Journal of Chemical Neuroanatomy 89 (2018) 73–81

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Journal of Chemical Neuroanatomy

journal homepage: www.elsevier.com/locate/jchemneu

Review

The error of Broca: From the traditional localizationist concept to a

connectomal anatomy of human brain
Hugues Duffaua,b,*
a
Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center, 80 Av Augustin Fliche, 34295 Montpellier, France
b
National Institute for Health and Medical Research (INSERM), U1051 Laboratory, Team “Brain Plasticity, Stem Cells and Glial Tumors”, Institute for
Neurosciences of Montpellier, Montpellier University Medical Center, 34091 Montpellier, France

A R T I C L E I N F O A B S T R A C T

Article history:
Received 12 August 2016 Neurology, especially aphasiology, was mainly built on behavioral-structural correlations (“lesion
Received in revised form 6 March 2017 method”). In this setting, Broca's area has been considered as the “speech area”; moreover, this
Accepted 12 April 2017 observation led to localizationism. However, advances in brain mapping techniques, as functional
Available online 14 April 2017 neuroimaging and direct electrical stimulation in patients undergoing awake surgery for gliomas, has
resulted in a paradigmatic shift regarding models of neural architecture. In fact, the brain is organized in
Keywords: distributed complex networks underpinning sensorimotor, visuospatial, language, cognitive and
Brain connectome emotional functions. In this connectomal workframe, cerebral processing is not conceived as the sum
Neuroplasticity
of segregated subfunctions, but results from the integration and potentiation of parallel (even if partially
Serial mappings
overlapped) subcircuits. Such a networking model, taking into account cortical and subcortical anatomic
Awake surgery
Direct electrical stimulation constraints, explains interindividual variability in physiology and after brain damage, particularly in
Low-grade gliomas aphasiology – e.g. double dissociations during electrostimulations, as comprehension versus naming
disorders, semantic versus phonemic paraphasias, or syntactic disturbances versus anomia. This dynamic
organization mediated by the well-synchronized functioning of delocalized groups of interconnected
neurons (rather than by discrete centers) also explains the huge potential of neuroplasticity following
cerebral insult, on the condition that the axonal connectivity is preserved. According to this principle,
massive surgical resection of brain regions dogmatically considered as “critical” in a localisationist view
can be achieved with no functional deficit, as the removal of Broca's area – which is not the speech area –
without disorders. This connectomal account of neural processing may have major implications in
cognitive neurosciences and in therapeutic management of brain-damaged patients.
© 2017 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... ... . . . . . 74

2. Methodological shortcomings inherent to the classical lesion method . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... ... . . . . . 74
3. Intraoperative electrical cortical and axonal mapping: an original technique to evoke a transient virtual lesion of neural network .. . . . . . 74
4. The huge brain plastic potential and its constraints by the axonal connectivity . . . . . . . . . . . . . . . . . . . . ..................... ... . . . . . 75
4.1. The concept of postlesional neuroplasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... ... . . . . . 75
4.2. Connectomal anatomy and the minimal common brain: towards atlases of cerebral plasticity . . ..................... ... . . . . . 76
4.3. Structural and functional axonal connectivity sustaining neural systems . . . . . . . . . . . . . . . . . . . . ..................... ... . . . . . 76
5. Clinical implications of a networking model of neural processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... ... . . . . . 77
5.1. Resection of Broca’s area: this region is not the area of speech . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... ... . . . . . 77
5.2. Resection of Wernicke's area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... ... . . . . . 77
5.3. Functional remapping over time: evidence by serial surgeries . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... ... . . . . . 78
5.4. Beyond surgical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... ... . . . . . 79

* Correspondence address: Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center, 80 Avenue Augustin Fliche, 34295 Montpellier,
France.
E-mail address: h-duffau@chu-montpellier.fr (H. Duffau).

http://dx.doi.org/10.1016/j.jchemneu.2017.04.003
0891-0618/© 2017 Elsevier B.V. All rights reserved.
74 H. Duffau / Journal of Chemical Neuroanatomy 89 (2018) 73–81
6. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
1. Introduction
As a consequence of the seminal lesional work of Broca (1861)
who described that a damage in the left inferior frontal gyrus
induced a reduced capacity for articulate speech, a decade before
Wernicke (1874), who associated speech comprehension with the
left superior posterior temporal gyrus, a localisationist view of the
organization of cerebral functioning (especially for language) was
inexorably established. According to this fixed work-frame, it has
been postulated that the organization of the human brain is based
upon highly specialized eloquent regions (such as Broca’s and
Wernicke’s areas) for which any damage results in permanent
neurological impairments, opposed to “non-eloquent” stuctures
for which no functional consequences occur in case of injury In
addition, such a dogma of localizationism implicitly resulted in the
principle of a similar brain functional anatomy between individu-
als, as for example the pars opercularis and pars triangularis of the
left “dominant” hemisphere, that is, the Broca's area, that is a priori
considered to the speech area in all human brains. Of note, this
traditional view of a static functional organization of the brain had
numerous implications not only in fundamental neurosciences, by
resulting notably in the elaboration of simplistic and rigid models
of conation and cognition, but also in clinical practice – especially
by claiming that surgery was impossible in the so-called
“eloquent” structures (Sawaya et al., 1998).
In this article, the aim is to break with this classical modular and
inflexible model by proposing a dynamic and connectomal
anatomy underlying neural circuits, that explains a major inter-
individual anatomo-functional variability (Duffau, 2016) and that
allows postlesional cerebral adaptive phenomena able to maintain
neurological and cognitive functions (Duffau, 2014a), opening the
window to new therapeutic strategies in brain-damaged patients,
especially in the field of neurooncology (Duffau and Taillandier,
2015). In this state of mind, recent data provided by serial
mappings performed in patients who underwent awake surgery
for diffuse glioma infiltrating eloquent structures will be reviewed.
2. Methodological shortcomings inherent to the classical lesion
method
The localizationist concept was mainly built on behavioral-
structural correlations based upon lesion method. However, this
methodology suffers from serious limitations (Herbet et al., 2015a).
The first is the size of the injuries, which are often large,
especially in stroke, with usually an inhomogeneous spatial
distribution of lesions and a small number of patients.
Secondly, the accurate three dimensional delineation of
damages was very difficult until development of MRI. Indeed,
recent MRIs of Leborgne’s and Lelong’s brain showed wide
damages involving not only the classical cortical “Broca’s area”
but also the insula and perisylvian white matter (Dronkers et al.,
2007) – meaning that the “motor aphasia” did not necessarily
result from injury to the inferior frontal operculum.
Thirdly, in lesion maps, one should be cautious before to
interpret that a “statistical epicenter” common to every patients is
the region which sub-serves the disrupted function. In fact, the
same neurological deficit may be due to insults in different
locations across patients, all of them being involved in a large
functional network around (but not including) the “epicenter”
thought to be crucial. In this spirit, the classical lesion method does
not address the potential impact of white matter fibre
disconnection in the validity of the lesion-deficit maps. However,
recent studies have demonstrated that the behavioral counterpart
of disconnection is at the very least significant (Herbet et al.,
2015b). For example, Herbet et al. have provided evidence that the
degree of disconnection of the right perisylvian white matter
network (including the arcuate and the lateral superior longitudi-
nal fasciculi) as well as the right cingulum was associated with a
decrease in low-level, face-based and high-level, inference-based
mentalizing performance, respectively – laying the foundation for
a dual-stream model of mentalizing processes (Herbet et al.,
2014a). In the same mind, Almairac et al. (2015) have shown that
the degree of disconnection of the left inferior fronto-occipital
fasciculus was correlated with deficit in language semantics
(decrease of semantic fluency scores in patients with a glioma
infiltrating this pathway). Thiebaut de Schotten et al. (2014) have
also evidenced that the most reliable predictor of chronic spatial
neglect was a disconnection of the layer II of the right superior
longitudinal fasciculus. These findings should prompt researchers
to reflect more deeply on how to fairly gauge the contribution of
white-matter injury in the emergence of neuropsychological
impairments (Bartolomeo, 2012). This is also true when consider-
ing more sophisticated and powerful lesion data analysis
techniques, such as voxel-based lesion-symptom mapping, since
any attempts to improve lesion-deficit mapping without taking
into account connectivity will be in vain (Herbet et al., 2015a).
