical stimulations (DES). This method, including electrical parameters and intraoperative clinical tasks, was described previously by the authors (Duffau et al., 2002, in press; Duffau, Gatignol, et al., 2005; Duffau, Lopes, et al., 2005). A bipolar electrode with 5 mm spaced tips delivering a biphasic current (pulse frequency of 60 Hz, single pulse phase duration of 1 ms, amplitude from 2 to 6 mA) (Nimbus, Hemodia) was applied to the brain of awake patients. In the first stage, cortical mapping was performed, after tumor and sulci/gyri identifications using ultrasonography, and before resection, in order to avoid any eloquent area damage. Sensorimotor mapping was performed first, to confirm a positive response (e.g. the induction of movement and/or paresthesia in the contralateral hemibody when the primary sensorimotor areas were stimulated in a

Table 1 Clinical and radiological and characteristics of the nine patients operated on for a LGG in the right hemisphere, using intraoperative language mapping Patient

Sex (age)

Preoperative examination

Glioma location

1 2 3 4 5 6 7 8 9

F (44) F (28) F (39) M (32) F (27) F (29) M (28) F (26) F (39)

Normal neurological examination Edinburgh score: −90; DO 80 score: 77/80 Normal neurological examination Edinburgh score: −100; DO 80 score: 79/80 Normal neurological examination Edinburgh score: −80; DO 80 score: 78/80 Normal neurological examination Edinburgh score: −80; DO 80 score: 76/80 Normal neurological examination Edinburgh score: −80; DO 80 score: 79/80 Normal neurological examination Edinburgh score: −80; DO 80 score: 79/80 Normal neurological examination Edinburgh score: −80; DO 80 score: 79/80 Normal neurological examination Edinburgh score: −70; DO 80 score: 80/80 Normal neurological examination Edinburgh score: −70; DO 80 score: 77/80

Fronto-mesial precentral Fronto-mesial precentral Fronto-mesial precentral Middle frontal gyrus (posterior part) IFG (posterior part) + rolandic operculum + insula Inferior parietal lobule Inferior parietal lobule Temporal lobe (excluding the Superior temporal gyrus) Temporal lobe (excluding the Superior temporal gyrus)

Abbreviations: LGG = Low-grade glioma; M = male; F = female; PMC = premotor cortex; IFG = inferior frontal gyrus.

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209

3199

Fig. 1. (A) Preoperative axial and coronal T1-weighted enhanced MRI, showing a low-grade glioma involving the right middle frontal gyrus, in front of the precentral sulcus (arrow). (B) Intraoperative photograph before tumor resection. The eloquent cortical sites identified using electrical stimulations were marked by numbers as follows: 1, 2 and 3: primary area of the hand; 10, 11: primary somatosensory of the hand (retrocentral gyrus); 20: primary area of the face; 6: primary somatosensory area of the face (retrocentral gyrus); 22 and 5: ventral premotor cortex inducing anarthria during stimulations (lateral part of the precentral gyrus); 21: speech arrest (pars opercularis of the IFG) (arrows: Precentral sulcus; A = anterior; P = posterior). (C) Intraoperative photograph after tumor resection, showing that the walls of the cavity were represented by language cortical sites and subcortical pathways, as follows: 42 and arrow: fibers eliciting reduction of spontaneous speech with planning disorders (transcortical motor aphasia) when stimulated, then constituting the medial limit of the resection (preventing the opening of the ventricle); they correspond to the subcallosal fasciculus, running to the head of the caudate (see Fig. 2D). 41: Subcortical pathways eliciting reproducible anarthria when stimulated, which constitute the posterior limit of the resection (laterally to the pyramidal pathways marked by 40); they come from the ventral premotor cortex (22) and run to the periventricular white matter. 44: Fibers under the pars opercularis of the IFG (21), generating speech arrest when stimulated; they correspond to the operculo-insular connection. 43: Postero-lateral limit of the resection, due to phonemic paraphasias induced by DES; this bundle likely corresponds to the anterior part of the superior longitudinal fasciculus (see Figs. 3 and 4). Star: Anteroinferior boundary, due to semantic paraphasias elicited by DES, at a site which corresponds to the anterior part of the inferior occipito-frontal fasciculus (in front of the pathways involved in language production). The patient presented transient postoperative dysarthria, which recovered within 2 months—following speech rehabilitation. (D) Postoperative axial and coronal T1-weighted enhanced MRI. The boundaries of the cavity are: medially, the subcallosal fasciculus (straight arrows), running from the supplementary motor area and cingulum to the head of the caudate superiorly; posteriorly, the fibers descending from the ventral premotor cortex to the perventricular white matter (curve arrows); laterally, the operculo-insular connections (big arrow on the coronal view). Between the two last vertical pathways, there is the anterior part of the superior longitudinal fasciculus, running to the parietal lobe (see Fig. 4). Finally, the antero-lateral and inferior limit of the cavity was represented by the anterior-superior part of the inferior occipito-frontal fasciculus (big arrow on the axial view).

3200

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209

Fig. 2. (A) Preoperative axial and coronal T1-weighted enhanced MRI, showing a low-grade glioma involving the right mid-temporal lobe, with preservation of the superior temporal gyrus (arrow = superior temporal sulcus). (B) Intraoperative photograph before tumor resection. The eloquent cortical sites identified using electrical stimulations marked by numbers as follows: 3: primary area of the face; 1 and 2: ventral premotor cortex inducing anarthria during stimulations (lateral part of the precentral gyrus); 4: speech arrest (pars opercularis of the IFG); 10, 11, 13: superior temporal gyrus, eliciting semantic paraphasia when stimulated; 12: posterior part of the middle temporal gyrus, generating semantic paraphasia during DES (small arrow: precentral sulcus; Big arrows: sylvian fissure; A = anterior; P = posterior). (C) Intraoperative photograph after tumor resection, showing that the depth of the cavity was represented by language subcortical pathway, running under the superior temporal sulcus, above the temporal horn of the ventricle, and inducing semantic paraphasia when stimulated: this bundle corresponds to the posterior part of the inferior occipito-frontal fasciculus (arrows). The patient presented transient postoperative semantic disturbances, which recovered within 3 months—following speech rehabilitation. (D) Postoperative axial and coronal T1-weighted enhanced MRI. The deep boundaries of the cavity are represented by the inferior occipito-frontal fasciculus, located between the lateral-superior part of the temporal horn of the ventricle and the depth of the superior temporal sulcus (arrows).

