Physrev 00033 2019

Physiological Reviews Review Article
REVISITING THE FUNCTIONAL ANATOMY OF THE

HUMAN BRAIN: TOWARD A META-NETWORKING
THEORY OF CEREBRAL FUNCTIONS
GRAPHICAL ABSTRACT AUTHORS
Guillaume Herbet and Hugues Duffau
CORRESPONDENCE
h-duffau@chu-montpellier.fr
KEYWORDS
central nervous system; connectome; functional
mapping; human brain; meta-network; white
matter tracts
CLINICAL HIGHLIGHTS
This is a comprehensive review on the new concept of meta-
networking organization underpinning brain functions, based on
transient changes of relationship within and across neural net-
works, able to result in more long-lasting modifications of net-
work properties, including use-dependent neuroplasticity. In
this context of dynamic inter-system integration, beyond the
fundamental implications in basic neurosciences, a huge poten-
tial of postlesional functional compensation may be very helpful
in brain-damaged patients. This review provides new insights
into such a meta-networking brain and original therapeutic av-
enues in neurosurgery, neurology, neurorehabilitation, and
psychiatry.
Guillaume Herbet and Hugues Duffau, 2020, Physiol Rev 100: 1181–1228
February 20, 2020; © 2020 the American Physiological Society
https://doi.org/10.1152/physrev.00033.2019
Downloaded from journals.physiology.org/journal/physrev (189.159.001.040) on October 26, 2022.
Physiol Rev 100: 1181–1228, 2020
First published February 20, 2020; doi:10.1152/physrev.00033.2019
REVISITING THE FUNCTIONAL ANATOMY OF THE

HUMAN BRAIN: TOWARD A META-NETWORKING
THEORY OF CEREBRAL FUNCTIONS
Guillaume Herbet and Hugues Duffau
Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center, Montpellier,
France; Team “Plasticity of Central Nervous System, Stem Cells and Glial Tumors,” INSERM U1191, Institute of
Functional Genomics, Montpellier, France; and University of Montpellier, Montpellier, France
Herbet G, Duffau H. Revisiting the Functional Anatomy of the Human Brain: Toward a Meta-
Networking Theory of Cerebral Functions. Physiol Rev 100: 1181–1228, 2020. First published
February 20, 2020; doi:10.1152/physrev.00033.2019.—For more than one century, brain
processing was mainly thought in a localizationist framework, in which one given function was
underpinned by a discrete, isolated cortical area, and with a similar cerebral organization across
individuals. However, advances in brain mapping techniques in humans have provided new insights
into the organizational principles of anatomo-functional architecture. Here, we review recent
findings gained from neuroimaging, electrophysiological, as well as lesion studies. Based on these
recent data on brain connectome, we challenge the traditional, outdated localizationist view and
propose an alternative meta-networking theory. This model holds that complex cognitions and
behaviors arise from the spatiotemporal integration of distributed but relatively specialized net-
works underlying conation and cognition (e.g., language, spatial cognition). Dynamic interactions
between such circuits result in a perpetual succession of new equilibrium states, opening the door
to considerable interindividual behavioral variability and to neuroplastic phenomena. Indeed, a
meta-networking organization underlies the uniquely human propensity to learn complex abilities,
and also explains how postlesional reshaping can lead to some degrees of functional compensation
in brain-damaged patients. We discuss the major implications of this approach in fundamental
neurosciences as well as for clinical developments, especially in neurology, psychiatry, neuroreha-
bilitation, and restorative neurosurgery.
central nervous system; connectome; functional mapping; human brain; meta-network; white
matter tracts
I. INTRODUCTION 1181
II. THE TRADITIONAL LOCALIZATIONIST... 1182 This is a comprehensive review on the new concept of meta-
III. THE ASSOCIATIONIST VIEW OF... 1183 networking organization underpinning brain functions, based on
transient changes of relationship within and across neural net-
IV. ADVANCES IN TECHNIQUES OF BRAIN... 1184
works, able to result in more long-lasting modifications of net-
V. THE CONNECTOME REVISITED:... 1194 work properties, including use-dependent neuroplasticity. In
VI. A META-NETWORKING MODEL OF... 1199 this context of dynamic inter-system integration, beyond the
VII. IMPLICATIONS 1208 fundamental implications in basic neurosciences, a huge poten-
VIII. CONCLUSIONS 1215 tial of postlesional functional compensation may be very helpful
in brain-damaged patients. This review provides new insights
into such a meta-networking brain and original therapeutic av-
enues in neurosurgery, neurology, neurorehabilitation, and
I. INTRODUCTION psychiatry.
For a long time, brain processes were mainly thought in a

localizationist way of thinking. Recent data gained from networks. Here, the purpose is to review new findings on
functional neuroimaging and direct electrical stimulation of the neural networks mediating “basic” brain functions such
the central nervous system (CNS) challenged this purely as action, visuospatial cognition, or language and on how
modular theory and allowed to progressively shift towards the dynamic interactions between these specialized func-
a connectomal account of cerebral processing. According to tional systems lead to high-level cognitive functions and
this more realistic model, complex cognitions and goal- flexible behaviors. In addition, the interactions between
directed behaviors arise from the spatiotemporal integra- such distributed subcircuits, capable of reshaping over time,
tion of parallel and interconnected large-scale distributed open the door to a huge potential for neuroplasticity, which
0031-9333/20 Copyright © 2020 the American Physiological Society 1181

GUILLAUME HERBET AND HUGUES DUFFAU
plays a pivotal role in learning and ontogeny. This meta- nervous system. Especially, we will review the cortico-sub-
network functioning also provides a great deal of flexibility cortical distributed networks mediating movement execu-
into the anatomo-functional architecture, allowing cognition and control, visual and spatial cognition, language pro-
tive resilience and functional compensation in brain-dam- cessing, working memory, and social cognition. A special
aged patients, provided that brain structures involved in focus will be given to the white matter structure allowing
within and between-network communication are preserved functional integration and communication within these
(e.g., connective tracts). Therefore, this paradigmatic shift functional systems.
in modeling the functional anatomy of the central nervous
system, from a rigid and localized framework to a flexible On the basis of these recent findings, in the fourth part, we
and highly distributed organization, has many applications, will propose a meta-networking model of human brain
both in basic neurosciences and clinical neurology. functions. In this connectomal account of brain processing,
high-level cerebral functions are conceived as the functional
The first part will review the traditional, and still deeply integration of large-scale distributed subnetworks underly-
rooted, localizationist model in which one discrete brain ing conation, cognition, and emotion. Furthermore, time-
area corresponds to one specific function (the so-called one- varying interactions between such distributed subcircuits
to-one mapping). According to this rigid paradigmatic result in a perpetual succession of new equilibrium states.
framework, the brain anatomo-functional organization This dynamic potential leads to considerable interindi-
consists of highly specialized eloquent regions (such as Ro- vidual anatomo-functional variations breaking with the old
landic and Wernicke’s areas) for which any insult necessar- model of “unique brain.” In addition, a meta-networking
ily leads to persistent neurological impairments, as opposed organization opens the doors to neuroplastic phenomena
to “noneloquent” structures for which no functional con- that allow structural and functional reshaping. In normal
sequences occur in the event of injury. In addition, such a physiological conditions, neuroplasticity plays a pivotal
localizationist approach implicitly resulted in the enduring role in brain development and learning. Postlesional neuro-
principle of a similar brain functional anatomy across indi- plasticity makes possible functional compensation in brain-
viduals, as for example the Broca’s area that has been a injured patients, at least to some extent, on the condition
that the white matter pathways are still intact. Indeed, the
priori considered to the output speech area in all human
limitation of this plastic potential will also be considered, in
brains. Unfortunately, this view of a static functional im-
particular axonal connectivity.
plementation of cerebral functions has had numerous and
lasting implications not only in fundamental neurosciences,
Finally, clinical implications of this meta-networking ap-
by resulting notably in the elaboration of simplistic and
proach of cerebral functions will be described, in various
rigid models of cognition, but also in clinical practice, espe-
neurological diseases, in neurorehabilitation, in psychiatry,
cially by claiming that neurosurgery was impossible in the
as well as in neurosurgery. The ultimate goal would be to
so-called “eloquent” structures.
restore neural functions. This aim can currently be envi-
sioned due to advances in brain-computer interface, based
In the second part, advances in brain mapping technique
on the better knowledge of this revisited dynamic functional
will be detailed, as a valuable supplement to lesion studies, anatomy of human brain.
which has provided us fundamental information about
brain physiological functioning, but which nonetheless suf-
fer from substantial limitations. First, noninvasive func- II. THE TRADITIONAL LOCALIZATIONIST
tional neuroimaging, with recent development of task- THEORY OF CEREBRAL ORGANIZATION
based and resting-state magnetic resonance imaging as well
as tractography, will be reviewed. In addition, the principle Two centuries ago, although Pierre Flourens proposed the
of direct electrical stimulation of both cortex and subcorti- theory of equipotentiality, according to which the whole
cal pathways, allowing for the first time to obtain direct brain, or at least a whole hemisphere, participates in per-
data regarding the function of the white matter tracts in forming a behavioral activity, Joseph Gall (179) provided
vivo in humans, especially during awake surgery for brain the foundations of phrenology, with the assumption that
tumor, will be explained. By combining neuroimaging and character, thoughts, and emotions are located in specific
intrasurgical mapping, it is now possible to perform serial parts of the brain. Based on this theory, Broca (57) reported
studies before, during, and after resection of a cerebral neo- that a neurological damage of the third frontal circumvolu-
plasm, which represents a unique opportunity to investigate tion caused a reduced capacity for speech articulation. In
neuroplasticity at the individual level. the same mind, a decade later, Wernicke (511) associated
word comprehension with the posterior part of the left tem-
In the third part, new insights into the neural foundations poral gyrus. This led them to reason that the human CNS
subserving the main human basic functional systems will be was formed by a mosaic of “critical” cerebral areas with a
analyzed, based on new findings issued from functional high degree of functional specialization, for which any in-
neuroimaging and direct electrostimulation of the central jury caused a permanent neurological impairment, as op-
1182 Physiol Rev • VOL 100 • JULY 2020 • www.prv.org

A META-NETWORKING THEORY OF BRAIN FUNCTIONS
posed to “noncritical” zones for which no neurological se- areas. In this context, high-order cognitions were, accord-
quelae arose following brain lesion. This kind of localiza- ing to him, the byproduct of the interplays between motor
tionist inferences have implicitly led to the enduring and sensory image areas through the associative fibers in-
principle of a “unique brain,” with similar and fixed neural terconnecting them. As recalled by Catani and ffytche (77),
foundations across individuals; this is for example reflected Wernicke did not believe that cognitive functions might be
in the fact that the pars opercularis and pars triangularis of assigned to specific cortical areas.
the left “dominant” hemisphere, referred to as Broca’s area,
is thought to be the cortical site allowing humans to speak Conduction aphasia is undoubtedly the most exemplary
since that time. description of the Wernicke’s theory, and more generally of
the associationist theory. According to Wernicke, the motor
On the basis of these first lesion studies, and despite the first images of speech were located in Broca’s area while the
descriptions by several pioneers of functional compensation sensory images of words were rather located in the posterior
after brain damage that could be related to neural remod-
part of the superior temporal gyrus, close to the temporo-
eling (41, 162, 341), the reductionist principle of a static
parietal junction (the so-called Wernicke area). Accord-
organization of CNS was settled. Yet, through regular ob-
ingly, damage to the Broca’s and the Wernicke’s areas
servations of postlesional functional improvements over de-
caused specific patterns of neuropsychological impair-
cades, this rigid view was progressively called into question
ments, respectively, motor aphasia (a syndrome mainly
(20, 96, 279, 296, 375, 412, 483). The concept of neuro-
plasticity was suggested, that is, a continuous process that characterized by expressive language disorders) and sen-
enables neuronosynaptic maps to adapt to optimize cere- sory aphasia (mainly characterized by comprehension dis-
bral functioning. This plastic potential is critical in normal orders). However, disruption of the associative connections
physiological conditions, in particular for learning and on- interconnecting them, later identified as the arcuate fascic-
togeny, as well as for recovery in brain-damaged patients. ulus, resulted in what has been labeled conduction aphasia,
Such a dynamic organization is nonetheless conceivable a disconnection syndrome clinically marked by difficulties
only in an integrative, not in a purely segregated account of in repeating words and sentences. This was the first demon-
neural processing. Interestingly, although a network distri- stration that associative white matter pathways played an
bution of CNS has already been proposed many decades important role in cognition, and that deprivation of the
ago (70), with special structural and functional consider- functional communication between two or more areas can
ations of the key role played by the white matter tracts (114, lead to lasting neuropsychological difficulties.
182, 273), the localizationist doctrine prevailed for almost
two centuries. Other physicians followed suit; it was during this period
that major parts of the known neuropsychological syn-
Here, our aim is to bring new insights gained by brain dromes were interpreted as disconnective breakdown. For
mapping techniques that challenge the localizationist view example, associative visual agnosia was thought as result-
of anatomo-functional organization, erected mainly on the ing from a disruption of associative fibers emanating from
basis of lesion studies in spite of their limitations. But before the visual cortex whereas apraxia the consequence of either
that, it is important to discuss alternative associationist ac- a rupture of the functional communication between the
count that has been developed in parallel in the history of sensory cortex and the motor cortex or a lack of inter-
behavioral neurology and that implicitly rely on a connec- hemispheric coordination due to callosal damage (293). It is
tionist view of cerebral organization. also during this period that high-order functions were fre-
quently modeled as diagrams (290), that is, schematic neu-
III. THE ASSOCIATIONIST VIEW OF roanatomical illustrations that can be considered as rudi-
CEREBRAL ORGANIZATION mentary forms of the connectograms we are able to gener-
ate today (75).
Although the concept of localizationism is the main foun-
dation on which modern behavioral neurology and neuro- It took many years before the disconnection paradigm re-
psychology have been built, it is important to keep in mind vived, in particular through the works of Norman Ge-
that alternative approaches have been developed at the schwind regarded as the founding father of the neo-associ-
same time. More specifically, the associationist school, led ationist school. Geschwind not only provided an impressive
by Carl Wernicke, considered associative connections as review of the available neurology literature (182), but also
central buildings blocks for high-order cerebral functions, extended in many directions the tenets of the classic associ-
in an era where neuroanatomical works were flourishing. In ationist school (for a review, see Ref. 77). In particular, he
particular, Wernicke thought that the brain was formed by sketched a schematic map of the known disconnection syn-
a myriad of areas in which memory images of motor acts dromes, drawing the readers into a connexionist perspec-
and sensory images were stocked. These memory images tive of how neurological disorders may arise. This work has
could be anatomically located in motor or sensory brain clearly influenced the conceptions later developed by Mar-
Physiol Rev • VOL 100 • JULY 2020 • www.prv.org 1183

sel Mesulam who proposed the very influential framework emphasizes that focal injury can potentially have wide-
of large-scale neurocognitive networks (331, 332). spread consequences on both whole-brain connectivity pat-
terns and intrinsic functional organization, as recently dem-
In closing, disconnection approach to neurological disor- onstrated in lesion (210) or lesion modeling studies (3, 240).
ders is an old but still important concept that has led to the
emerging framework of neural networks. The second aim of this review is to update this relatively
stable connectionist/associationist view of the cerebral or-
Another old but reviving concept is the notion of diaschisis. ganization, historically rooted in the concepts of disconnec-
First suggested by Brown-Séquard (59), who proposed that tion syndrome and diaschisis, to a modern version, taking
functional impairments observed after neurological insult dynamic transient and long-lasting changes of network
may be caused not only by the neuronal loss but also by properties into account.
remote effects, the term diaschisis was coined and compre-
hensively defined a few decades later by von Monakow
(340) (for a review, see Ref. 72). According to him, func- IV. ADVANCES IN TECHNIQUES OF BRAIN
tional impairments can occur due to the interruption of the MAPPING IN HUMANS
communication between the lesion and the remote cortical
areas in the event of a focal brain injury (i.e., the intercon-
nected but spared cortical areas no longer receive excitatory
A. How Lesion Studies Can Inform Us on
impulses), this diaschisis effect being temporary. As re- Brain Physiology
viewed by Carrera and Tononi (72), although the concept
of diaschisis was regularly discussed or evoked as a possible As mentioned, localizationism was mostly built on behav-
pathophysiological mechanism in clinical neurology, it was ioral-structural correlations derived from lesion studies and
difficult to experimentally demonstrate its clinical relevance has founded the core principles of behavioral neurology and
for explaining acute postlesional neuropsychological or neuropsychology. Initially, the lesion method consisted of
neurological impairments, possibly because the operational establishing a relationship between the patients’ clinical
principles of diaschisis were ill-defined. However, with the signs and the location of lesions coarsely determined after
development of metabolic imaging in the 1980s, it was now many years by post mortem examination. The most exem-
possible to show a decrease of glucose-related metabolic plary application of such “single-lesion” approach was pro-
activity in areas distant from the lesioned area. Yet only vided by the seminal works of Broca (57) who reported the
very few studies, if any, have succeeded to relate the pres- cases of two patients (Leborgne and Lelong). Both of them
ence of metabolic diaschisis and its resolution with, respec- developed a complex pattern of language impairments at-
tively, functional impairments and their recovery, casting tributed to the damage of the third frontal convolution.
shadow once again on the clinical relevance of diaschisis. However, at that time, the precise three-dimensional delin-
eation of damage was almost impossible, as MRI was not
Based on the available functional magnetic resonance im- yet developed, and the interpretations were thus based on
aging (MRI) literature, Carrera and Tononi (72) recently the most “visible” part of the lesion. In that respect, recent
proposed a re-evaluation of the concept of dascischis, in the MRIs of Leborgne’s and Lelong’s brain demonstrated wide
light of the latest developments in cognitive neuroscience. insults involving not only the so-called cortical “Broca’s
They define diaschisis as “the distant neurophysiological area” but also the insular and premotor cortices, and peri-
changes directly caused by a focal injury. To fulfill the def- sylvian white matter (WM) fibers (129, 461). This means
inition, these changes should additionally correlate with that the classical “motor aphasia” described by Broca was
behavior and tend to normalize with time.” They further not necessarily caused by an injury of the inferior frontal
distinguished two main forms of diaschisis, namely, focal cortex per se, but induced by a wider lesion implying the
and non-focal diaschisis, in an attempt to better character- deep WM connectivity. This is probably the reason why
ize the multifaceted nature of this physiological event. Focal the Broca’s conclusions of a “critical language epicenter” in
diaschisis can occur at rest (diaschisis at rest) or uniquely the posterior inferior frontal gyrus was quickly and severely
during stimulations (functional diaschisis); it is physiologi- criticized, as this finding was hardly replicable in reports
cally marked by an abnormal metabolism in the remote, including numerous cases (317). That being said, it must be
nonlesioned areas. Non-focal diaschisis is observed if selec- clearly recognized that seminal cases described in the liter-
tive changes in the functional coupling between two nodes ature using the “simple” lesion method, such as for example
of a given network distant from the lesion is identified, Phineas gage (205) or Henri Molaison (429), have provided
whether or not the patient is engaged in task performance considerable insights into the neural bases of cerebral func-
(connectional diaschisis) or if changes in the structural and tions (93, 405) even if these cases “should not considered to
functional connectome are identified in areas distant from be set in stone” (461) and thus need to be reappraised in the
the lesion (connectomal diaschisis). The new concept of light of current knowledge about the human anatomo-func-
non-focal diaschisis is especially interesting because it fairly tional organization.