Fourthly, compensatory mechanisms of neuroplasticity can
occur following neural insult, especially in slow-growing lesions
(Duffau, 2005; Desmurget et al., 2007), making correlation
between behavioral performance of patients and spatial location
of their injury very complex.
Therefore, due to these major methodological shortcomings of
lesion method, and because a localisationist account cannot
explain the regular observations of functional improvement after
insult involving the cerebral areas considered as essential, this
concept of modular and inflexible brain processing has recently
been questioned.
3. Intraoperative electrical cortical and axonal mapping: an
original technique to evoke a transient virtual lesion of neural
network
Advances in functional neuroimaging have recently provided
new insights into the neurobiology of cerebral functions, especially
with regard to language, by studying the whole brain during
functional tasks, both in healthy subjects and in brain-damaged
patients. Using task-based functional MRI, the classical concept of
language organization shifted towards distributed models
(Vigneau et al., 2006). However, functional MRI can not
differentiate cortical areas crucial for the neural functions from
those which can be compensated. In addition, recent studies
comparing preoperative functional MRI with intraoperative
electrophysiology have revealed a low reliability of neuroimaging,
with a sensitivity of only 37.1% and a specificity of only 83.4% for
language mapping (Kuchcinski et al., 2015). In the same vein,
although diffusion tensor imaging can give an indirect reflect of the
structure of white matter tracts in vivo, this method cannot study
directly the function of these subcortical fascicles (Duffau, 2014b).
Interestingly, although direct electrical stimulation (DES)
mapping has received only little attention in the past decades,
DES is nonetheless the sole technique that allows a real-time
investigation of the function of the cortical sites as well as the
 H. Duffau / Journal of Chemical Neuroanatomy 89 (2018) 73–81
subcortical fibers in humans (Duffau, 2015a). The principle is to
perform on-line anatomo-functional correlation in awake patients,
by means of DES (biphasic electrical current, 60 Hz, 1 ms, 1–4 mA)
that mimics a transitory virtual lesion, with the goal to benefit from
an individual mapping at both the level of the cortex and white
matter tracts. This intraoperative mapping enables to check
whether brain structures that have to be surgically removed for
oncological (e.g. involved by a glioma) or epileptological purposes
are still essential for neurological, neurocognitive and behavioral
functions. Indeed, DES of critical pathways causes a transient
disruption of the tasks continuously performed by the patient into
the operating theater, and this area – which is only a part of a more
complex neural network – has to be preserved (Duffau et al., 2008).
Therefore, DES offers a unique opportunity to map directly the
human connectome in vivo. In clinical routine, this technique that
permits to achieve resection up to individual functional boundaries
(Duffau, 2015b), has extensively been validated as an easy, reliable,
reproducible, and safe mapping method, and it is now considered
as the gold-standard in glioma surgery (De Witt Hamer et al.,
2012).
Of note, DES transitorily interacts locally with a small cortical or
axonal site, but also non-locally, as the focal perturbation will
indeed disrupt the whole corresponding subnetwork (Mandonnet
et al., 2010). In other words, DES does not evoke only a “focal
lesion” limited to the zone stimulated, but elicites a dyssynchro-
nization within a large-scale cortico-subcortical subcircuit medi-
ating a given subfunction. Thus, conversely to functional
neuroimaging, DES is able to detect the structures essential for
neural functions, particularly with regard to white matter bundles, by
inhibiting a subpathway during a few seconds – with the
possibility to validate if the same functional consequences are
reproduced when repeat stimulations are applied over the same
structure. Of note, by gathering all cortical and axonal sites where
the same type of errors has been caused by stimulation, one would
build up the subcircuit of the disrupted subfunction. As a
consequence, DES represents a unique tool to detect with a great
precision (about 5 mm) and reproducibility, in vivo in humans, the
structures that are crucial for neural functions. Indeed, DES
allowed the mapping of movement (including control of bimanual
coordination) (Schucht et al., 2013; Rech et al., 2014); somatosen-
sory function (Duffau and Capelle, 2001); visual function
(Gras-Combe et al., 2012); auditory-vestibular function (Spena
et al., 2006); spatial awareness (Thiebaut deSchotten et al., 2005);
language, by proposing a re-examination of the neural foundations
sustaining language according to a hodotopical model, including
spontaneous speech (not related to Broca's area, see below) and
counting, object naming, verbal comprehension, writing, reading,
syntax, bilingualism, language switching from one language to
another (Duffau et al., 2014); higher-order functions such as
calculation, memory, attention, cognitive control, cross-modal
judgment, non verbal comprehension (Duffau et al., 2002a, 2002b;
Plaza et al., 2008; Moritz-Gasser et al., 2013a, 2013b; Charras et al.,
2015); mentalizing and consciousness (Herbet et al., 2014b, 2015c,
2016a).
Once again, DES is currently the only technique capable to
investigate directly the functional role of the subcortical fascicles.
Indeed, by correlating neurological disorders caused by intra-
surgical DES with the anatomical data gained from post-operative
MRI, reliable structural-functional correlations have been
achieved. Such correlations resulted in the analysis of the
anatomical location of the critical sites detected by DES, that is,
by definition at the periphery of the surgical cavity, where the
resection was interrupted according to individual functional limits.
This methodology has extensively been validated in previous
investigations (Ius et al., 2011; Duffau, 2015a). Interestingly, in
comparison to the voxel-based lesion-symptom mapping, that
75
analyzes the relationship between tissue damage and behavior in
patients with a neurological deficit (Bates et al., 2003), electrical
mapping offers the possibility of studying the relationship
between brain and behavior in subjects with no or only very
slight neurological disorder.
Remarkably, original findings gained fomr DES in patients
undergoing awake surgery for a glioma, especially regarding the
functional connectivity, led to the proposal of revisited models of
cerebral processes, by switching from a modular to a delocalized
and dynamic view (Duffau, 2015a). In this frame-work, neural
functioning is sustained by large-scale subnetworks interacting
together and capable to compensate themselves after brain insult –
at least to some degrees. These new insights into the connectomal
anatomy mediating functional brain systems and the implication
for neuroplasticity will be discussed.
4. The huge brain plastic potential and its constraints by the
axonal connectivity
4.1. The concept of postlesional neuroplasticity
Neuroplasticity can be defined as a continuous process
subserving short, middle and long-term remodeling of the
neurono-synaptic organization, in order to optimize the function-
ing of neural networks – during phylogeny, ontogeny, physiological
learning and after brain insult (Duffau, 2006). Neural plasticity is
possible solely in a dynamic account of cerebral distribution, in
which the nervous system is an ensemble of complex subcircuits
that form, reshape and flush information dynamically (Duffau,
2014a). Consequently, brain reallocation is conceivable because of
the existence of multiple and overlapping redundancies hierar-
chically distributed. Neuronal aggregates around a lesion may
increasingly adopt the function of the injuried structure and switch
their own activation pattern to substitute the damaged area
whereas facilitating functional compensation (Duffau, 2006). In
this context, the concept of the brain connectome has recently
emerged. Its aim is to capture the characteristics of spatially-
distributed dynamical neural processes at multiple spatial and
temporal scales (Sporns et al., 2005). The new science of
“connectomics” is participating both in theoretical and computa-
tional models of the brain as a complex system, with the aim of
characterizing and scaling the functional organization of the
healthy and diseased nervous system (Honey et al., 2007).
