Download New insights into the anatomo-functional connectivity of the

doi:10.1093/brain/awh423
Brain (2005), 128, 797–810
New insights into the anatomo-functional
connectivity of the semantic system: a study
using cortico-subcortical electrostimulations
Hugues Duffau,1 Peggy Gatignol,2 Emmanuel Mandonnet,1 Philippe Peruzzi,3
Nathalie Tzourio-Mazoyer4 and Laurent Capelle1
Departments of 1Neurosurgery and 2Neurology,
Hôpital de la Salpêtrière, 47–83 Bd de l’Hôpital, 75651
Paris, Cedex 13, 3Department of Neurosurgery, Hôpital
Maison Blanche, Reims and 4UMR 6194 CNRS, CEA
Universités de Caen et Paris 5, GIP Cyceron BP 5222,
Bld Henri Becquerel, 14074 Caen Cedex, France
Correspondence to: Hugues Duffau, MD, PhD,
Department of Neurosurgery U 678, Hôpital Salpêtrière,
47–83 Bd de l’Hôpital, 75651 Paris, Cedex 13,
France
E-mail: [email protected]
Summary
Despite a better understanding of the organization of the
cortical network underlying the semantic system, very
few data are currently available regarding its anatomofunctional connectivity. Here, we report on a series of
17 patients operated on under local anaesthesia for a cerebral low-grade glioma located within the dominant hemisphere. Prior to and during resection, intraoperative
electrical stimulation was used to map sensorimotor and
language structures so that permanent neurological deficits
could be avoided. In a number of cases, cortical and subcortical stimulation caused semantic paraphasias. Using
postoperative MRI, we correlated these functional findings
with the anatomical locations of the sites where semantic
errors were elicited by stimulation, especially at the subcortical level, with the aim of studying the connectivity
underlying the semantic system. In temporal gliomas, cortical sites involved in semantic processing were found
around the posterior part of the superior temporal sulcus,
with subcortical pathways reproducibly located under the
depth of this sulcus. In insular gliomas, although stimulation elicited no semantic disturbances at the cortical level,
such semantic paraphasias were generated at the level
of the anterior floor of the external capsule. In frontal
tumours, cortical regions implicated in semantics were
detected in the lateral orbitofrontal region and dorsolateral
prefrontal cortex, with subcortical fibres located under the
inferior frontal sulcus. All these eloquent structures were
systematically preserved, thereby avoiding permanent
postoperative deficits. Our results provide arguments in
favour of the existence of a main ventral subcortical pathway underlying the semantic system, within the dominant
hemisphere, joining the two essential cortical epicentres of
this network: the posterior and superior temporal areas,
and the orbitofrontal and dorsolateral prefontal regions.
Such a ventral stream might anatomically partly correspond to the inferior fronto-occipital fasciculus.
Keywords: semantic; connectivity; language; electrical stimulation; glioma surgery
Abbreviations: BA = Brodmann area; BDAE = Boston Diagnostic Aphasia Examination; DTI = diffusion tensor imaging;
DLPFC = dorsolateral prefrontal cortex; IFC = inferior frontal cortex
Received July 13, 2004. Revised December 20, 2004. Accepted December 23, 2004. Advance Access publication
February 10, 2005
Introduction
Recent progress in neurofunctional imaging methods has
allowed an improved knowledge of the cortical organization
of the semantic system. Indeed, two regions within the left
hemisphere have been regularly reported as playing a major
role: the left posterior temporal regions and the left inferior
frontal cortex (IFC) (Mesulam, 1990; Papathanassiou et al.,
2000; Davis and Johnsrude, 2003; Friederici et al., 2003;
Heim et al., 2003a).
Regarding the left temporal lobe, in which semantic content has been described as highly organized and spatially
segregated (Bookheimer, 2002), the regions around the
posterior part of the superior temporal sulcus (superior and
# The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
798
H. Duffau et al.
middle temporal gyri) were reproducibly found to be
activated during comprehension tasks (Wise et al., 1991,
2001; Démonet et al., 1992; Tulving et al., 1994; Stromswold
et al., 1996; Müller et al., 1997; Bookheimer et al., 1998;
Schlosser et al., 1998; Mummery et al., 1999; Crinion et al.,
2003; Davis and Johnsrude, 2003; Devlin et al., 2003;
Hamberger et al., 2003; Tyler et al., 2003), whatever the
modalities of presentation of information (oral, visual or
somesthetic), supporting the supramodal feature of this region
in semantic processing (Michael et al., 2001; Booth et al.,
2002; Decety et al., 2002; Saygin et al., 2003). Moreover,
visual tasks such as reading or naming might recruit additional basal inferior temporal areas that are involved in
lexical retrieval (Lüders et al., 1991; Nobre et al., 1994;
Damasio et al., 1996; Schäffler et al., 1996; Price, 2000;
Jobard et al., 2003).
Concerning the semantic role of the IFC (Mazoyer et al.,
1993; Thompson-Schill et al., 1997, 1998; Wagner et al.,
1997, 2001; Chee et al., 1998; Bookheimer, 2002;
Homae et al., 2002), it would seem that its inferior and
anterior parts, i.e. the pars orbitalis [Brodmann area (BA)
47] (Gabrieli et al., 1998; Poldrack et al., 1999; Bookheimer,
2002; Noppeney and Price, 2002), pars triangularis (BA 45)
(Desmond et al., 1995; Gabrieli et al., 1996; Friederici et al.,
2000b) and even the dorsolateral prefrontal cortex (DLPFC)
(BA 46/9) (Kapur et al., 1994; Demb et al., 1995; Warburton
et al., 1996; Szatkowska et al., 2000; Noesselt et al., 2003)
might be more specifically implicated in the executive
aspects of semantic processing, while its more posterior
areas (notably the pars opercularis, BA 44) could be preferentially involved in syntactic (Dapretto and Bookheimer,
1999; Kang et al., 1999; Embick et al., 2000; Friederici
et al., 2000a; Moro et al., 2001; Heim et al., 2002,
2003b) and phonological processings (Démonet et al.,
1992; Zatorre et al., 1992; Paulesu et al., 1993; Fiez,
1997; Fiez and Peterson, 1998; Poldrack et al., 1999).
Despite the better understanding of this cortical network
organization, very few data are currently available about
the anatomo-functional connectivity underlying the
semantic system (Scott et al., 2000; Brugge et al., 2003),
in contrast to the phonological system, for which a ‘phonological loop’ was both modelled (Baddeley, 1992, 2003)
and described anatomically and functionally in vivo (Duffau
et al., 2003a).
Here, we report on a series of 17 patients operated on
under local anaesthesia for a cerebral low-grade glioma
located within the dominant hemisphere, with intraoperative
sensorimotor and language mapping in order to avoid postoperative definitive deficit, using cortical and subcortical
electrical stimulation, which all induced transient semantic
paraphasia. On the basis of the data of postoperative MRI,
we correlated these functional findings with the anatomical
locations of the sites where semantic errors were elicited
by stimulation, especially at the subcortical level, with the
aim of studying the connectivity underlying the semantic
system.
Materials and methods
Subjects
Among a series of 150 patients operated on awake for a low-grade
glioma located within the dominant hemisphere in our institution
between 1996 and 2003, 17 patients who presented transitory
semantic errors generated by the intraoperative electrical mapping
were reviewed retrospectively. These patients are not the same as
those described in our previous report of subcortical language
pathway stimulation (Duffau et al., 2002).
Preoperatively, all patients had had a neurological examination.
Language was tested by a speech therapist using the Boston
Diagnostic Aphasia Examination (BDAE) (Goodglass and Kaplan,
1972). Hemispheric dominance was assessed using a standardized
questionnaire (Edinburgh inventory) (Oldfield, 1971) and functional
MRI using a protocol previously reported (Léhericy et al., 2000).
The topography of the tumour was analysed accurately on a
preoperative MRI (T1-weighted and spoiled-gradient images
obtained before and after gadolinium enhancement in the three
orthogonal planes, and T2-weighted axial images).
Intraoperative mapping
All patients underwent surgery under local anaesthesia so that functional cortical and subcortical mapping could be carried out using
direct brain stimulation. This method, including the electrical parameters and the intraoperative clinical tasks, has been described
previously (Duffau et al., 2002, 2003b). A bipolar electrode with
5 mm spaced tips delivering a biphasic current with parameters nondeleterious for the CNS (pulse frequency of 60 Hz, single pulse
phase duration of 1 ms, amplitude from 2 to 8 mA) (Ojemann
Cortical Stimulator 1, Radionics*, Inc., Burlington, MA) was
applied to the brain of awake patients.