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209 patient at rest), since the boneflap allowed good exposure of the central region in all patients. Under local anaesthesia, the current intensity adapted to each patient was determined by progressively increasing the amplitude in 1 mA increments from a baseline of 2 mA, until a sensorimotor response was elicited, with 6 mA as the upper limit, with the goal of avoiding the generation of seizures (for an extensive review of the methodology, see Duffau, 2004, 2005). Then, the patient was asked to perform counting (regularly from 1 to 10 over and over) in order to check the parameters of stimulation – namely, until speech arrest was induced by stimulating the rolandic operculum (Duffau, Capelle, Denvil, Gatignol, et al., 2003; Duffau, Capelle, Denvil, Sichez, et al., 2003; Duffau, Gatignol, Denvil, Lopes, & Capelle, 2003) – before using naming as the gold standard throughout the procedure. Indeed, due to its high sensitivity, picture naming (preceeded by a short sentence to read, namely the French translation of “this is a . . .”, in order to verify that there were no seizures generating complete speech arrest if the patient was not able to name), remains the task the most often reported during intraoperative functional mapping—in order to identify the essential cortical language sites known to be inhibited by stimulations (Duffau, Capelle, Denvil, Gatignol, et al., 2003; Duffau, Capelle, Denvil, Sichez, et al., 2003; Duffau, Gatignol, et al., 2003; Duffau, Lopes, et al., 2005; Ojemann, Ojemann, Lettich, & Berger, 1989). For this naming task, we used the DO 80 (namely “Dénomination d’Objects” 80), which consists of 80 black and white pictures selected according to variables, such as frequency, familiarity, age of acquisition, and level of education (Metz-Lutz, Kremin, & Deloche, 1989). The patient was never informed when the brain was stimulated. The duration of each stimulation was 4 s. The patient had 4 s to provide the good answer to the speech therapist. At least one picture presentation without stimulation separated each stimulation, and no site was stimulated twice in succession, to avoid seizures. Each cortical site (size 5 mm × 5 mm, due to the spatial resolution of the probe) of the entire cortex exposed by the boneflap was tested three times. Indeed, it is nowadays accepted, since the landmark publication of Ojemann et al. (Ojemann et al., 1989), that three trials are sufficient to ascertain whether a cortical site is essential or not for language—that is, generating speech disturbances during all three stimulations, with normalization of language as soon as the stimulation is stopped. However, when results for the three trials are inconsistent (e.g. two errors, one correct), a fourth trial is performed. If a language disorder is again induced, the site is preserved. If no error is elicited, the decision to remove the site or not is taken later according to the additional information provided by the subcortical mapping—i.e. the resection will be made only when white matter stimulation under the cortical area does not generate any disturbance, with a continuous verification of the ability to speak during the removal. This limitation of trials and tasks is required by the duration of the surgical procedure, since the patient is awake. The type of language disturbances was detailed by a speech therapist routinely present in the operative room during the functional mapping. Each eloquent area was marked using a sterile number tag on the brain surface, and its location correlated to the anatomical landmarks (sulci/gyri/tumor boundaries) previously identified by ultrasonography. A photograph of the cortical map was systematically made before resection. Thereafter, the glioma was removed, by alternating resection and subcortical stimulations. The functional pathways were followed progressively from the cortical eloquent sites already mapped, to the depth of the resection. The patient had to continue to count and/or name when the resection became close to the subcortical language structures, which were also identified by language inhibition during stimulations as at the cortical level (Duffau et al., 2002; Duffau, Gatignol, et al., 2005; Duffau, Lopes, et al., 2005). Again, the type of language disturbances was detailed by a speech therapist throughout the resection. In order to perform the best possible tumor removal with preservation of the functional areas, all the resections were pursued until eloquent pathways were encountered around the surgical cavity, then followed according to functional boundaries. Thus, there was no margin left around the cortico-subcortical eloquent areas. Postoperative functional outcome was assessed systematically by the same neurosurgeons and speech therapist as preoperatively, using the same tasks, both during the immediate postoperative stage and 3 months after surgery. A control MRI was performed in all cases, immediately and 3 months after surgery. This imaging allowed firstly evaluation of the quality of glioma removal, and secondly analysis of the anatomical location of the language pathways. Indeed, since the resection was stopped according to functional boundaries, i.e. with no margin, especially at the subcortical level, the floors of the cavity shown on the postoperative MRI correspond by definition to the pathways essential for function. As a consequence, the shift between intraoperative view and postoperative imaging is not problematic, since the walls of the surgical cavity, whatever their eventual deformation, are the functional tracts. This methodology was extensively published by our team in previous reports (Duffau, Capelle, Denvil, Gatignol, et al., 2003; Duffau, Capelle, Denvil, Sichez, et al., 2003; Duffau et al., 2002; Duffau, Gatignol, et al., 2003; Duffau, Gatignol, et al., 2005; Mandonnet, Nouet, Gatignol, Capelle, & Duffau, 2007; Thiebaut de Schotten et al., 2005). 2.3. Analysis of the intraoperative naming disturbances Naming disorders were analyzed by distinguishing different types of language disorders, already defined in previous reports: phonetic paraphasias (dysarthria)

3201

(Duffau, Gatignol, et al., 2003); phonemic paraphasias (Duffau et al., 2002); semantic paraphasias (Duffau, Gatignol, et al., 2005); anomias (Gatignol, Capelle, Le Bihan, & Duffau, 2004), perseverations (Gil Robles, Gatignol, Capelle, Mitchell, & Duffau, 2005) and speech arrest (Duffau, Capelle, Denvil, Gatignol, et al., 2003; Duffau, Capelle, Denvil, Sichez, et al., 2003; Duffau, Gatignol, et al., 2003).

3. Results The surgical findings and postoperative course of the nine patients are summarized in Table 2. 3.1. Operative findings In the nine patients, language disturbances were elicited during both cortical and subcortical stimulations, demonstrating the existence of essential language sites within the RH in all cases. 3.1.1. Fronto-mesial gliomas 3.1.1.1. At the cortical level. Frontal cortical language sites were identified by stimulations in the 3 patients before resection, systematically generating production disorders. More precisely, DES elicited dysarthria/phonetic paraphasia at the level of one site of the ventral premotor cortex, i.e. the ventral compartment of area 6, covering the part of the precentral gyrus located anteriorly and inferiorly to the primary motor area of the face (also detected by DES). Furthermore, DES generated anomia in one patient, at the level of a discrete area of the inferior part of the dorsal premotor cortex, i.e. the dorsal part of area BA 6, covering the posterior part of the superior and middle frontal gyri, immediately in front of the central sulcus. 3.1.1.2. At the subcortical level. DES also reproducibly induced articulatory disturbances in the three patients, at the level of the postero-lateral wall of the cavity, i.e. during stimulations of the pathways lateral to the pyramidal fibers (also identified using subcortical DES, which elicited motor limb responses). These pathways involved in articulation processing come from the ventral premotor cortex, and converge deep to the periventricular white matter, lateral to the head of the caudate nucleus. Furthermore, in two patients, DES of the head of the caudate induced reproducible perserverations. 3.1.2. Glioma involving the posterior part of the middle frontal gyrus 3.1.2.1. At the cortical level (Fig. 1B). DES elicited dysarthria at the level of two sites within the ventral premotor cortex, as defined above, i.e. anteriorly and inferiorly to the primary motor area also identified. Moreover, a complete speech arrest was also induced during stimulation of one discrete area of the pars opercularis of the IFG. 3.1.2.2. At the subcortical level (Fig. 1C). Medially, the limit was represented by the medial wall of the surgical cavity, where reduction of speech was induced by stimulation of fibers joining the anterolateral border of the frontal horn of the ventricle. Intraoperative reduction of speech means that the patient was not able to give the name of the picture within 4 s (i.e. the duration of visual stimuli, as detailed in Section 2). But the patient was still able to name when the duration of presentation of each picture was extended beyond 4 s. For this reason, the ventricle could never be opened. This pathway, which connects the fronto-mesial precentral structures (namely, the supplementary motor area and cingulum, here preserved since not invaded by the tumor and still functional, contrary to the cases described above) to the head of the caudate, corresponds to the subcallosal fasciculus.

3202

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209

Table 2 Surgical findings and postoperative course Patient 1

Intraoperative electrical language mapping

Postoperative examination

Postoperative anatomical MRI

Cortical language mapping

Transient transcortical motor aphasia then recovery within 3 months; DO 80 score at 3 months: 78/80

Postero-lateral boundary: Articulatory pathway (from the ventral PMC to the PVWM)

Ventral PMC: anarthria Dorsal PMC: anomia Subcortical language mapping Posteriorly: articulatory pathway Head of the caudate: perseverations 2

Cortical language mapping

Deep boundary: head of the caudate nucleus Transient transcortical motor aphasia then recovery within 2 months; DO 80 score at 3 months: 78/80

Postero-lateral boundary: Articulatory pathway (from the ventral PMC to the PVWM)

Transient transcortical motor aphasia then recovery within 1 month; DO 80 score at 3 months 79/80

Postero-lateral boundary: Articulatory pathway (from the ventral PMC to the PVWM)

Transient dysarthria then recovery within 2 months; DO 80 score at 3 months: 77/80

Posterior boundary: Articulatory pathway (from the ventral PMC to the PVWM)

Ventral PMC: anarthria Subcortical language mapping Posteriorly: articulatory pathway 3

