M.D Hugues Duffau
email: duffau@chu-montpellier.fr

Prof Hugues Duffau

The death of localizationism: the concepts of functional connectome and neuroplasticity deciphered by awake mapping, and their implications for best care of brain-damaged patients

Keywords: Awake surgery, Brain connectome, Cognition, Glioma, Neuroplasticity, Neurorehabilitation, Quality of life, Stimulation mapping

Although clinical neurology was mainly erected on the dogma of localizationism, numerous reports have described functional recovery after lesions involving presumed non-compensable areas in an inflexible view of brain processing. Here, the purpose is to review new insights into the functional connectome and the mechanisms underpinning neural plasticity, gained from intraoperative direct electrostimulation mapping and real-time behavioral monitoring in awake patients, combined with perioperative neuropsychological and neuroimaging data.

Such longitudinal anatomo-functional correlations resulted in the reappraisal of classical models of cognition, especially by highlighting the dynamic interplay within and between neural circuits, leading to the concept of meta-network (network of networks), as well as by emphasizing that subcortical connectivity is the main limitation of neuroplastic potential.

Beyond their contribution to basic neurosciences, these findings might also be helpful for an optimization of care for brain-damaged patients, such as in resective oncological or epilepsy neurosurgery in structures traditionally deemed inoperable (e.g. in Broca's area) as well as for elaborating new programs of functional rehabilitation, eventually combined with transcranial brain stimulation, aiming to change the connectivity patterns in order to enhance cognitive competences following cerebral injury.

Introduction

Neurology was mainly erected on the dogma of localizationism, in which one discrete brain area underpins one specific function, with an ineluctable long-lasting neurological deterioration in the event of injury of such an area supposed to be non-compensable. The archetype of this inflexible view of cerebral architecture is Broca's area, established as the speech region, based upon a description of two cases, and considered as resulting inevitably in permanent motor aphasia if damaged [START_REF] Broca | Remarques sur le siège de la faculté du langage articulé, suivies d'une observation d'aphémie (perte de la parole)[END_REF]. However, numerous reports have described functional recovery after lesions involving presumed non-compensable structures and have challenged the localizationist concept in the older literature (for a review, see [START_REF] Desmurget | Contrasting acute and slow-growing lesions: a new door to brain plasticity[END_REF]). In particular, findings from epilepsy surgery supported that the left inferior frontal gyrus could be removed with no persistent language disorders if the rest of the hemisphere had a normal functioning [START_REF] Penfield | Speech and Brain Mechanisms[END_REF]. In the same way, surgical resection of tumors located within areas traditionally thought as "eloquent" were successfully performed in awake patients, with complete recovery allowing return to an active life [START_REF] Duffau | The huge plastic potential of adult brain and the role of connectomics: New insights provided by serial mappings in glioma surgery[END_REF], including following ablation of the left pars opercularis and pars triangularis [START_REF] Benzagmout | Resection of World Health Organization Grade II gliomas involving Broca's area: methodological and functional considerations[END_REF][START_REF] Plaza | Speaking without Broca's area after tumor resection[END_REF][START_REF] Lubrano | What makes surgical tumor resection feasible in Broca's area? Insights into intraoperative brain mapping[END_REF][START_REF] Rolston | Frontal operculum gliomas: language outcome following resection[END_REF]. Interestingly, although it might be argued that these observations were biased because the resection of Broca's area was made possible due to the presence of a glioma, in fact, a recent series demonstrated that even a stroke within Broca's area did not lead to long-term speech production impairment [START_REF] Gajardo-Vidal | Damage to Broca's area does not contribute to long-term speech production outcome after stroke[END_REF]. Taken together, these converging results in various cerebral diseases plead in favor of a more distributed and dynamic organization mediating brain processing, opening the window to a neuroplastic and connectomal philosophy.

Here, the purpose is to review new insights into the functional connectome and the mechanisms underlying neural plasticity, gained from intraoperative direct electrostimulation mapping and real-time behavioral monitoring combined with perioperative neuropsychological and neuroimaging data. These longitudinal anatomo-functional correlations resulted in the reappraisal of classical models of cognition, especially by highlighting the interplay within and between neural circuits and thus leading to the concept of meta-network (network of networks), as well as by emphasizing that subcortical connectivity is the main limitation of neuroplastic potential. Beyond their contribution to basic neurosciences, such findings might also be helpful for an optimization of care for braindamaged patients.

