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Nom original: Duffau.pdfTitre: Stimulation mapping of white matter tracts to study brain functional connectivityAuteur: Hugues Duffau

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REVIEWS
Stimulation mapping of white matter tracts
to study brain functional connectivity
Hugues Duffau
Abstract | Despite advances in the new science of connectomics, which aims to comprehensively map neural
connections at both structural and functional levels, techniques to directly study the function of white matter
tracts in vivo in humans have proved elusive. Direct electrical stimulation (DES) mapping of the subcortical
fibres offers a unique opportunity to investigate the functional connectivity of the brain. This original method
permits real-time anatomo-functional correlations, especially with regard to neural pathways, in awake patients
undergoing brain surgery. In this article, the goal is to review new insights, gained from axonal DES, into the
functional connectivity underlying the sensorimotor, visuospatial, language and sociocognitive systems.
Interactions between these neural networks and multimodal systems, such as working memory, attention,
executive functions and consciousness, can also be investigated by axonal stimulation. In this networking
model of conation and cognition, brain processing is not conceived as the sum of several subfunctions,
but results from the integration and potentiation of parallel—though partially overlapping—subnetworks.
This hodotopical account, supported by axonal DES, improves our understanding of neuroplasticity and its
limitations. The clinical implications of this paradigmatic shift from localizationism to hodotopy, in the context
of brain surgery, neurology, neurorehabilitation and psychiatry, are discussed.
Duffau, H. Nat. Rev. Neurol. 11, 255–265 (2015); published online 7 April 2015; doi:10.1038/nrneurol.2015.51

Introduction

Department of
Neurosurgery and
INSERM U1051,
Gui de Chauliac
Hospital, Montpellier
University Medical
Center, 80 Avenue
Augustin Fliche,
34295 Montpellier,
France.
h-duffau@
chu-montpellier.fr

For over a century, cerebral processing was mainly
conceived in a rigid, localizationist philosophy, despite
regular proposals of more-sophisticated neuro­psycho­
logical and computational models that attempted to
include connectivity information and post-lesional
plasticity phenomena.1–5 According to this principle of
localizationism, each region of the brain corresponds
to a given function, and a lesion in an ‘eloquent’ area,
therefore, is presumed to result in a massive and permanent neurological deficit. Recently, however, the
concept of the brain connectome has emerged, the goal
of which is to capture the characteristics of spatially distributed, dynamic neural processes at multiple spatial
and temporal scales.6 The new science of ‘connect­omics’,
which aims to map the neural connections, is contributing both to theoretical and computational models
of the brain as a complex system7 and, experimentally,
to new indices and metrics (for example, nodes, hubs,
efficiency and modularity), in order to characterize and
scale the functional organization of the healthy and diseased nervous system.8 According to new theories, the
CNS is an ensemble of complex networks that are continually formed and reshaped, and process information
dynamically, opening the door to a huge potential for
­neuroplasticity, even in adults.9,10
The human connectome has been investigated by
means of many techniques at multiple levels, including
Competing interests
The author declares no competing interests.

anatomical dissection of white matter tracts;11,12 imaging
modalities such as tractography using diffusion tensor
imaging (DTI), resting-state functional MRI, task-evoked
functional MRI, magnetoencephalography and EEG;13,14
lesion–symptom mapping;15 mapping of neurons organized into functional circuits;16 molecular properties of
individual synapses;17 biomathematical models; and
neuroinformatics tools.18 It is worth noting, however,
that none of these modalities can directly probe the function of the white matter tracts. Instead, they provide an
­indirect reflection of ‘functional connectivity’ through the
analysis of the structural connectome and effective connectivity, with no direct access to the actual functional
roles of the subcortical pathways. Consequently, some
experts have argued that many contemporary maps are
inaccurate surrogates of the true functional anatomy.19
In the past, direct electrical stimulation (DES)
mapping has received less attention than many other
modalities, despite the fact that DES of the white matter
fascicles is the only method that permits real-time
investigation of the function of subcortical fibres in
humans. Original findings from intraoperative axonal
DES in patients undergoing awake surgery for a brain
lesion led to the revisitation of models of cerebral processes, switching from a modular to a delocalized view,
in which brain functioning is underlain by large-scale
and dynamic subnetworks interacting together.20 The
goal of this article is to review how axonal DES mapping
in humans has provided unique data with regard to
­functional connectivity.