In a first stage, cortical mapping was performed, after tumour and
sulci/gyri identification using ultrasonography, and before resection,
in order to avoid any eloquent area damage. Sensorimotor mapping
was performed first, with the goal of obtaining a positive response
(e.g. the induction of movement and/or paraesthesia in the contralateral hemibody when the primary sensorimotor areas were stimulated
in a patient at rest), since the bone flap 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 from 1 to 1 mA, from a baseline of 2 mA,
until a sensorimotor response was elicited, with 8 mA as the upper
limit, with the goal of avoiding the generation of seizures. Once this
threshold was defined for sensorimotor mapping, the same intensity
was used for both cortical and subcortical language mapping. Then,
the patient was asked to perform an automatic task such as counting
(regularly from 1 to 10 over and over), in order to confirm that the
selected current amplitude allowed performance of reliable language
mapping, by inducing a typical speech arrest/anarthria during stimulation of the region of Broca/ventral premotor cortex. Indeed, the
essential cortical language sites are known to be inhibited by electrical stimulation (Berger, 1996; Ojemann et al., 1989; Duffau et al.,
2002, 2003b). At this time, we systematically used the task most
often reported during intraoperative language mapping (Ojemann
et al., 1989; Berger, 1996), i.e. picture naming, preceded by a
short sentence to read (the French translation of ‘this is a . . . ’), in
order to check that there were no seizures generating complete
speech arrest when the patient was not able to name, i.e. that he
was still capable of pronouncing ‘this is a . . . ’. For the naming task,
Connectivity of the semantic system
we used the DO 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 et al., 1991).
The patient was never informed when the brain was stimulated. The
duration of each stimulation was 4 s. At least one picture presentation
without stimulation separated each stimulation, and no site was stimulated twice in a row in order to avoid seizures. Each cortical site (size:
5 mm 3 5 mm, due to the spatial resolution of the probe) of the entire
cortex exposed by the bone flap was tested three times. Indeed, since
the seminal publication of Ojemann et al. (1989), nowadays it is
admitted that three tasks are sufficient to be sure whether or not a
cortical site is essential for language, e.g. generating speech disturbances during two or three stimulations out of three, with normalization
of language as soon as the stimulation is stopped. It is worth noting that
this limitation of trials is required by the timing of the surgical procedure; recall that the patient was awake—thus also explaining the
need to limit the number of language tasks.
The type of language disturbances was detailed by a speech
therapist who was always present in the operating 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/tumour boundaries) previously identified by ultrasonography. A photograph of the cortical
map was systematically made before resection.
During a second surgical stage, 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 or name when the resection became close to the subcortical
language structures (including both white matter pathways and
deep grey nuclei), which were also identified by language inhibition
during stimulation at the cortical level (Skirboll et al., 1996; Duffau
et al., 2002, 2003b). In order to perform the best possible tumour
removal while sparing functional areas, all 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 both during the
immediate postoperative stage and 3 months after the surgery. It was
performed by the same neurosurgeons and speech therapist who
carried out the preoperative functional evaluation, using the same
tasks, including the BDAE.
A control MRI was performed in all cases, immediately and
3 months after the surgery. This imaging allowed us first to evaluate
the quality of glioma removal, and secondly to analyse accurately
the anatomical location of the language pathways, i.e. at the periphery of the cavity, where the resection was stopped according to the
functional responses eliciting by intraoperative stimulation, a methodology that we used previously (Duffau et al., 2002).
Analysis of the intraoperative naming disturbances
Naming disorders, which can reflect a weakness of lexical access or
loss of the semantic system, may include linguistic deviations called
paraphasias.
Phonetic paraphasias
These affect the articulatory realization from one to several phonemes, by excess or failure of articulatory precision or related to
motor difficulties, e.g. simplification of substitution of a phoneme.
799
Phonemic paraphasias
These affect the phonological forms of the word. The target word is
transformed by substitutions, elision, addition or transposition from
one to several phonemes. Generally, the word target remains recognizable but, when errors are very frequent (>50%), one speaks about
neologisms which constitutes a phonemic ‘jargon’.
Semantic paraphasias
These are connected to the meaning of the word target. The word
target and the false production in oral meaning belong to the same
semantic field. Hence, there are three correlations: the same category
of meaning (e.g. orange/lemon), the opposite (e.g. low/high) and
usual proximity (e.g. cigarette/lighter). For example, for the word
‘apple’, it can be a hyperonym production such as ‘fruit’ (generic
term), a co-hyponym such as ‘peach’ (same category ‘fruit’ but with
visual error), hyponym or categorizations such as ‘pippin’, contextual relationships such as ‘tart’, more specific attributes such as
‘pips’ or functional access such as ‘can be eaten’.
In the present study, we analysed the patients who experienced
transient and reproducible semantic paraphasias during intraoperative electrical stimulation.
Although there was usually only one senior speech therapist in the
operating room, each error induced by stimulations was also classified intraoperatively by a student in speech therapy and by the
neurosurgeon. Moreover, each site, in particular if eliciting language
disturbances when stimulated, was systematically tested at least
three times, with the presentation of three different objects to
name. Thus, the classification of the different types of paraphasic
errors became unambiguous, particularly concerning semantic paraphasias, since the word produced by the patient was always perfectly
understandable as a ‘real’ word (which is not true for phonetic and/or
phonemic paraphasias), but was systematically wrong—while connected to the meaning of the word target, which differed for each
new task in order to confirm the exact nature of the disorder. In
addition, each error was recorded, then analysed postoperatively by
at least two speech therapists: the one present during the surgery and
one colleague.
Results
The clinical, radiological and surgical characteristics of the
17 patients are summarized in Table I.
Subjects
The series consisted of 11 males and six females, ranging in
age from 17 to 52 years (mean 33 years). Fourteen patients
were right-handed and three left-handed, as assessed by
neuropsychological examination. The presenting symptoms
were seizures in the 17 cases (four generalized, 13 partial with
transient speech disturbances). The preoperative clinical testing was normal in all patients, in particular without any
semantic disturbances on the BDAE.
The preoperative MRI showed in all cases a T1-weighted
hypointense and T2-weighted hyperintense corticosubcortical lesion, without enhancement after gadolinium
injection.
9
2
6
Frontal lobe
Insular lobe
Temporal lobe
4 M/2 F; 26
(17–43)
2 M; 32 and 33
5 M/4 F; 37
(25–52)
Sex and age
(years)
4 right-handed/
1 left-handed
No deficit
2 right-handed
No deficit
7 right-handed/
2 left-handed
No deficit
Preoperative
examination
Cortical language mapping:
semantic sites around the anterior
part of the IFS in five patients
Subcortical language mapping:
semantic pathways under the IFS
in all cases
Cortical language mapping: no
insular cortical semantic sites
detected
Subcortical language mapping:
semantic pathways within the
anterior floor of the external capsule
Cortical language mapping: semantic
sites around the posterior part of the
STS in four patients
Subcortical language mapping:
semantic pathways under STS
in all cases
Intraoperative electrical mapping
semantic paraphasias
M = male; F = female; IFS = inferior frontal sulcus; STS = superior temporal sulcus.
No. of
patients
Glioma location
Transient semantic disturbances
then recovery within 3 months
in all cases
Transient semantic disturbances
then recovery within 3 months
in all cases
Infero-lateral boundary:
IFS
Transient semantic disturbances
then recovery within 3 months
in all cases
Infero-mesial boundary:
supero-lateral temporal
horn of the ventricle
Deep boundary: temporal
part of the inferior frontooccipital
fasciculus
Superior boundary: STS
Deep boundary: frontal
part of the inferior
fronto-occipital fasciculus
Deep boundary: median
part of the inferior frontooccipital fasciculus
Postoperative anatomical
MRI
Postoperative examination
Table 1. Clinical, radiological and surgical characteristics of the 17 patients operated on for a low-grade glioma near the inferior fronto-occipital
fasciculus (dominant hemisphere)
800
H. Duffau et al.
Connectivity of the semantic system
Three different groups of tumour locations were found.