With the development of imaging techniques, especially sioned. This allows to generate statistical maps of the rela-
MRI, the lesion method has undergone progressive tionship between the location of the lesion and the deficit of
changes, by allowing to better delineate the patients’ le- interest. An alternative but quite similar method, referred to
sioned areas (101). As a consequence, it has become possi- as anatomo-clinical overlapping maps (AnaCOM) (268),
ble to study patients as a function of the lesion location or of rather works on a cluster-by-cluster basis and performs
the impaired behavioral function, and thus to make specific comparisons between patients and healthy controls to de-
assumptions about the role of a given area in a hypothesized termine the brain structures critical to a given cerebral pro-
function. In the lesion location approach, patients are cess. Although this alternative probably leads to results
grouped according to a brain area commonly damaged such with poorer specificity (404), the statistical power is better
as for example the insula. Their behavioral performances and the resulting statistical maps contain lesser false nega-
are then statistically contrasted to that of another patient tives (166).
group for whom the lesion epicenter is situated in a different
area (430). Although this method is still useful, especially to VLSM-like techniques became increasingly popular in re-
bring in light double anatomo-functional dissociations cent years (24, 66, 129, 186, 214, 490), but it became
(e.g., Ref. 431), it suffers from shortcomings; both the le- apparent that they suffer from important limitations that
sion positioning and the lesion size are most of the time not can severely affect the output results. First, VLSM-like tech-
the same across patients, and lesions may greatly extend to niques necessitate large samples of patients, as sample size
another areas. Hence, it cannot be entirely excluded that the has a considerable influence on the resulting statistical
damage of another brain area may in fact account for the maps; underpowered studies (due to low sample size) can
behavioral impairment under scrutiny. Moreover, this indeed lead to an over-estimation or to an under-estimation
method naturally leads to an underestimation of other po- of effect sizes, and more generally to unreliable effect sizes
tentially important areas, as the same neuropsychological (294). Second, as VLSM-like are mass-univariate ap-
impairment can be observed in different territories of the proaches, statistical maps must be severely corrected for
brain (167) due to the very distributed nature of higher- multiple comparisons as in neuroimaging studies, drasti-
order functions (331). The second classical approach con- cally decreasing the statistical power and potentially in-
sists of selecting patients showing a deficit of interest (e.g., creasing the number of false negative regions (267). For the
spatial neglect) and in superimposing their lesion into a same reason, they cannot account for both the relation of
common stereotactic space (129). The common lesioned contiguity that exists between the lesioned voxels (i.e., a
area is considered as the brain correlate of the studied def- voxel is never lesioned in isolation) and for the stereotyped
icit. A more advanced version of this technique is to sub- distribution of lesions that follows the vascular anatomy in
tract the lesion overlays of patients showing a deficit versus case of stroke or that is preferentially centered in specific
patients not showing this deficit, allowing to identify the regions in case low-grade glioma (217, 301, 519). Con-
brain areas the most frequently and the most specifically strained, nonrandom lesion distributions are indeed shown
lesioned in the impaired patients (214, 262, 462). Again, to significantly distort lesion-deficit maps (301), even if in-
this approach is not without limitations. First, most of the cluding correction factors such as “lesion size” among oth-
time, a cut-off score must be applied to decide whether a ers appears to reduce this systematic bias (263, 449). Fi-
given patient is impaired or not, leading to a loss of infor- nally, the distributed nature of higher-order functions (i.e.,
mation regarding behavioral variability (34). Second, it is behavioral functions are subserved by networks, not by
considered that the commonly damaged area specifically isolated areas) makes difficult the interpretability of statis-
mediates the impaired function or process. In fact, the same tical maps. Indeed, as several brain regions can be associ-
neurologic disturbance may result from lesions in distinct ated with the same neuropsychological impairment (i.e., in
structures between patients, all of them being part in a wide principle, any part of a given network can lead to the same
functional circuit around (but not necessary including) the deficit), this offers statistical counter-examples to massively
“epicenter” considered as “critical.” univariate methods and may consequently produce false
negatives (178). Furthermore, due to the typically large size
In this context, mass-univariate voxelwise lesion-deficit ap- of the lesions, especially in stroke injury, it is not possible to
proaches have emerged, especially voxel-based lesion- know whether the damage of one particular region is suffi-
symptom mapping (VLSM) (34). They have the advantage cient to produce the deficit under study.
to attenuate most of the limitations inherent to classical
lesion analyses and not to necessitate specific assumptions Although many solutions have been offered in recent years
about the location of cerebral processes under study. In that to overcome the limitations mentioned above with the use
respect, VLSM can be used as an exploratory tool. On a of model-based VLSM (65, 185) or multivariate analyses
voxel-by-voxel basis, VLSM statistically contrasts for all such as multivariate pattern analysis (MVPA) (445), multi-
voxels taken into consideration in the analysis of the behav- variate VLSM using support vector regression (531), or
ioral scores of patients having a given voxel lesioned with multivariate sparse canonical correlations (382), the main
the behavioral scores of patients not having this voxel le- shortcoming remains. Indeed, the functional weight of

structural disconnection (i.e., WM disruption) is not taken especially for bolstering evidence from other imaging mo-
into account or widely underestimated, which is of course dalities not allowing causal inferences such as functional
problematic considering that neurological conditions typi- MRI. However, the lesion method needs to be improved
cally used to generate lesion-deficit analyses mainly affect further, and perhaps radically changed in its founding prin-
WM connections; this is true for stroke, tumors, and trau- ciples (localizationist postulate). Indeed, as it is now estab-
matic brain injury as well. Yet, there is growing evidence lished that cognitive functions emerge from large-scale
suggesting that neurobehavioral symptoms observed in the structural and functional networks (56, 331, 332), we now
postlesional period arise not only from cortical injuries but need improved lesion methods that integrate these physio-
also from injuries of basal ganglia, thalamus, and cerebel- logical constraints in their operational logic (i.e., neurolog-
lum, as well as from the WM paths that link cortical epi- ical symptoms can be explained by large-scale network dys-
centers with each other and with the subcortical gray nuclei. function or impaired network dynamics caused by an iso-
As a matter of fact, a recent large-scale neuropsychological lated cortical or WM lesions). As we will see below, the
study not only confirmed that the majority of stroke oc- coupling of different imaging modalities seems to be an
curred subcortically and thus involved WM connectivity excellent avenue for a better understanding of the patho-
(pure cortical stroke in only 13% of cases), but also dem- physiological mechanisms underlying neurological impair-
onstrated that structural disconnections explained most of ments in brain-damaged patients.
the behavioral variability in multiple cognitive domains in-
cluding memory and attention (91). Furthermore, there are
B. Neuroanatomy: Beyond the Cortex, the
many studies now that draw clear associations between
Revival of Fiber Dissection
WM disconnections and behavioral impairments, reinvigo-
rating both the theories developed by the Associassonist
Because in the localizationist approach of cerebral func-
School late in the 19th century and the seminal work of
tions, one cortical area was theoretically associated with
Norman Geschwind (182) on disconnection syndromes.
one specific function or process (i.e., the so-called one-to-
For example, spatial neglect has been associated with layer
one mapping), with almost no consideration regarding the
II of the right superior longitudinal fasciculus (SLF) (27,
subcortical connectivity, WM tracts have received less at-
463) mentalizing impairments with the right arcuate fascic-
tention for many decades. This is also true concerning the
ulus (AF) (130, 197), cognitive empathy and mentalizing
structural anatomy that mainly focused on the cortical or-
with the cingulum (214, 219), and emotional empathy with
ganization until 2000s (357). Yet, anatomic dissections of
the right uncinate fasciculus (352). These results clearly
WM fibers have been achieved as early as the 17th century,
indicate that WM damage is an important pathophysiolog-
with the description of the tracts of the centrum ovale (493).
ical mechanism underlying neurological impairments, in ei- The gross dissection methodology in the 19th century re-
ther sudden or evolving conditions, that should not be over- sulted in the identification of distinct fiber fasciculi (64,
looked. Yet, most of the lesion studies using mass-univari- 393) and the recognition that these tracts may be considered
ate or multivariate approaches ignore or offer very few association, projection, or commissural (114, 335). Despite
interpretations on the possible impact of WM disconnec- the description of the clinical relevance of long-range fibers
tion on statistical maps, even if the identified statistical epi- by Dejerine, who reported alexia without agraphia from
centers greatly overlap with the known spatial positioning damage involving the splenium of the corpus callosum
of WM tracts. As the same neuropsychological impairment along with to the left occipital pole, and despite the im-
can be virtually reproduced by disrupting a given WM tract provement of the WM dissection method by Klinger who
along its full length (delocalized effect), this offers again proposed to freeze the brain, very few anatomic studies
statistical counter-examples, and especially for mass-uni- attempting to investigate the subcortical connectivity on
variate approaches whose core principle is to localize a human specimen have been achieved for several decades.
“functional module.” In the same vein, typical lesion-symp- Interestingly, in the modern era of noninvasive diffusion
tom analyses are ill-suited to map neurological deficits po- tractography imaging (DTI, see below), there was in paral-
tentially induced by other hodological mechanisms than lel a revival of blunt WM dissection, with the main goal to
WM disruptions such as diaschisis (72, 77), naming, which better define not only the exact trajectories of the fascicles
arise from the hypo-functioning of remote, nondamaged but also their endings. Indeed, to understand brain physiol-
but interconnected areas. ogy, it is crucial to improve our knowledge regarding the
anatomy of the WM fibers. Every zone of the neocortex
In closing, the lesion method has undergone far-reaching seems to be connected to other cortical and subcortical
changes in recent years and, in many respects, has provided structures by different groups of fiber tracts (422– 424).
critical insights into the neural correlates of cerebral func-
tions. It remains moreover one of the only ways to causally First, association bundles, which interconnect ipsilateral
relate neurological impairments to specific brain structures; cortical sites, comprise the SLF, AF, frontal aslant tract
in that, the lesion method is essential and will remain a (FAT), inferior fronto-occipital fasciculus (IFOF), inferior
method of choice in cognitive and clinical neurosciences, longitudinal fascicle (ILF), uncinate fasciculus (UF), middle

longitudinal fasciculus (MdLF), and the cingulate bundle. Second, projection fibers connect the cortical areas with the
The SLF is constituted by several subparts: SLF I, medially subcortical structures, the brain stem and the spinal cord.
located, that connects the medial part of the superior pari- They are constituted by the fronto-striatal tract (FST),
etal lobule with the frontal lobe supplementary and premo- which links the premotor cortex with the striatum, the
tor cortices (even though some authors questioned its exis- thalamo-cortical tracts, the optic tracts, and the pyramidal
tence; see Ref. 516); SLF II, more laterally located, that tracts (148, 269, 402).
connects the angular gyrus with the dorsolateral prefrontal
cortex (DLPFC); and SLF III (lateral perisylvian SLF) which Finally, commissural bundles pass to the contralateral
is part of the SLF/AF complex, itself constituted by three hemisphere and are composed of the corpus callosum, the
segments: 1) anterior segment of the lateral SLF, which links anterior and posterior commissures, the thalamic commis-
the supramarginal gyrus and superior temporal gyrus with sure, and the hippocampal commissure.
the ventral premotor cortex (lateral part of the precentral
gyrus); 2) posterior segment of the lateral SLF, which con-
C. Structural and Functional Neuroimaging
nects the posterior part of the middle temporal gyrus and
the angular gyrus; and 3) long segment of the AF, deeply
1. DTI
situated, that travels from the caudal part of the temporal
lobe, mainly the inferior and middle temporal gyri, that
runs around the insula and ends in the frontal lobe, mostly Beyond post mortem anatomical dissection, the develop-
in the posterior part of the middle and inferior frontal gyri ment of DTI (29, 30) has considerably participated to a
as well as in the precentral gyrus (79, 305). The FAT links better understanding of the network organization of the
human brain, by providing researchers a means to map WM
the supplementary motor area with the inferior frontal
connections in a more fine-tuned way that cadaveric dissec-
gyrus and, to a lesser extent, the ventral premotor cortex.
tion does. Indeed, DTI currently constitutes the sole tech-
The IFOF courses from the posterior occipital, parietal, and
nique allowing to noninvasively study axonal connectivity
temporal cortices within the sagittal stratum; it joins the
in humans, while other methods are available in animals,
roof of the temporal horn; it reaches the ventral part of
especially tract-tracing techniques (i.e., following the
the external/extreme capsule; it travels under the insular
course of axonal pathways by axonal transport of invasive
lobe within the temporal stem; and finally, it ends within the
tracers). Without going into too much technical details, the
frontal lobe (320). Several layers of the IFOF have been
basic principles of DTI are based on the biological con-
described (414). The superficial and dorsal subcomponent
straints imposed by cerebral tissues on molecular diffusion,
links the posterior part of the superior and middle occipital
especially on the diffusion of water molecules (6, 18, 30,
gyri, the superior parietal lobule, and the posterior portion 282, 342, 344, 376, 455, 471). In fact, water molecules
of the superior temporal gyrus to the pars triangularis and have a random displacement (i.e., Brownian motion), this
opercularis of the inferior frontal gyrus. The deep and ven- one being altered by the physical boundaries of cerebral
tral layer links the posterior portion of the inferior occipital tissues. On a voxel-by-voxel basis, DTI basically tracks this
gyrus, the posterior temporal-basal area including the fusi- displacement (i.e., the directionality) and is thus able to
form area at the occipito-temporal junction (Fusa), as well provide different measurements (e.g., mean diffusivity, frac-
as the posterior part of the middle temporal gyrus with the tional anisotropy, etc.) on both the microstructural proper-
orbito-frontal cortex, middle frontal gyrus, and DLPFC. ties and architecture of cerebral tissues, especially WM fi-
Other authors have described more layers, up to five (515). bers, and their integrity. Furthermore, as DTI measures the
The ILF that travels below the IFOF is constituted by two displacement distribution of water molecules, it constitutes
subcomponents: its posterior part that connects the occipi- a unique tool to study the spatial organization of cerebral
tal lobe to the posterior occipito-temporal junction (visual tissues (280). As a consequence, although DTI has been first
object form area) and its anterior part connects the poste- used in the context of clinical radiology (e.g., Refs. 272,
rior occipito-temporal area (Fusa) and the temporal pole 512, 514), it rapidly proved to be an excellent tool to map
(79, 225, 280). The UF links the temporal pole to the basi- the human WM networks (i.e., fiber tracking); indeed, good
frontal cortices by running within the anterior third of the correspondences were generally found between in vivo and
temporal stem (in front of the IFOF) (208). The MdLF links ex vivo dissections of human WM (76, 78, 342–344, 504).
the angular gyrus with the superior temporal gyrus up to the However, as DTI provides biomathematical models of WM
temporal pole and travels under the superior temporal sul- connectivity, and is shown to have inherent limitations no-
cus, lateral and superior to the IFOF (305, 306, 308). Fi- tably due to the three-dimensional complexity of WM fibers
nally, the cingulate bundle connects the anterior and poste- and to the need of anatomical priors (at least for determin-
rior parts of the cingulate gyrus with each other, and with istic DTI as opposed to probabilistic DTI; see Refs. 36,
the dorsolateral, orbital, and medial prefrontal cortices, as 364), validations are still required with anatomical dissec-
well as the parietal, retrosplenial, and ventral temporal cor- tions, the results of which reflect the true anatomy (280,
tices (including the parahippocampal gyrus and entorhinal 414). Indeed, although the visualization of WM connec-
cortex) (60, 423, 515). tions with DTI is a rapidly evolving field, with the develop-

ment of new well-working algorithms (i.e., q-ball tractog- behavioral impairments has prompted researchers to make
raphy, spherical deconvolution tractography) in recent use of such atlases with the intent of correlating WM dam-
years (251, 473), it is important to keep in mind that it age and neuropsychological syndromes. The advantage
remains still imperfect. More specifically, DTI tractography here is that there is no need to have native DTI sequences
can lead to both a disproportioned number of false positives that are not routinely acquired in most of medical centers.
and over-representation of easy-to-track versus under-rep- Such “trackwise lesions-symptom” analyses have provided
resentation of hard-to-track WM connections (396). The critical information about the processes that are broad-
combined use of both DTI and anatomical dissections (or casted by major long-range WM tracts. For example, the
anatomical priors from anatomical dissections) may help to right IFOF/ILF has been associated with emotion recogni-
overcome any individual limits. tion (374), the right SLF II with spatial neglect (462), the
right arcuate with social cognition (214, 350, 524), the left
By very nature, DTI-like methods are structural techniques IFOF with verbal semantic processing (8), the left arcuate
and, consequently, do not give any functional information with nonfluent aphasia (171, 241), and the left ILF with
about the role of WM connectivity in cognition and behav- anomic aphasia (221). The majority of these findings have
ior. However, as some DTI metrics can be used as proxy been now replicated using axonal stimulation mapping in
measures of WM integrity, combining DTI and behavioral “awake” surgery (see sect. IIID2), providing evidence for
assessments has the strong potential to inform us further the relative validity of this kind of lesion methods, even if
about the functional implications of WM pathways in both they have also inherent limitations.
patients and neurologically intact participants. In the con-
text of neurological conditions, the mixing of both investi- The acknowledgment that neurological/neuropsychologi-
gation techniques has led, for example, to a better under- cal impairments can result from structural disconnections,
standing of the pathophysiological bases underlying behav- and thus from network dysfunction, has motivated very
ior symptoms and verbal dysfluency in primary progressive recently the development of more automated methods for
aphasia (81, 103), emotion recognition impairment in associating cognition with WM tracts in brain-damaged
amyotrophic lateral sclerosis (97), theory of mind deficit in patients. Tractotron software, for example, allows to auto-
autism spectrum disorder (259), or even disrupted semantic matically compute both the damaged proportion and the
cognition in stroke patients (203). By this means, the disconnection probability of a wide range of short, long-
knowledge accumulated in the last 10 years has greatly range, and interhemispheric WM tracts induced by a lesion
contributed to the current view that cerebral disconnection (166, 402, 462). This method has been successively used to
is a rather common cause of neurological impairments relate analogical reasoning to certain frontal WM tracts
across various brain pathologies (77, 80, 91, 125, 217, (478) and social cognition to the right AF (350). Further-
505). In healthy participants, it is now well-established that more, the combined used of Tractotron and axonal stimu-
interindividual variability in a large array of behavioral lation mapping has helped disentangle the role of WM con-
measures can be predicted from variations in DTI measure- nections in verbal perseverations (313). A more advanced
ments, suggesting that the more developed WM fiber micro- approach is “disconnectome-symptom mapping” (166).
structural properties are, the more efficient cognition is Without going into the technicalities of the method, discon-
(236, 323, 460, 522). Likewise, a handle of studies has nectome maps are first generated on the basis of a tractog-
demonstrated that the degree of WM laterality is able to raphy-based atlas (402). These maps show the probability
predict behavioral performance, revitalizing the debate on with which the WM connections passing through or ema-
the hemispheric dominance of cerebral functions. For in- nating from the lesion are disconnected and that for each
stance, lateralization of the SFL II has been associated with voxel on the MNI152 template. They are then associated
visuospatial performance, confirming the previous finding with some behavioral measures to identify the network of
that the right hemisphere is dominant for spatial cognition WM fibers associated with the cognitive/behavioral impair-
(462). Another finding is that it exists a leftward lateraliza- ment under study (166, 287).
tion of the arcuate fasciculus in most of right-handed chil-
dren, adolescents, and young adults, and that this asymme- To conclude, DTI is an excellent tool not only to assess WM
try in WM predicts specific cognitive and language abilities integrity in a range of neurological conditions, but also to
(284). map neural connections in both the healthy and diseased
brain. However, as DTI does not intrinsically provide any
In recent years, successive DTI-based WM atlases have been functional information, anatomico-functional correlations
developed (76, 342, 402), first for mostly didactic purposes must be conducted with to determine the possible functions
(i.e., better visualize the geometrical and spatial course of of a given WM pathway. In future years, the improvement
WM tracts that cross the brain), and then for research pur- of DTI spatial resolution and, consequently, its ability to
poses. In fact, the growing awareness that typical lesion- identify the anatomical terminations of WM connections,
symptom methods were ill-conceived to appropriately will allow to better understand the multilayered architec-
gauge to weight of structural disconnections in postlesional ture of the main WM tracts as well as the functional path-