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Key points
■■ Currently, direct electrical stimulation (DES) is the only technique that allows
direct mapping of white matter tracts in vivo in humans
■■ Axonal DES has provided new insights into the functional connectivity underlying
the sensorimotor, visuospatial, language and sociocognitive systems
■■ Interactions between these neural networks and multimodal systems, such as
working memory, attention, executive functions and consciousness, can also be
investigated by axonal DES
■■ Such a connectionist account, supported by axonal DES, improves our
understanding of neuroplasticity, even in adults
■■ This paradigmatic shift from localizationism to hodotopy could have major clinical
implications in brain surgery, neurology, neurorehabilitation and psychiatry

Principles of DES of the brain

During surgery for a lesion (such as a tumour) involving both grey and white matter, it has become common
clinical practice to awaken patients with the aim of
investigating the functional role of restricted brain
areas. The surgeon can optimize the extent of resection,
and thereby improve overall survival without causing
permanent neuro­logical deficits, owing to individual-­
specific mapping and preservation of eloquent structures. Consequently, the resection is achieved according
to functional, as opposed to structural, boundaries.21 In
practice, patients perform several sensorimotor, visuo­
spatial, language, cognitive and/or emotional tasks, while
the surgeon uses DES to temporarily disrupt discrete
regions around the tumour. In this approach, a biphasic
electrical current (60 Hz, 1 ms, 1–4 mA) creates a ‘virtual
transient lesion’, initially at the level of the cortex. After
the completion of cortical mapping, resection of a part
of the brain involved by the tumour is achieved, giving
access to the white matter tracts. At the axonal level, DES
is again used to generate a virtual transient lesion when
the electrode is applied directly in contact with the white
matter fascicles. If the patient stops moving or speaking,
a

or produces an inappro­priate response, the surgeon
can avoid removing the s­ timulated site at the level of
­subcortical connectivity.22,23
The exact mechanism of DES remains controversial,
but the usual view is that the stimulation transitorily
interferes locally with a small cortical or axonal site.24
Interestingly, Logothetis et al.25 showed that as long as
the repetitive stimulation is <200 Hz, γ‑aminobutyric
acid-related inhibition prevents the stimulus from propa­
gating beyond the first synapse. Assuming that there is no
propagation of the stimulation to the entire connected
network, DES presumably informs us about the impact
on a network’s function when just a part of that network is
stimulated. Thus, DES is able to detect the structures—in
particular, white matter tracts—that are essential for brain
function by inhibiting a subcircuit for a few seconds, with
the possibility of checking whether the same effects are
reproduced when repeated stimulations are applied over
the same area.
By gathering all cortical and axonal sites in which
DES produces the same types of error, one can build up
a picture of the subnetwork underlying the disrupted
subfunction. DES has been extensively demonstrated to
identify, with great accuracy (within about 5 mm) and
reproducibility, the structures that are crucial for cognitive functioning in humans, and is currently the only way
to directly investigate the functional role of the subcortical
fascicles. By combining neurological disturbances elicited
by intrasurgical DES with anatomical data provided by
postoperative MRI, reliable anatomo-functional correlations can be performed. Such correlations have allowed
analysis of the anatomical location of the eloquent areas
detected by DES—in essence, at the periphery of the surgical cavity, where the resection was stopped according
to functional boundaries. This methodology has been
­extensively validated in previous studies (Figure 1).26–28

b

c

48
49
50
47
M1

Figure 1 | Anatomo-functional correlations obtained by intrasurgical corticosubcortical DES and perioperative
MRI.
Nature Reviews
| Neurology
a | Preoperative axial FLAIR MRI showing a right frontal WHO grade II glioma in a 26-year-old patient who experienced
seizures. Neurological and neuropsychological examinations were normal. b | Intrasurgical view following tumour resection.
Cortical DES of the lateral part of the precentral gyrus (ventral premotor cortex; tags 1, 4 and 5) produced speech arrest.
DES of other regions led to involuntary facial movement (tag 2) or involuntary hand movement (tag 3). After resection,
subcortical DES inhibited upper limb movement and speech (tags 48 and 49), movement of both upper limbs during a
bimanual coordination task (tag 50), or movement of left upper and lower limbs (tag 47). Short white arrow indicates
central sulcus. c | By comparing the surgical cavity (red) to a 3D postoperative tractography image, all four subcortical tags
were localized on the frontostriatal tract (blue–green) or frontal aslant tract (red–yellow). These fasciculi were surgically
preserved, and the patient recovered normal neurological and neuropsychological status. Abbreviations: DES, direct
electrical stimulation; M1, primary motor cortex of the upper limb. Parts b and c adapted with permission from
Kinoshita, M. et al. Role of frontostriatal tract and frontal aslant tract in movement and speech: an axonal mapping study.
Brain Struct. Funct. doi:10.1007/s00429‑014‑0863‑0, Springer Science and Business Media.