Despite a few literature reports on cases of functional recovery
or adaptation in various neurological contexts (Schumacher et al.,
1987; Feuillet et al., 2007; Philippi et al., 2012; Feinstein et al.,
2016), the most persuasive body of evidence for the brain’s
astonishing, lesion-induced plasticity, comes from the field of
neurosurgery in general and the removal of diffuse low-grade
glioma (DLGG) in particular (Herbet et al., 2016b). Indeed, the
surgical removal of large cerebral structures (including cortical
sites thought to act as critical cornerstones within large-scale
neurocognitive networks, as Broca's area) during DLGG resection
does not necessarily generate major, persistent cognitive or
sensorimotor impairments (Duffau et al., 2005; Desmurget
et al., 2007) – shaking the very foundation of behavioural
neurology. The massive excision of brain tissues is made possible
by the progressive, functional reallocation caused by the slow
growth of this kind of tumor (Desmurget et al., 2007). This may
explain, at least in part, why DLGG patients usually present with
mild, relatively non-specific cognitive deficits before surgery
(Heimans and Reijneveld, 2012). Indeed, the slow time course of
the tumor has resulted in a presurgical recruitment of perilesional
and/or remote regions within the ipsilesional hemisphere and/or
of contralateral areas. However, as illustrated by magnetoenceph-
alography, a focal glioma disturbs the functional and effective
76 H. Duffau / Journal of Chemical Neuroanatomy 89 (2018) 73–81
connectivity whithin the whole nervous system, and not only in
restricted zone outlying the tumor (Bartolomei et al., 2006). These
network dysfunctions are correlated to cognitive disturbances in
glioma patients (Bosma et al., 2008). Indeed, when objective
neuropsychological and health-related quality of life assessments
have been achieved, visuo-spatial, memory, attention, planning,
learning, emotional, motivational and behavioral deficits have
regularly been observed, even in patients with incidental DLGG
(Klein et al., 2012; Cochereau et al., 2016). Thus, these results show
that brain plastic potential has nonetheless some limitations that
have to be investigated at the individual level.
In other words, neural plasticity can be efficient only on the
condition that the subcortical connectivity is spared, to permit
spatial communication and temporal synchronization among large
inter-connected networks – according to the principle of hodotopy
(Catani, 2007; de Benedictis and Duffau, 2011). Indeed, in spite of
the observation of distinct patterns of subcortical plasticity, such as
unmasking of perilesional latent subcircuits, recruitment of
parallel long-distance association subnetworks, introduction of
additional relays within neurono-synaptic pathways, the actual
capacity to build a new structural subcortical connectivity
(“rewiring”) resulting in functional recovery was not shown in
humans (Duffau, 2009). Therefore, an improved knowledge of the
functional connectivity is crucial in humans.
4.2. Connectomal anatomy and the minimal common brain: towards
atlases of cerebral plasticity
While the plastic potential is high at the cortical level,
subcortical plasticity is low, implying that axonal connectivity
should be surgically preserved to allow postoperative compensa-
tion (Duffau, 2009, 2014a; Ius et al., 2011). By combining cortical
function and axonal connectivity, an updated model of neural
processes has been suggested, moving from the localizationist
model to a connectomal frame-work. In other words, one has to
take into account the complex functioning of a large-scale
distributed cortico-subcortical subnetwork to understand its
physiology as well as the functional consequences of a damage
in this subcircuit – with different disorders according the location
and the extent of the injury.
Recently, probabilistic atlases of functional plasticity were
computed in patients who underwent excision for a DLGG on the
basis of intrasurgical DES (Ius et al., 2011; Sarubbo et al., 2015;
Herbet et al., 2016b). Combining the intraoperative functional data
with postoperative anatomic MRI resulted in both a better
understanding of the functional limits of surgical resection, and
new data into neuroplasticity. Indeed, these atlases provided a
general frame-work to establish structural-functional correlations
by computing for each brain voxel its probability to be spared –
because of its functional role – on the postoperative MRI. Their
overlap with the cortical MNI template and a diffusion tensor
imaging tractography atlas enabled to investigate the potentialities
and the limitations of inter-individual variability and plasticity,
both for cortical regions and axonal fibers. Importantly, these
atlases highlighted the key role of the axonal fascicles in
postlesional reshaping. A low probability of residual gliomas
invading the cortex was revealed, while most of the areas with high
probability of residual tumor were situated in the white matter (Ius
et al., 2011; Sarubbo et al., 2015; Herbet et al., 2016b). In other
words, the functions sustained by long-range projection and
association tracts are less subject to inter-individual variability and
reorganization than cortical regions (except in primary unimodal
sites and in a small set of neural hubs) (Duffau, 2014a, 2016).
The low potential of remodeling could be explained for some
structures because they act as input or output regions: input sites
convey or are the first relay of information entering the brain,
while output sites are the last relay or the fiber bundles sending
information outside the brain. These structures comprise the
primary motor and somatosensory areas, the cortico-spinal and
thalamo-cortical tracts and the optic radiations, namely, the
projection fibers. Interestingly, these zones are mainly unimodal
and organized serially, with an absence of parallel alternative
pathway explaining the impossibility to restore their function after
any insult (Duffau, 2009). For other structures, their non-
resectability have to be investigated within a network account.
Indeed, complex cognitive processes are sustained by short- and
long-range subcircuits, with cortical hubs connected by U-shaped
fibers, associative and commissural pathways that enable proper
synchronization between several distant regions (Stam, 2010).
Therefore, these subcortical tracts as the inferior fronto-occipital
fasciculus (IFOF) and arcuate fasciculus (AF) can not be excised
because their damage would induce so major disturbances in the
subcircuit that the plastic potential would be overwhelmed
(Duffau, 2015a). Of note, in revisited models of cognition, some
cortical sites are conceived as “hubs” (Ueno et al., 2011). These
critical epicenters allow a plurimodal integration of multiple data
coming from the unimodal regions (Sarubbo et al., 2016). This
integration may result in the conceptualization, processed at the
level of a large subnetwork that comprises the hubs. Thus, because
these hubs are interconnected by axonal pathways, these
subcortical tracts are themselves essential for brain function, as
for example the IFOF and the AF. Importantly, the reproducibility of
these results, in spite of the inter-individual anatomo-functional
variability and plastic mechanisms, led us to propose the existence
of a “minimal common brain”, necessary for the basic cognitive
functions – even though probably not enough for more complex
functions such as multi-processing (Ius et al., 2011; Duffau, 2016).
This proposal is in good agreement with biomathematical models
that investigated the effect of a simulated focal lesion on the global
cerebral network topology (Alstott et al., 2009). For these
structures, even biological plasticity would fail on the long term
to restore the connectivity required to rebuild an effective
functional circuit (Duffau, 2009).
In summary, these atlases that shed new lights on the
topological organization of central nervous system, can be useful
in predicting the likelihood of recovery (as a function of lesion
topology), and, with respect to clinical applications, in giving
preoperatively an objective estimation of the expected extent of
resection for gliomas.
4.3. Structural and functional axonal connectivity sustaining neural
systems
Therefore, neuroscientists have to improve their knowledge of
white matter circuitery. Cognitive neurosciences are closely
related with neurosurgery, since the use of DES also provides
new insights into the circuits mediating cognitive and behavioral
functions.
For example, beyond the cortico-spinal (pyramidal) and
thalamo-cortical (somatosensory) tracts, the functional connec-
tivity underpinning movement planning and execution, also
comprising the “motor control subnetwork” (Schucht et al.,
2013), is partly subserved by the fronto-striatal tract (Kinoshita
et al., 2015). The visuospatial subnetwork is not only sustained by
the optic radiations (Gras-Combes et al., 2012), but also by the
inferior longitudinal fascicle (ILF) which is critical for visual
recognition (Fernández Coello et al., 2013), and the part II of the
superior longitudinal fascicle (SLF) which is crucial for spatial
cognition, especially in the right hemisphere (Thiebaut de Schotten
et al., 2005; Charras et al., 2015).