(i) In six patients, the lesion was located in the dominant
temporal lobe (five left and one right lesion), immediately
inferior and/or anterior to the posterior part of the superior
temporal gyrus: one within the mid-part of the middle temporal gyrus, one within the posterior part of the middle temporal gyrus and four involving the mid- and posterior parts of
the middle and inferior temporal gyri, and the fusiform gyrus
(three left, one right) (Fig. 1A). (ii) In two patients, the glioma
invaded the entire left insular lobe (Fig. 2A). (iii) In the nine
other patients, the lesion was located immediately above and/
or medially to the dominant IFC: four lesions within the
fronto-mesial structures (superior frontal gyrus, three left
and one right glioma), four lesions within the middle frontal
gyrus (three left, one right), and one tumour involving both
left superior and middle gyri (Fig. 3A).
Operative findings
Temporal gliomas
At the cortical level. In four patients with left tumour,
semantic paraphasias were reproducibly elicited by cortical
stimulations. These ‘semantic’ sites were located in the four
cases around the posterior part of the left superior temporal
gyrus, i.e. in the superior temporal gyrus immediately above
the superior temporal sulcus in one case, in the middle temporal gyrus immediately below the superior temporal gyrus
in one case, and in both gyri in two patients. In these four
patients, these language areas constituted the postero-superior
functional boundary of the glioma resection (Fig. 1B). In the
two other patients, one with a left mid-temporal glioma
within the middle temporal gyrus and one with a right glioma,
cortical stimulations within the posterior part of the middle
temporal gyri (posterior limit of the tumour removal) elicited
hesitations/slowness of naming, but without any semantic
paraphasia. However, following the opening of the superior
temporal gyrus in both patients, during the resection, other
stimulations of this buried cortex, at the postero-superior part
of the tumour, then elicited semantic paraphasias.
At the subcortical level. In the second surgical stage, stimulations of the white subcortical pathways were systematically
performed all along the tumour resection, as previously reported (Duffau et al., 2002, 2003b). Interestingly, they induced
semantic disturbances in the six patients, in all cases during
stimulations of the white bundle located under the superior
temporal sulcus, above the temporal horn of the ventricle
(opened in four patients). From anterior to posterior, this
pathway was identified from the occipito-temporal junction
posteriorly (posterior and deep functional boundary of the
resection), up to the junction between the anterior temporal
third and the mid-temporal third anteriorly, just below the
anterior part of the insular cortex, which generated articulatory but not semantic disorders when stimulated (Fig. 1C), as
we already observed (Duffau et al., 2000). At this level, it was
not possible to continue to follow this pathway, which seemed
801
to run under the anterior insula (antero-superior limit of the
resection in the depth).
Insular gliomas
At the cortical level. There was no language disturbance
elicited by the stimulations of the left insular cortex in the
two patients, due to the glioma invasion, while language sites
were detected within frontal (speech arrest) and temporal
opercula (anomia) not invaded by the tumour, as previously
described (Duffau et al., 2001).
At the subcortical level. Following resection of the anterior
part of the insula, stimulations of the deep white fibres, i.e.
corresponding to the anterior part of the external capsule (as
confirmed by postoperative MRI, see below), reproducibly
induced semantic paraphasias in both patients (Fig. 2B).
Frontal gliomas
At the cortical level. While frontal cortical language sites
were identified by stimulation in the nine patients before
resection, systematically generating production disorders
such as anarthria and/or speech arrest and/or anomia, as
we already reported (Duffau et al., 2003c), only five patients
presented semantic paraphasia during cortical electrical mapping (four left gliomas, one right). In these five patients, the
‘semantic sites’ were located within the orbito-frontal cortex
(i.e. the anterior and inferior part of the inferior frontal gyrus,
in front of the sites which generated articulation disturbances
when stimulated) or within the DLPFC [i.e. the middle fontal
gyrus, in front of the dorsal premotor cortex which elicited
anomia during stimulation, as previously described (Duffau
et al., 2003c)] (Fig. 3B). It is worth noting that all four
patients without any semantic site detected by cortical stimulation harboured a posterior frontal lesion, immediately in
front of the precentral gyrus, i.e. within the dorsal premotor
cortex (two in the posterior part of the superior frontal gyrusand two in the posterior part of the middle frontal gyrus;
three left gliomas, one right).
At the subcortical level. As in the two first groups of patients
(with temporal and insular lesions), subcortical stimulation
reproducibly elicited semantic paraphasia in the nine patients
with frontal gliomas. Concerning patients with resection
involving the middle frontal gyrus, these semantic disorders
were generated by stimulation of the white fibres under the
inferior frontal sulcus, above the anterior part of the superior
insulo-opercular sulcus, in front of the pathways involved in
language production that we previously detailed (Duffau
et al., 2002). Concerning patients with resection involving
only the superior frontal gyrus, the semantic paraphasias were
induced by stimulation of the deep white matter, at the level
of the antero-lateral edge of the cavity, laterally and above the
anterior part of the head of the caudate nucleus (frontal horn
opened in four patients), in front of the fibres coming from
802
H. Duffau et al.
A
B
Skull base
P
D
A
Vertex
C
Skull base
P
E
A
Vertex
Fig. 1 (A) Preoperative axial and coronal T1-weighted enhanced MRI, showing a low-grade glioma involving the mid- and posterior part of
the left temporal lobe: the middle and inferior gyri, and the fusiform gyri. Note, especially on the coronal slice, that despite sparing of the
temporo-mesial structures and of the superior temporal cortex, the tumour begins to invade the subcortical white matter between the
supero-lateral edge of the temporal horn of the ventricle (below) (curved arrow) and the depth of the superior temporal sulcus (above)
(straight arrow). (B) Intraoperative photograph before tumour resection. The eloquent cortical sites identified using electrical stimulations
were marked by numbers as follows: 1, primary motor area of the face; 10, ventral premotor cortex inducing anarthria during stimulations;
20, 21, 22, sites within the posterior part of the superior temporal gyrus (20, 21) or the middle temporal gyrus (22) eliciting semantic
paraphasia when stimulated; 23, non-reproducible hesitation. The letters correspond to the limits of the tumour identified using
intraoperative ultrasonography. Small arrow = superior temporal sulcus; large arrow = posterior part of the sylvian fissure; A = anterior;
P = posterior. (C) Intraoperative photograph after tumour resection, showing that the posterior and deep boundaries of the cavity were
represented by language cortical sites and subcortical pathways, as follows: 20, 21, 22, cortical semantic sites, which constituted the
posterior limit of the resection (the area under 23 was removed because the hesitation was not reproduced during re-stimulations, and
because of an invasion of this site by the glioma); 33, 32, 30, 31 (from posterior to anterior), subcortical pathway eliciting reproducible
semantic paraphasia when stimulated, running in a postero-anterior direction, located between the depth of the superior temporal sulcus
(above) and the temporal horn of the ventricle which was opened (below). Interestingly, this bundle continued anteriorly, by passing under
the anterior insular cortex, which was surgically identified then stimulated; it elicited articulation disorders, but no semantic disturbances
(29). Examples of semantic paraphasia during electrical mapping: ‘brush’ instead of ‘comb’; ‘zebra’ instead of ‘giraffe’; ‘pan’ instead of
‘ladle’; and ‘sideboard’ instead of ‘dresser’.The patient presented transient postoperative language semantic disturbances, which recovered
within 2 months, following speech rehabilitation. (D) Postoperative coronal T1-weighted enhanced MRI (two slices: one posterior, one
anterior), showing the resection of the left middle and inferior temporal gyri, and the fusiform gyrus. The boundaries of the cavity were: the
superior temporal sulcus (superiorly, with preservation of the superior temporal gyrus) (straight arrow); and the latero-superior part of the
horn of the ventricle (inferiorly, with preservation of the amygdalo-hippocampal structures) (curved arrow). Between these two limits,
a postero-anterior white bundle runs, which constituted the deep functional boundary of the resection, since it elicited semantic paraphasia
when stimulated. This is the reason why a tumoral residue was left at this level (T1 hyposignal, visible on both posterior and anterior slices).
(E) Postoperative axial T1-weighted enhanced MRI, showing the deep residual glioma (antero-posterior rim of hyposignal in the depth of
the cavity) (arrows), and the similarity of its location within the white matter in comparison with a tractography of the anterior part of the
temporo-occipital portion of the inferior fronto-occipital fasciculus; from Catani et al. (2002).
Connectivity of the semantic system
803
B
A
C
Fig. 2 (A) Preoperative coronal T1-weighted enhanced MRI, showing a low-grade glioma involving the left insular lobe. Note that the
tumour begins to invade the subcortical white matter at the level of the anterior part of the external capsule, since the signal abnormality
comes into contact with the lateral part of the lentiform nucleus (arrow). (B) Intraoperative photograph following tumour resection.