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Insights into functional connectivity
Sensorimotor system
It is well known that direct stimulation of pyramidal
fibres causes involuntary muscle contraction (whether
the stimulation is delivered to the corona radiata, posterior arm of the internal capsule or brainstem), and
that direct stimulation of somatosensory thalamocortical fibres produces reproducible dysaesthesia in awake
patients,29,30 but limited information is available on the
network subserving motor control. A so-called ‘negative
motor network’ has recently been described by means
of DES. Axonal stimulation of this network in a patient
asked to perform continuous movement generates disorders of motor initiation and control, which range from
complete arrest of movement to involuntary acceleration
of movement.31 Interestingly, unilateral subcortical DES
may disrupt movement of both hands in patients performing a task of bimanual coordination, supporting the
existence of a bilateral modulatory corticosubcortical
network that is able to supervise interlimb movement.32
By plotting the location of the subcortical stimulation
sites onto the postoperative MRI scan after resection
of tumours around the central region, a large veil-like
circuit was revealed, originating from the supplementary motor area, the lateral premotor cortex and the
depth of the precentral sulcus, and passing anterior to
the cortico­spinal tract. These projection fibres run to the
head of the caudate nucleus, corresponding to the fronto­
striatal tract (also called the subcallosal fascicle by some
authors).33 The caudate is one of the inputs of the basal
ganglia, which have a crucial role in initiation and execution of voluntary movements, as well as in the inhibition
of competing movements.34 Additional fibres project to
the anterior arm of the internal capsule, indicating a likely
course toward the spinal cord. An additional part of the
circuit runs posterior to primary somatosensory fibres.35
Precentral and retrocentral pathways are interconnected
by U fibres passing beneath the central region. The parietal lobe is known to have strong connections to the premotor areas of the frontal lobe36 and to contain motor
functions, as demonstrated through cortical ­stimulation
in macaques and lesion studies in humans.37,38
These original findings provide further evidence that
the motor control network extends beyond the frontal
lobe, since it includes frontal and parietal subcortical
fibres, as well as a projection pathway with inhibitory
and excitatory characteristics. Therefore, the dichotomy
between precentral motor and retrocentral sensory
structures needs to be revisited in a new connectionist model, which can explain the effects observed when
these white matter tracts are stimulated in the operating
theatre. A revised classification seems necessary to distinguish these motor control fibres with a modulatory
influence on movement from the classic corticospinal
tract originating from the precentral gyrus.31
Visuospatial system
Very few studies have examined the functional consequences of intraoperative DES of visual pathways.39,40
A protocol was recently proposed in which two images,

located in opposite quadrants on the same computer
screen, are shown to the awake patient. It is possible
to generate a transient visual field deficit subjectively
described by the patient, which is confirmed objectively
with this test (only one of the two objects can be seen
and, therefore, described) during axonal DES of the
optic radiations.41
Interestingly, DES can generate either ‘inhibitory phenomena’ such as blurred vision or impression of shadow,
or ‘excitatory phenomena’ such as phosphenes. In addition, complex responses such as visual hallucinations­
—for example, zoopsia or distortion of pictures
(­meta­morphopsia)­—have been described by patients
during stimulation. These findings might be explained
by the fact that DES of fibres joining the calcarine fissure
evokes visual suppression (homonymous hemianopia),
whereas DES of fibres joining the associ­ation visual cortex
for higher-order visual processing (outside the primary
visual system) evokes visual illusion.
In a similar vein, axonal stimulation of the inferior
longitudinal fascicle (ILF) generates contralateral visual
hemiagnosia, supporting the existence of an occipitotemporal pathway connecting occipital visual input to
higher-level processing in temporal lobe structures,
in particular the fusiform gyrus.42 These stimulation
findings support a crucial role for the ILF in visual recognition, with specialization of this bundle for visuo­
spatial processing in the right hemisphere and language
­processing in the left hemisphere (see below).
Stimulation of a specific part of the superior longitudinal fascicle (SLF), the SLF II, in the right hemisphere
can produce spatial cognition problems. Indeed, DES
of this structure generates rightward deviation in a line
bisection test.43 These data suggest that parietal–frontal
communication is necessary for symmetrical processing of the visual scene. In other words, spatial awareness
depends not only on the cortical areas of the temporal–
parietal junction, but also on a larger parietal–frontal
network communicating via the right SLF. Finally, stimulation of another subcircuit in the right SLF can cause a
central vestibular syndrome with vertigo, by disrupting
the vestibular inputs assembled in the temporoparietal
areas and the prefrontal cortex. This finding demonstrates the role of the SLF in the network coordinating body posture and spatially oriented actions, which
­controls vestibular function.44

Language
On the basis of DES findings, Duffau et al.45 have recently
proposed a dual model for visual language processing,
with a ventral stream involved in mapping visual information to meaning (the ‘what’ pathway) and a dorsal
stream dedicated to mapping visual information to
articulation through visuo-­phonological conversion.
These findings complete the seminal model by Hickok
and Poeppel 46—a pure cognitive model that did not
take into account anatomical constraints, especially
with regard to the white matter tracts. Of note, other
researchers, by means of functional neuroimaging, have
uncovered a dual pathway for language and semantic