Awake mapping, brain connectivity and neuroplasticity

Advantages of intraoperative electrical mapping (IEM)

Even though IEM is an invasive method which in essence can only be used in patients who undergo brain surgery, conversely to functional neuroimaging which gives an indirect reflect of cerebral processing [START_REF] Azad | Limitations of functional neuroimaging for patient selection and surgical planning in glioma surgery[END_REF][START_REF] Maier-Hein | The challenge of mapping the human connectome based on diffusion tractography[END_REF], stimulation offers the unique opportunity to provide direct information with regard to the individual functional organization of both cortical and subcortical structures, including white matter tracts and deep gray nuclei [START_REF] Duffau | Stimulation mapping of white matter tracts to study brain functional connectivity[END_REF]. Indeed, IEM in the awake patient is able to elicit a transient dis-synchronization within one specific neural circuit, resulting in reversible behavioral deterioration of the function mediated by this network, so that reliable and reproducible structural-functional correlations can be achieved [START_REF] Duffau | Brain connectomics applied to oncological neuroscience: from a traditional surgical strategy focusing on glioma topography to a meta-network approach[END_REF][START_REF] Duffau | Stimulation Mapping of Myelinated Tracts in Awake Patients[END_REF]. One step further, IEM can also disrupt the interactions across neural circuits, preventing the patient from achieving several tasks simultaneously, e.g. to move and to name, while he/she is still able to perform each task separately [START_REF] Duffau | What Direct Electrostimulation of the Brain Taught Us About the Human Connectome: A Three-Level Model of Neural Disruption[END_REF]. Therefore, IEM may provide immediate insight into the dynamics of the brain connectome and accordingly can validate or invalidate cognitive models.

Observations gained from IEM challenged localizationism

In epileptic patients, direct IEM of Broca's area evidenced that this region, instead of being implied in speech production, was involved in verbal short-term memory and syntax [START_REF] Ojemann | Human language cortex: localization of memory, syntax, and sequential motor-phoneme identification systems[END_REF]. Similarly, in a consecutive series of 165 glioma patients, speech output was detected at the level of the ventral premotor cortex (vPMC), that is, the lateral part of the precentral gyrus, but not in the classical Broca's area [START_REF] Tate | Probabilistic map of critical functional regions of the human cerebral cortex: Broca's area revisited[END_REF]. These findings have recently been confirmed in 598 subjects who underwent awake surgery in different centers and who spoke distinct languages (French, English and Chinese): 917 speech arrest sites have been identified, with the peak of complete interruption of articulation which was located in vPMC [START_REF] Lu | Functional maps of direct electrical stimulations-induced speech arrest and anomia: a multicenter retrospective study[END_REF].

Interestingly, three other clusters were detected, in the dorsal precentral gyrus, the supplementary motor area (SMA) and in the junction posterior superior temporal gyrus/supramarginal gyrus (pSTG/SMG) [START_REF] Lu | Functional maps of direct electrical stimulations-induced speech arrest and anomia: a multicenter retrospective study[END_REF]. This supports the existence of a large network subserving articulatory processes, with subcortical white matter allowing connections between these cortical epicenters. Indeed, the vPMC is directly connected to the pSTG/SMG via layer III of the superior longitudinal fasciculus (SLF), as demonstrated by anatomic dissection in cadavers and by tractography [19]. In addition, speech arrest is also evoked by direct IEM of this subcortical tract, which represents the main bundle underpinning the articulatory loop [START_REF] Van Geemen | Limited plastic potential of the left ventral premotor cortex in speech articulation: evidence from intraoperative awake mapping in glioma patients[END_REF]. In the same vein, vPMC is connected to the SMA through the frontal aslant tract (FAT), with speech initiation disorders generated by IEM of this tract, eventually resulting in stuttering [START_REF] Kemerdere | Role of the left frontal aslant tract in stuttering: a brain stimulation and tractographic study[END_REF]. Taken as a whole, these results explained why the two seminal cases described by Broca experienced a permanent speech production deficit, i.e., because of injury to white matter connectivity, as structurally evidenced by magnetic resonance imaging (MRI) of these two brains [START_REF] Dronkers | Paul Broca's historic cases: high resolution MR imaging of the brains of Leborgne and Lelong[END_REF].

Using the articulation circuit as a paradigm, IEM also revealed that other functions were not subtended by a unique cortical site, but by distributed networks, such as: the semantic system with strong involvement of the inferior fronto-occipital fasciculus (IFOF), a main bundle of the human brain which connects the frontal lobe to the posterior temporal, occipital and even parietal cortices [START_REF] Duffau | New insights into the anatomo-functional connectivity of the semantic system: a study using cortico-subcortical electrostimulations[END_REF]; lexical access with main participation of the inferior longitudinal fasciculus (ILF) and to a lesser extent the posterior SLF, both converging to a hub located within the mid-to-posterior part of the left inferior temporal gyrus [START_REF] Herbet | Converging evidence for a cortico-subcortical network mediating lexical retrieval[END_REF]; reading underpinned by posterior ILF and the posterior segment of the arcuate fasciculus (AF), with convergence of these pathways to the visual word form area (VWFA) [START_REF] Zemmoura | New insights into the neural network mediating reading processes provided by cortico-subcortical electrical mapping[END_REF]; mentalizing (critical for social cognition) subserved by different pathways, including the AF involved in low-level perceptive-based mentalizing, the cingulate involved in high-level inference-based mentalizing, and the ventral stream involved in facial emotion recognition [START_REF] Herbet | Inferring a dual-stream model of mentalizing from associative white matter fibres disconnection[END_REF][START_REF] Yordanova | Neural pathways subserving face-based mentalizing[END_REF]; and so forth.