Cortical language mapping

Ventral PMC: anarthria Subcortical language mapping Posteriorly: articulatory pathway Head of the caudate: perseverations 4

Cortical language mapping (Fig. 1) Ventral PMC: anarthria Pars opercularis of the IFG: speech arrest

•Medial limit: subcallosal fasciculus •Lateral limit: insulo-opercular connection •Postero-lateral and deep limit: anterior part of the superior longitudinal fasciculus •Antero-lateral limit: anterior part of the inferior occipito-frontal fasciculus •Lateral limit: insulo-opercular connection

Subcortical language mapping Posteriorly: articulatory pathway Medially: transcortical motor aphasia Laterally: speech arrest Postero-inferiorly: phonemic paraphasia Antero-inferiorly: semantic paraphasia 5

Cortical language mapping

Transient dysarthria then recovery within 7 days; DO 80 score at 3 months: 79/80

Posterior boundary: Articulatory pathway (from the ventral PMC to the PVWM) •Superior deep limit: anterior part of the superior longitudinal fasciculus •Inferior deep limit: insula

Transient phonological disorders then recovery within 2 weeks; DO 80 score at 3 months: 78/80

Deep boundary: Postero-superior loop of the superior longitudinal fasciculus

Transient phonological disorders then recovery within 2 months; DO 80 score at 3 months: 79/80

Deep boundary: Postero-superior loop of the superior longitudinal fasciculus

Transient semantic disorders then recovery within 1 month; DO 80 score at 3 months: 80/80

Deep boundary: posterior part of the inferior occipito-frontal fasciculus

Transient semantic disorders then recovery within 3 months; DO 80 score at 3 months: 79/80

Deep boundary: posterior part of the inferior occipito-frontal fasciculus

Ventral PMC: anarthria DLPFC: semantic paraphasia Anterior insular cortex: articulatory disorders Subcortical language mapping Posteriorly: Articulatory pathway Deeply: phonemic paraphasia 6

Cortical language mapping Ventral PMC: anarthria Supramarginal gyrus: phonemic paraphasia Subcortical language mapping Deeply: phonemic paraphasia

7

Cortical language mapping Ventral PMC: anarthria Supramarginal gyrus: phonemic paraphasia Subcortical language mapping Deeply: phonemic paraphasia

8

Cortical language mapping Ventral PMC: anarthria Superior temporal gyrus: semantic paraphasia Subcortical language mapping Deeply: semantic paraphasia

9

Cortical language mapping (Fig. 2) Ventral PMC: anarthria Superior temporal gyrus and posterior part of the middle temporal gyrus: semantic paraphasia Subcortical language mapping Deeply: semantic paraphasia

Abbreviations: PMC = Premotor cortex; DLPC = dorsolateral prefrontal cortex; PVWM = periventricular white matter; IFG = inferior frontal gyrus.

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209

3203

Posteriorly, the resection was stopped at the level of language pathways inducing dysarthria during DES, coming from the ventral premotor cortex and joining the periventricular white matter in the depth, as described above in the group of fronto-mesial gliomas. Laterally, the limit was represented by the subcortical pathways directly under the cortical language site eliciting speech arrest during DES, i.e. corresponding to the operculo-insular connections. Posteriorly and inferiorly, in the depth of the cavity, DES induced phonemic paraphasias, related to the anterior part of the superior longitudinal fasciculus. Anteriorly and inferiorly, in the depth of the cavity, DES generated semantic paraphasias, at a site which corresponds to the anterior part of the inferior occipito-frontal fasciculus, in front of the pathways involved in language production. 3.1.3. Insulo-opercular glioma 3.1.3.1. At the cortical level. DES elicited dysarthria at the level of three sites in the ventral premotor cortex, as defined above. Moreover, semantic paraphasias were induced during stimulation of two discrete areas within the antero-inferior part of the middle frontal gyrus, i.e. the dorso-lateral prefrontal cortex (DLPFC). In addition, following resection of a part of the tumor, allowing a good exposure of the insular cortex, DES of its anterior surface generated reproducible articulatory disorders. 3.1.3.2. At the subcortical level. The inferior limit was represented by the pathways eliciting phonetic disturbances when stimulated, namely the fibers connecting the insula to the frontal cortical language sites involved in production; the deep and superior boundary corresponded to the superior longitudinal fasciculus, inducing phonemic paraphasia when stimulated; and the posterior limit was represented by the fibers coming from the ventral premotor cortex, joining the periventricular white matter when descending under the insular lobe, and generating anarthria during stimulation. 3.1.4. Gliomas involving the inferior parietal lobule 3.1.4.1. At the cortical level. Again, DES elicited dysarthria at the level of two sites in the ventral premotor cortex, as defined above. Moreover, phonemic paraphasias were also induced during stimulation of two discrete areas within the antero-inferior part of the supramarginal gyrus. More inferiorly, i.e. at the level of the posterior part of the temporal lobe, DES generated reproducible semantic paraphasias at the level of two sites. 3.1.4.2. At the subcortical level. Inferiorly, behind the fibers involved in somatosensory function, deep DES induced phonemic paraphasias, at the level of the postero-superior loop of the superior longitudinal fasciculus (arcuate fasciculus). 3.1.5. Temporal gliomas 3.1.5.1. At the cortical level (Fig. 2B). In both patients, DES elicited dysarthria at the level of two sites in the ventral premotor cortex, as defined above. Furthermore, in both cases, semantic paraphasias were reproducibly induced by stimulation, all along the superior temporal gyrus/superior temporal sulcus once opened (at the level of three discrete areas in one patients, and of two areas in the other), and within the posterior part of both the superior and middle temporal gyri (two discrete sites in both patients). 3.1.5.2. At the subcortical level (Fig. 2C). DES induced semantic paraphasias in the two patients, during stimulation of the white bundle located under the superior temporal sulcus, above the temporal horn of the ventricle (opened in both patients). This pathway corresponds to the inferior occipito-frontal fasciculus.

Fig. 3. Schematic brain map summarizing the different sites at which naming disturbances occurred during stimulation across the nine patients: ( ) phonetic paraphasia (dysarthria); () semantic paraphasia; () phonemic paraphasia; () anomia; (䊉) speech arrest.

In all nine patients, cortico-subcortical eloquent structures identified by stimulations were systematically preserved, constituting the functional boundaries of the resection. The intraoperative results are condensed in a schematic brain map (Fig. 3) and Table 3. In summary, (1) at the cortical level: stimulation of the ventral premotor cortex induced anarthria in 9/9 cases; DES of the dorsal premotor cortex elicited anomia in 1/5 patients; DES of the DLPFC generated semantic paraphasia in 2/5 patients; DES of the pars opercularis of the IFG produced speech arrest in 1/5 patients; DES of the supramarginal gyrus induced phonemic paraphasia in 2/2 patients; DES of the superior temporal gyrus and/or posterior part of the middle temporal gyrus elicited semantic paraphasia in 2/2 patients. (2) At the subcortical level: Stimulation of the pathways coming from the ventral premotor cortex elicited anarthria in 5/5 patients; DES of the subcallosal fasciculus generated transcortical motor aphasia in 1/1 patient; DES of the operculo-insular connection produced speech arrest in 2/2 patients; DES of the superior longitudinal fasciculus induced phonemic paraphasia in 4/4 patients; DES of the inferior occipitofrontal fasciculus generated semantic paraphasia in 3/3 patients, and DES of the head of the caudate nucleus induced perseverations in 2/3 patients. 3.2. Postoperative course Postoperatively, only a qualitative analysis was done immediately after the operation, mostly due to patient fatigue in the days after an awake procedure preventing an extensive assessment. The nine patients presented transient language disorders, which resolved within 7 days to 3 months, irrespective of the location of the tumor. The patients operated on for a fronto-mesial glioma experienced a transient supplementary motor area syndrome (mutism and akinesia during 10 days); the patients operated on for a tumor involving the middle frontal gyrus or the insuloopercular structure presented speech production disorders with phonetic paraphasias and even anarthria; the patients operated on for a parietal glioma experienced transient phonemic paraphasias; and those operated on for a temporal glioma presented transitory semantic disturbances. These transient postoperative deficits have been in agreement with the disturbances induced by intraoperative mapping (e.g. postsurgical phonological deficit when phonemic paraphasias have been elicited by direct stimulation, and so on). All patients benefited from speech rehabilitation, which allowed a complete functional recovery systematically evaluated using the