ways mediated by these tracts. Indeed, it is likely that WM neuronal computations from different brain areas are inte-
tracts support a range of cognitive processes, as it is the case grated in a distributed and dynamic manner. These functional
for example for the ILF (225). interactions can be measured by estimating functional or ef-
fective connectivity from fMRI time-series (i.e., the acquisition
2. Task-based and resting-state functional MRI of fMRI data at multiple time points). Functional connectivity
is defined as the statistical interdependency between time-se-
A) TASK-BASED FUNCTIONAL MRI.Since its first development in the ries over time; its analysis allows to determine which cortical
early 1990s, functional MRI (fMRI) has been used in a regions communicate during a behavioral task (correlation
countless number of studies aiming at elucidating the neu- strengths between cortical areas). Effective connectivity is
roanatomy of various cerebral processes as well as at better rather concerned with how one brain region modulates the
understanding the pathophysiological mechanisms under- neural activity of another (172–174, 454). The analysis of
lying abnormal behavior and cognition in both psychiatric effective connectivity has the advantage of offering a way
and psychopathological diseases. It is also regularly used to of determining the top-down or bottom-up modulations of
assess functional plasticity following neurological insult given cortical area during stimuli processing; in other terms,
(98, 277) or cognitive training (150, 338) or as a biomarker the directionality of functional connections (i.e., forward or
of various pathological conditions, especially neurodegen- backward). For the sake of illustration, look at the results
erative diseases. Basically, fMRI captures the time-varying from a relatively recently published paper using dynamical
changes in metabolic activity as a result of task-induced causal modeling (151), the gold standard method of analyz-
mental activity or during unconstrained, free-task activity ing effective connectivity from fMRI data (175). In this
(i.e., not provoked by external stimuli). In most of the con- study, the authors aimed at disambiguating the functional
ventional studies, fMRI is based on BOLD (blood oxygen-
interactions among the cortical areas forming the face per-
level dependent) contrast, which measures neural response
ception network. This network is typically composed of
through susceptibility effects of deoxyhemoglobin. Com-
both a “core network” (i.e., the so-called occipital face and
pared with other imaging techniques, especially electroen-
fusiform face areas) and an “extended” network (i.e.,
cephalography (EEG) or magnetoencephalography (MEG),
amygdala, temporal pole, inferior frontal gyrus, and orbito-
fMRI has a greater spatial resolution but a much lower
frontal cortex). The authors showed that the core network,
temporal one. This is the reason why coupling both imaging
especially the fusiform area, exerted generally a directed
modalities (fMRI plus EEG) has been advocated as a means
influence over areas of the extended network in a feed-
of diminishing the temporal or spatial limitations inherent
forward manner during the processing of face. In addition,
to each one (99, 432).
they showed that modulating stimuli characteristics in-
In its very early stages, fMRI was relatively reductionist creased functional coupling between the fusiform face area
with regards to the statistical designs it employed. Pioneer- and the amygdala in the event of emotional faces, or the
ing fMRI experiments were mainly built on the principle of coupling between the fusiform face area and the orbitofron-
cognitive subtraction (i.e., a specific cognitive process can tal cortex in the event of famous face. Collectively, these
be identified by adding a cognitive component to a baseline results illustrate perfectly well the neural dynamics carried
behavioral task), but were rapidly superseded by studies out during the processing of stimuli, and how varying stim-
using more complex factorial designs capable of integrating uli content modulates the network in a stimulus-specific
a number of neurophysiological constraints in the process- way. Other studies have employed effective connectivity
ing of activation data (176). Although these sorts of fMRI measures in the context of, for example, language process-
investigations are able to determine which brain regions are ing (45, 145) or mental imagery (326).
involved in a particular behavior, they only assess one as-
pect of functional brain organization, namely, functional Interestingly, both functional and effective connectivity
segregation, which can be defined as the functional selectiv- during task processing can be used as a means of assessing
ity of certain neuron populations in a particular cerebral the consequences of structural lesions (including WM dam-
process. A well-known example of functional segregation is age) on functional integration or more generally on brain
the selective activation of neurons lodged at the very bottom dynamics in the context of ischemic stroke (194) or neuro-
of the temporo-occipital sulcus during reading of written degenerative diseases such as primary progressive aphasia
stimuli (112). (448). Indeed, it is now well established that lesion-induced
impaired distributed processing, characterized by within-
While activation fMRI is useful in identifying “functional network abnormal coupling, is associated with neurologi-
module” [even if it has greatly reinvigorated the outdated cal impairments, for example, in the motor or the language
quest of cerebral localization (111)], they do not interrogate domain (e.g., Ref. 329). In the same way, connectivity anal-
how brain regions interact during a particular behavior, a yses provide important clues on the physiological effects of
process which is known as functional integration. More cognitive rehabilitation in brain-damaged patients, by
specifically, functional integration reflects the fundamental showing how functional coupling between problematic ar-
neurophysiological principle according to which segregated eas can be “restrengthened” by targeted therapeutic inter-

ventions, up to sometimes complete normalization in pa- infant brain (124, 170), include without being exhaustive
tients with good functional recovery, or by identifying the the motor, visual, auditory, attention, executive, salient,
physiological patterns of connectivity redistribution that and default mode networks. The latter has been the target
appear to be maladaptive in patients with unsatisfactory of an unprecedented number of publications because, con-
functional recovery. trary to other networks that greatly overlap with the func-
tional networks identified during task-based fMRI experi-
In summary, task-based fMRI is a very popular and afford- ments (126, 468), it is characterized by a couple of distrib-
able method capable of capturing two dimensions of brain uted areas that are functionally deactivated during
processing, namely, segregation (specialized processing) constrained, goal-directed behavior (61, 195, 387, 388,
and integration (distributed processing). However, as re- 475). The default mode network mainly comprises the ven-
called by Friston (175), “functional segregation is only tral precuneus and the ventral posterior cingulate cortex,
meaningful in the context of functional integration and vice the lateral posterior parietal cortex, the medial prefrontal
versa.” Furthermore, it is conceivable that the more special- cortex, and the lateral temporal cortex. Current research
ized the process is, the more important segregation is, while suggests that the default mode network maintains a wide
the more complex the process is (e.g., cognitive flexibility), range of highly integrated, but self-directed and auto-
the more prominent distributed processing is. In other referential processes (i.e., internal cognition) (201) such
words, integration of local and distributed processing is an as, for example, mind-wandering (i.e., stimulus-indepen-
inherent characteristic of functional brain architecture, but dent thought) (13, 14, 275, 321), self-projection and self-
the weight of each of this physiological mechanism is cer- referential decision (13, 62, 451), social cognition (318,
tainly process-dependent. 420), or more generally self-awareness (106, 384). Inter-
estingly, dysfunction of the default mode network has
B) RESTING-STATE FMRI. Cerebral areas that frequently work to- been identified in a plethora of reports across a wide
gether form a functional circuit with a high level of ongoing, range of neurological conditions characterized by abnor-
strongly correlated spontaneous neural activity, even at rest mal internal cognitions (16), such as schizophrenia (356),
when individuals are not engaged in goal-directed behav- autism spectrum disorders (18, 508), or Alzheimer dis-
ioral activities (169). Resting-state fMRI provides a tech- ease (63, 196) among many others.
nique with which to measure functional connectivity (i.e.,
temporal correlations between time-series of anatomically In recent years, the coupling between resting-state func-
distributed regions) from spontaneous resting-state fMRI tional connectivity and behavioral measurements has dem-
low-frequency oscillations. Functional connections at rest onstrated the behavioral relevance of the intrinsic func-
were first demonstrated by Biswal et al. (43) in the motor tional networks in a number of cognitive domains in
domain (i.e., functional synchronization within and across healthy individuals, such as general intelligence (131, 435,
the sensorimotor cortex), and rapidly observed in other 446) or executive functions (394), as well in patients. In the
studies between areas forming the typical human task- latter case, for example, abnormal resting-state connectivity
based functional networks, in particular the language, au- has been repeatedly associated with poor cognitive func-
ditory, and visual networks (44, 92, 100, 109). Collectively, tioning in schizophrenia (433) or in multiple sclerosis (401)
these findings have led to the assumption that when the among other conditions. Thanks to the development of
brain is resting, it remains however peaceless (231), and the both user-friendly toolboxes and neuroimaging data shar-
patterns of observed resting-state correlations may reflect ing projects (such as the Human Connectome Project),
the stable and intrinsic architecture of the brain (63, 169). other interesting methods have been recently built with the
Not surprisingly, a number of studies suggest that these aim of establishing the role of the human functional net-
long-range functional connections are supported by axonal works in cognition via to the study of patients affected by
connectivity (197, 227, 228, 239, 240, 273), even if the sudden damage; “lesion network mapping” is one of these
relation between functional connectivity and structural emerging methods (167). Based on the resting-state func-
connectivity appears not to be always straightforward; in- tional connectivity data sets from numerous, well-charac-
deed, although most the cortical areas forming the resting- terized healthy individuals, it first consists of computing
state networks share direct WM connections (229), func- functional connectivity from the lesion locations causing
tional connectivity can be sometimes measured between the same clinical symptoms using standard seed-to-voxel
weakly interconnected areas (101) or even between the two analyses (i.e., which voxels are connected to the lesion).
cerebral hemispheres in the event of total callosotomy Then, the obtained “lesion functional network maps” are
(476). overlapped with the intent of identifying common pat-
terns of functional connections across patients. This
The analysis of resting-state fMRI data sets has repeatedly method has been successfully applied to disambiguate the
led up to the unmasking of a number of resting-state net- possible network basis of disorders of volition (112) or
works, irrespective of the methods employed to map them. bodily awareness (215), coma (159), bradykinesia (256),
These networks, which appear to be already present in the though cautions must be taken in interpreting the results

as no direct relationship is established between the iden- A key achievement of the HCP project was the recent estab-
tified network and the clinical sign. The key benefit here lishment of a comprehensive parcellation of the human ce-
is that there is no need to perform fMRI acquisitions in rebral cortex, based on multi-modal MRI (187) (FIGURE 1).
patients. More specifically, this semi-automated parcellation (180
areas, of which 97 are new), derived from the average data
A more causal application of “lesion network mapping” is of 210 participants, is built on the basis of myelin maps,
to combine resting-state functional analyses and direct cor- cortical thickness, task-related activation and functional
tical electrostimulation (see sect. IIID2 for a focus on direct connectivity maps, and rs-fMRI. Remarkably, in this study,
electrostimulation). Briefly, whole-brain seed-to-voxel a fully automated machine-learning classifier was able to
functional connectivity maps are computed from the ana- detect in a new sample of 210 participants more than 96%
tomical sites associated with a deficit-of-interest during cor- of the previously identified cortical areas, replicate the orig-
tical stimulation allowing to determine which cortical areas inal parcellation map, and, importantly, identify cortical areas
are coupled with the location of the stimulation sites. The in participants with atypical topographic areal organization.
Among many other achievements, the HCP data set has also
resulting functional connectivity maps can be contrasted to
enabled to capture the strong interindividual differences in the
other maps generated from the location of sites associated
functional connectome. For example, recent studies based on
with a different deficit to demonstrate specificity. In a very
HCP participants showed that functional connectivity profiles
recent study, it was shown that anatomical locations asso-
can be viewed as functional fingerprints that can be accurately
ciated with an impairment of face mentalizing was specifi- used to identify individuals across a large sample of partici-
cally coupled with a network of cortical areas that perfectly pants, whether or not they are engaged in some cognitive ac-
matched with that identified in meta-analyses of functional tivities (11, 158). Furthermore, this individual fingerprinting
activation data (523). This illustrates well how the mixing of functional connectivity seems to be behaviorally relevant. In
of two approaches (i.e., lesion model and resting-state func- the study by Finn et al. (158), although the identification of
tional analysis) can be used to map behaviorally relevant individual subjects based on whole-brain matrix was accurate,
functional networks, by transcending the limitations inher- individual differences in the functional connectivity of the
ent to each technique. fronto-parietal network were especially predictive of behav-
ioral variations in fluid intelligence measured with the Raven’s
C) THE HUMAN CONNECTOME PROJECT: STYLE. Here we wish to spend Progressive Matrices.
a short time to describe the advances made in our under-
standing of the human connectome thanks to the Human 3. PET imaging
Connectome Project (HCP) initiative. The HCP is a highly
funded project awarded by the National of Institutes of In the preceding paragraphs, the review was mainly focused
Health practically 10 years ago (485). The announced and on fMRI as a unique approach to map the functional net-
very ambitious objective was to acquire large-scale and works of the brain. Here, our aim is to promptly establish
high-quality MRI data sets and build cutting-edge neuroim- the merits of molecular imaging, in particular PET (positron
aging tools for mapping the human connectome (i.e., the emission tomography) imaging, as an additional method to
functional and structural connections of the brain). In a gain valuable data into the functional connectome. Histor-
recent article, an overview of the progresses made by the ically, PET approach to imaging cognitive processes has
HCP over the latter decade was given (188); this mainly been used in the 1880s, especially to identify patterns of
included the development of MRI acquisition protocols, the cerebral activations associated with reading words (373),
visual imagery, or lexical access (for a review, see Ref. 379).
gathering of an impressive collection of high-quality and
In addition, this is with PET imaging that the default mode
freely shared neuroimaging data, the development of pub-
network was formally identified in the early 2000s (439). In
licly neuroimaging and informatics tools, and most impor-
brief, activation PET imaging allows to identify task-in-
tantly maybe the establishment of a HCP-style paradigm for
duced changes in glucose metabolism, these changes reflect-
data acquisition and analysis considered as a significant ing local brain activity (509). Different radiotracers can be
alternative to traditional neuroimaging approaches. Re- considered, with 18F-fluorodeoxyglucose (FDG) being to-
garding the latter point, the HCP-style paradigm is thought day the most used in the context of cognitive neuroscience
to optimize MRI analyses by better integrating constraints and neurology because it provides a reliable indication of
related to human brain anatomy and physiology. Relevant the glucose rate consumed by the neuronal tissue (491).
to the topic of this review (see sect. VIIA), the HCP-style
paradigm includes an areal-feature-based registration that Due to both its especially invasive nature (ionizing radiation)
is able to compensate for individual variability across sub- and its lower spatiotemporal resolution, activation PET imag-
jects without using a data blurring approach (such as data ing has been largely superseded by fMRI as early as 1990s.
smoothing), which is a major advantage given the strong However, we are witnessing the revival of this imaging modal-
interindividual differences in gyral-level anatomy due to ity, as significant methodological developments have been re-
genetic and environmental factors. cently made (521), and PET imaging has certainly some ad-