All these illustrations show the urgent need to forget localizationism and to move towards a connectomal view of brain functions relying on interactions across parallel and partly overlapped large-scale delocalized cortico-subcortical neural (sub)networks.

IEM and perioperative functional neuroimaging mapping to investigate neuroplasticity

Based upon such a dynamic framework of cerebral processing, it is now possible to conceive mechanisms of structural and functional reorganization which occur along the lifespan, essential in a physiological context, in particular for development and complex learning, but also critical in brain-damaged patients [START_REF] Duffau | Brain plasticity: from pathophysiological mechanisms to therapeutic applications[END_REF]. Neuroplasticity can be defined as an adaptive property of the brain in response to internal and environmental stimuli, as well as in response to cerebral insults, since it may permit some degrees of postlesional neurological recovery. This phenomenon has especially been observed in slow-growing lesions such as diffuse low-grade glioma (DLGG), a tumor able to generate considerable cerebral reshaping [START_REF] Duffau | Lessons from brain mapping in surgery for low-grade glioma: insights into associations between tumour and brain plasticity[END_REF]. First, morphologically, voxel-based morphometry investigation showed that DLGG can induce an increase of gray matter volume in the contralateral homologous area, for example within the contralesional insula in the event of insular DLGG [START_REF] Almairac | Contralesional macrostructural plasticity of the insular cortex in patients with glioma: A VBM study[END_REF]. Remarkably, such a structural reshaping may pave the way to functional redeployment, since it has been evidenced using resting-state functional imaging insular-centered DLGG, the occurrence of a significant increase of the contra-hemispheric insular functional connectivity (FC) [START_REF] Almairac | Homotopic redistribution of functional connectivity in insula-centered diffuse lowgrade glioma[END_REF]. Such findings support that -beyond the recruitment of perilesional structures which can play a role in functional compensation, as illustrated by IEMs which usually detect critical areas in the periphery of the glioma (serving as limits to surgical resection) -homotopic plasticity might also be rapidly engaged before any treatment when the amount of cerebral tissue damaged is too wide to be compensated for by the surrounding cortex. Indeed, many preoperative studies in glioma patients have observed a highlighted FC in the contralesional side, with regard to the motor network [START_REF] Cirillo | Role of Functional Imaging Techniques to Assess Motor and Language Cortical Plasticity in Glioma Patients: A Systematic Review[END_REF][START_REF] Mallela | Altered Resting-State Functional Connectivity in the Hand Motor Network in Glioma Patients[END_REF], the language network [START_REF] Wang | Group independent component analysis and functional MRI examination of changes in language areas associated with brain tumors at different locations[END_REF][START_REF] Li | Functional Translocation of Broca's Area in a Low-Grade Left Frontal Glioma: Graph Theory Reveals the Novel, Adaptive Network Connectivity[END_REF], the visuo-spatial network [START_REF] Liu | Contralesional homotopic functional plasticity in patients with temporal glioma[END_REF] or executive functions [START_REF] Liu | Structural and Functional Reorganization Within Cognitive Control Network Associated With Protection of Executive Function in Patients With Unilateral Frontal Gliomas[END_REF][START_REF] Maesawa | Evaluation of resting state networks in patients with gliomas: connectivity changes in the unaffected side and its relation to cognitive function[END_REF]. The underlying mechanism could be explained by a modulation in the transcallosal inhibition and inter-hemispheric competition generated by the glioma, as previously described in stroke [START_REF] Murase | Influence of interhemispheric interactions on motor function in chronic stroke[END_REF]. Importantly, while neurological compensation was usually possible as long as the contra-hemispheric FC was maintained, even in case of reduced FC within the lesioned hemisphere, studies which showed altered long-distance FC have noted a high rate of functional impairments [START_REF] Park | Alteration of long-distance functional connectivity and network topology in patients with supratentorial gliomas[END_REF].