3204

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209

Table 3 Specific symptoms induced by stimulation of each brain region of the right hemisphere Brain areas

Cortical regions Ventral PMC Dorsal PMC DLPFC Pars opercularis IFG Supramarginal gyrus Superior/middletemporal gyri Subcortical structures Fibers from the ventral PMC Subcallosal fasciculus Operculo-insular connection Superior longitudinal fasciculus Inferior occipito-frontal fasciculus Head of caudate nucleus

Symptoms Anarthria

Anomia

Semantic paraphasia

Speech arrest

Phonemic paraphasia

Transcortical motor aphasia

Perseveration

9/9 1/5 2/5 1/5 2/2 2/2 5/5 1/1 2/2 4/4 3/3 2/3

Abbreviations: PMC = Premotor cortex; DLPFC = dorsolateral prefrontal cortex; IFG = inferior frontal gyrus. For each site, the first number is the number of transient language disorders elicited by stimulation, and the second number is the number of patients stimulated.

same BDAE as preoperatively, and showing a normalization of the scores. All patients returned to a normal socio-professional life, with no persistent language deficit. Histological examination revealed a WHO grade II glioma in all cases. There was no complementary treatment. 3.3. Radiological results In fronto-mesial gliomas, the infero-lateral limits of the cavity were represented by the premotor cortex, then the corresponding fibers, running to the periventricular white matter, and surrounding the head of the caudate nucleus (also preserved). Due to tumoral infiltration of these structures in one patient, the resection was subtotal in this case, while total in the two other cases. In the glioma invading the posterior part of the middle frontal gyrus (Fig. 1D), the medial boundary of the cavity was represented by the subcallosal fasciculus, running from the supplementary motor area and cingulum to the caudate. Posteriorly, the resection was stopped at the level of language pathways coming from the ventral premotor cortex and joining the periventricular white matter in the depth. Laterally, the limit was represented by the subcortical operculo-insular connections. The postero-inferior limit in the depth corresponded to the anterior part of the superior longitudinal fasciculus. Finally, the antero-inferior limit in the depth corresponded to the anterior part of the inferior occipito-frontal fasciculus, in front of the pathways involved in language production. The tumor resection was subtotal, due to an invasion of the deep language pathways. In the insulo-opercular glioma, the cavity came into contact with the premotor cortex and the corresponding pathways posteriorly and medially, the DLPC anteriorly and medially, and insular cortex in the depths of the cavity. The tumor removal was partial. In the gliomas involving the inferior parietal lobule, in both patients, the resection preserved the antero-inferior part of the supramarginal gyrus, then its corresponding fibers running into the postero-superior loop of the superior longitudinal fasciculus—which represented the deep wall of the cavity. One resection was complete and one partial. In the temporal gliomas (Fig. 2D), the cavity came into contact superiorly with the superior temporal sulcus in the two patients, up to the depth of this sulcus; and deeply, with the lateral-superior part of the temporal horn of the ventricle which was opened: between these two boundaries runs the temporal part of the inferior occipito-frontal fasciculus, that constituted the deep limit of

the resection. Because of an infiltration of this white bundle, the tumor removal was subtotal in both patients. 4. Discussion To our knowledge, this is the first report which studies the functional anatomy of the whole language network within the RH in left-handers, both at cortical and subcortical levels, using intraoperative electrical stimulation. 4.1. Cortical language organization within the RH 4.1.1. Frontal cortex In all patients, DES of the ventral premotor cortex (BA 6) elicited reproducible dysarthria. These findings suggest that, like in the LH in right-handed patients (Duffau, Capelle, Denvil, Gatignol, et al., 2003; Duffau, Capelle, Denvil, Sichez, et al., 2003; Duffau, Gatignol, et al., 2003; Fox, Kasner, Chatterjee, & Chalela, 2001), the homologous area of the so-called “lower motor cortex” (i.e. the rolandic operculum) in the RH is also implicated in motor aspects of articulation and speech, at least in left-handers. Moreover, DES of the pars opercularis of the IFG (BA 44) induced speech arrest (patients 4 and 5), as classically described during DES of the “Broca’s area” in the LH (Duffau, Capelle, Denvil, Gatignol, et al., 2003; Duffau, Capelle, Denvil, Sichez, et al., 2003; Duffau, Gatignol, et al., 2003; Ojemann et al., 1989). These results are in line the scarce previous electrocortical stimulation studies in the RH (Andy & Bhatnagar, 1984; Jabbour et al., 2005; Penfield & Roberts, 1959; Smith, 1980) as well as with repetitive transcranial magnetic stimulation studies (Thiel et al., 2005). Such results show that the right pars opercularis may make an essential contribution to speech production, explaining why (1) lesions within this area can generate speech production disorders (Kurowski, Blumstein, & Mathison, 1998), (2) activations of this region were observed by neurofunctional imaging during production tasks in healthy volunteers (Klein, Milner, Zatorre, Visca, & Olivier, 2002; Tzourio-Mazoyer et al., 2004), (3) recruitment of this area was demonstrated in cases of lesions of the left homologue area (Blank, Bird, Turkheimer, & Wise, 2003; Holodny, Schulder, Ybasco, & Liu, 2002). Thus, the organization of the right fronto-opercular region for language seems relatively similar to the configuration described in the LH (Poldrack et al., 1999). Interestingly, DES over the more anterior and/or superior structures, especially the DLPFC, elicited semantic paraphasias (patient

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209

5). This is in accordance with the findings reported in the LH (Duffau, Gatignol, et al., 2005), with a semantic area cluster around the antero-inferior IFG (Bookheimer, 2002; Poldrack et al., 1999), the pars triangularis (Friederici, Meyer, & von Cramon, 2000) and the DLPFC (Szatkowska, Grabowska, & Szymanska, 2000). DES of the inferior part of the dorsal premotor cortex, behind the DLPFC, generated anomia, as already reported in the left dorsal premotor cortex. It was interpreted as a transient disruption of a region involved in the processing of motoric aspects of objects semantics (Duffau, Capelle, Denvil, Gatignol, et al., 2003; Duffau, Capelle, Denvil, Sichez, et al., 2003; Duffau, Gatignol, et al., 2003; Grafton, Fadiga, Arbib, & Rizzolatti, 1997). Thus, frontal sites essential for language were detected in the nine left-handed patients. This is in accordance with reports arguing that handedness has a more direct relationship with frontal regions (Dassonville, Zhu, Ugurbil, Kim, & Ashe, 1997; Josse & Tzourio-Mazoyer, 2004; Szaflarski et al., 2002), that is, with regions dedicated to action, a finding that fits with the motor theory of language (Corballis, 2003). 4.1.2. Insular cortex In patient 5, DES of the anterior insula elicited articulatory disturbances. These findings fit well with the major role of the left insula in the complex planning of speech, as demonstrated by insular lesion (Dronkers, 1996), neurofunctional imaging (Wise, Greene, Buchel, & Scott, 1999) and intraoperative DES (Duffau et al., 2000). Moreover, the likely implication of the right insula in language was suggested, especially in intonation contours of verbal utterances and musical melodies (Ackermann & Riecker, 2004). The right insula can also be involved in language compensation in righthanded patients with a left insular tumor, in addition to perilesional recruitment (Duffau, Bauchet, Lehéricy, & Capelle, 2001). 4.1.3. Parietal cortex DES of the supramarginal gyrus induced reproducible phonemic paraphasias (patients 5, 6 and 7). These results are in accordance with those reported following lesions of the right supramarginal gyrus, which also showed phonological disturbances (Marien, Engelborghs, Paquier, & De Deyn, 2001) and with the activation of this structure using neurofunctional imaging during phonological tasks (Pillai et al., 2003). Moreover, the implication of the right supramarginal gyrus in language recovery following left stroke was observed (Abo et al., 2004). Thus, the right supramarginal gyrus, at least in left-handers, might subserve the same language role in phonological processing as previously described in the LH, by lesion (Sakurai et al., 1998), activation imaging (Tan, Laird, Li, & Fox, 2005) and electrostimulation studies (Duffau, Gatignol, et al., 2003; Ojemann et al., 1989). 4.1.4. Temporal cortex Here, in the three patients with temporal language mapping of the RH (patients 7, 8 and 9), we elicited reproducible semantic paraphasias by stimulating the regions centered around the posterior part of the right superior temporal sulcus—i.e. both the superior and middle temporal gyri. These findings are in line with the neurofunctional imaging studies, which showed very regular temporal activations within the RH during semantic tasks, both in left-handers (Tzourio-Mazoyer et al., 2004) and right-handers (Menard, Kosslyn, Thompson, Alpert, & Rauch, 1996). Indeed, it seems that handedness has weaker relationship with temporal regions than frontal regions, explaining the frequent bilateral temporal activations in comprehension tasks (Démonet, Thierry, & Cardebat, 2005). Moreover, our results are also in accordance with a recent electrocortical stimulation study in epileptic patients with bilateral language, which showed that stimulation over the right