FIGURE 1. Multi-modal parcellation map derived from the human connectome project (HCP) data set. This
semi-automated parcellation map is composed of 180 areas by cerebral hemisphere. RSC, retrosplenial
cortex; PSL, perisylvian language area; SFL, superior frontal language area; LIPv, lateral intraparietal (ventral);
POS, parieto-occipital sulcus; A1, primary auditory cortex; V1, primary visual cortex; MT, middle temporal
area. [From Glasser et al. (187), with permission from Springer Nature.]
vantages over fMRI (e.g., lower sensitivity to neurovascular other imaging modalities (especially fMRI), MEG has been
coupling among others). In particular, it is now possible to traditionally used much less frequently in cognitive neuro-
construct maps of the metabolic connectivity (285) similar to science presumably because of the complexity of the em-
those constructed with the time-series from BOLD fMRI. The ployed methodologies to extract the relevant MEG signals
computed maps reflect how the metabolic rate of glucose co- that are inherently rich and complex (22). MEG has the
varies between different interacting areas. Metabolic connec- advantage to noninvasively assess the large-scale electro-
tivity can be modeled using different methods such as indepen- physiological activity of the brain with a submillisecond
dent component analysis, sparse inverse covariance estima- temporal resolution not reached by other technologies, even
tion, and graph theory (521). For example, in a recent study if it is at the expense of spatial resolution which is rather
using both FDG-PET and rs-FMRI, metabolic and functional limited but superior to other electrophysiological methods
connectivity analyses were performed to assess the relation- such has EEG (see below). In short, MEG is based on the
ship between local glucose consumption and functional con- magnetic induction generated by the electrochemical cur-
nectivity of the default mode network (seed-based correlation rents propagating within and between neurons, whose
approach) (368). The obtained maps were very close from a strength can be remotely measured by specific devices (23).
topological standpoint, as evidenced by the results from a con- MEG is thus especially suitable for studying brain-wide
junction analysis. These interesting findings suggest a close electrophysiological dynamics during task-based or task-
relationship between metabolic activity and functional con- free paradigms.
nectivity, demonstrate the relevance of metabolic connectivity
for the mapping of human functional networks, and provide In recent years, the development of user-friendly toolboxes
insights into the energetic principles of whole-brain connectiv- [e.g., Brainstorms (457)] aiming to facilitate MEG signal
ity (i.e., the physiological basis of BOLD fMRI). processing according to various methodological ap-
proaches has encouraged the use of this imaging modality to
4. MEG map dynamically the brain activity associated with some of
the main cognitive systems, such as for example language
MEG is an already old technique since it was developed (121, 216, 299), semantics (381, 383, 440, 495), mentaliz-
shortly after the mid-20th century (87). Comparatively to ing (47, 499), or even conscious processing (37). Alterna-

tively, MEG has proven to be an effective means to char- neural activity (390). Rather, since TMS excites neurons in
acterize human resting-state networks with a high degree a suprathresholded fashion, it can be used to actually in-
of topological similarity when compared with those ob- duce neuronal activity, enabling to quantify circuit proper-
tained with fMRI, demonstrating its interest for the study ties, e.g., excitability and connectivity, or to interfere with
of functional connectivity (58, 234). MEG has also been ongoing spontaneous or task-related neural activity by gen-
regularly used to assess the degree to which neurological erating a virtual lesion (442).
conditions affect brain connectivity, such as in brain tu-
mors (26), Parkinson disease (500), or dyslexia (410), to 2. Direct electrical stimulation of cortex and WM
predict the epileptic locus in pediatric or adults present- fibers
ing with epilepsy (25, 351, 359, 513), or to generate
“road maps” of functional cortical areas for surgery pre- Remarkably, invasive direct electrical stimulation (DES) is
planning (304). currently the sole method that permits a real-time investi-
gation of the function of both the cortices as well as the
subcortical WM fibers in humans (136). The principle is to
D. Neurophysiology achieve online structural-functional correlation in awake
patients, by using DES (biphasic electrical current, 60 Hz, 1
As mentioned in the previous paragraph, although the aim ms, 1– 4 mA) which mimics a transitory virtual injury. The
of functional neuroimaging is to correlate specific spatio- aim is to perform an individual cortical and axonal map-
temporal activity patterns with certain brain functions, ping. This intraoperative mapping permits to ascertain
these techniques are not able to determine whether the ce- whether neural structures that have to be surgically excised
rebral structures mapped are essential for the correspond- for tumorological (e.g., invaded by a glioma) or epilepto-
ing cognitive functions. In contrast, brain stimulation meth- logical reasons are still necessary for cognitive and behav-
ods can interfere with a specific neural pattern, by inhibiting ioral functions. In fact, DES of essential structures causes a
or potentiating a population of neurons, to demonstrate transient disruption of the testing continuously performed
whether it is necessary (even if it could be not sufficient) for by the patient into the operating room: these sites, which
a certain cognitive function to be normally expressed. In are part of a more complex neuronal circuit, must be spared
other words, such a stimulation is capable of identifying to preserve the patient’s quality of life (139). Thus DES
the critical, non functionally-compensable structures gives a unique opportunity to map directly the human con-
within a large-scale network, by evidencing their actual nectome, in real-time in vivo. In clinical practice, this
behavioral relevance. Indeed, electrical stimulation may method that allows to maximize surgical resection up to
disrupt neural activity by changing the voltage gradient individual functional limits (136), has extensively been val-
across the neuronal membrane (498). When the current idated as an easy, reliable, reproducible and safe mapping
crosses neurons, it can modulate their membrane poten- technique. DES is currently the gold standard in glioma
tial and trigger responses. Two kinds of technique exist: surgery (110).
noninvasive transcranial brain stimulation and invasive
direct electrical stimulation of the cortical and subcorti- From a neurophysiological point of view, DES transito-
cal structures. rily interacts locally with a discrete cortical or subcortical
zone, but also nonlocally, because the focal perturbation
1. Noninvasive transcranial brain stimulation will indeed disrupt the whole corresponding subnetwork
(314). This means that DES does not cause only a “focal
Because the initial technique of transcranial electrical lesion” limited to the area stimulated, but possibly gen-
stimulation was painful, it was replaced by painless non- erates a dys-synchronization within a cortico-subcortical
invasive transcranial brain stimulation (NTBS), that is, subnetwork underpinning a specific process. In other
transcranial current stimulation (TCS) and transcranial words, on the contrary to functional neuroimaging, DES
magnetic stimulation (TMS). NTBS can be used “offline” is capable to identify the structures that are truly essential
or “online.” In the “offline” approach, NTBS can evoke for brain functions, in particular concerning WM tracts,
long-term potentiation-like or long-term depression-like by inhibiting a specific pathway during a few seconds,
plasticity. Accordingly, it will potentiate or inhibit a dis- with the possibility to confirm whether the same func-
crete cerebral site before a cognitive task or neuroimaging tional disturbances are reproduced when repeated DES
mapping. In the “online” approach, NTBS is performed are applied over the same zone. Importantly, by gather-
during a cognitive task or neuroimaging to assess its imme- ing all cortical and axonal areas where the same kind of
diate consequence on cognitive processes or neural activity dysfunction has been elicited by DES, it is possible to
(39). Although the principle of TCS is to pass the electric build up the subnetwork of the disrupted process. In fact,
current directly through scalp and skull, TMS bypasses the by associating the neurological disorders caused by intra-
scalp and skull by generating a magnetic field that elicits an surgical DES with the anatomical data provided by post-
electric current in the CNS. TCS is mainly capable to mod- operative MRI, reliable structural-functional relation-
ulate the level and timing of spontaneous or task-related ships have been achieved with a great precision (~5 mm),

allowing to elaborate first atlases of the structures that probe eloquent neural circuits such as sensorimotor, lan-
are crucial for cognitive and behavioral functions (415, guage, and cognitive networks (322).
459).
To sum up, DES is presently the only technique capable to V. THE CONNECTOME REVISITED:
map directly the functional role of the WM fasciculi in the NEURAL FOUNDATIONS
human brain. Evidence gained from this method has there- UNDERPINNING THE MAIN
fore a great value in cognitive and clinical neurosciences in FUNCTIONAL SUBSYSTEMS
general (116).
Such advances in structural and functional brain mapping
3. EEG/electrocorticographic recordings techniques have resulted in an improved knowledge of the
neurobiology underlying the main human functional sys-
EEG has regularly been utilized to noninvasively explore tems. Here, as a first step, the aim is to review what we have
the human brain, especially owing to the use of event- recently learned about the neural bases mediating each spe-
related brain potentials (ERP). Indeed, ERP represent cific functional pathway, with a special focus on the con-
small parts of the continuous EEG recording that are nectional anatomy that allows functional exchanges within
elicited in response to stimuli (38). Despite an excellent and between these systems.
temporal resolution, EEG/ERP has inherently low spatial
resolution and suffers from low signal-to-noise ratio as
well as poor sensitivity. In contrast, the invasive method A. Sensorimotor Cognition
of electrocorticography (ECoG) provides brain signals
with a very high signal-to-noise ratio, with less suscepti- Humans act purposefully on their environment. To perform
bility to artifacts than EEG, a high spatial resolution (less voluntary actions, a range of cerebral processes, regrouped
than 1 cm), and a high temporal resolution (⬍1 ms) under the umbrella concept of motor cognition (250), are
(233). ECoG allows measurement of electrical brain sig- needed to be succeeded, including general and motor inten-
nals by means of electrodes that are implanted on the tions, action planning, initiation, and action control. Al-
cortical surface. ECoG amplitudes in certain frequency though the cortical network involved in deliberate actions,
bands provide valuable data regarding task-related activ- including speech acts, are relatively well known, recent data
ity, for example, during motor movement (337), auditory obtained with electrostimulation mapping have permitted
processing and speech (82), or visual-spatial attention to gain a more complete picture of the neural circuitry un-
(200). Most of these spectral changes in cortical surface derlying action initiation and control, a network which is
potentials are captured in the high-frequency gamma far more complex than initially expected. Beyond the pyra-
range (~70 –110 Hz), explaining why gamma oscillations mid tract, running from the primary motor cortex to the
activity has been proposed as a robust marker of local spinal cord, that allows motor commands to be executed,
cortical function. In addition, ECoG can investigate func- another part of the circuit rather participates in the control
tional connectivity and resolve finer task-related spatial- of the action being performed (391). This motor subpath-
temporal dynamics (233). Beyond functional connectiv- way, which courses anterior to the corticospinal fibers, is
ity, which is inferred when spatially disparate neurophys- constituted by the supplementary motor area and the lateral
iological events appear to be temporally related, this premotor cortex, these areas being interconnected with the
technique can also study effective connectivity, which head of the caudate via the fronto-striatal tract (269). The
refers to the causal influence between brain regions, by caudate nucleus is an input of the deep gray nuclei, which
recording evoked responses using ECoG during DES. play a key role in both initiation and execution of volun-
Three kinds of evoked potentials may be generated by tary movements and the inhibition of competing move-
DES: 1) cortical evoked potential, called direct cortical ments. Some of these projection fibers also travel to the
response, when recording the cortex at the stimulation anterior arm of the internal capsule (427). An additional
site; 2) cortico-cortical evoked potential, when recording part of the network courses posterior to the primary
the cortex at a remote area from the stimulating site: they somatosensory tracts, with interconnections between
are induced by physiological propagation through WM precentral and retrocentral subcircuits via U fibers pass-
association fibers from the locally stimulated zone to- ing beneath the central region (9). Indeed, the parietal
wards the distant site; and 3) axono-cortical evoked po- lobe is strongly connected to the frontal premotor areas
tentials, when the cortex is distally recorded from a DES (156) and is implicated in motor functions, as revealed by
site at the level of the WM (497). While limited to pa- cortical electrostimulation and lesion studies (163). It is
tients undergoing brain surgery with intracranial elec- also of interest to underline the role of the frontal aslant
trodes, DES with ECoG recording, possibly combined tract (81), which provides dense intralobar connections
with noninvasive EEG recording over the contralateral between the supplementary motor area (pre- and proper)
hemisphere (51), opens a new window to investigate in- and the inferior frontal gyrus, in action and speech initi-
ter-areal connectivity in the living human brain and to ation. A transient disruption of this pathway can lead to

speech (speech arrest or stuttering) or movement initia- similar way, growing but still indirect evidence suggests that
tion disturbances (265, 269). the ventral infero-lateral network may carry out important
information in the service of the semantic system, support-
ing the observations made in certain neurodegenerative
B. Visual and Spatial Cognition conditions such as semantic dementia or the semantic vari-
ant of primary progressive aphasia; in both neurological
After the visual information arrives in the occipital pole via diseases, patients usually show semantic impairments along
both the optic tract and the optic radiations, it is then pro- with severe temporal atrophy of both the anterior temporal
cessed by the inferolateral occipito-temporal pathway structures and the white matter fibers forming the left ILF
within which signal transmission is supported by the ILF. (1, 5, 102, 472). Indeed, microstructural properties of the
This WM connectivity, which interconnects the occipital left ILF have been shown to predict success in verbal seman-
and temporo-occipital regions with the lateral and medial tic learning (399) and the richness of semantic autobio-
part of the temporal pole (78, 258, 280), broadcasts critical graphic memory (236).
information for visual cognition in general, and for object
recognition in particular (225). The current literature in- Lastly, it is worth mentioning that disruption of the ILF,
deed suggests that disruption of this tract by both neuro- particularly in the right hemisphere, has been associated
modulatory lesioning methods (85, 312) and sudden le- with both basic emotion recognition (374) and what is
sions, such as hemorrhagic stroke (328), causes visual hemi- called hypoemotionality (160), i.e., “a modality-specific in-
agnosia. ability to become aroused by visual cues” (35). This sug-
gests that functional connectivity permitted by the ILF fi-
By virtue of its connections between both the occipital and
bers between the occipital cortex and the amygdala (the
fusiform faces areas (face-selective regions), and the ante-
latter having an established role in emotion recognition and
rior temporal structures (189), the network supported by
regulation) is crucial for accessing the emotional content
the right ILF has been posited to play a prominent role in the
from visual scenes.
face processing network (93, 225). As a matter of fact,
patients with congenital or a progressive prosopagnosia
Alternatively, the pathway involved in spatial cognition and
(i.e., an inability to recognize familiar faces) typically show
attention is more dorsally located and is composed of two
abnormalities within this pathway (199, 466) or, more lo-
distinct but complementary systems (91, 502), both of
cally, at the level of the WM fibers emanating from the
which are identifiable in the spontaneous neural activity at
fusiform face area (189, 447). The involvement of the right
rest (168, 169). A dorsal subpathway may be concerned
ILF has been further confirmed by more indirect, correla-
with voluntary, goal-directed allocation of attention to-
tional studies conducted in healthy participants where mi-
crostructural properties of the tract were associated with wards specific locations or features, whereas a ventral at-
face recognition performances (235, 236, 477). tention subpathway may be rather engaged during the re-
orientation of attention towards unexpected, but behavior-
In the left hemisphere, the inferolateral occipito-temporal ally relevant stimuli. From an anatomical viewpoint, it is
pathway is rather related to reading, lexical retrieval, and now well established that the dorsal subpathway is formed
semantic processes, in accordance with the well-established by dorsal fronto-parietal areas, including the dorsolateral
left hemispheric dominance for language processing. First, prefrontal cortex, the frontal eye field, and the superior
the visual word form area, a word-specific selective area parietal lobule; it is likely that layer I of the SLF connects
located in the fusiform area (112, 113), which is associated together these dorsal areas (27, 28). In contrast, the ventral
with pure alexia when damaged (220), is likely to receive subpathway is rather constituted by the inferior frontal
cortical projection from the ILF (149). A disruption of the gyrus, dorsolateral prefrontal cortex, and the inferior pari-
ILF fibers connecting the occipital pole and the visual form etal lobule extending to the posterior temporal cortex; these
area (i.e., the posterior ILF) constitutes the pathophysiolog- areas are interconnected by the layer III of the SLF (28). In
ical mechanism conducting to pure alexia in neurosurgical agreement with the hemispheric dominance of the right
patients (149, 529). Moreover, individual variations in the hemisphere for visuospatial processes, the ventral attention
structural properties of the ILF, but bilaterally, predict network appears to be right-lateralized while the dorsal
word reading fluency and comprehension in individuals attention network is more bilateralized. Interestingly, the
with normal intelligence. SLF II that has cortical projections in both networks (305,
423) would play a central role in maintaining functional
At another level, recent studies suggest that the left ILF may exchange between them. This crucial implication is per-
be concerned with lexical retrieval, as electrostimulation fectly illustrated by the fact that damage of this WM tract,
(224) or lesion-related damage to this tract (221, 327) in- either by DES (464, 481) or by acute lesions (462), leads to
duces pure anomia or more generally naming difficulties, severe spatial neglect. Alternatively, some of the IFOF lay-
demonstrating that occipito-temporal transactions are cru- ers may also participate in the functional integration of the
cial in assessing the phonological form of a word. In a ventral and dorsal attention networks. Indeed, the IFOF is

organized in two layers (209, 414), or even more layers inferior temporal gyrus (320), a cortical node implied in
(515), that project in cortical areas involved in spatial phonological processing devoted to visual material, as well
awareness, such as the posterior DLPFC, the superior pari- as in semantic processing (494). The superficial component
etal lobule, and the angular gyrus. Therefore, some of these of the dorsal route is underlain by the lateral part of the SLF
layers could be devoted to some aspects of spatial attention, III (called also horizontal component of the AF) and is ded-
especially those linking the ventrolateral prefrontal [called icated to articulatory processing. Indeed, this tract links
the IFOF-III (515)] or the posterior DLPFC [that is, deep both the supramarginal gyrus and the posterior part of the
layer (209) or IFOF-IV (515)] to the posterior parietal cor- superior temporal gyrus, both of them receive feedback
tex (namely, the superior parietal lobule and angular gyrus). data from somatosensory and auditory regions, with the
Indeed, spatial neglect has been already reported after ventral premotor cortex (320), which receives afferences
chronic or transitory breakdown of the right IFOF (479). from the posterior regions allowing phonological/phonetic
data to be translated into articulatory motor programs
(180). During word repetition, this subcircuit also supports
C. Language and Semantics
the conversion of auditory inputs, which are processed in
the verbal working memory system, into phonological/ar-
The combined use of functional neuroimaging and neuro- ticulatory representations in the ventral premotor cortex.
physiological methods as well as neuromodulatory and le- This agrees with recent findings gained from cortical DES
sion approaches has revealed that language and semantic (map based on 771 stimulation sites), which evidenced that
processing is performed by a dual route (142, 232, 417). Broca’s area is not the speech output area, as previously
thought (459). Of note, the FAT is also involved in speech
First, the subnetwork underlying visual language consists of
initiation as well as in speech control (119, 269). On an-
a ventral subpathway, which is devoted to processing visual
other level, syntactic processing is mediated by a subcircuit
information into meaning (semantics), and a dorsal sub-
constituted by a number of distributed cortical areas includ-
pathway, rather involved in mapping visual information to
ing left inferior frontal and posterior temporal cortex, con-
articulation via visuo-phonological conversion (142, 232).
nected by a subcomponent of the left SLF/AF complex
The input is supported by the optic tract that sends primary
(525). This subnetwork interacts with but is independent of
visual signals to the occipital cortex, allowing visual percep-
the subpathway supporting phonological processing as re-
tion. Then, the posterior portion of the ILF forwards the
vealed by double dissociation between disruption of syntac-
visual information from the visual cortex to the fusiform
tic and naming processes during DES.
gyrus, either in the visual word form area in the left hemi-
sphere if the perceived object is a letter or a word, or in the
The ventral route, which has a more bilateral distribution, is
object word form area in other cases. These functionally
selective areas enable the perceived object to be recognized. composed of a direct WM subpathway, the IFOF, and an
Axonal DES studies have provided evidence for these disso- indirect subpathway supported by both the anterior ILF
ciated pathways within the left occipito-temporal WM, by and the UF (141). The IFOF, that links the occipital lobe,
showing that stimulation of the lower portion of the poste- superior parietal lobule, and fusiform gyrus with frontal
rior ILF causes pure alexia while stimulation of the upper regions, including the inferior frontal gyrus and dorsolat-
portion rather leads to anomia (83, 183). From this ventral eral prefrontal cortex, plays a pivotal role in verbal and
epicenter, the language network diverges into two parallel nonverbal semantic processing. Electrostimulation of this
but interconnected streams that usually process simultane- circuit generates semantic paraphasias in left hemisphere or
ously, not serially: the dorsal phonological stream and the nonverbal semantic impairments in both the left and right
ventral semantic one (417). The dorsal route, typically left- hemispheres (140, 222, 223, 347). The indirect pathway is
lateralized in right-handed individuals, is underpinned by formed by the anterior part of the ILF that links the visual
the SLF which is formed by two subcomponents with dis- object form area and the temporal pole. The latter area
tinct roles (84). The deep component, corresponding to the constitutes a semantic node enabling plurimodal integra-
classic AF (termed also fronto-temporal part of the AF), tion of the multiple semantic-related signals originating
provides connections between the posterior temporal struc- from the unimodal systems (238, 279). Then, the informa-
tures (mainly the middle and inferior temporal gyri) and the tion is relayed by the UF (139), which connects the temporal
inferior frontal gyrus (mostly the pars opercularis and tri- pole with the pars orbitalis of the inferior frontal gyrus
angularis) (320), but also in the most ventral part of the (208, 266, 501). Beyond semantic processing (207, 236),
posterior dorsolateral prefrontal cortex. Its injury induces the indirect subpathway is also involved in proper name
classically conduction aphasia which is characterized by retrieval, especially the UF (363), as well as in lexical access,
repetition disturbances along with phonemic paraphasia especially the anterior part of the ILF (221, 224). Of note,
(40, 120, 139, 307), and its microstructural properties the MdLF, that interconnects the angular gyrus with the
(522) or its leftward lateralization (284) predicts phonolog- superior temporal gyrus up to the temporal pole, might also
ical abilities in healthy individuals. Of note, one of the pos- be part of the ventral semantic route (306); however, this
terior cortical target of this tract is the posterior fusiform/ involvement is to date not established (FIGURE 2).