Therefore, since reduced FC of the ipsi-lesional damaged network was regularly observed, such preoperative network redistribution opened the door to massive brain resections while preserving functional networks [START_REF] Duffau | Functional mapping before and after low-grade glioma surgery: a new way to decipher various spatiotemporal patterns of individual neuroplastic potential in brain tumor patients[END_REF]. Interestingly, acute intrasurgical functional reallocation has been detected by repeating the mapping throughout the tumor removal [START_REF] Duffau | Acute functional reorganisation of the human motor cortex during resection of central lesions: a study using intraoperative brain mapping[END_REF]. Finally, post-operative functional neuroimaging studies evidenced further degrees of reallocation compared to the preoperative mapping, with a new balance between the peritumoral critical structures detected by IEM and which constituted the functional boundaries of resection, and the contra-hemispheric homologous areas, concerning both movement [START_REF] Vassal | Recovery of functional connectivity of the sensorimotor network after surgery for diffuse low-grade gliomas involving the supplementary motor area[END_REF] and language [START_REF] Deverdun | Language reorganization after resection of low-grade gliomas: an fMRI task based connectivity study[END_REF]. By performing serial resting-state functional MRI before, immediately after awake surgery and three months later in order to investigate large-scale network reconfigurations, a transient immediate postsurgical inter-hemispheric homotopic FC reduction was found in cortical and subcortical structures, with a secondary increase of this inter-hemispheric functional homotopy at three months, especially in parietal lobes, the cingulum and the putamen [START_REF] Coget | Transient immediate postoperative homotopic functional disconnectivity in low-grade glioma patients[END_REF]. Moreover, cross-network integration may also be helpful for post-lesional recovery, particularly for more widely distributed functions, based upon interaction of hubs not only within but also between different neural networks -in accordance with the concept of variable neuro-displacement reported in recovery from post-stroke aphasia [START_REF] Stefaniak | The neural and neurocomputational bases of recovery from post-stroke aphasia[END_REF]. For example, naming compensation after surgery within the language circuit relied on stronger interactions with the semantic network and the fronto-parietal attentional network [START_REF] Van Dokkum | Resting state network plasticity related to picture naming in low-grade glioma patients before and after resection[END_REF]. To sum up, despite the prominent role of homotopic plasticity, there are nonetheless important variations in the patterns of neural rearrangement [START_REF] Duffau | Functional mapping before and after low-grade glioma surgery: a new way to decipher various spatiotemporal patterns of individual neuroplastic potential in brain tumor patients[END_REF].

Towards new models of cognitive neuroscience: the concept of meta-network

Revisitation of the interplay within and across functional systems

In this whole-brain approach, the first lesson of IEM is the existence of major interindividual anatomo-functional variability, as demonstrated both in epilepsy [START_REF] Ojemann | Cortical language localization in left, dominant hemisphere. An electrical stimulation mapping investigation in 117 patients[END_REF] and in neurooncology [START_REF] Tate | Probabilistic map of critical functional regions of the human cerebral cortex: Broca's area revisited[END_REF][START_REF] Sanai | Functional outcome after language mapping for glioma resection[END_REF]. However, such variations are much more important at the cortical level than at the subcortical level [START_REF] Duffau | A two-level model of interindividual anatomo-functional variability of the brain and its implications for neurosurgery[END_REF]. This is a critical architectural parameter, because it is correlated with neuroplastic potential, itself more developed cortically than subcortically (see the next chapter) [START_REF] Ius | Evidence for potentials and limitations of brain plasticity using an atlas of functional resectability of WHO grade II gliomas: Towards a "minimal common brain[END_REF].

In addition, IEM allowed a reappraisal of the neural foundations underlying each cortico-subcortical functional system and the intercommunication between them. Typically, complex movements are based on interactions across pyramidal systems devoted to motor execution and the network involved in motor control [START_REF] Rech | A probabilistic map of negative motor areas of the upper limb and face: a brain stimulation study[END_REF] -mostly mediated by the frontostriatal tract (FST) which links the "negative motor cortex" (eliciting arrest of ongoing movement without resolution of tonus during IEM) and deep gray nuclei [START_REF] Rech | Disruption of bimanual movement by unilateral subcortical electrostimulation[END_REF]. Moreover, to achieve complex movement, a multimodal somatosensory feedback is necessary via the thalamocortical tracts [START_REF] Rolland | Awake Surgery for Gliomas within the Right Inferior Parietal Lobule: New Insights into the Functional Connectivity Gained from Stimulation Mapping and Surgical Implications[END_REF] and through a more integrated level of bodily awareness [START_REF] Herbet | The antero-dorsal precuneal cortex supports specific aspects of bodily awareness[END_REF].

In the same vein, the language system relies on interplay between a dorsal stream and a ventral route [START_REF] Duffau | A re-examination of neural basis of language processing: proposal of a dynamic hodotopical model from data provided by brain stimulation mapping during picture naming[END_REF]. The dorsal pathway is itself based upon intercommunication between an articulatory loop mainly subserved by the layer III of the SLF (see above) and a phonological circuit mainly underpinned by the AF, which links the frontal areas mostly with the posterior part of the middle and inferior temporal gyri [19], and which generates conduction aphasia with phonemic paraphasia and repetition disorders during IEM [START_REF] Maldonado | Does the left superior longitudinal fascicle subserve language semantics? A brain electrostimulation study[END_REF]. The ventral stream is constituted by a direct pathway subserved by the IFOF and its widespread cortical terminations (causing semantic paraphasia when stimulated) [START_REF] Duffau | New insights into the anatomo-functional connectivity of the semantic system: a study using cortico-subcortical electrostimulations[END_REF] which communicates with an indirect pathway engaging the ILF (implicated in visual recognition, especially reading in its posterior part connecting the visual cortex to the VWFA [START_REF] Zemmoura | New insights into the neural network mediating reading processes provided by cortico-subcortical electrical mapping[END_REF] as well as in lexical access and its more anterior part connected to the basitemporal cortex [START_REF] Herbet | Converging evidence for a cortico-subcortical network mediating lexical retrieval[END_REF][START_REF] Herbet | Functional Anatomy of the Inferior Longitudinal Fasciculus: From Historical Reports to Current Hypotheses[END_REF]) and the uncinate fasiculus, which links the temporal pole to the orbitofrontal cortex, and which may cause deficit of proper name retrieval when damaged [START_REF] Papagno | Long-term proper name anomia after removal of the uncinate fasciculus[END_REF].