3205

superior and middle temporal gyri produced errors of comprehension (Jabbour et al., 2005). Finally, such data fit well with reports of right temporal lesions which lead to word processing deficit (Tranel, Damasio, & Damasio, 1997), and reports which showed the recruitment of the right Wernicke’s areas in cases of lesions involving the left homologue area (Petrovich, Holodny, Brennan, & Gutin, 2004; Price & Crinion, 2005). Thus, these data support the implication of the right posterosuperior temporal structures in semantic processing. 4.2. Subcortical language anatomo-functional connectivity within the RH Little is currently known about the anatomo-functional connectivity of language within the RH. Here, we used intraoperative cortical and subcortical DES, which provides a unique opportunity to study directly the anatomical and functional connectivity simultaneously (Duffau et al., in press). Indeed, it is possible to perform an on-line evaluation of the functional consequences of each focal stimulation on awake patients (i.e. to analyze precisely the type of language disturbances transitorily induced), and to correlate each eloquent site to its exact anatomical location on the postoperative MRI—since the edges of the surgical cavity are the functional pathways, due to the fact that the resection was systematically stopped according to functional boundaries. 4.2.1. Superior longitudinal fasciculus: phonological loop In patient 4, with a glioma within the middle frontal gyrus, phonemic paraphasias were generated during DES of the white matter running in the postero-inferior wall of the cavity. We also elicited the same phonological errors by stimulating the deep wall of the cavity (especially in its superior part) in patient 5, harboring an insulo-opercular tumor. Thus, we detected several localizations of the same pathway, running under the IFG and under the inferior part of the middle frontal gyrus. Interestingly, phonological disturbances were equally elicited during stimulation of the white matter following resection of the supramarginalis gyrus in the patients 6 and 7 operated on for a glioma involving the inferior parietal lobule. Consequently, we can hypothesize that different parts of the same bundle were detected in these patients, since the same symptoms were induced when each was stimulated. Anatomically, such a pathway is in accordance with the superior longitudinal fasciculus in its anterior (fronto-parietal) part (Bossy, 1991; Catani, Jones, & Ffytche, 2005), because this pathway is known to play a major role in phonology, by connecting cortical structures involved in phonological processing (e.g. IFG and supramarginal gyrus). This right pathway could be the anatomo-functional homologue of the left superior longitudinal fasciculus, as described using DES in righthanded patients (Duffau et al., 2002). 4.2.2. Inferior occipito-frontal fasciculus: semantic loop In patients 8 and 9, with a temporal glioma, semantic paraphasias were systematically induced during DES of the white matter located under the superior temporal sulcus. Since the resection involved the anterior, mid- and posterior parts of the temporal lobe, it was possible to detect several subcortical sites eliciting semantic disturbances, from the occipito-temporal junction posteriorly to the junction between the anterior temporal third and the mid-temporal third anteriorly. Thus, we identified several sites of the same bundle, running in a longitudinal direction under the superior temporal sulcus, with an inferior limit just above the temporal horn of the ventricle, and a superior limit under the superior temporal gyrus. Moreover, in patient 4, harboring a frontal tumor within the middle frontal gyrus, subcortical DES in the anteroinferior wall of the cavity also generated semantic paraphasias, by

3206

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209

stimulating the white fibers under the inferior frontal sulcus, in front of the pathways involved in speech production. This implication of a white bundle in the semantic network seems in line with the locations of the cortical sites involved in semantic processing previously described, i.e. concordant with a convergence of fibers coming from the posterior temporal regions and the midpart of the superior temporal gyrus, which joins the antero-inferior frontal areas, at the level of the DLPFC and pars orbitaris (Vigneau et al., 2006). This pathway may correspond to the right inferior occipito-frontal fasciculus mirroring its left homologue (Gloor, 1997), previously demonstrated as underlying language semantics in the LH in right-handed patients (Duffau, Gatignol, et al., 2005). However, if the inferior occipito-frontal fasciculus is essential for semantic processing, an alterative route subserved by the inferior longitudinal fasciculus and relayed by the uncinate fasciculus at the level of the anterior temporal lobe is possible (Mandonnet et al., 2007). Thus, our observations are not incompatible with those of the literature showing semantic deficits in patients with degeneration of anterior temporal cortex (e.g. semantic dementia). On the contrary, such complementary data support the view of a language circuitry organized in parallel distributed networks (Duffau et al., in press). 4.2.3. Subcallosal fasciculus: control In patient 4, operated on for a glioma within the posterior part of the middle frontal gyrus, subcortical DES at the level of the medial wall of the cavity generated a reduction of spontaneous speech (but with preservation of normal articulation)—namely, a typical transcortical motor aphasia. This may be explained by a disruption between the fronto-mesial structures (supplementary motor area and cingulum) and the head of the caudate nucleus, i.e. by an inhibition of the subcallosal fasciculus. This bundle, known to have an effect on the inititation and preparation of speech movements (Naeser, Palumbo, Helm-Estabrooks, Stiassny-Eder, & Albert, 1989), was previously demonstrated to induce control disorders when stimulated in the LH in right-handed patients (Duffau et al., 2002). Moreover, the head of the caudate nucleus could itself have

an important inhibitory role in the control of cognition, since it elicits perseveration when stimulated (Gil Robles et al., 2005). Interestingly, we induced the same symptoms by stimulating the head of the right caudate in patients 1 and 2, reinforcing the hypothesis of the modulatory role of this structure in language. 4.2.4. Fibers running through the periventricular white matter: common final pathway for production In patients 1, 2 and 3, harboring a glioma within the precentral mesio-frontal structures, patient 4 with a glioma in the middle frontal gyrus, and patient 5 with an insulo-opercular tumor, the posterior subcortical boundary of the resection was systematically given by fibers coming from the ventral premotor cortex (laterally) and the primary motor cortex of the face. DES of this pathway, which runs through the periventricular white matter, induced articulatory disturbances in all patients, with sometimes a complete anarthria—as reported in the LH in right-handers (Duffau et al., 2002). Indeed, it is well known in the dominant LH that a lesion in this region “may interrupt the pathways necessary for motor execution” (Naeser et al., 1989). Thus, the bundle identified here in the RH might be a “mirror” of the articulatory pathway essential for speech production classically described in the LH. The cortical/subcortical model of language processing is summarized in Fig. 4. The first point of note is that essential language sites were present within the RH in all patients. Although observations of RH activation using neurofunctional imaging during a language task are relatively common, especially in left-handers (Hund-Georgiadis et al., 2002; Pujol et al., 1999; Szaflarski et al., 2002; Tzourio et al., 1998), the functional relevance of such activities is still controversial, because neuroimaging can only demonstrate which brain regions are involved but cannot prove whether a brain area is essential for a task (Price & Crinion, 2005; Price, Mummery, Moore, Frakowiak, and Friston, 1999). Here, we used intraoperative DES, which elicited a transient “virtual” and focal lesion (in contrast to the Wada testing, which inactivates a major part or even the whole hemisphere) (Kloppel & Buchel, 2005). Indeed, intraoperative DES

Fig. 4. Diagram summarizing the cortical/subcortical model of language production processing that is outlined in the discussion. ( ) Inferior occipito-frontal fasciculus: ) superior longitudinal fasciculus: phonological dorsal stream; ( ) subcallosal fasciculus: control; ( ) final common pathway: semantic ventral stream; ( speech production.