The eloquent cortical sites identified using electrical stimulations were marked by numbers as follows: 1, 13, speech arrest (Broca’s area);
10, 11, 12, ventral premotor cortex inducing anarthria during stimulations. After opening of the sylvian fissure, because of no identification
of the functional site in the insular cortex, the glioma was removed, until eloquent areas were encountered within the white matter in the
depth of the cavity: at this level, stimulations elicited semantic paraphasias (tags 2 and 45). A = anterior; P = posterior. The patient
presented transient slight postoperative language semantic disturbances, which recovered within 1 month, following speech rehabilitation.
(C) Postoperative coronal T1-weighted enhanced MRI, showing partial resection of the left insular glioma. The boundaries of the cavity
were superiorly, the subcortical part of Broca’s area, still functional despite its tumoral infiltration (curve arrow); and deeply, the anterior
part of the external capsule, eliciting semantic paraphasia when stimulated; this is the reason why a thin rim of tumoral residue was left at
this level (T1 hyposignal, straight arrow).
the posterior part of the middle frontal gyrus (i.e. the dorsal
premotor cortex), eliciting anomia during stimulation (Duffau
et al., 2003c) (Fig. 3C).
In the 17 patients, cortico-subcortical eloquent structures
identified by stimulations were systematically preserved, constituting the functional boundaries of the surgical resection.
Independent of the tumour location, the semantic paraphasias elicited most frequently were (i) use of a generic term
(‘bird’ for ‘eagle’ or ‘woodpecker’; ‘animal’ for ‘lion’ or
‘tiger’; ‘flower’ for ‘rose’); and (ii) use of a co-hyponym
(‘brush’ instead of ‘comb’; ‘horse’ for ‘donkey’; ‘zebra’ instead
of ‘giraffe’; ‘pan’ instead of ‘ladle’; ‘sideboard’ instead of
‘dresser’; or ‘Little Red Riding Hood’ for ‘Father Christmas’).
Postoperative course
Postoperatively, the 17 patients presented transient semantic
paraphasias which resolved within 7 days to 3 months, whatever the temporal, insular or frontal location of the tumour.
All patients had speech rehabilitation, which allowed a
complete functional recovery systematically evaluated using
the same BDAE as preoperatively, and showing a normalization of the scores. All patients returned to a normal socioprofessional life.
Histological examination revealed a low-grade glioma in
all cases.
Radiological results
In temporal lesions, the cavity came into contact superiorly
with the superior temporal sulcus in six patients, up to the
depth of this sulcus; and deeply, with the latero-superior part
of the temporal horn of the ventricle which was opened (the
middle, inferior temporal and fusiform gyri were removed,
with preservation of the amygdalo-hippocampal structures
since they were not invaded by the tumour). Between
these two boundaries runs a postero-anterior white matter
fibre bundle that constituted the deep functional boundary
804
H. Duffau et al.
A
B
D
C
E
Fig. 3 (A) Preoperative axial and coronal T1-weighted enhanced MRI, showing a low-grade glioma involving the left fronto-mesial
structures. Note that the tumour invades the subcortical white matter up to the antero-superior part of the head of the caudate nucleus
(straight arrow). (B) Intraoperative photograph before tumour resection. The eloquent cortical sites identified using electrical stimulations
were marked by numbers as follows: 1, 3, primary motor area of the hand; 12, dorsal premotor cortex inducing anomia during stimulations;
10, 11, ventral premotor cortex inducing anarthria during stimulations; 13, speech arrest site, within the pars opercularis; 14, site within the
pars orbitaris of the inferior frontal gyrus, eliciting semantic paraphasia when stimulated. The letters correspond to the limits of the tumour
identified using intraoperative ultrasonography. Small arrows = precentral gyrus; large arrow = sylvian fissure; curved arrow = inferior
frontal sulcus; A = anterior; P = posterior. (C) Intraoperative photograph after tumour resection, showing that the posterior, inferior and
deep boundaries of the cavity were represented by language cortical sites and subcortical pathways, as follows: 14, cortical semantic site,
which constituted the inferior limit of the resection; 48, subcortical pathway eliciting reproducible semantic paraphasia when stimulated,
running under the inferior frontal sulcus with was opened anteriorly (since the anterior part of the middle frontal gyrus was removed in
addition to the superior frontal gyrus), and under the inferior frontal gyrus. These fibres run laterally and anteriorly to the head of the
caudate nucleus, marked by the tag 46 under the retractor, since the lateral horn of the ventricle was opened (curved arrow). Note that more
posteriorly and superiorly to this head of the caudate, subcortical stimulations elicited anomia (tag 47), at the level of pathways
corresponding to the cortical site found within the dorsal premotor area (tag 12), thus constituting the postero-lateral boundary of the
resection. The patient presented transient postoperative language semantic disturbances with slowness of speech, which recovered within
3 months, following speech rehabilitation. (D) Postoperative axial and coronal T1-weighted enhanced MRI, showing the resection of the
left superior frontal gyrus, and the anterior part of the middle frontal gyrus, with opening of the inferior frontal sulcus (axial slice).
The subcortical bundle which runs under the depth of this inferior frontal sulcus, in a postero-anterior and infero-superior direction,
corresponds to the white fibres which converge in front of and laterally to the head of the caudate nucleus (between the antero-lateral
striatum and the anterior part of the superior insulo-opercular sulcus) (curve arrows): this pathway induced semantic paraphasia when
stimulated, and thus represented the deep functional boundary of the resection. (E) Postoperative sagittal T1-weighted enhanced MRI, with
projection of the surgical cavity (blue line) on a similar MRI view, which visualizes the entire fronto-occipital fasciculus in green using
diffusion tensor magnetic resonance tractography (from Catani et al., 2002): such a superimposition shows the similarity of the location of
the deep inferior eloquent sites which elicited semantic paraphasias during stimulations (i.e. functional boundaries of the resection) with the
tractography of the anterior part of the inferior fronto-occipital fasciculus.
Connectivity of the semantic system
of the resection, since they corresponded to the subcortical
pathways eliciting semantic paraphasia when stimulated: this
is the reason why a tumoral residue was left on the entire
surface of the deep wall of the cavity in two patients, as
shown by the immediate postoperative MRI (abnormal
antero-posterior rim of the T1 hyposignal in the depth)
(Fig. 1D). Interestingly, this subcortical bundle corresponds
to the temporal part of the inferior fronto-occipital fasciculus, with radiations coming from the middle, inferior temporal and fusiform gyri within posterior temporal and
occipital cortex, then running medially in the temporal
lobe and continuing antero-superiorly to the frontal lobe
via the anterior floor of the external capsule under the insular
lobe (Crosby et al., 1962; Nieuwenhuys et al., 1988; Gloor,
1997; Catani et al., 2002), as shown by a comparison
between the residual tumour on postoperative MRI and a
similar MRI slice with delineation of the posterior part of
this fronto-occipital fasciculus using diffusion tensor
imaging (DTI) tractography (from Catani et al., 2002)
(Fig. 1E).
In insular lesions, the (anterior) deep boundary of the cavity was the anterior part of the external capsule, since it also
elicited semantic paraphasias during electrical stimulation.
Postoperative MRI showed the preservation of the white
pathways running at the junction of the temporal and frontal
lobes, i.e. at the level where the fibres of the inferior frontooccipital fasciculus compact and pass through the anterior
floor of the external capsule (no claustrum was still visible
at depth) (Fig. 2C).
In frontal gliomas, the infero-lateral limits of the cavity
were by the infero-lateral and dorso-lateral frontal cortex and
their corresponding white fibres, which converged in front of
and laterally to the head of the caudate nucleus, in order to
run posteriorly under the anterior insula. This point of convergence constituted the deep inferior and lateral boudary of
the resection, since white fibres at this level induced
semantic paraphasia when stimulated (Fig. 3D): they correspond to the frontal part of the inferior fronto-occipital
fasciculus, as shown by the projection of the surgical cavity
on a similar MRI view with visualization of the entire frontooccipital fasciculus using DTI (from Catani et al., 2002)
(Fig. 3E).
Discussion
The results of the present study appears to provide new
insights into the anatomo-functional connectivity of the
semantic network.