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processing.47,48 In addition, Ueno et al.5 entered connectivity information directly into an implemented computational model of dual-­pathway language processing and,
consequently, were able to simulate many of the classic
aphasia subtypes.
According to the revisited model of picture naming
derived from axonal stimulation,45 the first step is visual
perception and recognition. As mentioned above, DES
of the optic pathways can elicit reversible phosphenes
or visual loss in the contralateral visual field owing to
inhib­ition of visual perception.41 Visual formal para­
phasia can also been elicited by electrical interference
with a second stage of visual processing, that is, visual
recognition. These disturbances are generated by DES of
the posterior part of the ILF, which links the visual cortex
with the visual object form area. This area, which participates in object recognition and lies close to the visual
word form area (which receives afferent input from
another subpart of the ILF), corresponds to a subpathway
involved in reading, the stimulation of which generates
alexia.49 Indeed, subcortical DES of distinct subcomponents within the left occipitotemporal white matter can
evoke a double dissociation between alexia (lower fibres)
and anomia (upper fibres) in the same patients.50,51 Thus,
these data support the existence of parallel pathways
emanating from the occipital cortex that are specifically
involved in word versus object recognition.
The language network is supported by two main
pathways that work in parallel and also interact: the
phonological dorsal pathway and the semantic ventral
pathway.52 A double dissociation between phonemic and
semantic errors has been observed during axonal DES,53
demonstrating that the two processes are not performed
serially. The dorsal pathway is subserved by the SLF and
consists of two subparts.54 The deep part is the classic
arcuate fascicle (AF), which connects the posterior temporal structures (mostly the middle and inferior gyri)
to the inferior frontal gyrus (essentially its pars opercularis).55,56 DES of this subpart results in conduction
aphasia, that is, a combination of phonemic para­phasia
(supporting a role for the subpart in phonological processing) and repetition disorders,53,57 but without semantic paraphasia. Interestingly, the posterior cortical origin
of this tract corresponds to the visual object form area,49
a functional hub involved both in phonological processing dedicated to visual material, and in semantics
(see below).58
The superficial portion of the dorsal stream is subserved by the lateral part of the SLF (also called the
SLF III), DES of which induces anarthria.59 This lateral
operculo-opercular component of the SLF is involved
in articulation, by connecting the junction between the
posterior part of the superior temporal gyrus (which
receives feedback information from somatosensory and
auditory areas) and the supramaginal gyrus with the
ventral premotor cortex (which receives afferents bringing phonological–­phonetic information to be translated
into articulatory motor programmes).60 During word
repetition, this loop also enables the conversion of auditory input, which is processed in the verbal working
258  |  MAY 2015  |  VOLUME 11

memory system (see below), into phonological and
articulatory representations within the ventral premotor
cortex. This observation is in agreement with recent data
obtained from cortical DES (probabilistic atlas based on
771 stimulation sites), which demonstrated that Broca’s
area is not the speech output region, thereby challenging
the classic theories on language.61
The ventral pathway is divided into a direct bundle—
the inferior frontal occipital fascicle (IFOF)—and an
indirect pathway formed by the anterior ILF and the
uncinate fascicle (UF).62 These fascicles relay information
to one another in the temporal pole. The IFOF connects
the posterior occipital lobe and visual object form area
to anterior cortical frontal areas, including the infer­ior
frontal gyrus and dorsolateral prefrontal cortex.63,64 DES
of this fascicle demonstrated a major role in l­anguage
semantics, because its stimulation reproducibly e­licited
semantic paraphasias.27,65 Therefore, information pretreated by the visual recognition system is subsequently
processed by the semantic system (in parallel to the
dorsal phonological stream, as already mentioned),
before being processed by the executive system.
The indirect ventral semantic pathway has a relay at
the level of the temporal pole, which represents a semantic ‘hub’ that allows plurimodal integration of the multi­
ple signals emanating from the unimodal systems.66–68
This indirect ventral stream includes the anterior part
of the ILF, which connects the visual object form area
with the temporal pole,69 and information is then relayed
by the UF, which links the temporal pole with the pars
orbitaris of the inferior frontal gyrus.62,70 DES of this
indirect pathway does not generate semantic para­phasia,
but may nonetheless induce nonverbal semantic dis­
orders (see below), in agreement with other studies that
have p
­ rovided evidence in support of a semantic role for
the UF.71
The ventral semantic pathway seems to contribute to
repetition of real words or pseudowords,57 and may also
participate in proper name retrieval.72 The difference
between UF and IFOF stimulation on picture naming
might reflect their different frontal terminations.73 Basic
picture naming requires minimal levels of semantic
control,74 which might explain the negligible effects of
UF DES on this process. Naming at a more specific level
(including naming of people) might be somewhat more
executively demanding and, thus, UF DES does have
an effect.
Of note, the middle longitudinal fascicle, which connects the angular gyrus with the superior temporal gyrus
up to the temporal pole, could also be part of the ventral
semantic route.75 However, subcortical DES of this fascicle failed to induce any naming disorders,76 so its exact
functional role is still unclear.
Beyond picture naming, DES demonstrated that syntactic processing was subserved by delocalized cortical
regions (left inferior frontal gyrus and posterior middle
temporal gyrus) connected by a subpart of the left SLF.
Axonal stimulation of the SLF can elicit specific disorders
of grammatical gender, thus disrupting one subfunction without interfering with the others. Interestingly,