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209

has been extensively demonstrated to represent a reliable, accurate and reproducible method for the detection of both cortical and subcortical structures crucial for function (Duffau et al., 2002, in press; Duffau, Gatignol, et al., 2005; Duffau, Lopes, et al., 2005; Ojemann et al., 1989; Thiebaut de Schotten et al., 2005). It is worth noting that the deficits produced by the stimulation technique were previously demonstrated to be the same as those produced by resection. Indeed, it was shown by Haglund, Berger, Shamseldin, Lettich, and Ojemann (1994) that a resection too close to the areas inducing language disturbances when stimulated produced a postoperative permanent language deficit. As a consequence, the data provided by intraoperative stimulation in our present study give a reliable insight into the anatomo-functional organization of language within the right hemisphere in left-handers. Here, DES supports an essential role in language of wellorganized networks within the RH in left-handers—in accordance with a possible large representation of ambilaterality (Satz, 1979). These data are in line with many observations which reported that a RH lesion in left-handers can induce permanent language disturbances, such as speech apraxia, comprehension disorders or alexia (Basso, Farabola, Grassi, Laiacona, & Zanobio, 1990; Delis, Knight, & Simpson, 1983; Naeser & Borod, 1986; Sugishita et al., 1987; Winkelman & Glasson, 1984). Furthermore, a recent study using repetitive transcranial magnetic stimulation both in right-handers and left-handers showed the existence of essential language function in the RH: an increased number of essential language sites detected in the RH correlated with very low left hemispheric lateralization, i.e. very slight involvement of the left hemisphere in language (Knecht et al., 2002). Previous electrocortical stimulation mapping studies (but without subcortical mapping) also found language areas within the RH, in epileptic patients with bilateral language (some of them being left-handed) (Andy & Bhatnagar, 1984; Jabbour et al., 2005). However, in our study, because we performed neither preoperative neurofunctional imaging nor transcranial magnetic stimulation over the LH, the actual participation of the LH and the interhemispheric relationship during language processing could not be determined in the nine patients. Thus, we should underline that, even if we found essential language regions in the RH, it did not exclude that the LH might also be involved in speech. Moreover, we also have to acknowledge the possibility that the intraoperative stimulation also has an effect on homologous regions in the left hemisphere. However, while this phenomenon is possible in cortical stimulation, it is very unlikely in subcortical stimulation—i.e. direct stimulation of the intra-hemispheric (and not inter-hemispheric) long-distance white matter tracts. Indeed, while callosal fibers may pass through the intra-hemispheric bundles, the density of these fibers is very low proportionally to the density of intra-hemispheric fibers. Moreover, the corpus callosum was cut in the 3 patients with fronto-mesial glioma (see Fig. 1D). In addition, the fact that the nine patients presented postoperative transient language worsening is a strong argumentation in favor of the real implication of the RH in language, supporting the findings given by intraoperative stimulation. Furthermore, while there were no right-handed control patients in the present study, we previously reported that we have operated on a homogeneous series of 41 right-handed patients harboring the same pathology (low-grade glioma) located within the right hemisphere (frontal, temporal, parietal and insular location). The patients underwent surgery under general anesthesia, without intraoperative language mapping. The rate of postoperative language disturbances, even transient, was nil (Duffau, Capelle, Denvil, Sichez, et al., 2003). These results strongly support the fact that the findings reported in the present work, namely transitory language problems after surgery, are typical for left handed patients.

3207

However, we have to underline that the nine patients described in our series harbored a slow-growing low-grade glioma, known to induce mechanisms of brain functional reorganization (Desmurget, Bonnetblanc, & Duffau, 2007). It may explain the high incidence of RH language among left-handers in this population (100%) compared to patients examinated with other methods like the Wada test. Above all, our study provides new insights into the anatomofunctional organization of the cortico-subcortical language networks in the RH. Indeed, DES, which enables the accurate and reliable identification of both cortical sites and subcortical pathways essential for language (Duffau, Capelle, Denvil, Gatignol, et al., 2003; Duffau, Capelle, Denvil, Sichez, et al., 2003; Duffau et al., 2002, in press; Duffau, Gatignol, Denvil, Lopes, & Capelle, 2003; Duffau, Gatignol, et al., 2005; Duffau, Lopes, et al., 2005; Ojemann et al., 1989) also allows on-line analysis of the type of language disturbances induced by each stimulation and then the correlation of the clinical symptoms with the location of the stimulated site (Duffau et al., 2002; Duffau, Gatignol, Denvil, Lopes, & Capelle, 2003; Duffau, Gatignol, et al., 2005; Gatignol et al., 2004; Mandonnet et al., 2007). Such anatomo-functional studies help to determine the role and the interactions of different eloquent subregions within a wider network, in this case the language circuitry in the RH in left-handers. Moreover, from a clinical point of view, on the basis of our results, we can now suggest to extent the indications of awake mapping. Our proposal is to replace the invasive Wada test by a systematic combination of language functional MRI and extensive language assessment in all (right-handed, left-handed, ambidextrous) patients harboring a lesion not only within the left hemisphere but also in the right hemisphere. If there is any doubt concerning the presence of atypical language laterality (given by the index of laterality on functional MRI and/or a possible deficit – even slight – on language assessment and/or transient language disturbances during possible preoperative seizures), we propose to systematically perform intrasurgical language mapping under local anesthesia, even in right-handed patients with a right tumor. 5. Conclusions The use, for the first time to our knowledge, of both cortical and subcortical electrical stimulation for mapping of the language networks within the RH in a homogeneous series of left-handed patients, provides strong arguments in favor of a pattern of language distribution quite similar to the configuration classically reported in the LH in right-handers. Indeed, our results support the existence of a ventral semantic stream, a dorsal phonological stream, a cortico-striato-prefrontal control, and a common articulatory pathway from the ventral premotor/motor areas through the periventricular white matter—as previously described in the LH (Duffau, 2008; Duffau et al., 2001, 2002; Duffau, Capelle, Denvil, Gatignol, et al., 2003; Duffau, Capelle, Denvil, Sichez, et al., 2003; Duffau, Gatignol, Denvil, Lopes, & Capelle, 2003; Duffau, Gatignol, et al., 2005; Gatignol et al., 2004; Gil Robles et al., 2005). This improved knowledge of the pattern of language distribution in the RH may have important clinical implications, notably regarding surgical indications and preplanning, as well as speech rehabilitation. Further studies about the relative contributions of each hemisphere and interrelationships between the two sides in language are mandatory, both in left- and right-handers. Acknowledgement The authors thank Vanessa Andean for English editing.