Language is underlain by dorsal and ventral pathways (Duffau
et al., 2014; Sarubbo et al., 2016). Schematically, the medial part of
 H. Duffau / Journal of Chemical Neuroanatomy 89 (2018) 73–81
dorsal stream (AF) mediates phonological and repetition processes
(Maldonado et al., 2011; Moritz-Gasser and Duffau, 2013), and the
lateral part of the SLF subserves speech articulation, while
representing the limiting factor of plastic potential of the left
ventral premotor cortex in case of injury (Van Geemen et al., 2014).
The ventral stream, mostly underpinned by the IFOF (direct ventral
route), subserves language semantics (Duffau et al., 2005, 2013),
while the ILF (indirect ventral route) plays a key role in lexical
retrieval (Herbet et al., 2016) and reading (Zemmoura et al., 2015).
Concerning the subnetwork sustaining mentalizing (theory of
mind), which is essential for emotion and social cognition,
intraoperative DES combined with pre- and post-operative
behavioral examinations revealed that this function is made
possible by parallel processes of two subsystems: accuracy of
identification (mirror system, namely, the ability to appreciate
other people's emotions) and attribution of mental states (high-
level inferential mentalizing) are subserved by the AF/SLF complex
and the cingulum, respectively (Herbet et al., 2014a, 2015d).
To sum up, the vision of the neural basis of cognition begins to
shift. For a long time, neurocognitive and behavioral functions have
been considered in associationist terms of areas and tracts, the
global principle being that data were processed in localized cortical
sites with the serial passage of information between zones through
white matter fibers. In the connectomal account, neural functions
are conceived as resulting from parallel delocalized processes
achieved by distributed subgroups of connected neurons rather
that discrete epicenters. Breaking with the traditional serial
models in which one process should be finished before than the
data reach another level of processing, this new view of
“independent subcircuits” states that distinct processes can be
performed simultaneously with interactive feedbacks. In this
hodotopical model, neural function is generated by the synchroni-
zation between several hubs, working in phase during a given task:
this explains why the same epicenter could participate in distinct
functions depending on the other cortical zones with which it is
temporarily connected. Importantly, brain processing should not
be considered as the sum of several subfunctions. Rather, neural
function results from the integration and potentiation of parallel
(while partially overlapped) subnetworks (Duffau, 2015a).
To illustrate this multimodal model of networking brain, DES
evidenced the existence of an amodal executive subsystem,
comprising prefrontal cortex, anterior cingulum and caudate
nucleus, that plays a key role in the cognitive control of more
dedicated subcircuits – as for instance the subnetwork sustaining
language switching in multilingual subjects (itself constituted by a
wide cortico-subcortical network that includes postero-temporal
areas, supramarginal and angular gyri, inferior frontal gyrus and
SLF) (Moritz-Gasser and Duffau, 2009). In the same vein, according
to the data issued from axonal DES correlated with perioperative
neurocognitive assessments, the multimodal (verbal and non-
verbal), working memory and attention functions seem to be
underpinned by distinct subparts of the SLF (Moritz-Gasser et al.,
2013a, 2013b; Charras et al., 2015). In fact, simultaneous
recruitment of these subnetworks in addition to the subcircuits
more specifically dedicated to language and visuo-spatial cogni-
tion is mandatory if a subject performs a sustained double task,
combining for instance speech and line bisection test every 4 s
during hours. Indeed, dual task is regularly asked to awake patients
during electrostimulation with the aim of optimizing the reliability
of functional mapping, because each axonal DES is capable to
disrupt specifically a subfunction without causing consequences
on the others (Duffau, 2015a). The future step is to explore
interactions between large-scale cortico-subcortical subcircuits
participating in different levels of consciousness, such as noetic
consciousness (the awareness of knowing and understanding the
world and the self, while being aware of such an awareness)
77
(Moritz-Gasser et al., 2013a, 2013b) and consciousness of the
external environment (Herbet et al., 2014b, 2016a).
5. Clinical implications of a networking model of neural
processes
From a clinical perspective, such a paradigmatic shift from
localizationism to connectomics results in numerous implications.
In brain surgery for tumors or epilepsy, it is in fine possible to
achieve massive excisions in “eloquent” structures wrongly
conceived as inoperable for many decades, with nonetheless
preservation or even improvement of the quality of life. Especially
in surgical neurooncology, owing to the phenomenon of adaptive
neuroplasticity, glioma removal can be performed with a minimal
morbidity in spite of tumor location within “cruciall” regions, as
the Broca's area or Wernicke's area (Duffau, 2005, 2014a;
Desmurget et al., 2007; Herbet et al., 2016b)
5.1. Resection of Broca’s area: this region is not the area of speech
Remarkably, a recent probabilistic map for critical cortical
epicenters of human brain functions, based upon over 700 DES
data obtained in 165 consecutive patients who underwent awake
mapping for surgical excision of DLGG, challenged the traditional
theories of neural organization. Indeed, this atlas has revealed that
Broca's area is not the speech output region (Tate et al., 2014, 2015).
In fact, extensive resection of tumors such as DLGG situated
within the pars opercularis and/or triangularis of the left inferior
frontal gyrus can be achieved without causing any permanent
language impairment (Plaza et al., 2009; Lubrano et al., 2010;
Duffau, 2012). Language compensation (if needed) may be
supported by the recruitment of adjacent structures, mainly the
ventral premotor cortex, the pars orbitalis of the inferior frontal
gyrus, the dorsolateral prefrontal cortex as well as the insula
(Duffau et al., 2003; Benzagmout et al., 2007). Indeed, the left
ventral premotor cortex (i.e. the lateral part of the precentral gyrus,
anatomically situated behind the pars opercularis) cannot be
excised because it represents the real final common pathway for
speech (Van Geemen et al., 2014; Tate et al., 2014). On the contrary,
Broca's area can be compensated after surgical removal (Duffau,
2012). This assumption was supported by the fact that extensive
neuropsychological examinations following resection of Broca’s
area confirmed a complete functional recovery (Plaza et al., 2009).
However, one could argue that resection of Broca's area was
possible since this region was invaded by a glioma. In fact, a
transopercular surgical approach through Broca's area, even
though not infiltrated by the tumor, has been reported in insular
DLGG with the goal to avoid splitting the Sylvian fissure and
therefore in order to minimize the risk of vascular injuries:
interestingly, no lasting language deficits have been observed
(Duffau et al., 2009; Michaud and Duffau, 2016).
5.2. Resection of Wernicke's area
Language compensation following surgical excision of gliomas
infiltrating the posterior part of the left “dominant” superior
temporal gyrus (and its junction with the inferior parietal lobule) is
possible because this complex function is organized in multiple
parallel subnetworks. As a result, in addition to the recruitment of
structures immediately adjacent to the surgical cavity, the long-
term reshaping is supported by a progressive recruitment of
remote sites within the left dominant hemisphere – such as the
supramarginal gyrus, the pars triangularis of inferior frontal gyrus,
or even other left frontolateral regions – as well as controlateral
sites in the right hemisphere thanks to mechanisms of trans-
callosal disinhibition (Duffau et al., 2002a, 2002b, 2003; Sarubbo
78 H. Duffau / Journal of Chemical Neuroanatomy 89 (2018) 73–81

et al., 2012a). Indeed, a multimodal investigation combining
functional MRI and DES evidenced the existence of a large bilateral
cortico-subcortical network able to compensate surgical resection
of left Wernicke's area infiltrated by glioma (Sarubbo et al., 2012b).