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this subcircuit interacts with but is independent of the
subnetwork involved in naming, as demonstrating by
double dissociation between disruption of syntactic and
naming processes during DES. These findings support
parallel rather than serial theory, calling into question
the concept of the ‘lemma’—an abstract lexical representation of a word before its phonological properties
are assigned.77
DES allowed a re-examination of the classic Broca–
Wernicke localization model, which took precedence
over all others for many decades. The new findings from
axonal stimulation provide a distributed framework for
future studies of language networks and for manage­ment
of patients with aphasia.45 This new model is based on
multiple direct and indirect cortico­subcortical interacting subnetworks involved in syntactic, semantic,
phono­logical and articulatory processes. It offers several
advantages in comparison with previous models. For
example, it explains double dissociations during lesioning of the ventral versus dorsal stream (semantic and
phonemic disorders, respectively). Also, it takes into
account the cortical and subcortical anato­mical constraints. It is important to note that DES is not the only
form of evidence that supports a reformulation of the
classic Wernicke–Lichtheim (single-pathway) model:
neuropsychological studies of semantic dementia,
fMRI and transcranial magnetic stimulation studies of
semantic processing, and electrocorticography and grid
electrode work68,78,79 have reached similar conclusions,
which are consistent with recent theories by Hickok and
Poeppel46 and Ueno and colleagues.5

Sociocognitive system
In the field of cognitive neuroscience, it is increasingly
accepted that mentalization (theory of mind) is subserved
by a large frontotemporoparietal network. However, the
connectivity underlying such a complex circuit is still
poorly understood. Recently, emotion recognition tasks
have been performed on awake patients to improve our
understanding of and preserve structures that support
mentalization.80
Intraoperative DES, combined with preoperative and
postoperative behavioural examinations, has shown that
mentalization is made possible by parallel functioning of
two neurocognitive subsystems.81 The first subcircuit, the
mirror system, processes low-level perceptual aspects—
that is, the ability to appreciate other people’s emotions
—­and is subserved by the right AF–SLF complex. This
observation is in agreement with dissection studies and
DTI-based studies, which have shown that the anterior part of the mirror neuron system (including the
posteroinferior frontal gyrus and the ventral premotor
cortex) is connected to posterior temporoparietal areas
by the perisylvian network.56,82,83 The second subcircuit,
the mental­ization system itself, is essential for highlevel mental processing—namely, the ability to attribute
intention to others (a social metacognitive skill)—and
is supported mostly by the right cingulum. Given that
the cingulum provides strong connections between the
rostral medial prefrontal cortex–anterior cingulate and

the medial posterior parietal cortex (including the pos­
terior cingulate cortex and ventral precuneus), the cingu­
lum is likely to shape the structural connectivity of the
default mode network, as recently suggested by two
m­ultimodal imaging studies.84,85
In summary, accuracy of identification (emotional
empathy) and attribution of mental states (high-level
inferential mentalization) correlate with the degree of
virtual disconnection in the AF–SLF complex and the
cingulum, respectively.81

Toward an integrated multimodal model

The original insights provided by DES strongly support
the idea that cerebral functions are underpinned by
extensive circuits comprising both cortical epicentres
(‘topos’, or sites) and connections between these ‘hubs’,
created through association of bundles of white matter
(‘hodos’, or pathways).86,87 In this hodotopical model,
which challenges the traditional localizationist view,
neuro­logical function arises from synchronization
between different epicentres, working in phase during
a given task. The model also explains how the same
hub can participate in several functions, depending
on the other cortical areas with which it is temporarily
­connected at any one time.
Knowing that DES provides a unique opportunity to
directly map each bundle stimulated, the goal of this
Review is not to assign one function to a single tract but,
rather, to report the functional disturbances observed
during repeated DES of specific tracts. Moving forward,
it is crucial to consider that complex brain processes
are possible only because dynamic interactions exist
between these parallel delocalized subnetworks, with different levels of subcircuit recruitment according to the
task required. In other words, brain processing should
not be conceived as the sum of several subfunctions.
Instead, cerebral function results from the integration
and potentiation of parallel—but partially overlapping
—­subnetworks (Figure 2).
To illustrate this multimodal model of the networking
brain, DES revealed the existence of an amodal executive
system (including prefrontal cortex, anterior cingulum
and caudate nucleus) that is involved in the cognitive
control of more-dedicated subcircuits, for example, the
subnetwork underlying language switching in multi­
lingual individuals (itself consisting of a wide corticosubcortical network comprising posterior temporal areas,
supramarginal and angular gyri, inferior frontal gyrus,
and a subpart of the SLF).88 Similarly, the frontal aslant
tract, which connects the presupplementary motor area
and anterior cingulate with the inferior frontal gyrus,89
seems to have a role in the control of language, especially
with regard to planning of articulation. Axonal DES of
this bundle generates disorders in initiation of speech.33
A corticosubcortical loop involving the deep grey nuclei,
in particular the caudate nucleus, was shown to participate in the control of language (selection/inhibition), as
DES of the head of the caudate nucleus in the left hemisphere generated highly reproducible perseverations.90
This corticostriatal loop could be anatomically supported

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Primary
motor cortex

Supplementary
motor area
Caudate nucleus
Basal ganglia

Executive
control

Input
Superior parietal lobule

Anterior
cingulate
cortex

Prefrontal
cortex

High-level mentalization
Consciousness of environment

Inferior frontal gyrus
(pars opercularis
and triangularis)