Participation in
Control
Supplementary
Caudate nucleus
Motor Area
Speech Output
Primary Motor
Link with area
executive functions
Dorsolateral Link with

Prefrontal Ventral Premotor Cortex working memory
cortex Anterior insula
Supramarginal gyrus
Orbito-frontal
area
Frontal Dorsal Phonological Stream
Postero-superior
Operculum Temporal Area Angular
Gyrus
Syntactic processing
(through the dorsal stream)
Syntactic processing
Postero-middle (through the dorsal stream)
Temporal Area
Ventral semantic stream Posterior-inferior Temporal

Visual
Area
Temporal Pole Areas
(Visual Object Form Area) Visual
recognition
Arcuate fasciculus (deep layer of the superior longitudinal fasciculus) Uncinate fasciculus
Lateral portion of the superior longitudinal fasciculus (anterior part) Frontal aslant Tract
Visual input
(optic radiations)
Lateral portion of the superior longitudinal fasciculus (posterior part) U-fibers
Inferior fronto-occipital fasciculus
Inferior longitudinal fasciculus
FIGURE 2. The dual-route model of language processing. This model is based on double anatomo-functional
dissociations obtained with cortico-subcortical electrostimulation during a naming task (visual input). See text
for a comprehensive description. [Adapted from Duffau et al. (142), with permission from Elsevier.]
To sum up, information preprocessed by the visual recog- anatomical properties and working memory performances
nition system is subsequently treated by the semantic system have been reportedly described in healthy participants, both
in parallel to the dorsal phonological route, under the con- in adults and infants (104, 356, 400, 438, 458, 492). In
trol of the executive system. It is worth noting that we have addition, tumor-related damage of the SLF is known to
insisted on the language system with visual input. However, affect working memory performances (270). Likewise, DES
a similar dual-stream model has also been reported with of the lateral part of the SLF impairs span task performance,
auditory stimuli (232). a typical behavioral paradigm to assess verbal working
memory abilities (360). Lastly, integrity of this frontopari-
D. Working Memory etal connection has been related to verbal working memory
impairments in recent-onset schizophrenia patients (261).
Working memory, a critical feature of cognitive functioning In the spatial domain, a recent longitudinal study combining
facilitating planning, reasoning, and problem-solving (94), activation fMRI and probabilistic tractography showed that
is defined as the ability to temporarily maintain and manip- microstructural parameters (especially fractional anisotropy)
ulate information during the execution of ongoing tasks of both the fronto-striatal and the fronto-parietal connections
and activities (281). Current literature suggests that work- were able to predict spatial working memory performances
ing memory is mostly underpinned by a network of fronto- two years later, suggesting that the efficiency of these white
parietal cortical areas (mainly including the posterior pari- matter tracts are important for the development of this cogni-
etal cortex and both the inferior and middle prefrontal tive ability (105; see also Ref. 271). This agrees with a recent
gyri), potentially interconnected by SLF layer III. This is in lesion study in which postoperative spatial working memory
good agreement with the Baddeley’s model, in which pho- impairments were associated with a damage of both the layer
nological working memory is divided into a phonological I and the layer II of the right SLF (270).
store (mainly involving the left supramarginal gyrus) and an
articulatory rehearsal mechanism that can revitalize the In the more restricted context of language processing, be-
transiently stored information (rather distributed over both cause words are a combination of basic phonemes, the ar-
the left inferior frontal gyrus and the ventral premotor cor- ticulatory fronto-parietal loop would allow the brain to
tex) (21, 369). As a matter of fact, correlations between SLF store transiently the phonological information contained in

a word or even in sentence. Therefore, this phonological UF, a recent systematic review failed to show that this anatom-
working memory is critical for the phonological system, as ical connection has a general role in episodic memory, rather
demonstrated by fMRI investigations. Indeed, in a meta- in associative learning (501). Lastly and in a similar way, evi-
analysis of task-based fMRI studies, phonological working dence for a role of the cingulum in episodic memory is rather
memory has been associated with a fronto-parietal loop, scarce and inconsistent across studies. According a very recent
linking the dorsal part of the pars triangularis to the dorsal meta-analysis (60), although associations have been regularly
part of the supramarginal gyrus (494). This loop also seems found between cingulum fibers and aspects of episodic mem-
to be involved in repetition, which in essence needs to tran- ory in various neurological or neurodegenerative conditions
sitorily maintain the phonological information. DES over (e.g., immediate and delayed visuospatial memory or verbal
the posterior part of the superior temporal gyrus and over episodic memory), the findings have been to date difficult to
the supramarginal gyrus (i.e., the posterior cortical termi- replicate in neurologically intact participants. As a conse-
nations of the lateral part of the SLF as well as the SLF itself) quence, it is unclear in which kind of memory processes the
can generate disturbances in repetition (346, 385, 386). cingulum may be involved.
E. Episodic Memory F. Mentalizing and Social Cognition
While lesion studies have generally identified medial tem- Social cognition refers to the set of cognitive, affective, and
poral (i.e., parahippocampal cortex and hippocampus) and emotional processes involved in the understanding of other
diencephalic (i.e., thalamus) structures as central in the net- peoples’ behavior. Among these processes, mentalizing (or
work supporting episodic memory (429, 453), that is, the theory of mind) and empathy are currently considered as
function by which individuals encode and retrieve daily the main foundation on which social cognition is built
experiences (122), fMRI studies rather suggest that this (291). More specifically, mentalizing is defined as the ability
mnemonic function relies on a large-scale network that is to make assumptions on mental states (such as intentions,
largely modulated by task demands (67, 161, 444). More desire, knowledge, etc.) to both anticipate and predict oth-
specifically, current fMRI literature suggests that this neu- er’s behavior (380). Research inquiry, mainly using fMRI
rocognitive system extends to areas of the temporal, frontal, and the lesion method, has highlighted that mentalizing is
and parietal cortices, the diverse interconnections within performed by a brain-wide neural network extending to
this distributed network supporting different aspects of ep- both the lateral and medial aspects on the brain, including
isodic memory. For example, it is thought that the func- the ventral precuneus/posterior cingulate cortex and the
tional interactions between the prefrontal cortex (in partic- medial prefrontal cortex, the temporo-parietal junction
ular, the ventrolateral and the dorsolateral prefrontal cor- along with the posterior superior temporal sulcus, the tem-
tex) and the medial temporal structures are important for poral pole, and inferior frontal gyrus (177, 318, 341, 441,
the processes of encoding and retrieving (444). Further- 486). Some of these cortical areas are engaged by all men-
more, interactions between the parietal cortex and the me- talizing tasks, irrespective of the mental state under study,
dial temporal structures may be required when attention is while others are more task-specific (73, 341).
needed during a mnemonic activity. In particular, a recent
account of the role of the parietal cortex in memory sug- In agreement with the growing view that mentalizing is
gests that the dorsal aspect of the posterior parietal cortex is functionally multi-determined (418), recent studies have
solicited when attention is directed by retrieval goals, suggested that this social cognition function is rather under-
whereas the ventral aspect of the posterior parietal cortex pinned by several but complementary and interactive neural
mediates attention that is captured by relevant memory cues subnetworks. The participation of each of these compo-
or recovered memory (67; see also Ref. 503). nents is likely to be context-dependent, to the extent that
situations in which individuals are engaged in mentalizing
At the subcortical level, research inquiry is less flourishing. are especially various and complex. This operating princi-
However, important advances have been made in recent years, ple has been probably underestimated because of the highly
the majority of the studies being naturally focused on the white reductionist approach typically employed in activation
matter tracts that directly project in the medial temporal struc- fMRI studies where stimuli are overtly simplistic with a very
tures, especially the fornix, the cingulum, and the uncinate low ecological value. As a matter of fact, anatomo-func-
fasciculus. Not surprisingly, the fornix, a limbic subcortical tional dissociations have been obtained between distinct
structure that allows direct connectivity between the hip- subpathways and mentalizing task performances. In partic-
pocampus and the diencephalic structures (75), is associated ular, damage to the cingulum, linking together two well-
with severe anterograde amnesia when disrupted (4, 68). Its established medial areas of the mentalizing system, is asso-
microstructural properties or its volume correlate with differ- ciated with high-level, inference-based mentalizing or cog-
ent mnemonic processes in normal aging, including delayed nitive empathy (a synonym term for cognitive mentalizing)
verbal episodic memory abilities, spatial learning (237), recol- difficulties in the right (214) and the left hemisphere (219,
lection (206, 334), and source retrieval (107). Regarding the 350), respectively. Alternatively, low-level, perceptive-

based mentalizing is impaired following injury of the peri- VI. A META-NETWORKING MODEL OF
sylvian network, including the AF and the lateral SLF (214). HUMAN BRAIN FUNCTIONS
Interestingly, this dorsal route interconnects cortical re-
gions belonging to the “mirror neuron” network, typically
involved in low-level social cognition processing such as A. Global Integration of Functional Systems
emotional empathy and imitation, including the inferior
frontal gyrus, the supramarginal gyrus, and the superior Despite an improved knowledge of the structural and func-
temporal sulcus. Lastly, a recent study showed that transi- tional anatomy of major functional systems, it is worth
tory lesioning of the right IFOF, which has been previously noting that brain processing cannot be only conceived in a
implicated as an important connectivity for basic emotion segregated view, with parallel networks acting in isolation.
recognition and face processing, caused mentalizing diffi- Rather, a meta-networking framework must be considered.
culties on face-based mentalizing tasks, suggesting that this This view holds that if specialized processes are conceivably
ventral pathway carries important information for mental- underpinned by relatively modular networks, complex be-
izing when visual affective cues have to be processed (524). haviors and cognitions emerge from spatiotemporal dy-
Collectively, these findings suggest that mentalizing is sup- namic interactions between these function-specific systems,
ported by three neural pathways (213), even though this opening the door to important interindividual functional
triple-route model needs to receive further experimental variabilities. In other words, regions of the brain continu-
evidence (FIGURE 3). ously process and exchange functional information at the
service of adaptive, context-specific behaviors (85, 231,
To conclude this section, we propose two illustrations re- 437). In this setting, a meta-network can be operationalized
suming the current knowledge about the topological orga- as a context-sensitive state of between-system integration
nization of the main human functional systems, with a spe- transiently generated to succeed cognitive demanding, func-
cial focus on the WM connections that mediate functional tionally multi-determined behavior tasks. The concept of
exchanges within these systems (FIGURE 4 for the left hemi- “meta-system” has already been proposed by Cocchi et al.
sphere and FIGURE 5 for the right hemisphere). (85) as “transitory, task-induced changes in integration be-
Dorsomedial Cingulum PCC

PFC Precuneus
Ventral SLF III

PMC SMG
posterior
DLPFC Angular
AF Gyrus
IFG Posterior
(triagularis and opercularis) STG
IFOF Occipital
cortex
posterior
ITG/fusa
Medial stream: High-level, inference-based mentalizing

Dorsal stream: Low-level, perceptive-based mentalizing
Ventral stream: Facial emotion recognition
FIGURE 3. Triple-route model of mentalizing derived from lesion and electrostimulation studies. This
anatomo-functional model is mainly derived from causal inferences permitted by lesion and electrostimulation
study (see text). DLPFC, dorsolateral prefrontal cortex; PFC, prefrontal cortex; PMC, premotor cortex; IFG,
inferior frontal gyrus; ITG, inferior temporal gyrus; SMG, supramarginal gyrus; STG, superior temporal gyrus.
[From Herbet and Duffau (213), with permission from Elsevier.]

Medial system RIGHT HEMISPHERE Multimodal inputs
Thalamus Movement control
OUTPUTS
SMA
inference-based mentalizing
Prec. dMPFC
Dorsal system
Spatial attention (dorsal)

SPL Movement initiation FEF Striatum
Spatial attention and visuo-motor processing
Somatosensory Cortex MC
dlPFC
Spatial attention (ventral)
AG
Langage articulation
SMG vPMC
Perceptive-based mentalizing
pIFG
Auditory cortex
Ventral system
pSTG
Emotion recognition/affective mentalizing
Non verbal semantics
pMTG OFC
Visual memory
HIP
Behavioral inhibition
Occipital Pole
Emotion recog.
Visual inputs
AMG
Scene percept.
PPA
Face perception
OFA FFA
Object recog.
LOG pITG ATL
Inferior longitudinal fasciculus Arcuate fasciculus Superior longitudinal fasciculus (layer I)

Uncinate fasciculus Superior longitudinal fasciculus (lateral) Cingulum
Inferior fronto-occipital fasciculus Superior longitudinal fasciculus (layer II) Frontal Aslant Tract
Fronto-striatal tract U-shape fibers Thalamo-Cortical pathways
FIGURE 4. Functional brain networks supported by the left hemisphere. This figure is mainly based on the
anatomo-functional correlations provided by electrostimulation and lesion studies. AG, angular gyrus; AMG,
amygdala; ATL, anterior temporal lobe; dlPFC, dorsolateral prefrontal cortex; dmPFC, dorsomedial prefrontal
cortex; HIP, hippocampus; MC, motor cortex; OFC, orbito-prefrontal cortex; FEF, frontal eye field; pITG,
posterior inferior temporal gyrus; pIFG, posterior inferior frontal gyrus; PPA, para-hippocampal cortex; pMTG,
posterior middle temporal gyrus; pSTG, posterior superior temporal gyrus; Prec., precuneus; SMA, supple-
mentary motor area; SMG, supramarginal gyrus; SPL, superior parietal lobule; vPMC, ventral premotor
cortex; VWFA, visual word form area.
tween brain regions encompassing specialized functional networks (sect. VIC). In other words, the continuous pro-
systems. This cross-systems interaction allows the resulting cess at the service of adaptive behaviors may result not only
meta-systems to support functions that transcend those of in short-term between-system integration transiently gener-
specialized networks.” Here, our goal is to go beyond by ated in response to a specific context, but also in long-term
introducing the concept of “meta-networking” (i.e., net- structural and functional remodeling to succeed cognitive
works of networks), which integrates not only a global demanding, functionally multi-determined behavior tasks
integration of functional systems (sect. VIA) and a dynamic (sect. VIC). Such ability of lasting across-networks archi-
succession of equilibrium states (sect. VIB), but which ex- tecture reshaping may explain the considerable interindi-
tends from the principle of transient changes of relationship vidual anatomo-functional variability (sect. VIIA), and
within and across networks to more long-lasting changes of underlies the mechanisms of physiological neuroplastic-
network properties, including use-dependent plasticity of ity (subserving learning and ontogeny) as well as the

Multimodal inputs LEFT HEMISPHERE
Medial system
Movement and language control Thalamus
OUTPUTS
SMA
Cognitive empathy
dMPFC Prec.
Dorsal system
Spatial attention (dorsal)
Striatum FEF Movement and SPL

language initiation
Visuo-motor processing
MC Somatosensory Cortex
dlPFC
AG
Langage articulation and working memory
vPMC SMG
Phonological processing
Lexical retrieval
pIFG
Ventral system
Auditory cortex pSTG
Verbal semantics
Amodal semantics
OFC pMTG
Proper name retrieval
Visual memory
HIP
Semantics
Occipital Pole
Emotion recog.
Visual inputs
AMG
Scene percept.
PPA
Object recognition
Lexical retrieval
ATL pITG Reading
Reading comprehension VWFA
Inferior longitudinal fasciculus Arcuate fasciculus Superior longitudinal fasciculus (layer I)