5.3. Functional remapping over time: evidence by serial surgeries
Postoperative plasticity also plays a role in the resectability of
structures for a long time conceived as “unresectable”. Again, since
these sites are nodes within a wide circuit, after their removal, the
whole neural network will self-reorganize thanks to dynamical
plasticity, and the function will finally be spared. In fact, the good
clinical status evidenced by extensive neuropsychological testing a
few months after surgery, as well as the return to a normal life
(including to work), argue for efficient plasticity mechanisms
(Teixidor et al., 2007; Duffau et al., 2008; Charras et al., 2015). Such
a remodeling caused by surgical resection within eloquent areas
was also explored by performing postoperative functional
neuroimaging once the patient has recovered his presurgical
functional status. In particular, patients were examined following
the removal of gliomas situated within the supplementary motor
area: such a resection generated a transient postsurgical syn-
drome, with akinesia and possibly mutism. Task-based and
resting-state functional MRI revealed, in comparison to the
preoperative imaging, the occurrence of activations of the
supplementary motor area and premotor cortex contralateral to
the lesion, with changes in the interhemispheric functional
connectivity: the contrahemispheric homologous thus participat-
ed in the post-surgical functional compensation (Krainik et al.,
2004; Vassal et al., 2016).
From an oncological point of view, because a relapse is often
observed in DLGG, a reoperation may be considered several
years after the first surgery, in patients who usually continue to
enjoy a normal familial, social and professional life (Capelle
et al., 2013). An improvement of the extent of resection with
preservation of quality of life is nonetheless possible only on
condition that further phenomenon of biological plasticity occur
meanwhile. Remarkably, because this is a non-invasive tech-
nique, longitudinal functional neuroimaging can be easily
repeated with the aim of comparing the more recent maps
to those obtained before the first intervention. Subtraction
between pre- and post-operative functional MRI acquired many
years later may reveal a possible additional functional
reallocation, generated by (i) the first surgical excision itself
(ii) the postsurgical functional rehabilitation (iii) the re-growth
of the residual DLGG voluntarily left for functional reasons
(Gil Robles et al., 2008). Such findings resulted in the proposal
of new treatment strategies based upon multistep surgical
approach, which, beyond the clinical interest for the patient,
offers a unique opportunity to explore functional remodeling in
the same patient over time (Duffau, 2014a). This is made
possible due to the fact that second surgery is also conducted
under intraoperative cortical and subcortical mapping, with the
goal to validate the mechanisms of neural remodeling suggested
by preoperative functional neuroimaging – before to achieve
subsequent surgical excision (Martino et al., 2009). This concept
of repeat resections enables to observe changes of cortical
maps, in particular with disappearance of functional epicenters
which were identified by DES during the initial intervention,
but that evoked no disturbances when stimulated during the
reoperation (Duffau et al., 2002a, 2000b). Such a dynamical
remapping was valuable to maximize the extent of resection in
traditional “critical” structures, such as Broca's (Fig. 1) or
Wernicke's area (Duffau, 2005, 2006, 2014a, 2014c). It is worth
noting that the functional recovery following the second
resection was confirmed by objective postoperative cognitive
and behavioral assessments, in patients who were capable to
resume a normal life – especially to work. Thanks to this plastic

Fig. 1. A) Preoperative axial FLAIR-weighted MRI showing a left frontal diffuse low-grade glioma in a 32-year-old right-handed medical doctor who enjoyed a normal life: the
tumor was incidentally discovered because of headaches. The neurological and neuropsychological examinations were normal. B) Intrasurgical view following resection. The
electrical cortical and subcortical mapping in awake patient allowed the identification of the structures crucial for brain functions (tag numbers), which represented the
boundaries of resection as follows: 1: ventral premotor cortex (lateral part of the precentral gyrus) eliciting speech arrest when stimulated; 2: retrocentral gyrus inducing
articulatory disorders during stimulation; star: pars opercularis of the inferior frontal gyrus, generating hesitation when stimulated (increase of reaction time during naming
task); 8 (subcortical site in the depth of the cavity): frontal part of the inferior fronto-occipital fascicle, running to the prefrontal cortex, and evoking semantic paraphasia
during stimulation. Because the glioma was incidentally discovered, it was decided not to take any risks and thus to stop the resection posteriorly into the contact of the pars
opercularis (because of hesitations) – even though no speech arrest was induced at this level during stimulation. Yellow arrow: precentral sulcus; a: anterior; p: posterior. C)
Intrasurgical view following the second resection. Indeed, following the first surgery, the patient completely recovered, resumed a normal life, but the glioma (DLGG
histologically confirmed) recurred 4 years later, especially posteriorly (where no margin was taken). As a consequence, a reoperation was proposed. Again, the electrical
cortical and subcortical mapping in awake patient allowed the identification of the structures crucial for brain functions (tag numbers), which represented the boundaries of
resection as follows: 1 and 4: ventral premotor cortex (lateral part of the precentral gyrus) eliciting speech arrest when stimulated; 2: dorsolateral prefrontal cortex inducing
semantic paraphasia during stimulation (not detected during the first surgery); 46: anterior part of the superior longitudinal fascicle, running to the ventral premotor cortex,
and generating anarthria when stimulated; 47 and 48: frontal part of the inferior fronto-occipital fascicle, running to the dorsolateral prefrontal cortex, and evoking semantic
paraphasia during stimulation. Of note, no hesitation was induced during stimulation of the pars opercularis of the left inferior frontal gyrus, contrasting with the results of
the first awake mapping achieved 4 years before the reoperation: thus, this time, the “Broca's area” was removed, by preserving the subcortical connectivity. Yellow arrow:
precentral sulcus; a: anterior; p: posterior. D) Postoperative axial FLAIR-weighted MRI showing a complete glioma resection, thanks to an extensive left frontal lobectomy. The
patient recovered a normal neurological and neuropsychological status, and resumed a normal life (working full-time as a medical doctor, no seizures, no antiepileptic drug),
despite the resection of the so-called “Broca’s area”. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
 H. Duffau / Journal of Chemical Neuroanatomy 89 (2018) 73–81
potential, the median survival was significantly prolonged in
DLGG patients while the rate of lasting functional deficits was
significantly reduced (Duffau and Taillandier, 2015).
5.4. Beyond surgical applications
In neurological diseases, these concepts can also be helpful for
the prediction of functional recovery after cerebral insult, as well as
for the elaboration of personalized programs of neurological,
cognitive and behavioral rehabilitation (Herbet et al., 2016b). In
psychiatry, original theories gained from functional connectomics
may lead to a better understanding of deficits that affect social
cognition, especially in neuropathological conditions character-
ized by atypical/aberrant structural connectivity, such as autism
spectrum disorders (Herbet et al., 2014a). The future step could be
to use this better knowledge of the complex cerebral circuitry that
supports interactions between action, cognition and behavior, in
order to progress in brain-computer interfaces approaches with
the ultimate aim of restoring neural functions (Mandonnet and
Duffau, 2014).