The same paradigm may be declined for other functions, such as: visuo-spatial cognition (interaction across visual system and spatial awareness, mainly mediated by layer II of the right SLF which links the frontal cortex with the parieto-temporal junction [START_REF] De Schotten | Direct evidence for a parietal-frontal pathway subserving spatial awareness in humans[END_REF]); the non-verbal semantic system relying on a bilateral network involving both IFOF and its cortical terminations [START_REF] Moritz-Gasser | Mapping the connectivity underlying multimodal (verbal and non-verbal) semantic processing: a brain electrostimulation study[END_REF], particularly the right and left dorsolateral prefrontal cortices [START_REF] Herbet | Electrical stimulation of the dorsolateral prefrontal cortex impairs semantic cognition[END_REF]; the mentalizing system based upon the interplay between the dorsal stream, constituted by parallel circuits (right AF and its cortical terminations involved in theory of mind, cingulate implicated in the attribution of others' intentions [START_REF] Herbet | Inferring a dual-stream model of mentalizing from associative white matter fibres disconnection[END_REF]), and the ventral route underlying facebased mentalizing [START_REF] Yordanova | Neural pathways subserving face-based mentalizing[END_REF][START_REF] Herbet | Awake Craniotomy and Bedside Cognitive Mapping in Neurosurgery[END_REF]; the executive system underpinned by fronto-parietal network mainly relying on the SLF [START_REF] Cochereau | Network-behavior mapping of lasting executive impairments after low-grade glioma surgery[END_REF] but also with the involvement of cortico-subcortical projection pathways such as the FST (typically evoking perseverations when the input to the head of the caudate is disrupted by IEM [START_REF] Mandonnet | Electrically induced verbal perseveration: A striatal deafferentation model[END_REF]); and so on… Taken as a whole, these IEM findings which provide complementary data to the neuroscience literature based upon functional neuroimaging sounds the death knell of localizationism and invites us to revisit the classical models of cognition.

A meta-network perspective

Beyond the interplay across multiple subcircuits forming one specific functional system -e.g. coordination between the left articulatory loop, the dorsal phonological stream, and the ventral verbal semantic route (without mentioning subcircuits devoted to syntax or to prosody) forming language function -at a more integrated level, global and multimodal intercommunication between relatively specialized networks sustaining conation, cognition and emotion is necessary to make appropriate behavior possible. Indeed, to explain the propensity of the human brain for complex learning and creativity, a meta-network perspective, i.e. an organization founded on a network of networks has been introduced [START_REF] Herbet | Revisiting the functional anatomy of the human brain: Toward a meta-networking theory of cerebral functions[END_REF].

According to this concept, brain processes rely on a perpetual succession of new equilibrium states, constituting a breeding ground for behavior adapted to moment-to-moment environmental influences. Various combinations of intra-and inter-network spatiotemporal integration, based on constant changes in synchronization between multiple cortical regions widely distributed over both hemispheres and interconnected by white matter tracts, result in a meta-network transitorily generated to reach a complex goal (Fig. 1). This continuous switch from highly segregated to highly integrated neural functioning provides the flexibility needed for maturation and acquisition of new skills in physiological conditions, as well as for some degrees of neurological compensation in brain-damaged patients. Interestingly, such an infinity of spatiotemporal patterns across specialized and more integrated networks paves the way for an infinitude of creative behaviors [START_REF] Herbet | Revisiting the functional anatomy of the human brain: Toward a meta-networking theory of cerebral functions[END_REF].

In order to study the interactions between networks, IEM can be used in awake patients performing multitasking, which necessitates the simultaneous recruitment of several neural circuits. When multimodal hubs are stimulated, as for example the dorsolateral prefrontal cortex, although the patient can continue to achieve each task separately, he/she can no longer achieve all the tasks simultaneously, due to a transient disruption of the communication across networks, even though each functional system is still able to work alone [START_REF] Duffau | What Direct Electrostimulation of the Brain Taught Us About the Human Connectome: A Three-Level Model of Neural Disruption[END_REF]. In addition, functional neuroimaging may also be used before and after resection, with the aim of investigating changes induced by the tumor and then surgery in the interplay between circuits underpinning various functions and allowing complex behavior, such as dialogue across the default-mode network, the executive control network, and the salience network [START_REF] Duffau | Functional mapping before and after low-grade glioma surgery: a new way to decipher various spatiotemporal patterns of individual neuroplastic potential in brain tumor patients[END_REF].