Precuneus/posterior
cingulate cortex

Articulatory loop
Working memory

Ventral premotor
cortex

Middle frontal
gyrus
Orbitofrontal
area

Speech output
and movement

Negative motor network

Dorsal phonological stream
Theory of mind

Somatosensory
input
Thalamus

Supramarginalis
gyrus

Auditory input
Posterosuperior
temporal area

Angular
gyrus

Anterior insula

Posterior middle
temporal area

Superior and
middle
occipital gyri
Visual input

Ventral stream
Semantics and noetic consciousness
Temporal pole

Superficial layer of the IFOF
Deep layer of the IFOF
Inferior longitudinal fascicle
Uncinate fascicle

Posteroinferior
temporal cortex/fusa

Arcuate fascicle (deep part of the SLF)
Lateral portion of the SLF (anterior segment)
Cingulum
Frontal aslant tract

Visual
recognition

Inferior
occipital
gyrus

Frontostriatal tract
Middle longitudinal fascicle
U fibres

Nature Reviews
| Neurology
Figure 2 | A hodotopical model of functional connectivity in the human brain. The model was constructed
on the basis
of
structural–functional correlations derived from intraoperative direct electrical stimulation, and incorporates anatomical
constraints. Abbreviations: IFOF, inferior frontal occipital fascicle; SLF, superior longitudinal fascicle.

by the frontostriatal tract.33 Interestingly, this pathway
seems to be a multimodal tract, because it is also involved
in the control of movement, as previously mentioned.33
According to this example, at least three subnetworks—­
multimodal corticosubcortical frontostriatal tract, corticocortical frontal aslant tract, and dedicated language
network, itself consisting of distinct parellel subcircuits—­
interact to allow language production, including not
only its elaboration but also its monitoring. An additional subnetwork will be recruited if a switch from the
native language to another language is required during a
conversation. Interestingly, as already described for the
different subcomponents of language (semantic, syntactic, phonemic and articulatory processes, with possible
double dissociations of language disorders during DES),
each specific subcircuit sustaining each subfunction can
be specifically disrupted by axonal DES without inter­
fering with the other subnetworks, for example, disorders
of initiation with normal language content, or involuntary
language switching with normal initiation and language
content. These findings demonstrate that axonal stimulation represents a unique opportunity to study interactions
between subnetworks.
A similar reasoning can be applied to the multimodal (verbal and nonverbal) working memory and
attentional functions, which seem to be supported by
distinct subparts of the superior longitudinal fascicle,
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according to data provided by axonal DES combined
with peri­operative neurocognitive assessments.57,60,91,92
Simultaneous recuitment of these subnetworks, in
addition to the distinct circuits specifically involved
in l­anguage and visuospatial cognition, will be necessary
if an individual performs a sustained double task. For
example, to increase the reliability of functional mapping
during brain tumour surgery, an awake patient might be
asked to perform a combined speech and line bisection
test at 4 s intervals over several hours while undergoing
electrostimulation.93 In this scenario, each axonal DES
can disrupt a specific subfunction with no consequences
for the others.
The next step will be to use DES to explore the inter­
actions between corticosubcortical circuits involved in
different types of consciousness. In a semantic associ­
ation task (for example, the Pyramids and Palm Trees
Test), axonal DES of a deep layer of the IFOF, which
connects a wide subnetwork comprising the left
postero­superior temporal area and dorsolateral prefrontal cortex, generates disturbances of comprehension,
including nonverbal semantic processing as well as cross­
modal judgment.65,94,95 Interestingly, the IFOF—perhaps
the most important bundle in humans—does not seem
to exist in nonhuman primates. This discovery has
led to the following suggestion: “the IFOF is the proper
human fascicle that allows the human to produce and



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REVIEWS
understand language, to manipulate concepts, to apprehend and understand the world, and that contributes to
make the human what he is, in all his complexity and
with his infinite wealth of mind. The transient semantic
disorganization observed when stimulating the IFOF
would, therefore, be caused by a dis-synchronization
within this large-scale network, interrupting simultaneously the bottom-up transmission and the top-down
control mechanisms. Thus, this fascicle might play a
crucial role not only in semantic processing but also in
the awareness of amodal semantic knowledge, namely
noetic consciousness.”65
In the same spirit, axonal DES has shown that disruption of the subcortical connectivity of the left posterior
cingulate cortex reliably induces a breakdown in conscious experience.96 This acute phenomenon was mainly
characterized by a transient behavioural unresponsiveness with loss of external connectedness (the patient
described himself as in a dream, outside the operating
room). This finding suggests that functional integrity of
posterior cingulate connectivity is necessary to maintain
consciousness of the external environment.
In summary, axonal DES can open the door to the
investigation of several phenomena, one of which is
the connectomal anatomy underlying distinct levels of
awareness, including the pathways involved in monitoring of the human level of consciousness related to
semantic memory (noetic consciousness), as well as
the pathways that sustain consciousness of the external world. Axonal DES can also be used to explore the
dynamic interactions between these subcircuits, and
possible functional regulation of the intrinsic activity
of these subcircuits by other subnetworks, such as the
cingulothalamic system.96