6. Conclusions and perspectives
It is time to switch from a modular to a connectomal
(delocalized) and dynamic model of neural processes, breaking
with the traditional localisationist dogma. Multimodal investiga-
tions based upon combination of serial peri-operative functional
neuroimaging and intraoperative DES has resulted in original
individual and integrative models of functioning of neurono-
synaptic circuits. Such networking account permits a greater
knowledge of the dynamic potential of spatiotemporal reallocation
of parallel and interconnected subnetworks, namely, a better
understanding of the mechanisms underlying neuroplasticity – but
also a better understanding of its limitations, mostly represented
by the subcortical axonal connectivity (Ius et al., 2011; Herbet et al.,
2016b). In fact, for the first time in the history of cognitive
neurosciences, DES of the white matter bundles offers a unique
opportunity to explore the function of the connectomal anatomy in
humans in vivo. This technique that allows real-time structural-
functional correlations to be made in awake patients, has provided
original insights into the functional connectivity sustaining the
sensorimotor, visuospatial, language and sociocognitive subsys-
tems (Duffau, 2015a). On the basis of these unique data in the
literature, the first functional atlas of human white matter has
recently been built (Sarubbo et al., 2015). In addition, interactions
between these neural subnetworks and multimodal subsystems,
such as working memory, attention, executive functions and even
consciousness, can be explored by axonal stimulation. As
mentioned, in this networking model, neural function results
from the integration and potentiation of parallel, but partially
interconneted, subcircuits (Duffau, 2015a). Last but not the least, in
this connectomal frame-work, surgical excision of lesions in
structures traditionally considered as “untouchable”, such as
Broca's area – which is definitely not the speech area
(Tate et al., 2014, 2015) – is therefore possible while preserving
cerebral functions.
References
Almairac, F., Herbet, G., Moritz-Gasser, S., de Champfleur, N.M., Duffau, H., 2015. The
left inferior fronto-occipital fasciculus subserves language semantics: a
multilevel lesion study. Brain Struct. Funct. 220, 1983–1995.
Alstott, J., Breakspear, M., Hagmann, P., Cammoun, L., Sporns, O., 2009. Modeling the
impact of lesions in the human brain. PLoS Comput. Biol. 5, e1000408.
Bartolomei, F., Bosma, I., Klein, M., Baayen, J.C., Reijneveld, J.C., Postma, T.J., Heimans,
J.J., van Dijk, B.W., de Munck, J.C., de Jongh, A., Cover, K.S., Stam, C.J., 2006. How
do brain tumors alter functional connectivity? A magnetoencephalography
study. Ann. Neurol. 59, 128–138.
79
Bartolomeo, P., 2012. The elusive nature of white matter damage in anatomo-
clinical correlations. Front. Hum. Neurosci. 6, 229.
Bates, E., Wilson, S.M., Saygin, A.P., Dick, F., Sereno, M.I., Knight, R.T., Dronkers, N.,
2003. Voxel-based lesion-symptom mapping. Nat. Neurosci. 6, 448e450.
Benzagmout, M., Gatignol, P., Duffau, H., 2007. Resection of World Health
Organization Grade II gliomas involving Broca's area: methodological and
functional considerations. Neurosurgery 61, 741–752.
Bosma, I., Douw, L., Bartolomei, F., Heimans, J.J., van Dijk, B.W., Postma, T.J., Stam, C.J.,
Reijneveld, J.C., Klein, M., 2008. Synchronized brain activity and neurocognitive
function in patients with low-grade glioma: a magnetoencephalography study.
Neuro-Oncology 10, 734–744.
Broca, P., 1861. Nouvelle observation d’aphémie produite par une lesion de la moitié
postérieure des deuxième et troisième circonvolutions frontale. Bull. Soc. Anat.
6, 337–393.
Capelle, L., Fontaine, D., Mandonnet, E., Taillandier, L., Golmard, J.L., Bauchet, L.,
Pallud, J., Peruzzi, P., Baron, M.H., Kujas, M., Guyotat, J., Guillevin, R., Frenay, M.,
Taillibert, S., Colin, P., Rigau, V., Vandenbos, F., Pinelli, C., Duffau, H., 2013.
Spontaneous and therapeutic prognostic factors in adult hemispheric World
Health Organization Grade II gliomas: a series of 1097 cases. J. Neurosurg. 118,
1157–1168.
Catani, M., 2007. From hodology to function. Brain 130, 602–605.
Charras, P., Herbet, G., Deverdun, J., de Champfleur, N.M., Duffau, H., Bartolomeo, P.,
Bonnetblanc, F., 2015. Functional reorganization of the attentional networks in
low-grade glioma patients: a longitudinal study. Cortex 63, 27–41.
Cochereau, J., Herbet, G., Duffau, H., 2016. Patients with incidental WHO grade II
glioma frequently suffer from neuropsychological disturbances. Acta Neurochir.
(Wien) 158, 305–312.
de Benedictis, A., Duffau, H., 2011. Brain hodotopy: from esoteric concept to practical
surgical applications. Neurosurgery 68, 1709–1723.
De Witt Hamer, P.C., Robles, S.G., Zwinderman, A.H., Duffau, H., Berger, M.S., 2012.
Impact of intraoperative stimulation brain mapping on glioma surgery
outcome: a meta-analysis. J. Clin. Oncol. 30, 2559–2565.
Desmurget, M., Bonnetblanc, F., Duffau, H., 2007. Contrasting acute and slow
growing lesions: a new door to brain plasticity. Brain 130, 898–914.
Dronkers, N.F., Plaisant, O., Iba-Zizen, M.T., Cabanis, E.A., 2007. Paul Broca's historic
cases: high resolution MR imaging of the brains of Leborgne and Lelong. Brain
130, 1432–1441.
Duffau, H., Capelle, L., 2001. Functional recuperation after resection of gliomas
infiltrating primary somatosensory fields: study of peroperative electric
stimulation. Neurochirurgie 47, 534–541.
Duffau, H., Taillandier, L., 2015. New concepts in the management of diffuse low-
grade glioma: proposal of a multistage and individualized therapeutic
approach. Neuro-Oncology 17, 332–342.
Duffau, H., Denvil, D., Lopes, M., Gasparini, F., Cohen, L., Capelle, L., Van Effenterre, R.,
2002a. Intraoperative mapping of the cortical areas involved in multiplication
and subtraction: an electrostimulation study in a patient with a left parietal
glioma. J. Neurol. Neurosurg. Psychiatry 73, 733–738.
Duffau, H., Denvil, D., Capelle, L., 2002b. Long term reshaping of language, sensory
and motor maps following glioma resection: a new parameter to integrate in
the surgical strategy. J. Neurol. Neurosurg. Psychiatry 72, 511–516.
Duffau, H., Capelle, L., Denvil, D., Sichez, N., Gatignol, P., Lopes, M., Mitchell, M.C.,
Sichez, J.P., Van Effenterre, R., 2003. Functional recovery after surgical resection
of low grade gliomas in eloquent brain: hypothesis of brain compensation. J.
Neurol. Neurosurg. Psychiatry 74, 901–907.
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 stimulations. Brain 128, 797–810.
Duffau, H., Gatignol, P., Mandonnet, E., Capelle, L., Taillandier, L., 2008.
Intraoperative subcortical stimulation mapping of language pathways in a
consecutive series of 115 patients with Grade II glioma in the left dominant
hemisphere. J. Neurosurg. 109, 461–471.
Duffau, H., Moritz-Gasser, S., Gatignol, P., 2009. Functional outcome after language
mapping for insular World Health Organization Grade II gliomas in the
dominant hemisphere: experience with 24 patients. Neurosurg. Focus 27, E7.
Duffau, H., Herbet, G., Moritz-Gasser, S., 2013. Toward a pluri-component,
multimodal, and dynamic organization of the ventral semantic stream in
humans: lessons from stimulation mapping in awake patients. Front. Syst.
Neurosci. 7 (44) .
Duffau, H., Moritz-Gasser, S., Mandonnet, E., 2014. A re-examination of neural basis
of language processing: proposal of a dynamic hodotopical model from data
provided by brain stimulation mapping during picture naming. Brain Lang. 131,
1–10.
Duffau, H., 2005. Lessons from brain mapping in surgery for low-grade glioma:
insights into associations between tumour and brain plasticity. Lancet Neurol. 4,
476–486.
Duffau, H., 2006. Brain plasticity: from pathophysiological mechanisms to
therapeutic applications. J. Clin. Neurosci. 13, 885–897.
Duffau, H., 2009. Does post-lesional subcortical plasticity exist in the human brain?