Implications for the best care of brain-damaged patients

Improved functional and oncological outcomes in glioma patients

Regarding clinical implications in neurosurgery, this better knowledge of dynamic cross-network interactions sustaining brain functions led to a paradigmatic shift, from traditional image-guided resection to connectome-based resection. In brain tumor patients, this means that part of the parenchyma invaded by neoplastic cells is removed up to functional circuits, identified by means of IEM at cortical and axonal levels, thus taking into account the individual network reconfiguration induced by the growing lesion, which had already occurred prior to surgery. In practice, this means that awake mapping should be achieved systematically, regardless of tumor location, by adapting intraoperative behavioral monitoring to the patient's own definition of his/her quality of life [START_REF] Duffau | Brain connectomics applied to oncological neuroscience: from a traditional surgical strategy focusing on glioma topography to a meta-network approach[END_REF]. Optimized selection of tasks to be performed during the resection must be determined à la carte, according to the patient's own personal needs (based on occupation, leisure activities, lifestyle, and so forth) and environment [START_REF] Duffau | New philosophy, clinical pearls and methods for intraoperative cognition mapping and monitoring "à la carte" in brain tumor patients[END_REF].

By applying this new concept to glioma surgery, the risk of generating severe permanent neurological deficit declined dramatically, with a rate less than 2% in series with awake mapping [START_REF] Sanai | Functional outcome after language mapping for glioma resection[END_REF][START_REF] Duffau | Intraoperative subcortical stimulation mapping of language pathways in a consecutive series of 115 patients with Grade II glioma in the left dominant hemisphere[END_REF][START_REF] Boetto | Low rate of intraoperative seizures during awake craniotomy in a prospective cohort with 374 supratentorial brain lesions: electrocorticography is not mandatory[END_REF]. Furthermore, post-operative objective neuropsychological assessment compared with preoperative examination demonstrated that cognitive scores were stable in the vast majority of patients, including for complex functions such as metacognition (knowledge of knowing) [START_REF] Lemaitre | Preserved metacognitive ability despite unilateral or bilateral anterior prefrontal resection[END_REF], and even with possible improvements at least in some domains [START_REF] Barzilai | Improvement in cognitive function after surgery for low-grade glioma[END_REF][START_REF] Ng | Neuropsychological assessments before and after awake surgery for incidental low-grade gliomas[END_REF][START_REF] Duffau | Updated perspectives on awake neurosurgery with cognitive and emotional assessment for patients with low-grade gliomas[END_REF]. In addition, over 97% of patients returned to work after surgery, including when they had undergone resection for incidentally discovered glioma [START_REF] Ng | Return to Work Following Surgery for Incidental Diffuse Low-Grade Glioma: A Prospective Series With 74 Patients[END_REF]. Finally, quality of life can also be improved by controlling seizures in glioma patients suffering from presurgical epilepsy [START_REF] Pallud | Epileptic seizures in diffuse low-grade gliomas in adults[END_REF][START_REF] Ghareeb | Intractable epilepsy in paralimbic Word Health Organization Grade II gliomas: should the hippocampus be resected when not invaded by the tumor?[END_REF]. It is worth noting that these favorable functional outcomes have been obtained also for neoplasms infiltrating structures deemed inoperable in a localizationist framework, especially Broca's area (Fig. 2), Wernicke's area, Rolandic region, and so on [START_REF] Duffau | The huge plastic potential of adult brain and the role of connectomics: New insights provided by serial mappings in glioma surgery[END_REF][START_REF] Benzagmout | Resection of World Health Organization Grade II gliomas involving Broca's area: methodological and functional considerations[END_REF][START_REF] Plaza | Speaking without Broca's area after tumor resection[END_REF][START_REF] Lubrano | What makes surgical tumor resection feasible in Broca's area? Insights into intraoperative brain mapping[END_REF][START_REF] Rolston | Frontal operculum gliomas: language outcome following resection[END_REF].