Connectivity and neuroplasticity

According to the hodotopical model, the CNS is organized into parallel networks that not only interact but
are also able to compensate for each other, to a certain
extent at least.10 In other words, functional maps can
be redistributed within remote networks, enabling the
striking phenomenon of neuroplasticity, both physiologically (ontogeny and learning) and after brain injury.97,98
Interestingly, in patients with slow-growing lesions, such
as diffuse low-grade gliomas, DES has demonstrated
massive functional reshaping that allowed broad surgical resection of brain regions traditionally deemed to be
inoperable.99 For example, extensive removal of diffuse
tumour invading the classic ‘Broca’s area’ in the left
hemisphere has been carried out without causing permanent neurological deficit.20,100,101 In addition, resection of the pars opercularis and/or pars triangularis of
the left i­nferior frontal gyrus is possible without risking
aphasia, for two reasons. First, in a networking model of
the human brain based on a probabilistic map of critical
regions built from 771 stimulation sites, it has recently
been demonstrated that Broca’s area is not the speech
output region.61,102 Second, tissue loss in this area can be
compensated for by recruitment of adjacent regions, primarily the ventral premotor cortex (the crucial epicentre

for speech articulation), and the pars orbitalis of the
infer­ior frontal gyrus, the dorsolateral prefrontal cortex,
or the insula.20,100
In a similar vein, removal of Wernicke’s area invaded
by a diffuse tumour has been accomplished without eli­
citing permanent language disorders.103 Once again, the
functional compensation following resection of the posterosuperior part of the left temporal lobe (and its junction with the inferior parietal lobule) can be explained
by reorganization of complex language functions into
remote networks. In addition to recruiting areas immedi­
ately around the lesion, remapping may involve distant
regions in the left hemisphere (particularly the supramarginal gyrus and the pars triangularis of the inferior
frontal gyrus), as well as contralateral sites in the right
hemisphere owing to transcallosal disinhibition, as
demonstrated by combining intraoperative DES with
­perioperative functional neuroimaging.103
Factors that might allow reorganization of function
have also been explored using other methods, including
transcranial magnetic stimulation104 and computational
models.105 The latter models show how function can be
redistributed across an interconnected network, and why
this process is maximal in the case of slow, as opposed
to fast, neurological damage (for example, low-grade
versus high-grade glioma). Nonetheless, it is crucial to
insist that subcortical connectivity should be preserved,
so as to avoid functional deficit. Indeed, although great
potential for plasticity has been demonstrated at the
cortical level, subcortical plasticity is low, implying that
axonal connectivity should be preserved to allow post­
lesional compensation.106 Stroke studies have taught us
that damage to white matter tracts generate more-severe
­neurological worsening than do lesions of the cortex.
Recently, a probabilistic postsurgical residue atlas was
proposed, computed on a series of patients who underwent incomplete resection for a glioma on the basis of
intraoperative cortical and axonal DES.28 The anatomofunctional correlations obtained by combining intra­
surgical functional data with postoperative anatomical
MRI findings provided new insights into the potentials and limitations of cerebral plasticity. This probabilistic atlas highlighted the crucial role of the axonal
pathways—­that is, the connectivity—in brain remapping after damage. It provided a general framework to
establish anatomo-functional correlations by computing
the probability of preservation of each brain voxel on the
postoperative MRI scan, thereby providing an indication
of the functional importance of different brain regions.
The overlap of this new atlas with the Montreal
Neurological Institute cortical template and a tractographic atlas offered a unique tool to analyse the potentialities and limitations of interindividual variability and
plasticity, for both cortical areas and axonal pathways.
As a rule, the probability of residual tumours on the cortical surface was low; most of the regions with a high
probability of residual tumour were located in the deep
white matter. Thus, projection and association axonal
pathways, especially the AF, SLF and IFOF, seem to
have critical roles in the proper functioning of the brain.

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In other words, the brain functions subserved by longrange axonal pathways seem to be less subject to interindividual variability and reorganization than cortical
sites.28,107 The reproducibility of these results may lead
us to suggest the existence of a ‘minimal common brain’
that is necessary for the unimodal functions but probably not sufficient for more-complex functions such as
multimodal processing.

Limitations of the DES approach

Although DES opens up an array of opportunities, it
also has some intrinsic limitations. First, owing to the
restricted availability of the procedure, the number of
patients studied and reported has so far been small.
Second, the limited time available during surgery does
not permit the range of assessments and stimuli that are
possible in standard neuropsychological evaluations.
Third, partial resection is often required to access the
white matter for DES, and the resection itself could
modulate the effects of stimulation. Last, by definition, the patients under investigation do not have an
intact brain and, in the case of low-grade glioma, could
exhibit reorgan­i zation of function before surgery.
However, because subcortical plasticity is relatively low,
as discussed above, DES still has considerable value
for investi­gating brain processing, especially in white
matter tracts, even in patients with cerebral lesions. If
plasticity enabled compensation for all areas involved by
the tumour, it would not be possible to identify crucial
neural structures in a probabilistic map based on patients
with glioma, as has been accomplished by Tate et al.61,102
and Ius et al.28
The ability to detect critical cortical as well as axonal
structures with a high rate of probability by inducing a
reproducible deficit during intraoperative DES (such as
anarthria during stimulation of the SLF III, or semantic
disturbances during stimulation of the IFOF), despite
cerebral reshaping, has considerable implications for
understanding the normal functional anatomy of the
brain. The connectivity of the brain is particularly
amenable to this approach, owing to its relatively low
­potential for reshaping.108