Neurosci. Res. 65, 131–135.
Duffau, H., 2012. The frontal syndrome revisited: lessons from electrostimulation
mapping studies. Cortex 48, 120–131.
Duffau, H., 2014a. The huge plastic potential of adult brain and the role of
connectomics: new insights provided by serial mappings in glioma surgery.
Cortex 58, 325–337.
Duffau, H., 2014b. The dangers of Magnetic Resonance imaging Diffusion Tensor
tractography in brain surgery. World Neurosurg. 81, 56–58.
80 H. Duffau / Journal of Chemical Neuroanatomy 89 (2018) 73–81
Duffau, H., 2014c. Diffuse low-grade gliomas and neuroplasticity. Diagn. Interv.
Imaging 95, 945–955.
Duffau, H., 2015a. Stimulation mapping of white matter tracts to study brain
functional connectivity. Nat. Rev. Neurol. 11, 255–265.
Duffau, H., 2015b. Resecting diffuse low-grade gliomas to the boundaries of brain
functions: a new concept in surgical neuro-oncology. J. Neurosurg. Sci. 59, 361–
371.
Duffau, H., 2016. A two-level model of interindividual anatomo-functional
variability of the brain and its implications for neurosurgery. Cortex doi:http://
dx.doi.org/10.1016/j.cortex.2015.12.009 pii: S0010-9452(16).00011–00013,
Epub ahead of print.
Feinstein, J.S., Khalsa, S.S., Salomons, T.V., Prkachin, K.M., Frey-Law, L.A., Lee, J.E.,
Tranel, D., Rudrauf, D., 2016. Preserved emotional awareness of pain in a patient
with extensive bilateral damage to the insula, anterior cingulate, and amygdala.
Brain Struct. Funct. 221, 1499–1511.
Fernández Coello, A., Duvaux, S., De Benedictis, A., Matsuda, R., Duffau, H., 2013.
Involvement of the right inferior longitudinal fascicle in visual hemiagnosia: a
brain stimulation mapping study. J. Neurosurg. 118, 202–205.
Feuillet, L., Dufour, H., Pelletier, J., 2007. Brain of a white-collar worker. Lancet 370,
262.
Gil Robles, S., Gatignol, P., Lehéricy, S., Duffau, H., 2008. Long-term brain plasticity
allowing multiple-stages surgical approach for WHO grade II gliomas in
eloquent areas: a combined study using longitudinal functional MRI and
intraoperative electrical stimulation. J. Neurosurg. 109, 615–624.
Gras-Combes, G., Moritz-Gasser, S., Herbet, G., Duffau, H., 2012. Intraoperative
subcortical electrical mapping of optic radiations in awake surgery for glioma
involving visual pathways. J. Neurosurg. 117, 466–473.
Heimans, J.J., Reijneveld, J.C., 2012. Factors affecting the cerebral network in brain
tumor patients. J. Neurooncol. 108, 231–237.
Herbet, G., Lafargue, G., Bonnetblanc, F., Moritz-Gasser, S., de Champfleur, N. Menjot,
Duffau, H., 2014a. Inferring a dual-stream model of mentalizing from
associative white matter fibres disconnection. Brain 137, 944–959.
Herbet, G., Lafargue, G., de Champfleur, N.M., Moritz-Gasser, S., le Bars, E.,
Bonnetblanc, F., Duffau, H., 2014b. Disrupting posterior cingulate connectivity
disconnects consciousness from the external environment. Neuropsychologia
56, 239–244.
Herbet, G., Lafargue, G., Duffau, H., 2015a. Rethinking voxel-wise lesion-deficit
analysis: a new challenge for computational neuropsychology. Cortex 64, 413–
416.
Herbet, G., Latorre, J.G., Duffau, H., 2015b. The role of cerebral disconnection in
cognitive recovery after brain damage. Neurology 84, 1390–1391.
Herbet, G., Lafargue, G., Moritz-Gasser, S., Bonnetblanc, F., Duffau, H., 2015c.
Interfering with the neural activity of mirror-related frontal areas impairs
mentalistic inferences. Brain Struct. Funct. 220, 2159–2169.
Herbet, H., Lafargue, G., Moritz-Gasser, S., de Champfleur, N. Menjot, Costi, S.,
Bonnetblanc, F., Duffau, H., 2015d. disconnection account of subjective empathy
impairments in diffuse low-grade glioma patients. Neuropsychologia 70, 165–
176.
Herbet, G., Lafargue, G., Duffau, H., 2016a. The dorsal cingulate cortex as a critical
gateway in the network supporting conscious awareness. Brain 139, e23.
Herbet, G., Maheu, M., Costi, E., Lafargue, G., Duffau, H., 2016b. Mapping the
neuroplastic potential in brain-damaged patients. Brain 139, 829–844.
Herbet, G., Moritz-Gasser. S., Boiseau, M., Duvaux, S., Cochreau, J., Duffau, H., 2016.
Converging evidence for a cortico-subcortical network mediating lexical
retrieval. Brain. pii: aww220. [Epub ahead of print] PMID: 27604309.
Honey, C.J., Kötter, R., Breakspear, M., Sporns, O., 2007. Network structure of cerebral
cortex shapes functional connectivity on multiple time scales. Proc. Natl. Acad.
Sci. U. S. A. 104, 10240–10245.
Ius, T., Angelini, E., Thiebaut de Schotten, M., Mandonnet, E., Duffau, H., 2011.
Evidence for potentials and limitations of brain plasticity using an atlas of
functional resectability of WHO grade II gliomas: towards a minimal common
brain. Neuroimage 56, 992–1000.
Kinoshita, M., de Champfleur, N. Menjot, Deverdun, J., Moritz-Gasser, S., Herbet, G.,
Duffau, H., 2015. Role of fronto-striatal tract and frontal aslant tract in
movement and speech: an axonal mapping study. Brain Struct. Funct. 220,
3399–3412.
Klein, M., Duffau, H., De Witt Hamer, P.C., 2012. Cognition and resective surgery for
diffuse infiltrative glioma: an overview. J. Neurooncol. 108, 309–318.
Krainik, A., Duffau, H., Capelle, L., Cornu, P., Boch, A.L., Mangin, J.F., Le Bihan, D.,
Marsault, C., Chiras, J., Lehéricy, S., 2004. Role of the healthy hemisphere in
recovery after resection of the supplementary motor area. Neurology 62, 1323–
1332.
Kuchcinski, G., Mellerio, C., Pallud, J., Dezamis, E., Turc, G., Rigaux-Viodé, O.,
Malherbe, C., Roca, P., Leclerc, X., Varlet, P., Chrétien, F., Devaux, B., Meder, J.F.,
Oppenheim, C., 2015. Three-tesla functional MR language mapping: comparison
with direct cortical stimulation in gliomas. Neurology 84, 1–9.
Lubrano, V., Draper, L., Roux, F.E., 2010. What makes surgical tumor resection
feasible in Broca's area? Insights into intraoperative brain mapping.
Neurosurgery 66, 868–875.
Maldonado, I.L., Moritz-Gasser, S., Duffau, H., 2011. Does the left superior
longitudinal fascicle subserve language semantics? A brain electrostimulation
study. Brain Struct. Funct. 216, 263–264.
Mandonnet, E., Duffau, H., 2014. Understanding entangled cerebral networks: a
prerequisite for restoring brain function with brain-computer interfaces. Front.
Syst. Neurosci. 8, 82.
Mandonnet, E., Winkler, P.A., Duffau, H., 2010. Direct electrical stimulation as an
input gate into brain functional networks: principles, advantages and
limitations. Acta Neurochir. (Wien) 152, 185–193.