Uncinate fasciculus Superior longitudinal fasciculus (lateral) Cingulum
Inferior fronto-occipital fasciculus Superior longitudinal fasciculus (layer II) Frontal Aslant Tract
Fronto-striatal tract U-shape fibers Thalamo-Cortical pathways
Superior longitudinal fasciculus (posterior)
FIGURE 5. Functional brain networks supported by the right hemisphere. This figure is mainly based on the
anatomo-functional correlations provided by electrostimulation and lesion studies. AG, angular gyrus; AMG,
amygdala; ATL, anterior temporal lobe; dlPFC, dorsolateral prefrontal cortex; dmPFC, dorsomedial prefrontal
cortex; HIP, hippocampus; MC, motor cortex; OFA, occipital face area; OFC, orbito-prefrontal cortex; FEF,
frontal eye field; FFA, frontal eye field; LOG, lateral occipital gyrus; pITG, posterior inferior temporal gyrus; pIFG,
posterior inferior frontal gyrus; PPA, para-hippocampal cortex; pMTG, posterior middle temporal gyrus; pSTG,
posterior superior temporal gyrus; Prec., precuneus; SMA, supplementary motor area; SMG, supramarginal
gyrus; SPL, superior parietal lobule; vPMC, ventral premotor cortex.
potential of postlesional compensation in brain-damaged in motor execution, and a more cognitive demanding work-
patients (sect. VIC). ing memory task (i.e., n-back-task) potentially necessitating
the coordination of multiple functional networks. In accor-
A good illustration of the meta-network functioning comes dance with the assumptions developed by the authors, it
from the findings reported in a recently published paper was found that segregated, within-network exchanges were
(88). Using graph theoretical modeling of fMRI data sets, characteristic of motor execution, whereas distributed, be-
the authors assessed the large-scale functional network tween-network integration was critical for working mem-
properties of the brain at rest and during the completion of ory. Moreover, the observed changes from resting state to
two behavioral tasks: a basic sequence tapping task thought task-induced network configurations were predictive of be-
to engage a relatively circumscribed brain network involved havioral performance. Beyond demonstrating that the brain

is able to flexibly reconfigure its brain networks as a func- tem often needs to cooperate with more domain-general
tion of the behavioral task, the reported results strongly systems (e.g., working memory and cognitive control) de-
suggest that complex cognitions are supported by a tran- pending on task demands (154). For example, processing
sient meta-network characterized by a specific pattern of syntactically simple canonical sentences is strongly associ-
large-scale between-system integration, as anticipated by ated with local functional activity within the left inferior
the same research group a couple of years before (118). frontal gyrus, whereas participation of long-range synchro-
Such kind of findings have been replicated in the working nization between the inferior frontal gyrus and the posterior
memory domain (436) but also in others. For example, superior temporal gyrus via the AF in left hemisphere is
dynamic interactions between the default mode network needed for processing syntactically more complex non-ca-
and the lateral fronto-parietal network have been associ- nonical sentences (526), with the intervention of other neu-
ated with rapid memory recollection (164), with a special rocognitive systems when attentional and working memory
role of the dorsal posterior cingulate cortex in facilitating demands increase. On the same line, language switching
this cross-network integration. Other authors have high- abilities in multilingual individuals necessitates the upregu-
lighted the role of between-network integration in the main- lation of the language network by the cognitive control
tenance of attention over time or cognitive control effi- system (comprising the prefrontal, anterior cingulate, and
ciency (437). striatal structures) to select and monitor the required lan-
guage over time; disruption of this physiological interaction
A further question is the extent to which the brain’s ability with direct electrostimulation leads to aberrant and uncon-
to context-dependent network reconfiguration (meta-net- trolled switching between the two language alternatives
work) is behaviorally relevant. Although several fMRI stud- (345).
ies have demonstrated correlations between network inte-
gration indices and variations in behavioral performance, In a recent data-driven meta-analysis study based on 110
the necessary behavioral conditions for shifting from segre- papers, Bottenhorn et al. (53) have sought to identify which
gated processing to highly distributed processing remain functional networks were systematically involved during
poorly understood. In a recent in-depth review, however, the completion of ecological, realistic behavioral paradigms
several interesting paths have been discussed enabling to (versus highly controlled, reductionist paradigms). Using a
partially clarify this issue (437). First, the complexity of the K-means clustering approach, they showed that natural-
employed behavior paradigm seems to be an important pa- istic paradigms were associated with seven recurrent pat-
rameter, as performance on a basic task is associated with terns of functional activations that overlapped with the
segregated processing, whereas performance on a cognitive networks typically involved in sensory input, top-down
demanding task is rather associated with cross-network in- attention control, domain-specific processing (e.g., lan-
tegration (85, 211). This is not surprising given that increas- guage) and motor planning. These important findings
ing difficulty often necessitates the intervention of multiple suggest that the range of flexible, complex behaviors trig-
cognitive abilities, especially working memory, attention, gered by lifelike situations are supported by the integra-
and executive functions. Second, the behavioral distinction tion of neural information coming from distinct but co-
between effortful, goal-directed versus effortless, automatic operating networks.
behavior may be physiologically reflected in the dialectic
relationship between segregation and integration. In a sim- The meta-network theory implies that some cortical nodes
ilar vein, conscious processing may be predictive of integra- with highly connective properties are especially important
tive processing, whereas unconscious processing may be for cross-network integration (55, 366, 367). This is nota-
predictive of segregated processing. All these potential be- bly the case for the medial posterior parietal cortex (203),
havioral constraints reviewed by Shine and Poldrack (437) which is the most densely connected region of the brain, or
offer empirically well-testable hypotheses. for other regions such as the posterior dorsolateral prefron-
tal cortex which receives connections from at least three
Here are just a few examples of this potential physiological associative WM connectivities (IFOF, SLF II and III). fMRI
modus operandi. First, in the domain of language process- studies showed, for example, that the dorsal aspect of the
ing, several direct and indirect cortico-subcortical relatively posterior cingulate cortex (PCC) played a central role in
specialized subpathways, respectively involved in syntactic, coordinating functional transactions between otherwise
semantic, phonological and articulatory processes, have to more segregated networks, especially the default mode net-
work together as a function of the language task to be work and the executive fronto-parietal network (85, 229,
performed (142). This multiple network organization of 269, 286), at the service of efficient cognitive control.
language processing explains double anatomo-functional Other authors have suggested that both the insula and the
dissociations in aphasic patients; lesions damaging the ven- PCC may be of importance in integrating functional ac-
tral pathway are more likely to cause semantic deficits while tivities from the mirror neuron and the mentalizing net-
damage to dorsal pathways is rather associated with im- work for the optimal mapping of social environment
paired phonological and articulatory skills. This “core” sys- (336). In that respect, recent works in social cognition

have suggested that the mentalizing network is in fact As functional integration across distant cortical regions and
composed of several subnetworks (see sect. IVB). Which segregated networks is mainly supported by associative and
cortical regions integrate and balance activities from interhemispheric connectivities, the meta-network theory
these multiple pathways as a function of the current so- predicts that lesion-related cortico-cortical disconnections
cial demands to allow social flexibility are however at the should be associated with marked cognitive impairments.
present time unknown. In that respect, the study by He et al. (210) provided impor-
tant clues. The authors studied the impact of stroke injuries
As mentioned above, the dorsal PCC is currently pointed on both task-based (i.e., Posner paradigm) and resting-state
out as a “central” cortical structure in performing cross- functional connectivity in the acute and chronic phase.
system integration and thus permitting the instantiation of Overall, they found that sudden-onset damage had severe
transient functional meta-systems physiologically reflecting consequences on functional connectivity in both the ventral
the current cognitive demands. If true, it should be expected and the dorsal attention network, even if this disruptive
that damage to this structure impairs a number of highly effect only persisted chronically for the ventral network.
integrated cognitive functions often necessitating coordina- The most interesting finding concerned, however, the inter-
tion of several networks, as previously hypothesized (72, action between functional connectivity, structural discon-
286). However, due to its topographical situation, the dor- nections, and behavior; indeed, the more damaged the
sal PCC is almost never the target of focal damage. The fronto-parietal WM tracts (including WM fibers corre-
current knowledge about the behavioral role of this brain sponding to the SLF II) were, the more disrupted functional
areas is therefore highly correlative in nature because it is connectivity was, and the more severe spatial neglect was.
uniquely derived from fMRI or from the behavior profiles As discussed in more recent papers (e.g., Refs. 28, 462), this
of patients with neurodegenerative diseases where neuronal suggests that damage to the SLF II, which provides cortical
disruptions are at the very least widespread. In that context, projections in associative areas belonging to both the ven-
it is worthy of note that two successive neuromodulation tral and the dorsal attention network, is associated with
studies revealed that stimulation of the WM fibers emanat- severe forms of spatial neglect, allowing these networks to
ing from the dorsal PCC led to an altered but transient state cooperate in normal physiological circumstances. This
of consciousness mainly characterized by a behavioral un- agrees with the conclusions of a recent study combining
responsiveness and a loss of environmental connectedness DTI-tractography and 14 meta-analyses of fMRI data sets
(216, 218). One of the hypotheses developed by the authors which shows that functional integration of the both ventral
(among others) was that the between-system integration and attention networks via the cortical regions intercon-
achieved by the dorsal PCC (i.e., especially between the nected by the SLF II may support flexible behaviors and
default and the frontoparietal networks) was of major im- conscious processing (365). In a similar vein, a recent report
portance for both conscious information processing and showed that WM damage caused by sudden traumatic in-
external awareness. This finding is in agreement with the jury interfered with the dynamical interactions between the
fact that PCC’s functional connectivity is aberrant or absent default mode network and the salient network during the
in patients with altered states of consciousness, including completion of a stop signal task. Moreover, the more dis-
vegetative state (487), anesthesia (48), different sleep states rupted the WM fibers connected to the salient cortical net-
(242), or drug-related states (71), suggesting that functional work were, the more impaired functional coupling with the
exchanges of the PCC with other distributed areas is re- two networks was (252). These findings are reminiscent of
quired for awareness and arousal (286). a previous study published by the same research group
showing that traumatic-related axonal lesions damaging
On the same line, lesion or lesion modeling studies have the WM pathway interconnecting the dorsal cingulate cor-
confirmed that focal disruption of connector or participat- tex and the insulae (the salient network) disrupted the func-
ing hubs, that is, cortical structures that interface with mul- tional inhibition that normally performs the salient net-
tiple functional systems (191), had widespread conse- work over the default mode network during cognitive con-
quences on both global network dynamics (10, 193) and the trol (49). Lastly, in a recent well-conducted study
brain’s ability to efficiently perform cross-network func- performed with 114 stroke patients, it was shown that
tional interactions (146), leading to important behavioral structural disconnection was a better predictor than dam-
impairment (443, 506). These studies also showed that the age to connector, transmodal cortical hubs, in explaining
observed network dysfunction not only concerned the le- patterns of functional connectivity disruption within and
sioned hemisphere but also widely extended to the non- between neural systems (198). Furthermore, this study re-
damage hemisphere. Taken as a whole, these findings sug- vealed a low-dimension relationship between structural dis-
gest that high-level cognitive impairments, not sensory or connection, network dysfunction, and behavioral impair-
motor ones (506), might result from the damage of associa- ments. Collectively, the reported findings suggest that le-
tive areas that flexibility integrate information flows from sion-induced WM disruption has widespread effect on
different networks, as anticipated by Mesulam 30 yr ago between-system integration, with important behavioral
(331). consequences.

Neuromodulation studies using direct axonal stimulations in connectivity patterns are also important features of hu-
that cause, by very nature, an impairment of distributed man neural networks (69). As already evidenced in chemi-
processing (i.e., disruption of functional integration be- cal networks (397), nonequilibrium of these systems is an
tween the different nodes forming a given functional net- important aspect that leads to self-organization and evolu-
work) have provided critical insights into the role of WM tionary processes, as phylogenetics, ontogeny, and learning
tracts in cognition and behavior (136). However, it must be (31). These temporal changes in connectivity can occur at
recognized that, given the nature of the behavioral tasks multiple time scales, from a couple of years in the event of
typically employed (i.e., the behavior paradigms are rela- skill acquisition to a few seconds, and even sometimes less,
tively easy to performed given the constraints imposed by in the event of behavioral adaptation to a novel situation
the simulation time), the behavioral manifestations ob- (190). Indeed, the fMRI literature has long implicitly as-
served during WM stimulations are likely to affect func- sumed that functional connectivity patterns remained sta-
tional integration within relatively segregated functional tionary over time (69, 245), for example, during the com-
networks (e.g., stimulation of the left arcuate fasciculus, by pletion of a behavioral task in the scanner (i.e., leading to
depriving the phonological network from functional trans- average functional connectivity patterns over the relevant
actions between the inferior frontal gyrus and the posterior period of scanning). However, this view was called into
temporal cortex, will lead to phonological paraphasia). question because of the systematic, and sometimes impor-
Having said that, this is certainly not always the case. For tant, variations of functional connectivity both at rest and
example, stimulation of the right SLF II frequently evokes during stimuli processing (87). Nonstationarity of func-
transitory but marked spatial neglect (465), a behavioral tional connectivity patterns in BOLD fMRI is currently re-
syndrome which is likely to be the consequence of a break- ferred to as dynamic functional connectivity (409), a core
down of the functional communication between the ventral component of what has been called the “dynome” (274) or
and dorsal attention networks (29; see above). Likewise, the “chronectome” (69). A number of emerging method-
acute disruption of the functional exchanges carried out by ological approaches have been recently developed in the
the IFOF, bilaterally, is known to impair amodal semantic fMRI literature to capture this time-varying aspect of net-
processing, with most of the time a complete loss of insight work dynamics, such as the sliding window correlation ap-
(347), suggesting dysregulation of the mental flow charac-
proach (527) or the dynamic conditional correlation ap-
terizing noetic consciousness. This latter finding is interest-
proach (292) among others. In other words, these new sta-
ing to consider in the context of the cortical terminations
tistical approaches are meant to assess how “brain states”
provided by the IFOF which are widely distributed in at
(i.e., the whole-brain functional patterns measured at one
least three, otherwise four, cerebral lobes (209, 515), nota-
point in time) varies over time at rest or during the course of
bly in transmodal areas known to act as neural hubs with
behavioral activities. The results gained from these ap-
high level of centrality (e.g., lateral parietal cortex, precu-
proaches generally show that the brain networks are in a
neus, posterior dorsolateral prefrontal cortex) (202, 230).
perpetual dynamic state and that constant variations of
While the physiological counterpart of axonal stimulation
functional connectivity measured with BOLD signals share
on dynamic system-level integration is to date unknown,
some relationships with direct electrophysiological mea-
the coupling of WM stimulation and EEG/ECoG will pre-
sumably allow to better understanding in the next future the sures derived from EEG, ECoG, and MEG (87, 245). For
interplay between associative connectivity, behavior, and example, studies combining EEG and fMRI have shown
“meta-networked” functioning. that EEG microstates, i.e., the succession of momentary but
stable states in the global coordination of neuronal activity
Lastly, it is worth mentioning that dynamic reorganization over time (336), are related to fMRI resting state networks
of network properties may follow age-related or disease- (348).
related changes in neurotransmitters such as dopamine.
Hanakawa et al. (204) have shown decreased dopamine in Even if the field of dynamical functional connectivity is still
Parkinson’s disease patients change network properties of in its infancy, and needs further validation of the methods
multiple and parallel cortico-basal ganglia circuits, thereby employed (245), a range of studies have suggested that mo-
showing both bradykinesia and bradyphrenia in a parallel ment-to-moment changes in functional connectivity, within
manner. and between networks, are behaviorally relevant. In one of
this study reported by Elton and Gao (147), it was shown
that the variability of functional connectivity, measured at
B. Dynamic Succession of Equilibrium three different spatial scales (i.e., regional, within-network,
States and between-network level) decreased from the resting state
to the task state, especially regarding between-network in-
Although between-network spatial communication (meta- teractions. Furthermore, this decrease in functional connec-
networking functioning) appears to reflect the brain’s abil- tivity variability was associated with better performance on
ity to adapt to an often complex and fast-moving environ- a task probing attention abilities. In another study, this
ment, current research suggests that time-varying changes variability at rest, between cortical regions forming the ven-

tral default mode network, was found to positively corre- dynamically (135). In other words, cerebral remodeling is
late with the propensity to mind-wandering, as measured by conceivable due to the existence of multiple and interactive
a daydreaming frequency scale filled outside the scanner, redundant subcircuits (253, 389). It occurs across the lifes-
but not during sensory stimulation, suggesting that nonsta- pan, either physiologically in the setting of development or
tionarity of the default connectivity at rest may reflect stim- learning, or as a compensatory mechanism after cerebral
ulus-independent thoughts (275). Likewise, an increase in injury to support functional recovery.
between-network dynamical functional connectivity, espe-
cially regarding the default and frontoparietal networks, 1. Structural plasticity
was found to correlate with cognitive flexibility (127).
Other works have also demonstrated the relevance of dy- Structural changes of the gray matter can arise, including
namic cross-network reconfiguration for working memory in adults, as evidenced by studies using “voxel-based
and more generally when task demands increase (436). Col- morphometry” (VBM) (17). These morphological modi-
lectively, these findings among others (see Ref. 195 for a fications have been observed for a high number of behav-
review) suggest that the temporal evolution of functional ioral tasks, e.g., motor tasks (54, 128, 192, 249), visu-
connectivity patterns over short time scales, within and be- ospatial tasks (123), spatial memory and navigation (300),
tween networks, at rest or during behavioral engagement, is memory tasks during training in students (128), linguistic
important for cognitive functioning but also for behavior. tasks (325), calculation (19), reasoning tasks (298), creative
Indeed, a recent study using dynamic condition correlation and “artistic” tasks (458), as well as music (226). Such
has shown that psychotic-like experiences were associated macroscopic changes have been reported during simple
with changes in brain-wide network dynamics, especially tasks (192) or more complex tasks (e.g., visuomotor tasks
with brain states characterized by hypoconnectivity of both such a juggling, golf, dance), with controlled tasks or in
the visual and the default mode network (23). In patients ecological conditions [e.g., uncontrolled leisure activities
with major depressive disorders, both severity of depression (42), in the long term, as in London licensed taxi drivers
and recent ruminative thinking were found to correlate with (300) or in the short term (128, 323) and for over-training
more variable dynamical resting-state connectivity in net- or for suppression of a task]. Structural changes can occur
works typically involved in attention and self-referential in young people (128), including children (246), as well as
thinking (257). In the resting state, major changes in large- in elderly subjects (42, 53). Of note, these morphological
scale network dynamics have been also observed in individ- modifications are reversible, with a possible focal reduction
uals with schizophrenia (99, 530). These latter findings sug- of the gray matter in the corresponding areas associated
gest that altered brain network dynamics may participate in with the withdrawal of the task (128, 458). It is not com-
the pathophysiology of cognitive and behavioral abnormal- pletely understood if these changes are related to a specific
ities in psychiatric patients. skill itself or to the learning of a new skill, since correlations
between the intensity of the macroscopic changes in VBM
To summarize, the current literature partially reviewed here and the subject’s performance at the task are inconsistently
(for complete review, see Refs. 69, 87) indicate that time- found (128). Interestingly, a retrogression of these morpho-
varying aspect of functional connectivity is relevant for cog- logical changes has been observed without concomitant de-
nitive activities and that temporal network reconfiguration crease in the subject’s performance during the task (117,
is engaged during complex, cognitive demanding tasks. 123), supporting that these changes could be linked to novel
This perpetual intra- and internetworks temporal reorgani- learning.
zation opens the door to considerable interindividual vari-
ability and to a huge potential of neuroplasticity, even in Furthermore, the nature of the structural changes may be
adults. Indeed, such a structural and functional variability dependent on the experimental conditions [e.g., training
across individuals can be conceived only in a dynamic task in healthy volunteers versus brain injury such as after
framework of brain processing, allowing experience-driven stroke and the neuroanatomy, e.g., hippocampus or neo-
reshaping during development, learning, and even in case of cortex (467)]. For example, a recent VBM investigation
cerebral injury. showed that slow-growing but massive tumoral infiltration
of the insula induced marked increase of gray matter vol-
ume in the contralateral one. These findings support a ho-
C. Neuroplastic Potential: from Learning to motopic reorganization that might be a physiological basis
Postlesional Reshaping for the high level of functional compensation generally ob-
served in glioma patients (6). Given the slow-growth kinet-
Structural and functional neuroplasticity is an intrinsic ics of this neoplasm, the long-lasting neural adaptation
adaptive property of the brain in response to environmental could be mediated by a multistep process involving not only
stimulus, cognitive demands, or behavioral experience. fast-adjusting neuronal systems (i.e., synaptic changes)
Neural plasticity is possible solely in a dynamic account of (520), but also a combination of slow-evolving mechanisms
brain processing, in which the CNS is an ensemble of com- such as myelination, axonal remodeling, or angiogenesis
plex networks that form, reshape, and flush information (108, 437). Indeed, the underlying neurobiological basis of