Cortical organization of the semantic system
Numerous lesion, stimulation and neuroimaging works have
allowed a better understanding of the cortical organization
of the semantic system that is based on two essential
‘epicentres’: the dominant posterior temporal areas and the
IFC/DLPFC.
805
Posterior temporal areas
As mentioned in the Introduction, implication of left posterior
temporal areas in semantic processing is supported by neurofunctional imaging (Wise et al., 1991; Bookheimer et al.,
1998; Tyler et al., 2003), lesion studies in aphasic patients
(Hart and Gordon, 1990; Mummery et al., 1999; Saygin et al.,
2003), as well as reports of cortical stimulation (Lüders
et al., 1991; Boatman et al., 2000; Ilmberger et al., 2001;
Hamberger et al., 2003; Gatignol et al., 2004).
Interestingly, in our study, electrical stimulation identified
cortical sites involved in semantic processing in four patients
with a temporal glioma. In all four cases, sites were located
around the posterior part of the left superior temporal sulcus,
i.e. in the superior temporal gyrus immediately above it (one
case), or in the middle temporal gyrus immediately below
it (one case), or both (two cases). Thus, our intraoperative
results support data recently provided by functional
neuroimaging.
The lack of detection of a cortical ‘semantic area’ in two
cases could be explained first by the fact that, due to the
location of the lesions within the mid-part of the temporal
lobe in the two patients (one left, one right), the cortical
exposure has not been sufficient posteriorly to map the
semantic cortical sites. Secondly, since the ‘epicentre’ for
comprehension seems to be represented by the superior
temporal sulcus, according to neurofunctional imaging studies, we can consider that a major part of this cortex is not
accessible to a cortical electrical stimulation before resection,
due to the fact that this semantic cortex is buried within the
sulcus, and not located at the surface of the brain. This hypothesis was verified in the two patients in which the lesion
came in contact with the superior temporal sulcus. In these
case, the sulcus was opened in order to perform the tumour
resection, and stimulation of the buried cortex then elicited
semantic paraphasias.
IFC
Numerous lesion (Alexander et al., 1989; Otsuki et al., 1998),
stimulation (Schäffler et al., 1993, 1996; Devlin et al., 2003)
and neuroimaging (Poldrack et al., 1999; Bookheimer, 2002)
studies have supported the notion that there are separate
subsystems within the IFG responsible for different aspects
of language: phonological, syntactic and semantic processing.
As detailed in the Introduction, it would seem that phonological (Poldrack et al., 1999) and syntactic (Embick et al.,
2000) regions (particularly recruited in cases of syntactic
complexity) (Stromswold et al., 1994; Just et al., 1996;
Caplan et al., 1998) are centred around the posterior superior
IFG at the border of BA 44 and BA 6, both mutually interactive (Keller et al., 2001). Conversely, semantic areas cluster around the antero-inferior IFG (BA 47) (Noppeney and
Price, 2002), the pars triangularis (BA 45) (Friederici et al.,
2000b) and the DLPFC (BA 46) (mid-part of the middle
frontal gyrus) (Noesselt et al., 2003). BA 45/46/47 appear
important for executive aspects of semantic processing that
806
H. Duffau et al.
involve semantic working memory, directing semantic search
or drawing comparisons between semantic concepts in working memory (Bookheimer, 2002). This region seems to be
both modality and content independent.
In our experience, we identified cortical sites involved in
semantic processing in five patients using electrical stimulations. Interestingly, in the five cases, these ‘semantic sites’
were located within the infero-lateral frontal cortex (i.e. the
anterior and inferior part of the inferior frontal gyrus, in front
of the sites which generated production disorders when stimulated) or within the dorso-lateral prefrontal cortex (i.e. the
middle frontal gyrus, in front of the dorsal premotor cortex
which elicited anomia when stimulated). Thus, our intraoperative results support the data recently provided by
functional neuroimaging.
However, the lack of induction of semantic disorders
during frontal mapping in the other four patients could be
explained by the fact that all harboured a posterior frontal
lesion, immediately in front of the precentral gyrus and thus
within the dorsal premotor cortex (three left, one right).
Consequently, it is likely that the cortical exposure has not
been sufficient antero-laterally (i.e. at the level of the IFC
and/or the lateral prefrontal cortex) to map the semantic cortical areas. Therefore, we elicited only anomia or dysarthria
during stimulations of the premotor cortex, as previously
reported (Duffau et al., 2003c). Moreover, similar to the
temporal epicentre, it is possible that at least a part of the
cortex implicated in the semantic processing was buried
within the sulci, and thus not accessible to the stimulation
before resection (Rutten et al., 1999).
Subcortical anatomo-functional connectivity
of the semantic system
Despite recent improvement of our understanding of the
intra-cortical organization of semantic processing, little is
currently known concerning the anatomo-functional connectivity of this system. This can be explained by the fact
that functional neuroimaging methods (PET, fMRI and MEG)
up until recently have been unable to study the white matter
bundles. Due to the recent development of DTI, it now
becomes possible to track non-invasively in vivo the subcortical fibres (Conturo et al., 1999; Jones et al., 1999; Basser
et al., 2000). An excellent illustration is given by the work of
Catani et al. (2002), who defined in healthy volunteers the
main white pathways of the brain. However, studies using
DTI are currently limited only to the identification of the
anatomy of the bundles, i.e. they allow the direct study of
the anatomical connectivity but they do not allow the direct
study of the functional connectivity. Conversely, the recent
use of computational algorithms applied to quantities on
types of functional imaging data that vary in spatial, temporal
and other features have permitted the study of functional
connectivity (Horwitz et al., 1998; Newman et al., 2002).
Nevertheless, these methods are not able simultaneously
to provide information regarding anatomical connectivity.
Consequently, despite the first experience with fusion of
these complementary methods, Horwitz (2003) mentions in
a recent review concerning brain connectivity, that ‘until it is
understood what each definition means in terms of an underlying neural substrate, comparisons of functional and/or
effective connectivity across studies may appear inconsistent
and should be performed with great caution’.
The use of intraoperative cortical and subcortical electrical stimulation currently gives a unique opportunity to
study directly both the anatomical and functional connectivity at the same time, as previously described (Duffau et al.,
2002, 2003a,b). Indeed, in spite of the invasive feature of
this method, direct brain stimulation offers the advantage of
identifying with accuracy and reliability the corticosubcortical structures essential for language (and not only
those involved in this function), by eliciting language disturbances when these areas are stimulated (Ojemann et al.,
1989; Berger, 1996; Duffau et al., 2002, 2003a). Thus, it is
possible to perform an on-line evaluation of the functional
consequences of each focal stimulation on awake patients
(i.e. to analyse 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. This anatomo-functional
study can help to determine different eloquent subregions
within a wider area. Although all our patients had structural
lesions, language disorders only occurred when stimulating
at specific electrode positions. In addition, motor responses
to stimulation had a distribution (hand/finger superior, face/
mouth inferior) appropriate for primary motor cortex, systematically found at least in patients operated on for a frontal
lesion—since the bone flap did not expose the whole central
region in cases of temporal tumours. Consequently, these
findings strongly suggest that our observations accurately
reflect the functional anatomy of the regions tested, particularly at the subcortical level, where brain plasticity phenomena induced by tumour growth seem less than at the cortical
level (Duffau et al., 2003d ). Note, nevertheless, that subcortical mapping is time consuming, and thus there is a
limitation on the number of (language) tasks which can
be performed by the awake patient during the surgical
procedure.
Interestingly, using this method, we were able to identify
subcortical sites eliciting semantic disorders when stimulated,
both within the temporal lobe and near the IFC.
Temporal lobe
In the six cases of intraoperative mapping of the dominant
temporal lobe, semantic disturbances were systematically
induced during stimulations of the white matter located
under the superior temporal sulcus. Due to the fact that the
removed lesions involved the mid- and posterior parts of the
temporal lobe, it was possible to detect several subcortical
Connectivity of the semantic system
sites eliciting semantic errors, from the occipito-temporal
junction posteriorly to the junction between the anterior temporal third and the mid-temporal third anteriorly (approximately below the anterior part of the insula). Thus, we could
hypothesize that we have 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 (since this ventricle was opened without
inducing any language disorders in four patients), and a
superior limit under the superior temporal gyrus.
Such a white bundle implicated in the semantic network
would seem in accordance with the literature about the locations of the cortical sites involved in semantic processing
(discussed above), i.e. concordant with a possible convergence of fibres coming from the posterior temporal regions
(basal infero-temporal area, posterior part of the middle and
superior gyri) and from the mid-part of the superior temporal
gyrus, in particular concerning its cortex buried within the
temporal superior sulcus.