3208

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209

References Abo, M., Senoo, A., Watanabe, S., Miyano, S., Doseki, K., Sasaki, N., et al. (2004). Language-related brain function during word repetition in post-stroke aphasics. Neuroreport, 15, 1891–1894. Ackermann, H., & Riecker, A. (2004). The contribution of the insula to motor aspects of speech production: A review and a hypothesis. Brain and Language, 89, 320–328. Andy, O. J., & Bhatnagar, S. C. (1984). Right-hemispheric language evidence from cortical stimulation. Brain and Language, 23, 159–166. Annett, M. (1996). In defense of the right shift theory. Perceptual and Motor Skills, 82, 115–137. Basso, A., Farabola, M., Grassi, M. P., Laiacona, M., & Zanobio, M. E. (1990). Aphasia in left-handers. Comparison of aphasia profiles and language recovery in non-right-handed and matched right-handed patients. Brain and Language, 38, 233–252. Blank, S. C., Bird, H., Turkheimer, F., & Wise, R. S. J. (2003). Speech production after stroke: The role of the right pars opercularis. Annals of Neurology, 54, 310–320. Bookheimer, S. (2002). Functional MRI of language: New approaches to understanding the cortical organization of semantic processing. Annual Review of Neuroscience, 25, 151–188. Bossy, J. (1991). Les hémisphères cérébraux. In J. P. Chevrel (Ed.), Neuroanatomie. Berlin: Springer. Broca, P. (1861). Nouvelle observation d’aphémie produite par une lesion de la moitié postérieure des deuxième et troisième circonvolutions frontale. Bulletin de la Société Anatomique, 6, 337–393. Catani, M., Jones, D. K., & Ffytche, D. H. (2005). Perisylvian language networks of the human brain. Annals of Neurology, 57, 8–16. Corballis, M. C. (1998). Cerebral asymmetry: Motoring on. TICS, 2, 152–157. Corballis, M. C. (2003). From mouth to hand: Gesture, speech, and the evolution of right-handedness. The Behavioral and Brain Sciences, 26, 199–208. Dassonville, P., Zhu, X. H., Ugurbil, K., Kim, S. G., & Ashe, J. (1997). Functional activation in motor cortex reflects the direction and the degree of handedness. Proceedings of National Academy of Science of the United States of America, 94, 14015–14018. Delis, D. C., Knight, R. T., & Simpson, G. (1983). Reversed hemispheric organization in a left-hander. Neuropsychologia, 21, 13–24. Démonet, J. F., Thierry, G., & Cardebat, D. (2005). Renewal of the neurophysiology of language: Functional neuroimaging. Physiological Review, 85, 49–95. Desmurget, M., Bonnetblanc, F., & Duffau, H. (2007). Contrasting acute and slowgrowing lesions: A new door to brain plasticity. Brain, 130, 914–989. Dronkers, N. F. (1996). A new brain region for coordinating speech articulation. Nature, 384, 159–161. Duffau, H., Bauchet, L., Lehéricy, S., & Capelle, L. (2001). Functional compensation of the left dominant insula for language. Neuroreport, 12, 2159–2163. Duffau, H., Capelle, L., Denvil, D., Gatignol, P., Sichez, N., Lopes, M., et al. (2003). The role of dominant premotor cortex in language: A study using intraoperative functional mapping in awake patients. Neuroimage, 20, 1903–1914. Duffau, H., Capelle, L., Denvil, D., Sichez, N., Gatignol, P., Taillandier, L., et al. (2003). Usefulness of intraoperative electrical subcortical mapping during surgery for low-grade gliomas located within eloquent brain regions: Functional results in a consecutive series of 103 patients. Journal of Neurosurgery, 98, 764–778. Duffau, H., Capelle, L., Lopes, M., Faillot, T., Sichez, J. P., & Fohanno, D. (2000). The insular lobe: Physiopathological and surgical considerations. Neurosurgery, 47, 801–811. Duffau, H., Capelle, L., Sichez, N., Denvil, D., Lopes, M., Sichez, J. P., et al. (2002). Intraoperative mapping of the subcortical language pathways using direct stimulations. An anatomo-functional study. Brain, 125, 199–214. Duffau, H., Gatignol, P., Denvil, D., Lopes, M., & Capelle, L. (2003). The articulatory loop: Study of the subcortical connectivity by electrostimulation. Neuroreport, 14, 2005–2008. Duffau, H. (2004). Peroperative functional mapping using direct electrical stimulations. Methodological considerations. Neurochirurgie, 50, 474–483. Duffau, H. (2005). Lessons from brain mapping in surgery for low-grade glioma: Insights into associations between tumour and brain plasticity. The Lancet Neurology, 4, 476–486. Duffau, H. (2008). The anatomo-functional connectivity of language revisited: New insights provided by electrostimulaton and tractography. Neuropsychologia, 46, 927–934. Duffau, H., Gatignol, P., Mandonnet, E., Capelle, L., & Taillandier, L. (in press). Contribution of intraoperative electrical subcortical mapping of language pathways during resection of WHO grade II glioma within the left dominant hemisphere. Journal of Neurosurgery. Duffau, H., Gatignol, P., Mandonnet, E., Peruzzi, P., Tzourio-Mazoyer, N., & Capelle, L. (2005). New insights into the anatomo-functional connectivity of the semantic system: A study using cortico-subcortical electrostimulations. Brain, 128, 797–810. Duffau, H., Lopes, M., Arthuis, F., Bitar, A., Sichez, J. P., Van Effenterre, R., et al. (2005). Contribution of intraoperative electrical stimulations in surgery of low grade gliomas: A comparative study between two series without (1985-96) and with (1996–2003) functional mapping in the same institution. Journal of Neurology, Neurosurgery, and Psychiatry, 76, 845–851. Fox, R. J., Kasner, S. E., Chatterjee, A., & Chalela, J. A. (2001). Aphemia: An isolated disorder of articulation. Clinical Neurology and Neurosurgery, 103, 123–126.