gray matter changes is not clear (528). It could be the re- especially between paralimbic, limbic, and association re-
flection of many suspected factors, including neurogenesis gions (456). The reconfiguration of functional connectivity
(372), gliogenesis (46, 406), glial hypertrophy (408), possi- from childhood to adulthood (from local to distributed) is
bly mediated by the interactions between astrocytes and further accompanied by a weakening of short-distance
neurons (since the molecular and functional profiles of as- structural connections and a strengthening of long-distance
trocytes seem to be regulated by the neurons via the sonic structural connections (456). Other results are interesting
hedgehog pathway) (152), increased cell size or spine den- to consider. For example, a recent resting-state functional
sity, synaptogenesis (mediated by astrocytes) (12), or even imaging study showed that the default mode network,
changes in blood flow or interstitial fluid. Interestingly, which is associated with self-referential cognition, was im-
some changes have also been reported at the level of the mature in children compared with adults (303). Further-
WM tracts, which could be related to an increased myeli- more, another study demonstrated that the development of
nation (mediated by oligodendrocytes) (12, 46) or axonal reasoning ability from childhood to adolescence was pre-
sprouting, possibly involving NogoA, mainly expressed by dicted by the reinforcement of long-range functional con-
the oligodendrocytes (215, 372). For example, changes in nections between the dorsolateral prefrontal cortex and the
the WM microstructure have been observed following the inferior parietal lobule (510). On the same line, develop-
acquisition of a second language (421) or a new motor skill mental changes in between-network integration of the cin-
(425). Furthermore, this WM plasticity can be especially gular-opercular and salience networks have been linked to
rapid; indeed, a recent study conducted with struggling better performance in inhibitory control, suggesting that an
school-aged readers showed that an intensive reading inter- efficient integration between these relatively specialized net-
vention over a short period of 8 wk induced widespread works is required for mature cognitive control (315).
changes in WM tissue properties that correlated with im- Lastly, there exists a progressive lateralization of the lan-
proved reading abilities (243). These changes were mainly guage network from preschool childhood to adolescence
observed at the level of the associative connectivities known and adulthood. Indeed, functional connectivity between the
to form the classical reading network including the left ILF left inferior frontal gyrus and its right-hemispheric homolog
and the left AF. The same kinds of findings have been ob- is predominant in children, while intra-hemispheric connec-
tained for the left AF following a 2-month intensive training
tivity between the left inferior frontal gyrus and the left
of math abilities (254). At another level, WM tracts can also
posterior superior temporal sulcus is more characteristic of
serve as compensatory pathways after stroke injury. In a
adults (517, 518). Interestingly, covariations between syn-
recent DTI study, for example, it was shown that intensive
tactic processing skills and bilateral intra-hemispheric (be-
language rehabilitation over a short period of only 3 weeks
tween inferior frontal gyrus and posterior superior tempo-
induced a structural reinforcement of the left ILF. This
ral sulcus) connectivity were observed (518), suggesting
structural plasticity was associated with a significant reduc-
that a more pronounced bilateral distribution of the lan-
tion of semantic paraphasia (324).
guage network in children is behaviorally relevant. At an-
other level, using DES, maturational differences in the spa-
In brief, training-induced morphological changes, at both
tial topography of critical language areas in perisylvian re-
the cortical and WM levels, can be induced, in the context
of the acquisition of either basic or complex learning/cog- gions have been identified between children and patients
nitive expertise. older than 16 yr. Indeed, language sites were significantly
smaller in children, suggesting the flourishing of new lan-
2. Functional plasticity guage-related eloquent areas across development (353).
Beyond morphological changes during brain development, Besides developmental plasticity, mechanisms of network
functional modifications have also been found by compar- reconfiguration still exist during novel learning in adults.
ing distribution of functional networks between children Especially, the changes in the functional connectivity in-
and adults. In a general way, it appears that functional duced by training have been studied using fMRI, as it can be
networks in adults are more distributed, while in children modulated by the expertise of the subject for a task. For
they are more locally organized, even if both populations example, modifications in the resting-state functional con-
display similar small-world architecture (150). This differ- nectivity can be induced by musical practice (153), working
ence in network properties has been confirmed in several memory training (255), visual perceptual learning (413),
studies, especially for interregional connectivity. In fact, spatial memory and navigation (371), or motor-sequence
although adult circuits mainly consist of prominent cortico- learning (95). In that respect, the study provided by Bassett
cortical connections, children show more abundant connec- et al. (32) is especially informative. The authors showed
tions between subcortical and cortical areas. More specifi- how the brain functional architecture evolved over time
cally, functional connections are stronger between subcor- from initial training to complete control of a simple motor
tical regions and primary sensory, association, and skill. More specially, the functional connectivity analyses
paralimbic regions in children as opposed to young adults performed in this study indicated that when automaticity
for whom cortico-cortical connections are more developed, was progressively reached, there was a functional predom-

inance of sensorimotor systems along with a disengagement duction of additional relays within neurosynaptic path-
of cortical areas known to play a role in cognitive control ways, the actual capacity to build new structural subcortical
(i.e., cingulate and frontal areas). This suggests that learn- pathways (“rewiring”) resulting in functional recovery is
ing new skills requires coordination of multiple functional not clearly evidenced in humans (134). Therefore, whereas
networks and that this cross-domain integration is no lon- the plastic potential is high at the cortical level, the subcor-
ger critical when automaticity is reached, the sensorimotor tical plasticity is rather low, implying that axonal connec-
network being sufficient to perform the task. tivity should be preserved to allow postlesional functional
compensation in the context of neurosurgery (220, 248).
3. Postlesional plasticity Recently, probabilistic atlases of functional plasticity were
computed in patients who underwent surgery resection for
Neuronal aggregates around, or remotely located to, a a low-grade glioma by means of intraoperative DES map-
brain insult can increasingly and dynamically adopt the ping (220, 248, 415; see FIGURE 6). The general principle
function of the injured structure and switch their own acti- consists of combining both stimulation mapping data sets
vation patterns to substitute the damaged area while facili- and postoperative structural MRIs to compute for each
tating functional compensation (131, 132). The most per- voxel of the brain the probability of observing a functional
suasive body of evidence for lesion-induced plasticity comes response under stimulation despite tumor infiltration; a re-
from the field of glioma neurosurgery (220), even if spec- gion that remains systematically functional despite infiltra-
tacular cases of almost complete functional recovery have tion will be considered as weakly plastic (no functional
also been observed, but more sporadically, in other patho- compensation) and, conversely, an infiltrated region that
physiological contexts (155, 428). Indeed, the surgical re- never responds to stimulation will be considered as strongly
moval of large cerebral territories, including brain areas
plastic (high functional compensation). The resulting prob-
that are known to act as critical structures within the func-
abilistic map is then projected onto both a stereotaxic tem-
tional architecture (such as the insula), does not induce the
plate (i.e., the MNI152 template) and a WM atlas to inves-
cognitive, affective, or sensorimotor impairments that one
tigate the potentialities and the limitations of plasticity,
might expect (115, 133). For example, it is regularly possi-
both for cortical regions and axonal fibers. The most so-
ble to remove Broca’s area without causing permanent ex-
phisticated version of this atlas, based on 231 patients and
pressive language disorders. This functional reallocation is
scaled according 340 levels of probability, highlighted the
generally explained by the slow-growth kinematics of this
dual relationships between cortical and subcortical plastic-
diffuse, low-grade tumor (115). This may partially account
ity (248) (FIGURE 6). Indeed, it appears that cortical plastic-
for the particularly low occurrence of neuropsychological
ity is generally strong, except for unimodal areas and a
impairments typically observed at the time of diagnosis
(212), despite sometimes very large tumors; this strongly handful of neural hubs, whereas axonal plasticity is clearly
contrasts with clinical observations made in patients with refractory to functional compensation, agreeing with the
sudden lesions (as stroke injury) for whom functional diag- previously described low level of interindividual subcortical
nostic is much worse (488). variability. This low potential of remodeling could be ex-
plained for some structures because they correspond to in-
Although the physiological mechanisms of functional comput or output subcircuits, as the primary motor and so-
pensation are currently understudied in the context of dif- matosensory areas, the cortico-spinal and thalamo-cortical
fuse low-grade glioma, several patterns of functional re- tracts and the optic radiations, namely, the projection fi-
modeling have been observed, especially the recruitment of bers. These zones are mainly unimodal and organized seri-
perilesional and/or remote regions within the ipsilesional ally, with an absence of parallel alternative pathway ex-
hemisphere and/or of homotopic contralateral areas (7, plaining the impossibility to restore their function after any
115). However, as illustrated by MEG studies, a focal gli- insult (134). Likewise, associative WM tracts such as the
oma can disturb the functional and effective connectivity at IFOF or the SLF/AF cannot be compensated for because
the brain-wide level, not only in areas infiltrated by the their injury would induce major breakdowns in both net-
tumor (26). These network dysfunctions are moreover cor- work and between-network communication that the plastic
related with cognitive disturbances in glioma patients (52). potential would be overwhelmed (136). These noncompen-
This means that brain plastic potential has nonetheless sable structures, that correspond to those with a low level of
some limitations that have to be investigated at the individ- interindividual variability (see above), have been proposed
ual level. In fact, lesion-induced neuroplasticity can be effi- as constituting a “minimal common brain,” a set of critical
cient only on the condition that the WM connectivity is regions necessary for the maintenance of basic cognitive
spared. Indeed, disrupted WM pathways prevent distrib- functions, even though probably not enough for more com-
uted cortical areas or large-scale cognitive networks to complex functions such as cognitive control or multi-tasking
municate and synchronize. Although a number of studies (220, 248).
have identified distinct patterns of WM plasticity, such as
unmasking of perilesional latent subcircuits, recruitment of To conclude this general section, we propose an illustration
parallel long-distance association subnetworks, and intro- describing the meta-networking we discussed (FIGURE 7).

Functional compensation map

-41 -29 -23 -17 -11 -5 1 7
1
Functional compensation index

0.80
0.60
13 19 25 31 37 43 49 61 0.40
0.20
FIGURE 6. Probabilistic map of neuroplasticity potential. This probabilistic map is derived from both anatomic
MRI results and intraoperative mapping data on 231 patients having undergone a surgery for a diffuse
low-grade glioma. The “black” color (corresponding to a value of 0) means that the probability of detecting a
functional response during electrostimulation is null (i.e., high functional compensation index). In contrast, the
red color (corresponding to a value of 1) means that the probability of detecting a functional responsive during
electrostimulation is maximal despite tumor infiltration (i.e., low functional compensation index). The map is
thresholded according 340 levels of probability. It is shown that structures with a low level of functional
compensation are located in the deep white matter connectivity and at the level of primary or unimodal regions.
[From Herbet et al. (220), with permission from Oxford University Press.]
VII. IMPLICATIONS there are interhemispheric differences both at the cortical

level (260) as well as concerning WM tracts (74). However,
These new insights into such a meta-networking brain have it is worth noting that, contrary to the cortex, there is not a
physiological implications regarding the considerable inter- myriad of fiber patterns at the subcortical level, but only a
individual anatomo-functional variability and open origi- few subgroups with basic recurring themes. For instance,
nal therapeutic avenues in clinical neurosurgery, neurology, the use of DTI revealed the existence of three categories of
neurorehabilitation, and psychiatry, as discussed in the fol- lateralization of language bundles, with strong left lateral-
lowing. ization in 62.5% of cases, bilateral left lateralization in
20% of cases, and bilateral symmetrical in 17.5% of cases
(74). Of note, a certain degree of variability concerning the
A. Physiological Implications cortical terminations of the WM tracts was nonetheless ob-
served, as for example regarding the posterior terminations
1. Morphological variability of the IFOF (319).
The anatomy of the CNS is highly variable across individ- To sum up, due to this huge interindividual variability of
uals, especially at the cortical (especially sulcal) level (283, the cerebral cortex, the accurate localization of cytoarchi-
470). Indeed, morphologic atlases elaborated manually tectonic areas and their borders is difficult to evaluate from
(357) as well as recent automated methods have evidenced anatomical structures as gyri or sulci (419). This is a major
a myriad of sulcal patterns that exist at the level of the issue for the systematic study of the functional-structural
cortical surface, in particular in some perisylvian frontal relationships (403) and also to understand the significance
and temporoparietal regions (260, 407). For instance, He- of spatial arrangement of cortical areas, since the spectrum
schl’s gyrus, a part of the superior temporal plane, can be of cortical functions may emerge from structural con-
composed of one to three gyri per hemisphere, with the straints (243).
number of gyri varying between hemispheres (316). The
structural variations of the occipital sulci are important 2. Functional variability
(247, 309). Likewise, the frontal opercula have been classi-
fied into four distinct patterns of sulci formation (144). Thanks to noninvasive methods of functional neuroim-
Such an anatomic variability has been explained by a “sul- aging, the existence of a considerable intersubject vari-
cal root” model based on gyri buried in the depth of the ability has been revealed regarding the cortical distribu-
sulci (392). Morphometric variations in adults are thought tion of functional networks as the circuits mediating
to result from a chaotic behavior of the folding process speech and language (474). In a meta-analysis of phonol-
(465), in addition to genetic factors (469). Furthermore, ogy, semantics, and syntax, 30 activation clusters which

high-level, distributed networks Transient meta-networks

Low-level, local Networks Higher-order, cognitive and Complex, goal-directed and Low-level, local Networks
basic sensory processes emotional processes flexible behaviors and cognitions Basic motor execution
Working memory
Spatial cognition Language
inputs Outputs
Within network
Visual integration
network (between relatively Semantics
specialized areas)
Premotor
Somatosensory and
network motor
Working memory network
Memory
Auditory Language
network Semantics
Emotion
Social cognition local integration
between relatively Social cognition Emotion
Attention specialized cortical
unities Attention
Highly segregated Local and within-network integration Context-sensitive, cross-network integration Highly segregated
Functional Neuroplasticity
Very LOW Very HIGH Very LOW
Behavioral variability
FIGURE 7. The meta-networking approach of complex cerebral functions. Basic sensory inputs are pro-
cessed by anatomically highly segregated and local networks. Higher-order cognitive and emotional functions
are rather sustained by cortical networks that are widely distributed at the whole-brain level. The information
processed by the different cortical unities forming a relatively specialized cortical area is integrated locally (local
integration); then, the information from each cortical area forming the specialized network is integrated globally
(within-network integration). In the context of highly complex, goal-directed, and flexible cognitions/behaviors,
the information coming from different specialized networks is integrated in a context-sensitive manner (i.e., as
a function of current cognitive demands). This specific pattern of between-network integration corresponds to
a functional meta-network transiently generated to reach a complex goal or to produce a flexible behavior. This
hierarchical functioning, from highly segregated to highly distributed, provides the flexibility needed for complex
learning or functional compensation in the event of brain damage.
defined the functional fields constituting three distributed pected locations according to the classical Broca-Wernicke
networks of frontal and temporal areas have been re- model, as in midfrontal, midparietal or posterior temporo-
ported, pleading in favor of a distributed rather than parietal regions (288, 295, 370, 482). In particular, in the
modular organization of language processes (494). posterior part of the left inferior frontal gyrus or the left
Moreover, thanks to advances in functional connectivity- superior temporal gyrus, enough variability existed so that
based analysis of fMRI data, between-subject variation the so-called Broca’s area or Wernicke’s area, respectively,
in resting-state brain metabolism in areas belonging to were occasionally not implied in language (354). This vari-
the default-mode network and the dorsal attention cir- ability in language localization also exceeded even the con-
cuit has been observed, and it has been correlated with siderable anatomic and cytoarchitectonic variations, both
memory capacities in normal aging (33). More generally, in adults and in children (411). This functional theory is in
we currently know that interindividual variations in rest- line with the structural “sulcal root” generic model
ing-state connectivity is associated with individual differ- which hypothesizes that anatomic variability of the cor-
ences in a wide range of cognitive and behavioral do- tex in adults can be due to differences in the folding
mains (480), but also with personality styles (2, 276). process during morphogenesis (420). Moreover, in a DES
study of 250 patients who underwent awake surgery for
On the same lines, by using DES in patients who underwent gliomas, 145 patients had at least one site with an intra-
awake surgery for epilepsy in the left hemisphere, Ojemann operative stimulation-induced speech arrest, 82 patients
et al. (354, 355) proposed a reappraisal of the traditional experienced anomia, and 23 patients had alexia (411).
model of language localization. They observed that lan- Cortical maps built based on these intraoperative DES
guage epicenters formed mosaics, with substantial interin- language data showed substantial variability in language
dividual variations in the exact location of these nodes, localization (FIGURE 8A). Interestingly, the “negative
partly correlated with the patients’ sex and verbal intelli- sites,” i.e., not essential areas for language, have fre-
gence (355). These data are in agreement with previous DES quently been found in anatomical locations correspond-
investigations that have also revealed variations in the lo- ing to the classical Broca’s area and Wernicke’s area
calization of language, especially with epicenters in unex- (411). In a recent bilateral map generated from DES in

Motor Anarthria/Arrest Dysarthria SemanticL

Sensory Anomia PhonologicL
B
80 80
Dorsal Dorsal
70 70
60 pDLPFC 60 pDLPFC
50 50
40 40
30 30
z (mm)
20 20
10 10
Rostral MNI coordinates Caudal Caudal MNI coordinates Rostral
0 0
-10 -10
-20 -20
-30 Ventral -30 Ventral
-40 -40 IFGtri
-50 IFGtri -50
-60 -60
60 40 20 0 -20 -40 -60 -80 -100 -100 -80 -60 -40 -20 0 20 40 60
FIGURE 8. Interindividual variability in the neural implementation of cerebral functions revealed by stimulation
mapping. A: from a topographical viewpoint, anatomical sites associated with language (anomia, semantic
paraphasia, phonological paraphasia) or speech (anarthria, speech arrest) difficulties during direct electrical
stimulation show a high degree of interindividual variability. [From Tate et al. (459), with permission from Oxford
University Press.] B: anatomical sites related to verbal semantic cognition are widely distributed over the whole
cortical surface of both Boca’s area (triangularis and opercularis) and the posterior dorsolateral prefrontal
cortex (pDLPFC) in the left frontal lobe, highlighting the strong interindividual differences in the spatial
positioning of semantic areas. IFGtri, inferior frontal gyrus triangularis. [From Herbet et al. (223), with
permission from Wolters Kluwer Health, Inc.]
165 patients operated on for a low-grade glioma, the tionship with the so-called cognitive control network and
wide distribution of cortical representations within and the default mode network. The two networks are strongly
between critical functions of the human brain has been anticorrelated at rest (526), and the amount of this anticor-
evidenced (459). In the same way, a marked anatomo- relation predicts higher behavioral performance both dur-
functional variability in the positioning of functional ing the completion of the task and at rest (264). Likewise,
sites for semantic cognition, especially at the level of the optimal cognitive control performance in adolescents re-
dorsolateral prefrontal cortex and inferior frontal gyrus lates to functional interactions of specific cortical structures
(223), and social cognition (524) has also been observed belonging to both the cognitive control network and the
using DES mapping (FIGURE 8B). Taken as a whole, the default mode network, not to increased integration of the
reported findings suggest that the neural implementation cognitive control network alone (143). In the same vein,
of cognitive functions is particularly variable from one global connectivity in the lateral prefrontal cortex, includ-
individual to another. This functional variability has ing functional connections within and outside the prefron-
been probably underestimated due to the recurrent use of tal cortex, is closely associated with fluid intelligence (89).
fMRI that averages functional activations across individ- Lastly, variation in brain-wide functional dynamic connec-
uals. tivity appears to better predict interindividual differences in
a range of behavioral tasks (e.g., sustained attention, epi-
At the network system level, current research suggests that sodic memory) than statistical functional connectivity does
interindividual variability in high-order cognitive abilities is (220). These findings, among others, suggest that individual
partially dependent on the context-sensitive coordination differences in dynamical network reconfiguration is one of
of specialized networks. For example, cognitive control has the neurophysiological mechanisms leading to functional
been reportedly linked to the antagonist, competitive rela- variability.