From an oncological perspective, early and maximal resection (even with possible "supramaximal" excision when functionally feasible, that is, extending beyond the FLAIRabnormality visible on the preoperative MRI [START_REF] Yordanova | Awake surgery for WHO Grade II gliomas within "noneloquent" areas in the left dominant hemisphere: toward a "supratotal" resection[END_REF]) resulted in a significant increase in overall survival, both in high-grade gliomas [START_REF] Zigiotto | Effects of supra-total resection in neurocognitive and oncological outcome of high-grade gliomas comparing asleep and awake surgery[END_REF][START_REF] Esquenazi | The Survival Advantage of "Supratotal" Resection of Glioblastoma Using Selective Cortical Mapping and the Subpial Technique[END_REF] and DLGG -with a life expectancy now over 15 years [START_REF] Capelle | Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases: clinical article[END_REF][START_REF] Obara | Adult diffuse low-grade gliomas: 35-year experience Nancy France neurooncology unit[END_REF][START_REF] Hamdan | Extending the multistage surgical strategy for recurrent initially low-grade gliomas: functional and oncological outcomes in 31 consecutive patients who underwent a third resection under awake mapping[END_REF] instead of six to seven years two decades ago [START_REF] Pignatti | Prognostic factors for survival in adult patients with cerebral low-grade glioma[END_REF][START_REF] Van Den Bent | Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial[END_REF]. Furthermore, second and even third operations -achieved in situations where complete DLGG resection during a first surgery was precluded by critical infiltration of brain structures, subsequently followed by months or years of cerebral reallocation -have been able to extend the resected area while preserving quality of life because of the postsurgical functional reshaping that had occurred in the meantime [START_REF] Hamdan | Extending the multistage surgical strategy for recurrent initially low-grade gliomas: functional and oncological outcomes in 31 consecutive patients who underwent a third resection under awake mapping[END_REF][START_REF] Robles | Long-term brain plasticity allowing a multistage surgical approach to World Health Organization Grade II gliomas in eloquent areas[END_REF][START_REF] Picart | Iterative Surgical Resections of Diffuse Glioma With Awake Mapping: How to Deal With Cortical Plasticity and Connectomal Constraints[END_REF]. Based on these optimized oncological and neurological outcomes, general population screening has recently been proposed, paving the way to "preventive functional surgical neuro-oncology" [START_REF] Duffau | Higher-Order Surgical Questions for Diffuse Low-Grade Gliomas: Supramaximal Resection, Neuroplasticity, and Screening[END_REF].

Probabilistic atlases of critical networks and neuroplastic potential

It is nonetheless worth noting that such results can be achieved only by taking into consideration the limitations of plastic potential. As mentioned, the dynamic framework with continuous changes of intra-and inter-circuits spatiotemporal integration can lead to longlasting modulations of network properties, including use-dependent and postlesional neuroplasticity. However, this capacity of network redeployment is not infinite after cerebral injury, especially at the level of white matter connectivity. This is illustrated by the fact that before any treatment in glioma patients, neurocognitive impairments, which can be detected at diagnosis thanks to extensive neuropsychological evaluation, are correlated with tumoral migration along the main subcortical pathways -as semantic disorders due to invasion of the left IFOF [START_REF] Almairac | The left inferior fronto-occipital fasciculus subserves language semantics: a multilevel lesion study[END_REF], or visuo-spatial deficits because of involvement of the right SLF [START_REF] Liu | Alterations of white matter integrity associated with cognitive deficits in patients with glioma[END_REF]. In the same spirit, correlations across intrasurgical IEM, functional-guided surgical DLGG resection, and cognitive results have resulted in the development of several probabilistic atlases of cortico-subcortical neural networks critical for brain functions (conversely to atlases based on functional neuroimaging that are unable to distinguish between essential and compensable structures) [START_REF] Tate | Probabilistic map of critical functional regions of the human cerebral cortex: Broca's area revisited[END_REF][START_REF] Sarubbo | Towards a functional atlas of human white matter[END_REF]. Recently, on the basis of 1,162 cortical and 659 subcortical highly-specific IEM-derived responses during real-time neuropsychological testing of 16 functional domains in 256 patients who underwent awake surgery, the first integrated and comprehensive cortico-subcortical atlas of structures critical for human brain functions was computed in the Montreal Neurological Institute (MNI) template [START_REF] Sarubbo | Mapping critical cortical hubs and white matter pathways by direct electrical stimulation: an original functional atlas of the human brain[END_REF]. Moreover, a probabilistic atlas of functional plasticity derived from both anatomic MRI results and IEM data from 231 awake-operated DLGG patients has been generated (also in the MNI template): these unique findings demonstrated that plastic potential is high in the cortex while rather low in connective associative and projection tracts [START_REF] Herbet | Mapping neuroplastic potential in brain-damaged patients[END_REF]. These findings have resulted in the definition of a "minimal common brain", mostly composed of primary unimodal cortical areas (such as visual and somatosensory input or motor output) and a small subset of neural hubs (such as the dorsolateral prefrontal cortex) as well as white matter fibers, with low interindividual variability and low post-lesional compensation potential [START_REF] Ius | Evidence for potentials and limitations of brain plasticity using an atlas of functional resectability of WHO grade II gliomas: Towards a "minimal common brain[END_REF]. Interestingly, this "structural and functional skeleton" of the brain constitutes a cornerstone for surgical selection and planning. For example, a multistage surgical approach seems possible when glioma regrowth mainly involves high-plastic cortical structures, but not in the event of wide diffusion in subcortical bundles: optimal indications for second and third operations can be determined by taking into consideration such connectomal constraints [START_REF] Hamdan | Extending the multistage surgical strategy for recurrent initially low-grade gliomas: functional and oncological outcomes in 31 consecutive patients who underwent a third resection under awake mapping[END_REF][START_REF] Picart | Iterative Surgical Resections of Diffuse Glioma With Awake Mapping: How to Deal With Cortical Plasticity and Connectomal Constraints[END_REF].