IFC
While no patient in this series had a lesion directly involving the IFC, all patients harboured a frontal tumour coming
into contact with the ‘semantic pathways’, since in the nine
patients, subcortical stimulations generated semantic paraphasias. In the patient with a glioma invading the middle
frontal gyrus, the semantic disorders were elicited by the
stimulations of the white fibres under the inferior frontal sulcus, above the anterior part of the superior insulo-opercular
sulcus, in front of the pathways involved in speech production.
In the patients with a fronto-mesial glioma, the semantic disturbances were systematically generated by the stimulation of
the white matter at the level of the antero-infero-lateral edge of
the cavity, laterally and in front of the anterior part of the head
of the caudate nucleus (frontal horn opened in found patients),
and thus in front of the fibres coming from the posterior part of
the middle frontal gyrus (the dorsal premotor cortex, inducing
anomia when stimulated).
The locations of these subcortical ‘semantic sites’ are in
accordance with the current literature regarding the cortical
organization of the semantic system, since all these sites were
situated around the IFC, at the level of the superior (medial)
and anterior deep boundaries of the DLPFC and pars orbitaris,
i.e. converging laterally and in front of the head of the caudate
nucleus, and running to the anterior portion of the external
capsule, under the anterior part of the insular lobe.
Indeed, in the two patients operated on for an insular lowgrade glioma, while there was no language site detected at the
surface of this lobe using electrical mapping, despite the
contribution of this structure to motor aspects of speech
(Duffau et al., 2000; Ackermann and Riecker, 2004), probably due to cortical functional reshaping induced by the
glioma (Duffau et al., 2001), semantic paraphasias were
reproducibly elicited during stimulation of the anterior floor
of the external capsule, at the end of the resection.
807
In summary, our results provide arguments in favour of the
existence of a main pathway underlying the semantic system,
within the left or right dominant hemisphere, and joining the
two essential epicentres of this network: the posterior and
superior temporal areas and the IFC/DLPFC. Interestingly,
anatomical studies (Crosby et al., 1962; Nieuwenhuys et al.,
1988; Gloor, 1997) and more recent DTI studies (Catani et al.,
2002) identified a bundle which connects infero-lateral and
dorso-lateral frontal cortices with the posterior temporal
cortex and the occipital lobe: the inferior fronto-occipital
fasciculus. This fasciculus runs posteriorly from mainly prefrontal cortical areas immediately superior to the uncinate in
the frontal lobe. At the junction of the frontal and temporal
lobes, the fasciculus narrows in section as it passes through
the anterior floor of the external capsule. As the uncinate
hooks away anteromedially, the inferior fronto-occipital
fasciculus continues posteriorly before running medially in
the temporal lobe above and internal to the lateral ventricle,
and radiating to the occipital lobe. These radiations terminate
in the middle and inferior temporal gyri and in the lingual and
fusiform gyri.
Due to the concordance between the anatomy of this
fasciculus and the semantic pathway defined using intraoperative subcortical stimulation in our study, we suggest
that the inferior fronto-occipital fasciculus might constitute
the anatomic support for what could be called the ‘semantic
loop’. Indeed, this bundle allows the connection between
two essential epicentres of the semantic network, i.e. the
IFC/DLPFC and the temporal posterior regions within the
dominant hemisphere, known to work together in comprehension (Mesulam, 1990; Papathanassiou et al., 2000; Davis
and Johnsrude, 2003; Friederici et al., 2003; Heim et al.,
2003a), with likely interactive top-down and bottom-up
modulation (Tomita et al., 1999; Noesselt et al., 2003).
However, it is important to note that in addition to the
inferior fronto-occipital fasciculus, primate anatomical studies have indicated at least one other tract in the temporal lobe,
connecting mid-temporal and frontal regions (Petrides and
Pandya, 1988). Consequently, it is possible that this bundle
may also participate in subserving semantic processing.
Further studies combining intraoperative subcortical stimulations and perioperative DTI are thus mandatory, in order to
take a multiple pathway view underlying semantic networks.
Conclusions
On the basis of our findings, we can hypothesize the existence
of a dual route in language connectivity: (i) a ventral semantic
stream, connecting the IFC/DLPFC and the posterior temporal regions, via the inferior fronto-occipital fasciculus
(6other fronto-temporal tracts); and (ii) a dorsal phonological stream, connecting the IFC/ventral premotor cortex
(Duffau et al., 2003c) and the supramarginalis gyrus/posterosuperior temporal cortex, via cortico-cortical connections
(Duffau et al., 2003a) and the arcuate fasciculus (Duffau
et al., 2002).
808
H. Duffau et al.
Interestingly, this model is in accordance with the diagram
recently proposed by Gold and Buckner (2002), showing
common prefrontal regions co-activated with dissociable
posterior regions during controlled semantic (posterior
middle temporal gyrus) and phonological (supramarginalis
gyrus) tasks.
Such an organization of the anatomo-functional connectivity might support the hypothesis put forward by TzourioMazoyer (2003), which consists of applying the hierarchical
perception/action sensorimotor model of Fuster (1998) to the
organization of language, on the basis of the classification of
the cortical architecture suggested by Mesulam (1985) at
three levels: processing and production of language sounds
via the primary auditive and motor areas; a phonological
network including the superior temporal areas and the IFC/
ventral premotor cortex (unimodal associative areas); and a
semantic network constituted by the posterior part of the
superior temporal sulcus and pars triangularis and orbitaris
of IFC (multimodal associative areas).
Finally, a better knowledge of the anatomo-functional
organization of these distributed subnetworks of language
may have important implications concerning the planning
of brain surgery of lesions involving these structures.
Acknowledgements
We wish to thank Bernard Mazoyer for helpful comments on
the manuscript.
References
Ackermann H, Riecker A. The contribution of the insula to motor aspects of
speech production: a review and a hypothesis. Brain Lang 2004; 89: 320–8.
Alexander MP, Benson DF, Stuss DT. Frontal lobes and language. Brain
Lang 1989; 37: 656–91.
Baddeley A. Working memory. Science 1992; 255: 556–9.
Baddeley A. Working memory: looking back and looking forward. Nat Rev
Neurosci 2003; 4: 829–39.
Basser P, Pajevic S, Pierpaoli C, Duda J, Aldroubi A. In vivo fiber tracking
using DT-MRI data. Magn Reson Med 2000; 44: 625–32.
Berger MS. Minimalism through intraoperative functional mapping. Clin
Neurosurg 1996; 43: 324–37.
Boatman D, Gordon B, Hart J, Selnes O, Miglioretti D, Lenz F.
Transcortical sensory aphasia: revisited and revised. Brain 2000; 123:
1634–42.
Bookheimer S. Functional MRI of language: new approaches to understanding the cortical organization of semantic processing. Annu Rev
Neurosci 2002; 25: 151–88.
Bookheimer SY, Zeffiro TA, Blaxton TA, Gaillard WD, Malow B,
Theodore WH. Regional cerebral blood flow during auditory responsive
naming: evidence for cross-modality neural activation. Neuroreport 1998;
9: 2409–13.
Booth JR, Burman DD, Meyer JR, Gitelman DR, Parrish TB, Mesulam M.
Modality independence of word comprehension. Hum Brain Mapp 2002;
16: 251–61.
Brugge JF, Volkov IO, Garell PC, Reale RA, Howard MA III. Functional
connections between auditory cortex on Heschl’s gyrus and on the lateral
superior temporal gyrus in humans. J Neurophysiol 2003; 90: 3750–63.
Caplan D, Alpert N, Waters G. Effects of syntactic structure and propositional
number on patterns of regional cerebral blood flow. J Cogn Neurosci 1998;
10: 541–52.
Catani M, Howard RJ, Pajevic S, Jones DK. Virtual in vivo interactive dissection of white matter fasciculi in the human brain. NeuroImage 2002; 17:
77–94.
Chee MW, O’Craven KM, Bergida R, Rosen BR, Savoy RL. Auditory
and visual word processing studied with fMRI. Hum Brain Mapp 1998;
7: 15–28.
Conturo TE, Lori NF, Cull TS, Akbudak E, Snyder AZ, Shimony JS, et al.
Tracking neuronal fiber pathways in the living human brain. Proc Natl
Acad Sci USA 1999; 96: 10422–7.