3. A two-level model of interindividual variability more is increased in patients with cerebral lesions, such as
tumor or epilepsy, due to neuroplasticity phenomena), im-
On the basis of these overall findings, a two-level model of ply that brain functions cannot be reliably localized on an-
interindividual anatomo-functional variability has recently atomic criteria alone (e.g., it cannot be claimed that Broca’s
been suggested (137). The first level is the cortical one, with area is crucial for some language components), and more
a high variability across subjects, concerning both the mor- especially as the more complex the functions are, the less
phology (as shown by the anatomic studies) and the func- anatomically segregated they are (see sects. IIIC2 and VA).
tion (as especially evidenced by functional neuroimaging Therefore, in the context of neurosurgery, intraoperative
investigations as well as by DES). It is noted however that, stimulation mapping is mandatory to optimize the extent of
even at the level of the cortex, there is almost no intersubject resection while sparing cognitive functions and thus im-
anatomo-functional variation for some regions as revealed proving patients’ quality of life in the case of brain tumor,
by functional atlases derived from DES (459). Indeed, these and must be considered in a systematic manner in all neu-
sites act as input or output areas: input zones convey or are rosurgical patients with no or only mild preoperative defi-
the first relay of information entering the CNS, whereas cits (110). Currently, only DES mapping is able to distin-
output zones are the last relay sending information outside guish essential from merely participating cortical areas with
the brain. These sites are mostly unimodal, and they include a high temporo-spatial resolution (459), and tractography
the primary somatosensory and the visual cortex (input) as imaging is still too imperfect (302) to be trustworthily used
well as the primary motor cortex and the ventral premotor in the clinical context of neurosurgery. Tailored resections
cortex (output). The second level is the subcortical one, achieved in “awake” conditions up to the individual func-
with a low variability concerning both the structure (espe- tional limits (determined by DES) are currently leading to
cially regarding the stem of the WM tracts) and the func- the development of a “functional neuro-oncology” and a
tion. In fact, although some different patterns of interhemi- “connectome-based neurosurgery” (138, 311). In addition,
spheric asymmetry have been described concerning the the concept of “eloquent” cortex, mainly used in the clinical
main associative pathways (74, 463), no considerable intra- fields, should be revised. According to this simplistic view
hemispheric anatomical variations of the WM fibers have derived from the traditional localizationist model, patients
been observed, in particular regarding their trajectory (even with lesions involving these “critical” anatomical sites were
though some degree of variability may exist concerning deemed inoperable on the ground that surgery would irre-
their cortical projections). Indeed, a recent subcortical atlas vocably cause severe neurological or neuropsychological
of WM tract functions identified by means of axonal DES impairments, a view which still is broadly shared among
revealed a high reproducibility in the structural-functional neurosurgeons. As a matter fact, the lack of functional dis-
correlations across patients (415). This seems to be related
turbances has regularly been reported during DES mapping
to structural constraints, because the main tracts are com-
of anatomic regions classically considered to be “eloquent,”
posed of converging fibers that have to run within small
such as Broca’s area and Wernicke’s area (354, 411, 459).
spaces (as capsulae) bordered by anatomic landmarks such
This “noneloquence” has been confirmed by removing
as the depth of the sulci, the ventricles, and the deep gray
these regions without generating persistent functional defi-
nuclei. Again, this is in agreement with the sulcal root
cits (115, 378, 416). Conversely, other areas usually
model, in which the main architectural constraints corre-
thought as “noneloquent” can nonetheless be essential for
spond to the WM fibers, despite distinct folding solutions
brain functions such as for example the crucial role of the
during cortical morphogenesis from the tensegrity point of
both the right inferior frontal gyrus and the right dorsolat-
view, explaining the variability of adult cortex (392). This
eral prefrontal cortex in mentalizing (524), of the right dor-
means that the fiber-related tension may be the main expla-
nation of the pattering of cortical folds (484). solateral prefrontal cortex in nonverbal semantic process-
ing (223), of the possible crucial role for language of the left
In summary, this two-level model of interindividual vari- anterior temporal lobe (355), or of right-sided language-
ability (high cortical variation vs. low subcortical variation) related structures in right-handed patients (489). Thus
breaks with the classical “single brain” standpoint and “cortical eloquence” must be redefined in a connectomal
opens the door to the potentials and limitations of neuro- account of brain functioning, with the goal of avoiding not
plasticity. to select patients who could safely benefit from surgical
resection despite a tumor located within classical “elo-
quent” areas and, in contrast, to perform awake mapping
B. Clinical Implications when achieving surgery in presumed “noneloquent” re-
gions. On the other hand, the low likelihood of WM tracts
1. Neurosurgery to be compensated for, and subsequently the possible
marked consequences of WM disruption on both within
Both the brain-wide distribution and the underlying dy- and between-network integration (184, 415), highlights the
namics of neural networks, resulting in considerable inter- utmost importance of preserving a core of connectivity
individual anatomo-functional variability (which further- through the main associative pathways, the so-called “min-

imal common brain” (220, 248) (see above). As a conse- chological deficits can result from large-scale network dys-
quence, DES-based digitalized atlases of WM pathways function (167). Multimodal approaches, coupling for example
(415) may have major implications for surgical selection network science methods and behavior measurements in
and planning, even though the complexity of the subcortical brain-damaged patients, are likely to provide important find-
pathways still imposes to achieve a systematic intraopera- ings in future years on the pathophysiological bases of deficits
tive DES mapping. in sudden or evolving diseases.
On a different matter, although the use of simple, well- On another but interconnected matter, it is well established
controlled behavioral tasks to map online the range of spe- that intra- and interhemispheric functional connectivity are
cialized functional networks (e.g., reading) is the basics of disrupted in a variety of neurodegenerative diseases, some-
stimulation mapping in “awake” surgery, other behavioral times very early in the disease time course; this is for exam-
tasks are also used to monitor more complex functions ple the case for Alzheimer’s disease or multiple sclerosis
during the entire duration of the surgical procedure, in par- (157, 196, 377, 426, 434). Recently, it has been suggested
ticular multiple-tasking (213). By very nature, this kind of that a possible mechanism common to these conditions, and
behavioral activity necessitates the involvement of at least especially in Alzheimer’s disease, is the involvement of neu-
two specialized functional networks in the event of dual- ral hubs with a high level of centrality that are typically
task demands (for example, the language and the motor located in the associative cortex (453). Furthermore, the
networks when patients are asked to perform simultane- degenerative disruption of these integrative structures
ously both a naming task and a complex motor movement) has been associated with the impairment of high-level
in addition to more domain-general networks, especially functions mainly including working memory, attention,
both the working and the executive networks to ensure task and cognitive control (453). As a consequence, we have a
monitoring and coordination. It sometimes happens that lot to learn about how structural compromise of these
DES disturbs markedly dual-tasking abilities (and suppos- hubs impacts network coordination, and how the loss of
edly cross-network interactions) but not the ability to per- this central neurophysiological process might account for
form the two behavioral tasks in a serial manner. This is a the gradual installation of highly-integrative cognitive
good illustration of how well DES mapping may help iden- impairments.
tify the cortical or subcortical regions that may be behav-
iorally relevant for network coordination (FIGURE 9). 3. Neurorehabilitation
Lastly, as developed in the corpus of this review, patients It is now widely known that brain lesions can greatly affect
harboring a diffuse low-grade glioma are characterized by functional connectivity, all the more that anatomical con-
efficient functional compensation (115, 132, 220). From a nectivity is disrupted (198, 210). Furthermore, the extent to
topological standpoint, diffuse low-grade gliomas are often which functional connectivity is impaired often predicts the
located in cortical structures that have been identified in severity of neuropsychological difficulties (50, 181, 198,
connectomics studies as central (the so-called connector or 210, 253, 423, 507). Likewise, cerebral lesions can disrupt
participating hubs) in coordinating network activity, such the between-network communication normally seen in neu-
as for instance the dorsolateral prefrontal cortex or the rologically healthy participants during the completion of
superior frontal gyrus (191, 450). Future studies conducted behavioral task, partially accounting for the observed be-
with glioma patients should enable to assess the brain abil- havioral difficulties (253). Recent research showed that
ity to redeploy its neural hubs to maintain efficient context- neuro-rehabilitation can improve functional connectivity
dependent network reconfiguration and thus efficient com- between areas of a given specialized network and is associ-
pensation of complex cerebral functions. ated, at least in some extent, with behavioral recovery
(117). However, at the present time, it is unknown how
2. Neuropsychology and neurology specific programs of rehabilitation can improve network
coordination and lead to a reduction or a complete disso-
The meta-networked functioning we described in this re- lution of the high-level cognitive impairments often ob-
view may prompt researchers and scholars in the domain of served following stroke or traumatic brain injury. In this
neuropsychology to go beyond using standard anatomo- context, a better knowledge of how functional networks
functional approaches to study the neural bases of high- communicate and reconfigure their patterns of functional
level, multidetermined cognitive functions in brain-dam- connectivity as a function of various behavioral demands
aged patients. High-level cognitive impairments seem to be may help to select rehabilitation strategies meant to rein-
better explained by the lesion’s physiological consequences force or normalize between-network communication. For
on cross-network interactions, especially when it is located example, the language network is not a static and a unitary
in the frontal or parietal heteromodal cortices or disrupts entity, but is rather constituted by several subnetworks, the
the WM associative connectivity (198). The heuristic value ventral and the dorsal network being generally the most
of VLSM-like techniques based on the localizationist as- discussed. However, efficient language abilities require the
sumption is thus very limited in explaining how neuropsy- intervention of other functions such as working memory,

A Multitasking functioning B Serial functioning
Motor network Semantic network Motor network Semantic network

Behavioral Behavioral
Output Output
Upper limb movement Semantic association Upper limb movement Semantic association
dlPFC dlPFC
Network coordination Lack of network coordination
induced by DES
Goal maintenance Goal maintenance
Working memory network Working memory network
The patient is able to perform each task serially but not

The patient is able to perform the dual-task adequately
conjointly
C ‘Uni-network’ dysfunctioning D ‘Uni-network’ dysfunctioning
Motor network Semantic network Motor network Semantic network

Behavioral Behavioral
Output Output
DES-related DES-related
disturbance disturbance
Upper limb movement Semantic association Upper limb movement Semantic association
dlPFC Network coordination
dlPFC Network coordination
Goal maintenance Goal maintenance
Working memory network Working memory network
The patient is able to maintain the goal task, but only the The patient is able to maintain the goal task, but only the
motor task is feasible semantic task is feasible
FIGURE 9. Illustration of how direct electrical stimulation (DES) mapping may inform on the meta-networking
functioning of the brain. During complex cognitive activities, such as dual-tasking, the brain needs to coordinate
its networks to reach the task goal. In awake surgery, the patient is commonly asked to achieve a dual-task
consisting in performing a complex movement of the upper limb in concert with a semantic association task.
In normal circumstances (A), the neural activity from the semantic (semantic processing), the motor (motor
initiation, control, and execution), and the working memory (goal maintenance) networks needs to be inte-
grated to perform the task efficiently thanks to highly integrative hubs such as the dorsolateral prefrontal cortex
(dlPFC). When the dlPFC is impaired by DES (B), the brain has difficulties to coordinate its networks, and the
patient is only able to perform the tasks serially but not conjointly. When the semantic network is impaired by
DES (C), the patient is able to maintain the task goal, but only the motor task is performed. In contrast, when
the motor network is disturbed (D), the patient is still able to maintain the task goal, but only the semantic task
is performed.

attention, and executive functions. In this context, multi- arise from a failure of the CNS to integrate information
modal therapeutic interventions, not only based on the im- flows from different specialized networks (such as the face
paired language process, but also on otherwise participat- perception, the mentalizing, the mirror, the emotion net-
ing functions, may help the brain reconfigure the way that works). Such a pathophysiological mechanism would result
the functional networks usually communicate to reach a in difficulties to flexibly adapt in novel social situations,
new functional equilibrium state capable of compensating which are especially various. This line of reasoning also
the observed language difficulties. applies to other conditions in which both social cognition
and functional connectivity are disrupted, such as schizo-
On a different matter, the coupling of TMS and constraint- phrenia. Indeed, patients with schizophrenia are marked by
induced cognitive therapeutic intervention has been regu- a reduced brain capacity in coordinating neural activity
larly discussed as a possible avenue to potentiate the in- across large-scale functional networks (297), explaining
volvement of compensatory pathways and subsequently difficulties in some aspects of cognitive functioning
improve neuropsychological difficulties, especially in the (398). As a consequence, in future years, an improved
context of aphasia patients (349). In the same way, recent knowledge on how the brain coordinates its functional
studies provided interesting data on the ability of TMS to networks to produce socially adapted behaviors (see sect.
modulate network activity and enhance cognitive func- VA) will pave the way for new hypotheses regarding the
tions. For example, it was recently shown that anodal stim-
cognitive pathophysiology of various psychiatric or de-
ulation (using tDCS) of the right anterior insula/inferior
velopmental conditions where social communication,
frontal gyrus, a core area of the salience network whose
among other clinical features, is problematic. In a more
structural disruption impairs the coordination between
general way, a better understanding of moment-to-mo-
both the default and the salience network and results in
ment network reconfiguration may help disentangling
cognitive control difficulties (49), remotely modulated the
the mechanisms that lead to psychotic symptoms. For
functional connectivity of the default mode network and
was associated with better performance in response inhibi- example, in a very recent study, it was shown that some
tion task (289). This kind of finding offers new perspectives time-varying patterns of the functional connectome were
on how brain stimulation can help modulate between-net- especially predictive of psychiatric symptoms in patients
work interactions and eventually lead to cognitive improve- with psychotic illness (395).
ment in brain-damaged patients.
5. Brain-computer interface: towards restoration of
4. Psychiatry brain functions
It is now well established that a number of psychopatholog- A brain-computer interface (BCI) provides a novel nonmus-
ical or psychiatric conditions are characterized by an abnor- cular communication method via brain signals decoding
mal structural and functional connectome (165). This is for (266). Recent advances in new algorithms and biosignal
example the case for autism spectrum disorders (ASD) in
acquisition technologies enable the real-time analysis of
which anatomo-functional architecture is, in many ways,
biosignals, to quantify relevant insights, such as subjects’
radically different from healthy individuals (330). From a
mental and emotional states. For example, concerning lan-
neuropsychological standpoint, social cognition disorders,
guage, a direct-speech BCI acquires neural signals corre-
especially mentalizing impairments, constitute the main
sponding to imagined speech, then processes and decodes
marker of this psychopathology. As a consequence, patients
these signals to produce a linguistic output in the form of
presenting with ASD have severe difficulties in navigating
the surrounding social environment. Unsurprisingly, a phonemes, words, or sentences (15, 90, 361). The new con-
number of studies have shown an abnormal functional in- nectomal model may lead to change the paradigm of BCI,
tegration between the cortical nodes of the default mode that is, to move from a single recording device placed in the
network, a brain-wide neural system that greatly overlaps speech motor cortex, to interfacing multiple cortical areas
with the mentalizing network, suggesting that this atypical thanks to several electrodes placed in regions that encode
physiological functioning may account for the patients’ in- words at higher level of abstraction (e.g., phonology, se-
ability to process socially relevant stimuli (360). Other stud- mantics) and that work together as parts of a large-scale
ies have suggested that a breakdown of the functional com- language network. The purpose would be to restore the
munication between the mirror and the mentalizing net- long-range communication between these epicenters after
work during the visualization of social scenarios may an injury of their connections that resulted in aphasia (310).
constitute a pathophysiological basis for mentalizing im- In other words, restoring a synchronized link between the
pairments in these patients (225). Given that mentalizing, areas of one or even several neural networks that were
and more generally social cognition, is likely to necessitate disconnected following cerebral insult, based on a better
the coordination of several networks in a context-sensitive comprehension of the postlesional reaction dynamics of the
manner (see sect. IVE), a possible hypothesis to be devel- individual functional architecture, might allow functional
oped is that social cognition disorders in ASD patients may restoration.

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Physiological Reviews Review Article

REVISITING THE FUNCTIONAL ANATOMY OF THE

REVISITING THE FUNCTIONAL ANATOMY OF THE

For a long time, brain processes were mainly thought in a

0031-9333/20 Copyright © 2020 the American Physiological Society 1181

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Dorsolateral Link with

Ventral semantic stream Posterior-inferior Temporal

Physiol Rev • VOL 100 • JULY 2020 • www.prv.org 1197

E. Episodic Memory F. Mentalizing and Social Cognition

1198 Physiol Rev • VOL 100 • JULY 2020 • www.prv.org

Dorsomedial Cingulum PCC

Ventral SLF III

Medial stream: High-level, inference-based mentalizing

Physiol Rev • VOL 100 • JULY 2020 • www.prv.org 1199

Medial system RIGHT HEMISPHERE Multimodal inputs

Thalamus Movement control

Spatial attention (dorsal)

Non verbal semantics

Inferior longitudinal fasciculus Arcuate fasciculus Superior longitudinal fasciculus (layer I)

1200 Physiol Rev • VOL 100 • JULY 2020 • www.prv.org

Multimodal inputs LEFT HEMISPHERE

Striatum FEF Movement and SPL

Inferior longitudinal fasciculus Arcuate fasciculus Superior longitudinal fasciculus (layer I)

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Functional compensation map

Functional compensation index

VII. IMPLICATIONS there are interhemispheric differences both at the cortical

1208 Physiol Rev • VOL 100 • JULY 2020 • www.prv.org

high-level, distributed networks Transient meta-networks

Spatial cognition Language

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Motor Anarthria/Arrest Dysarthria SemanticL

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A Multitasking functioning B Serial functioning

Motor network Semantic network Motor network Semantic network

Goal maintenance Goal maintenance

Working memory network Working memory network

The patient is able to perform each task serially but not

C ‘Uni-network’ dysfunctioning D ‘Uni-network’ dysfunctioning

Motor network Semantic network Motor network Semantic network