Friederici, A. D., Meyer, M., & von Cramon, D. Y. (2000). Auditory language comprehension: An event-related fMRI study on the processing of syntactic and lexical information. Brain and Language, 74, 289–300. Gatignol, P., Capelle, L., Le Bihan, R., & Duffau, H. (2004). Double dissociation between picture naming and comprehension: An electrostimulation study. Neuroreport, 15, 191–195. Geschwind, N. (1965). Disconnection syndromes in animals and man. Part 1. Brain, 88, 237–294. Geschwind, N., & Levitsky, W. (1968). Human brain: Left-right asymmetries in temporal speech regions. Science, 161, 186–187. Gil Robles, S., Gatignol, P., Capelle, L., Mitchell, M. C., & Duffau, H. (2005). The role of dominant striatum in language: A study using intraoperative electrical stimulations. Journal of Neurology, Neurosurgery, and Psychiatry, 76, 940–946. Gloor, P. (1997). The temporal lobe and the limbic system. New York: Oxford Univ. Press. Goodglass, H., & Kaplan, E. (1972). The assessment of aphasia and related disorders. Philadelphia: Lea and Fibiger. Grafton, S. T., Fadiga, L., Arbib, M. A., & Rizzolatti, G. (1997). Premotor activation during observation and naming of familiar tools. NeuroImage, 6, 231–236. Haglund, M. M., Berger, M. S., Shamseldin, M., Lettich, E., & Ojemann, G. A. (1994). Cortical localization of temporal lobe language sites in patients with gliomas. Neurosurgery, 34, 567–576. Holodny, A. I., Schulder, M., Ybasco, A., & Liu, W. C. (2002). Translocation of Broca’s area to the contralateral hemisphere as the result of the growth of a left inferior frontal glioma. Journal of Computer Assisted Tomography, 26, 941–943. Hund-Georgiadis, M., Lex, U., Friederici, A. D., & von Cramon, D. Y. (2002). Noninvasive regime for language lateralization in right- and left-handers by means of functional MRI and dichotic listening. Experimental Brain Research, 145, 166– 176. Jabbour, R. A., Hempel, A., Gates, J. R., Zhang, W., & Risse, G. L. (2005). Right hemisphere language mapping in patients with bilateral language. Epilepsy Behaviour, 6, 587–592. Josse, G., & Tzourio-Mazoyer, N. (2004). Hemispheric specialization for language. Brain Research. Brain Research Reviews, 44, 1–12. Klein, D., Milner, B., Zatorre, R. J., Visca, R., & Olivier, A. (2002). Cerebral organization in a right-handed trilingual patient with right-hemisphere speech: A positron emission tomography study. Neurocase, 8, 369–375. Kloppel, S., & Buchel, C. (2005). Alternatives to the Wada test: A critical view of functional magnetic resonance imaging in preoperative use. Current Opinion in Neurology, 18, 418–423. Knecht, S., Floel, A., Drager, B., Sommer, J., Henningsen, H., Ringelstein, E. B., et al. (2002). Degree of language lateralization determines susceptibility to unilateral brain lesions. Nature Neuroscience, 5, 695–699. Kurowski, K. M., Blumstein, S. E., & Mathison, H. (1998). Consonant and vowel production of right hemisphere patients. Brain and Language, 63, 276–300. Mandonnet, E., Nouet, A., Gatignol, P., Capelle, L., & Duffau, H. (2007). Does the left inferior longitudinal fasciculus play a role in language? A brain stimulation study. Brain, 130, 623–629. Marien, P., Engelborghs, S., Paquier, P., & De Deyn, P. P. (2001). Anomalous cerebral language organization: Acquired crossed aphasia in a dextral child. Brain and Language, 76, 145–157. Mazaux, M., & Orgogozo, J. M. (1982). Echelle d’évaluation de l’aphasie adaptée du Boston diagnostic aphasia examination. Paris: E.A.P. Editions Psychotechniques. Menard, M. T., Kosslyn, S. M., Thompson, W. L., Alpert, N. M., & Rauch, S. L. (1996). Encoding words and pictures: A positron emission tomography study. Neuropsychologia, 34, 185–194. Metz-Lutz, M. N., Kremin, H., & Deloche, G. (1989). Standardisation d’un test de dénomination orale: Contrôle des effets de l’âge, du sexe et du niveau de scolarité chez les sujets adultes normaux. Neuropsychology Review, 1, 73–95. Naeser, M. A., & Borod, J. C. (1986). Aphasia in left-handers: Lesion site, lesion side, and hemispheric asymmetries on CT. Neurology, 36, 471–488. Naeser, M. A., Palumbo, C. L., Helm-Estabrooks, N., Stiassny-Eder, D., & Albert, M. L. (1989). Severe nonfluency in aphasia. Role of the medial subcallosal fasciculus and other white matter pathways in recovery of spontaneous speech. Brain, 112, 1–38. Ojemann, G. A., Ojemann, J. G., Lettich, E., & Berger, M. S. (1989). Cortical language localization in left, dominant hemisphere. An electrical stimulation mapping investigation in 117 patients. Journal of Neurosurgery, 71, 316–326. Oldfield, R. C. (1971). The assessment and analysis of handedness: The Edinburgh inventory. Neuropsychologia, 9, 97–113. Penfield, W., & Roberts, L. (1959). Speech and brain mechanisms. Princeton, NJ: Princeton University Press. Petrovich, N. M., Holodny, A. I., Brennan, C. W., & Gutin, P. H. (2004). Isolated translocation of Wernicke’s area to the right hemisphere in a 62-year-man with a temporo-parietal glioma. American Journal of Neuroradiology, 25, 130–133. Pillai, J. J., Araque, J. M., Allison, J. D., Sethuraman, S., Loring, D. W., Thiruvaiyaru, D., et al. (2003). Functional MRI study of semantic and phonological language processing in bilingual subjects: Preliminary findings. NeuroImage, 19, 565–576. Poldrack, R. A., Wagner, A. D., Prull, M. W., Desmond, J. E., Glover, G. H., & Gabrieli, J. D. (1999). Functional specialization for semantic and phonological processing in the left inferior prefrontal cortex. NeuroImage, 10, 15–35. Price, C. J., & Crinion, J. (2005). The latest on functional imaging studies of aphasic stroke. Current Opinion of Neurology, 18, 429–434. Price, C. J., Mummery, C. J., Moore, C. J., Frakowiak, R. S., & Friston, K. J. (1999). Delineating necessary and sufficient neural systems with functional imaging studies

H. Duffau et al. / Neuropsychologia 46 (2008) 3197–3209 of neuropsychological patients. Journal of Cognitive Neurosciences, 11, 371– 382. Pujol, J., Deus, J., Losilla, J. M., & Capdevila, A. (1999). Cerebral lateralization of language in normal left-handed people studied by functional MRI. Neurology, 52, 1038–1043. Rasmussen, T., & Milner, B. (1977). The role of early left-brain injury in determining lateralization of cerebral speech functions. Annals of the New York Academy of Sciences, 299, 355–369. Sakurai, Y., Takeuchi, S., Kojima, E., Yazawa, I., Murayama, S., Kaga, K., et al. (1998). Mechanism of short-term memory and repetition in conduction aphasia and related cognitive disorders: A neuropsychological, audiological and neuroimaging study. Journal of Neurological Science, 154, 182–193. Satz, P. (1979). A test of some models of hemispheric speech organization in the leftand right-handed. Science, 203, 1131–1133. Smith, B. (1980). Cortical stimulation in speech timing: A preliminary observation. Brain and Language, 10, 80–97. Sugishita, M., Konno, K., Kabe, S., Yunoki, K., Togashi, O., & Kawamura, M. (1987). Electropalatographic analysis of apraxia of speech in a left hander and in a right hander. Brain, 110, 1393–1417. Szaflarski, J. P., Binder, J. R., Possing, E. T., McKiernan, K. A., Ward, B. D., & Hammeke, T. A. (2002). Language lateralization in left-handed and ambidextrous people: fMRI data. Neurology, 59, 238–244. Szatkowska, I., Grabowska, A., & Szymanska, O. (2000). Phonological and semantic fluencies are mediated by different regions of the prefrontal cortex. Acta Neurobiologiae Experimentalis (Warsz), 60, 503–508.

3209

Tan, L. H., Laird, A. R., Li, K., & Fox, P. T. (2005). Neuroanatomical correlates of phonological processing of Chinese characters and alphabetic words: A meta-analysis. Human Brain Mapping, 25, 83–91. Thiebaut de Schotten, M., Urbanski, M., Duffau, H., Volle, E., Levy, R., Dubois, B., et al. (2005). Direct evidence for a parietal-frontal pathway subserving spatial awareness in humans. Science, 309, 2226–2228. Thiel, A., Habedank, B., Winhuisen, L., Herholz, K., Kessler, J., Haupt, W. F., et al. (2005). Essential language function of the right hemisphere in brain tumor patients. Annals of Neurology, 57, 128–131. Tranel, D., Damasio, H., & Damasio, A. R. (1997). A neural substrate for the retrieval of conceptual knowledge. Neuropsychologia, 35, 1319–1327. Tzourio, N., Crivello, F., Mellet, E., Nkanga-Ngila, B., & Mazoyer, B. (1998). Functional anatomy for speech comprehension in left handers versus right handers. NeuroImage, 8, 1–17. Tzourio-Mazoyer, N., Josse, G., Crivello, F., & Mazoyer, B. (2004). Interindividual variability in the hemispheric organization for speech. NeuroImage, 21, 422–435. Vigneau, M., Beaucousin, V., Hervé, P. Y., Duffau, H., Crivello, F., Houdé, O., et al. (2006). Meta-analysing left-hemisphere language areas: Phonology, semantics, and sentence processing. NeuroImage, 30, 1414–1432. Wernicke, C. (1874). Der aphasische symptomen complex. Breslau: Cohn et Weigert. Winkelman, M. D., & Glasson, C. C. (1984). Unilateral right cerebral representation of reading in a familial left-hander. Neuropsychologia, 22, 621–626. Wise, R. J., Greene, J., Buchel, C., & Scott, S. K. (1999). Brain regions involved in articulation. Lancet, 353, 1057–1061.