Crinion JT, Lambon-Ralph MA, Warburton EA, Howard D, Wise RSJ.
Temporal lobe regions engaged during normal speech comprehension.
Brain 2003; 126: 1193–201.
Crosby EC, Humphrey T, Lauer EW. Correlative anatomy of the nervous
system. New York: Macmillian; 1962.
Damasio H, Grabowski TJ, Tranel D, Hichwa RD, Damasio AR. A neural
basis for lexical retrieval. Nature 1996; 380: 499–505.
Dapretto M, Bookheimer SY. Form and content: dissociating syntax and
semantics in semantic comprehension. Neuron 1999; 24: 427–32.
Davis MH, Johnsrude IS. Hierarchical processing in spoken language
comprehension. J Neurosci 2003; 23: 3423–31.
Decety J, Chaminade T, Grezes J, Meltzoff AN. A PET exploration of the
neural mechanisms involved in reciprocal imitation. Neuroimage 2002;
15: 265–72.
Demb J, Desmond J, Wagner A, Vaidya C, Glover G, Gabrieli J. Semantic
encoding and retrieval in the left inferior prefrontal cortex: a functional
MRI study of task difficulty and process specificity. J Neurosci 1995; 15:
5870–8.
Démonet JF, Chollet F, Ramsay S, Cardebat D, Nespoulos JL, Wise R, et al.
The anatomy of phonological and semantic processing in normal subjects.
Brain 1992; 115: 1753–68.
Desmond JE, Sum JM, Wagner AD, Demb JB, Shear PK, Glover GH, et al.
Functional MRI measurement of language lateralization in Wada-tested
patients. Brain 1995; 118: 1411–9.
Devlin JT, Matthews PM, Rushworth MFS. Semantic processing in the left
inferior prefrontal cortex: a combined functional magnetic resonance
imaging and transcranial magnetic stimulation study. J Cogn Neurosci
2003; 15: 71–84.
Duffau H, Capelle L, Lopes M, Faillot T, Sichez JP, Fohanno D. The insular
lobe: physiopathological and surgical considerations. Neurosurgery 2000;
47: 801–11.
Duffau H, Bauchet L, Lehéricy S, Capelle L. Functional compensation of the
left insula dominant for language. Neuroreport 2001; 12: 2159–63.
Duffau H, Capelle L, Sichez N, Denvil D, Lopes M, Sichez JP, et al.
Intraoperative mapping of the subcortical language pathways using direct
stimulations. An anatomo-functional study. Brain 2002; 125: 199–214.
Duffau H, Gatignol P, Denvil D, Lopes M, Capelle L. The articulatory loop:
study of the subcortical connectivity by electrostimulation. Neuroreport.
2003a; 14: 2005–8.
Duffau H, Capelle L, Denvil D, Sichez N, Gatignol P, Taillandier L, et al.
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. J Neurosurg.
2003b; 98: 764–78.
Duffau H, Capelle L, Denvil D, Gatignol P, Sichez N, Lopes M, et al.
The role of dominant premotor cortex in language: a study using intraoperative functional mapping in awake patients. Neuroimage 2003c; 20:
1903–14.
Duffau H, Capelle L, Denvil D, Sichez N, Gatignol P, Lopes M, et al.
Functional recovery after surgical resection of low grade gliomas in
eloquent brain: hypothesis of brain compensation. J Neurol Neurosurg
Psychiatry 2003d; 74: 901–7.
Embick D, Marantz A, Miyashita Y, O’Neil W, Sakai KL. A syntactic specialization for Broca’s area. Proc Natl Acad Sci USA 2000; 97: 6150–54.
Fiez J. Phonology, semantics, and the role of the left inferior prefrontal cortex.
Hum Brain Mapp 1997; 5: 79–83.
Fiez JA, Petersen SE. Neuroimaging studies of word reading. Proc Natl Acad
Sci USA 1998; 95: 914–21.
Connectivity of the semantic system
Friederici AD, Opitz B, von Cramon DY. Segregating semantic and syntactic
aspects of processing in the human brain: an fMRI investigation of different
word types. Cereb Cortex 2000a; 10: 698–705.
Friederici AD, Meyer M, von Cramon DY. Auditory language comprehension: an event-related fMRI study on the processing of syntactic and lexical
information. Brain Lang 2000b; 74: 289–300.
Friederici AD, Rüschemeyer SA, Hahne A, Fiebach CJ. The role of left
inferior frontal and superior temporal cortex in sentence comprehension:
localizing syntactic and semantic processes. Cereb Cortex 2003; 13:
170–177.
Fuster JM. Linkage at the top. Neuron 1998; 21: 1223–4.
Gabrieli JDE, Desmond JE, Demb JB, Wagner AD. Functional magnetic
resonance imaging of semantic memory processes in the frontal lobes.
Psychol Sci 1996; 7: 278–83.
Gabrieli JDE, Poldrack RA, Desmond JE. The role of left prefrontal cortex
in language and memory. Proc Natl Acad Sci USA 1998; 95: 906–13.
Gatignol P, Capelle L, Le Bihan R, Duffau H. Double dissociation between
picture naming and comprehension: an electrostimulation study. Neuroreport 2004; 15: 191–5.
Gloor P. The temporal lobe and the limbic system. New York: Oxford
University Press; 1997.
Gold BT, Buckner RL. Common prefrontal regions coactivate with dissociable posterior regions during controlled semantic and phonological tasks.
Neuron 2002; 35: 803–12.
Goodglass H, Kaplan E. The assessment of aphasia and related disorders.
Philadelphia: Lea and Fibiger; 1972.
Hamberger MJ, Seidel WT, Goodman RR, Perrine K, McKhann GM.
Temporal lobe stimulation reveals anatomic distinction between auditory
and naming processes. Neurology 2003; 60: 1478–83.
Hart J Jr, Gordon B. Delineation of single-word semantic comprehension
deficits in aphasia, with anatomical correlations. Ann Neurol 1990; 27:
226–31.
Heim S, Opitz B, Friederici AD. Broca’s area in the human brain is involved
in the selection of grammatical gender for language production: evidence
from event-related functional magnetic resonance imaging. Neurosci Lett
2002; 328: 101–4.
Heim S, Opitz B, Friederici AD. Distributed cortical networks for syntax
processing: Broca’s area as the common denominator. Brain Lang 2003a;
85: 402–8.
Heim S, Opitz B, Müller K, Friederici AD. Phonological processing
during language production: fMRI evidence for a shared production–
comprehension network. Cogn Brain Res 2003b; 16: 285–96.
Homae F, Hashimoto R, Nakajima K, Miyashita Y, Sakai KL. From
perception to sentence comprehension: the convergence of auditory and
visual information in the left inferior frontal cortex. Neuroimage 2002; 16:
883–900.
Horwitz B. The elusive concept of brain connectivity. Neuroimage 2003; 19:
466–70.
Horwitz B, Rumsey JM, Donohue BC. Functional connectivity of the angular
gyrus in normal reading and dyslexia. Proc Natl Acad Sci USA 1998; 95:
8939–44.
Ilmberger J, Eisner W, Schmid U, Reulen HJ. Performance in picture
naming and word comprehension: evidence for common neuronal
substrates from intraoperative language mapping. Brain Lang 2001; 76:
111–118.
Jobard G, Crivello F, Tzourio-Mazoyer N. Evaluation of the dual route theory
of reading: a metanalysis of 35 neuroimaging studies. Neuroimage 2003;
20: 693–712.
Jones DK, Simmons A, Williams SCR, Horsfield MA. Non-invasive assessment of axonal fiber connectivity in the human brain via diffusion tensor
MRI. Magn Reson Med 1999; 42: 37–41.
Just MA, Carpenter PA, Keller TA, Eddy WF, Thulborn KR. Brain activation
modulated by sentence comprehension. Science 1996; 274: 114–16.
Kang A, Constable R, Gore J, Avrutin S. An event-related fMRI study of
implicit phrase level syntactic and semantic processing. Neuroimage 1999;
10: 555–61.
809
Kapur S, Rose R, Liddle PF, Zipursky RB, Brown GM, Stuss D, et al. The role
of the left prefrontal cortex in verbal processing: semantic processing or
willed action? Neuroreport 1994; 5: 2193–6.
Keller T, Carpenter P, Just MA. The neural bases of sentence comprehension:
an fMRI examination of syntactic and lexical processing. Cereb Cortex
2001; 11: 223–37.