Martino, J., Taillandier, L., Moritz-Gasser, S., Gatignol, P., Duffau, H., 2009. Re-
operation is a safe and effective therapeutic strategy in recurrent WHO grade II
gliomas within eloquent areas. Acta Neurochir. (Wien) 151, 427–436.
Michaud, K., Duffau, H., 2016. Surgery of insular and paralimbic diffuse low-grade
gliomas: technical considerations. J. Neurooncol. Epub ahead of print.
Moritz-Gasser, S., Duffau, H., 2009. Cognitive processes and neural basis of language
switching: proposal of a new model. Neuroreport 20, 1577–1580.
Moritz-Gasser, S., Duffau, H., 2013. The anatomo-functional connectivity of word
repetition: insights provided by awake brain tumor surgery. Front. Hum.
Neurosci. 7, 405.
Moritz-Gasser, S., Herbet, G., Duffau, H., 2013a. Mapping the connectivity
underlying multimodal (verbal and non-verbal) semantic processing: a brain
electrostimulation study. Neuropsychologia 51, 1814–1822.
Moritz-Gasser, S., Herbet, G., Duffau, H., 2013b. Mapping the connectivity
underlying multimodal (verbal and non-verbal) semantic processing: a brain
electrostimulation study. Neuropsychologia 51, 1814–1822.
Philippi, C.L., Feinstein, J.S., Khalsa, S.S., Damasio, A., Tranel, D., Landini, G., Williford,
K., Rudrauf, D., 2012. Preserved self-awareness following extensive bilateral
brain damage to the insula, anterior cingulate, and medial prefrontal cortices.
PLoS One 7, e38413.
Plaza, M., Gatignol, P., Cohen, H., Berger, B., Duffau, H., 2008. A discrete area within
the left dorsolateral prefrontal cortex involved in visual-verbal incongruence
judgment. Cereb. Cortex 18, 1253–1259.
Plaza, M., Gatignol, P., Leroy, M., Duffau, H., 2009. Speaking without Broca's area
after tumor resection. Neurocase 9, 1–17.
Rech, F., Herbet, G., Moritz-Gasser, S., Duffau, H., 2014. Disruption of bimanual
movement by unilateral subcortical stimulation. Hum. Brain Mapp. 35, 3439–
3445.
Sarubbo, S., Latini, F., Sette, E., Milani, P., Granieri, E., Fainardi, E., Cavallo, M.A.,
2012a. Is the resection of gliomas in Wernicke's area reliable?: Wernicke's area
resection. Acta Neurochir. (Wien) 154, 1653–1662.
Sarubbo, S., Le Bars, E., Moritz-Gasser, S., Duffau, H., 2012b. Complete recovery after
surgical resection of left Wernicke's area in awake patient: a brain stimulation
and functional MRI study. Neurosurg. Rev. 35, 287–292.
Sarubbo, S., de Benedictis, A., Merler, S., Mandonnet, E., Balbi, S., Granieri, E., Duffau,
H., 2015. Towards a functional atlas of human white matter. Hum. Brain Mapp.
36, 3117–3136.
Sarubbo, S., De Benedictis, A., Merler, S., Mandonnet, E., Barbareschi, M., Dallabona,
M., Chioffi, F., Duffau, H., 2016. Structural and functional integration between
dorsal and ventral language streams as revealed by blunt dissection and direct
electrical stimulation. Hum. Brain Mapp. doi:http://dx.doi.org/10.1002/
hbm.23281 Epub ahead of print.
Sawaya, R., Hammoud, M., Schoppa, D., Hess, K.R., Wu, S.Z., Shi, W.M., Wildrick, D.M.,
1998. Neurosurgical outcomes in a modern series of 400 craniotomies for
treatment of parenchymal tumors. Neurosurgery 42, 10441055.
Schucht, P., Moritz-Gasser, S., Herbet, G., Raabe, A., Duffau, H., 2013. Subcortical
electrostimulation to identify network subserving motor control. Hum. Brain
Mapp. 34, 3023–3030.
Schumacher, H.W., Wassmann, H., Linke, D.B., 1987. Plasticity of the brain after
extensive cerebral infarction: report of a case and discussion. Regulation of
cerebral blood flow and metabolism neurosurgical treatment of epilepsy
rehabilitation in neurosurgery. Springer, Berlin Heidelberg, pp. 302–305.
Spena, G., Gatignol, P., Capelle, L., Duffau, H., 2006. Superior longitudinal fasciculus
subserves vestibular network in humans. Neuroreport 17, 1403–1406.
Sporns, O., Tononi, G., Kötter, R., 2005. The human connectome: a structural
description of the human brain. PLoS Comput. Biol. 1, e42.
Stam, C.J., 2010. Characterization of anatomical and functional connectivity in the
brain: a complex networks perspective. Int. J. Psychophysiol. 77, 186–194.
Tate, M.C., Herbet, G., Moritz-Gasser, S., Tate, J.E., Duffau, H., 2014. Probabilistic map
of critical functional regions of the human cerebral cortex: broca's area
revisited. Brain 137, 2773–2782.
Tate, M.C., Herbet, G., Moritz-Gasser, S., Tate, J.E., Duffau, H., 2015. Reply:
probabilistic map of language regions: challenge and implication. Brain 138,
e338.
Teixidor, P., Gatignol, P., Leroy, M., Masuet-Aumatell, C., Capelle, L., Duffau, H., 2007.
Assessment of verbal working memory before and after surgery for low-grade
glioma. J. Neurooncol. 81, 305–313.
Thiebaut de Schotten, M., Urbanski, M., Duffau, H., Volle, E., Levy, R., Dubois, B.,
Bartolomeo, P., 2005. Direct evidence for a parietal-frontal pathway subserving
spatial awareness in humans. Science 309, 2226–2228.
Thiebaut de Schotten, M., Tomaiuolo, F., Aiello, M., Merola, S., Silvetti, M., Lecce, F.,
Bartolomeo, P., Doricchi, F., 2014. Damage to white matter pathways in
subacute and chronic spatial neglect: a group study and 2 single-case studies
with complete virtual In vivo tractography dissection. Cereb. Cortex 24,
691e706.
Ueno, T., Saito, S., Rogers, T.T., Lambon Ralph, M.A., 2011. Lichtheim 2: synthesizing
aphasia and the neural basis of language in a neurocomputational model of the
dual dorsal-ventral language pathways. Neuron 72, 385–396.
Van Geemen, K., Herbet, G., Moritz-Gasser, S., Duffau, H., 2014. Limited plastic
potential of the left ventral premotor cortex in speech articulation: evidence
from intraoperative awake mapping in glioma patients. Hum. Brain Mapp. 35,
1587–1596.
 H. Duffau / Journal of Chemical Neuroanatomy 89 (2018) 73–81 81

Vassal, M., Charroud, C., Deverdun, J., Le Bars, E., Molino, F., Bonnetblanc, F., Boyer, A.,
Dutta, A., Herbet, G., Moritz-Gasser, S., Bonafé, A., Duffau, H., de Champfleur, N.
M., 2016. Recovery of functional connectivity of the sensorimotor network after
surgery for diffuse low-grade gliomas involving the supplementary motor area.
J. Neurosurg. 1–10 Epub ahead of print.
Vigneau, M., Beaucousin, V., Herve, P.Y., Duffau, H., Crivello, F., Houdé, O., Mazoyer,
B., Tzourio-Mazoyer, N., 2006. Meta-analyzing left hemisphere language areas:
phonology, semantics, and sentence processing. Neuroimage 30, 1414–1432.
Wernicke, C., 1874. Der Aphasische Symptomen Complex. Cohn etWeigert, Breslau.
Zemmoura, I., Herbet, G., Moritz-Gasser, S., Duffau, H., 2015. New insights into the
neural network mediating reading processes provided by cortico-subcortical
electrical mapping. Hum. Brain Mapp. 36, 2215–2230.