Clinical implications

Beyond the role of DES in fundamental research, intraoperative electrical mapping and the hodotopical view
of cerebral processing have dramatically improved the
results of brain surgery, particularly in neuro-oncology.
In a recent meta-analysis of over 8,000 patients with
glioma,109 awake surgery with DES was found to be a
well-tolerated procedure that identifies cortical and
subcortical structures that are crucial for brain function,
allowing surgery to be performed in ‘eloquent’ areas previously considered unresectable (such as as Broca’s area
or Wernicke’s area). In addition, this approach reduces
the risk of permanent postoperative neurological deficits to under 2%, even when operating in these ‘crucial’
structures, and enables resections to be made according
to functional limits, without a margin, thereby optimizing tumour removal and increasing overall survival.
262  |  MAY 2015  |  VOLUME 11

As a consequence, universal implementation of intra­
operative DES as standard of care for glioma surgery has
been proposed.109
Improved understanding of the connectivity under­
lying the sensorimotor network enables us to predict that
its damage might cause a permanent deficit in complex
movements, even after ‘recovery’ from a transient postoperative supplementary motor area syndrome with
akinesia.32 This information should be provided in a
systematic manner to patients who are due to undergo
surgical removal of a tumour involving this area, in order
to decide whether the boundaries of resection should be
represented by the traditional corticospinal tract (to
avoid paresis) or by the negative motor network (with
more-limited tumour excision but better preservation of
quality of life). Such considerations led to the concept
of ‘onco-functional balance’ in neuro-oncology.110
Similarly, lesioning of the circuit underpinning the
visuospatial system can generate a deficit that may be
incapacitating in everyday life. Homonymous hemi­
anopia caused by damage to the optic radiation prevents the patient from driving (if only for medicolegal
reasons), injury of the ILF can generate prosopagnosia
with consequences for social cognition, and lesioning of
the SLF results in hemineglect. Therefore, understanding and mapping the organization of the corticosub­
cortical network is particularly crucial for brain surgery,
­including in patients with epilepsy.41
Reformulation of the classical Broca–Wernicke model
of language explains the possible recovery from aphasia
following a lesion within the ‘classic’ language areas. For
instance, in neurosurgical practice (especially epilepsy
surgery), left anterior temporal lobectomy can be carried
out without causing severe permanent language problems, despite the ablation of the indirect ventral pathway
(ILF–temporal pole–UF), because of compensation by
the ventral direct pathway (IFOF).111
In neurological diseases, these concepts can be helpful
for the prediction of recovery following cerebral injury,
and for the elaboration of individualized programmes of
neurological, cognitive and behavioural rehabilitation.
Improved knowledge of the connectivity that mediates
the sociocognitive system is also important to avoid postoperative deficits of social cognition and personality and,
thus, enable patients to return to a normal occupational
life.112 The emergence of the dual-stream model subserving this system might lead to a better understanding
of some psychiatric diseases that affect mentalization,
especially in neuropathological conditions characterized
by atypical or aberrant structural connectivity, such as
autism spectrum disorders.81

Conclusions and perspectives

For the first time in the history of cognitive neuro­sciences,
DES mapping of the white matter tracts offers a unique
opportunity to investigate the function of the connect­
omal anatomy in humans. This original method­ology, in
which real-time anatomo-functional correlations are performed in awake patients, has provided new insights into
the functional connectivity underlying the sensorimotor,



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REVIEWS
visuospatial language and sociocognitive systems. In
addition, interactions between these neural networks
and multimodal systems, such as working memory, attention, executive functions and even c­ onsciousness, can be
­investigated by axonal stimulation.
In this networking model, cerebral function results
from the integration and potentiation of parallel, but
partially overlapping, subnetworks. For example, it has
recently been suggested that a distributed neural pattern
underlying supramodal semantics and behaviour provides both a cognitive and an emotional context that
allows the emergence of spontaneous creative activity,
such as music improvisation.113 Finally, this hodotopical account, supported by axonal DES, offers the possibility to better understand the mechanisms and limits
of neuro­plasticity within and between delocalized and
dynamic large-scale subcircuits, both during develop­
ment and in adults. Overall, these findings allow a
reappraisal of the classic neuropsychological models of
conation and cognition.
From a clinical point of view, this paradigmatic
shift from localizationism to hodotopy has numerous
implications. In brain surgery for tumours or epilepsy,
extensive resections can now be achieved in supposedly
‘eloquent’ regions, with preservation or even improvement of quality of life. In neurological diseases, these
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VOLUME 11  |  MAY 2015  |  265
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