Lehéricy S, Cohen L, Bazin B, Samson S, Giacomini E, Rougetet R, et al.
Functional MR evaluation of temporal and frontal language dominance
compared with the Wada test. Neurology 2000; 54: 1625–33.
Lüders H, Lesser RP, Hahn J, Dinner DS, Morris HH, Wyllie E, Godoy J.
Basal temporal language area. Brain 1991; 114: 743–54.
Mazoyer B, Dehaene S, Tzourio N, Frak V, Cohen L, Murayama N, et al. The
cortical representation of speech. J Cog Neurosci 1993; 5: 467–79.
Mesulam MM. Principles of behavioral neurology. Philadelphie: F.A. Davis;
1985.
Mesulam MM. Large-scale neurocognitive networks and distributed processing for attention, language and memory. Ann Neurol 1990; 28:
597–613.
Metz-Lutz MN, Kremin H, Deloche G, Hannequin D, Ferrand L, Perrier D,
et al. 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.
Rev Neuropsychol 1991; 1: 73–95.
Michael EB, Keller TA, Carpenter PA, Just MA. FMRI investigation of
sentence comprehension by eye and by ear: modality fingerprints on
cognitive processes. Hum Brain Mapp 2001; 13: 239–52.
Moro A, Tettamanti M, Perani D, Donati C, Cappa SF, Fazio F. Syntax and the
brain: disentangling grammar by selective anomalies. Neuroimage 2001;
13: 110–8.
Müller RA, Rothermel RD, Behen ME, Muzik O, Mangner TJ,
Chakraborty PK, et al. Receptive and expressive language activations
for sentences: a PET study. Neuroreport 1997; 8: 3767–70.
Mummery CJ, Ashburner J, Scott SK, Wise RJ. Functional neuroimaging of
speech perception in six normal and two aphasic subjects. J Acoust Soc Am
1999; 106: 449–57.
Nieuwenhuys R, Voogd J, van Huijen C. The human central nervous system.
Berlin: Springer-Verlag; 1988.
Newman SD, Just MA, Carpenter PA. The synchronization of the human
cortical working memory network. Neuroimage 2002; 15: 810–22.
Nobre AC, Allison T, McCarthy G. Word recognition in the human inferior
temporal lobe. Nature 1994; 372: 260–3.
Noesselt T, Jon Shah N, Jäncke L. Top-down and bottom-up modulation of
language related areas—an fMRI study. BMS Neurosci 2003; 4:13.
Noppeney U, Price CJ. A PET study of stimulus- and task-induced semantic
processing. Neuroimage 2002; 15: 927–35.
Ojemann GA, Ojemann JG, Lettich E, Berger MS. Cortical language localization in left, dominant hemisphere. An electrical stimulation mapping
investigation in 117 patients. J Neurosurg 1989; 71: 316–26.
Oldfield RC. The assessment and analysis of handedness: the Edinburgh
inventory. Neuropsychologia 1971; 9: 97–113.
Otsuki M, Soma Y, Koyama A, Yoshimura N, Furukawa H, Tsuji S.
Transcortical sensory aphasia following left frontal infarction. J Neurol
1998; 245: 69–76.
Papathanassiou D, Etard O, Mellet E, Zago L, Mazoyer B, TzourioMazoyer N. A common language network for comprehension and production: a contribution to the definition of language epicenters with PET.
Neuroimage 2000; 11: 347–57.
Paulesu E, Frith CD, Frackowiak RSJ. The neural correlates of the verbal
component of working memory. Nature 1993; 362: 342–5.
Petrides M, Pandya DN. Association fiber pathways to the frontal cortex from
the superior temporal region in the Rhesus monkey. J Comp Neurol 1988;
273: 52–66.
Poldrack RA, Wagner AD, Prull MW, Desmond JE, Glover GH, Gabrieli JD.
Functional specialization for semantic and phonological processing in the
left inferior prefrontal cortex. Neuroimage 1999; 10: 15–35.
Price CJ. The anatomy of language: contributions from functional neuroimaging. J Anat 2000; 3: 335–59.
810
H. Duffau et al.
Rutten GJ, van Rijen PC, van Veelen CW, Ramsey NF. Language area
localization with three-dimensional functional magnetic resonance
imaging matches intrasulcal electrostimulation in Broca’s area. Ann
Neurol 1999; 46: 405–8.
Saygin AP, Dick F, Wilson W, Dronkers F, Bates E. Neural resources for
processing language and environmental sounds: evidence from aphasia.
Brain 2003; 126: 928–45.
Schäffler L, Luders HO, Dinner DS, Lesser RP, Chelune GJ. Comprehension
deficits elicited by electrical stimulation of Broca’s area. Brain. 1993; 116:
695–715.
Schäffler L, Lüders HO, Beck GJ. Quantitative comparison of language
deficits produced by extraoperative electrical stimulation of Broca’s,
Wernicke’s, and basal temporal language areas. Epilepsia 1996; 37:
463–75.
Schlosser MJ, Aoyagi N, Fulbright RK, Gore JC, McCarthy G. Functional
MRI studies of auditory comprehension. Hum Brain Mapp 1998; 6: 1–13.
Scott SK, Blank CC, Rosen S, Wise RJ. Identification of a pathway for
intelligible speech in the left temporal lobe. Brain 2000; 123: 2400–6.
Skirboll SS, Ojemann GA, Berger MS, Lettich E, Winn R. Functional cortex
and subcortical white matter located within gliomas. Neurosurgery 1996;
38: 678–85.
Stromswold K, Caplan D, Alpert N, Rauch S. Localization of syntactic
comprehension by positron emission tomography. Brain Lang 1996; 52:
452–73.
Szatkowska I, Grabowska A, Szymanska O. Phonological and semantic
fluencies are mediated by different regions of the prefrontal cortex.
Acta Neurobiol Exp (Wars) 2000; 60: 503–8.
Thompson-Schill SL, D’Esposito M, Aguirre GK, Farah MJ. Role of left
inferior prefrontal cortex in retrieval of semantic knowledge: a reevaluation. Proc Natl Acad Sci USA 1997; 94: 14792–7.
Thompson-Schill SL, Swick D, Farah MJ, D’Esposito M, Kan IP,
Knight RT. Verb generation in patients with focal lesion lesions: a
neuropsychological test of neuroimaging findings. Proc Natl Acad Sci
USA 1998; 95: 15855–60.
Tomita H, Ohbayashi M, Nakahara K, Hasegawa I, Miyashita Y. Top-down
signal from prefrontal cortex in executive control of memory retrieval.
Nature 1999; 401: 699–703.
Tulving E, Kapur S, Markowitsch HJ, Craik FIM, Habib R, Houle S.
Neuroanatomical correlates of retrieval in episodic memory: auditory
sentence recognition. Proc Natl Acad Sci USA 1994; 91: 2012–5.
Tyler LK, Stamatakis EA, Dick E, Bright P, Fletcher P, Moss H. Objects and
their actions: evidence for a neurally distributed semantic system.
Neuroimage 2003; 18: 542–57.
Tzourio-Mazoyer N. Les réseaux neuraux dédiés au langage chez l’adulte.
In: Etard O, Tzourio-Mazoyer N, editors. Traité des sciences cognitives:
cerveau et langage. Paris: Hermes; 2003. p. 67–101.
Wagner A, Desmond J, Demb J, Glover G, Gabrieli JD. Semantic
repetition priming for verbal and pictorial knowledge. J Cogn Neurosci
1997; 9: 714–26.
Wagner AD, Pare-Blagoev EJ, Clark J, Poldrack RA. Recovering meaning:
left prefrontal cortex guides controlled semantic retrieval. Neuron 2001;
31: 329–38.
Warburton E, Wise RJ, Price CJ, Weiller C, Hadar U, Ramsay S, et al. Noun
and verb retrieval by normal subjects. Studies with PET. Brain 1996; 119:
159–79.
Wise R, Chollet F, Hadar U, Friston K, Hoffner E, Frackowiak R. Distribution
of cortical networks involved in word comprehension and word retrieval.
Brain 1991; 114: 1803–18.
Wise R, Scott S, Blamk S, Mummery C, Murphy K, Warburton E.
Separate neural subsystems within ‘Wernicke’s area’. Brain 2001; 124:
83–95.
Zatorre RJ, Evans AE, Meyer E, Gjedde A. Lateralization of phonetic
and pitch discrimination in speech processing. Science 1992; 256:
846–7.