Finally, besides their fundamental implications in neuroscience and their neurosurgical applications, these atlases can also be valuable in predicting the likelihood of recovery in various neurological diseases (e.g. after stroke), a critical parameter for improving the care of brain-damaged patients. In addition, improved knowledge of between-network coordination might help to better understand mechanisms underlying progressive installation of highly integrative cognitive deterioration, such as disruption of intra-and interhemispheric FC in degenerative dementia [START_REF] Filippi | Brain network connectivity differs in early-onset neurodegenerative dementia[END_REF][START_REF] Pievani | Functional network disruption in the degenerative dementias[END_REF].

Implications for neuro-rehabilitation

Neuro-rehabilitation can improve FC across specific regions within a given specialized circuit and may result, at least to some extent, in behavioral improvement after cerebral insult such as traumatic brain injury, stroke or glioma [START_REF] Desowska | Dynamics of brain connectivity after stroke[END_REF][START_REF] Richard | Cognitive rehabilitation for executive dysfunction in brain tumor patients: a pilot randomized controlled trial[END_REF]. This dynamic metanetworking approach can be a precious contribution to the prediction of FC reconfiguration patterns and thus to the elaboration of appropriate cognitive remediation strategies. For instance, a better analysis of mechanisms explaining postlesional language disorders may lead to adapt therapeutic interventions. Indeed, as mentioned, the language circuit is not a unitary entity, but rather a composition of several subcircuits (including dorsal and ventral streams) that need the engagement of other networks -especially sustaining executive functions and attentional processing -for optimal efficiency. Therefore, neuro-rehabilitation programs designed to normalize inter-circuit communication should take into account the disrupted language processes (e.g., with the aim of reinforcing the ventral route in the event of damage involving the dorsal pathway) as well as their disconnection with the other networks [START_REF] Herbet | Revisiting the functional anatomy of the human brain: Toward a meta-networking theory of cerebral functions[END_REF]. To illustrate this principle, longitudinal functional MRI investigations before and after DLGG surgery close to language networks have demonstrated that patients given cognitive therapy recovered by intra-system modulation and inter-systems interplay [START_REF] Deverdun | Language reorganization after resection of low-grade gliomas: an fMRI task based connectivity study[END_REF][START_REF] Van Dokkum | Resting state network plasticity related to picture naming in low-grade glioma patients before and after resection[END_REF]. Typically, naming improvement was dependent on the recruitment of semantic and fronto-parietal attentional circuits, demonstrating that language cannot be rehabilitated in isolation [START_REF] Van Dokkum | Resting state network plasticity related to picture naming in low-grade glioma patients before and after resection[END_REF]. In the same vein, serial functional MRI studies in epilepsy surgery have shown compensation of verbal memory troubles by using intact nonverbal memory abilities thanks to tailored cognitive remediation programs [START_REF] Mosca | Rehabilitation of verbal memory by means of preserved nonverbal memory abilities after epilepsy surgery[END_REF]. Thus, the goal is to restore a new equilibrium between networks to permit functional recovery.

Perspectives in functional restoration

Interestingly, neuroplasticity could also be facilitated by means of repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS), able to neuromodulate cortical excitability into an inhibitory or excitatory direction, leading to improvement of behavioral performances in healthy volunteers as well as in brain-damaged patients [START_REF] Fiori | Transcranial direct current stimulation improves word retrieval in healthy and nonfluent aphasic subjects[END_REF]100]. For instance, by using excitatory stimulation of perilesional areas in aphasic patients, anodal tDCS of the left inferior frontal gyrus allowed an improvement of speech, Such a meta-network perspective could also be applied to brain-machine interfaces, which consists in recording and decoding neural signals emanating from cognitive states, e.g. imagined movement or language, with the aim of translating these biosignals into a devicecontrol (robotic limb or exoskeleton) or speech output, respectively [111,112]. Yet, so far, following a localizationist viewpoint, a unique array has commonly been implanted over the primary motor cortex or speech cortex [113,114]. Remarkably, taking a connectomal approach might suggested that several electrodes could be placed over multiple cortical areas disconnected by brain insult, resulting in cognitive deterioration, in order to restore inter-area communication. The selected hubs could belong to the same (sub-)network but also to distinct (sub-)networks according to the function(s) lost after the brain damage: interfacing these epicenters might facilitate recovery based upon re-synchronization within and across neural circuits via an external computer [115].

Conclusive remarks

In a reductionist localizationist framework, the traditional anatomo-functional approaches to explore neural foundations mediating higher-order, multi-determined cognitive dysfunctions in brain-damaged patients are very limited. They are poorly adapted to investigate how complex cognitive impairment may result from a cerebral lesion, particularly when it involves heteromodal cortices and/or the white matter connectivity [116]. A metanetworking model facilitates understanding of behavioral disturbances in reaction to brain injury, as the consequence of disrupted intra-and inter-system communication [START_REF] Herbet | Revisiting the functional anatomy of the human brain: Toward a meta-networking theory of cerebral functions[END_REF]. Such better comprehension could be very useful for improving care of patients suffering from neurological diseases, by tailoring individual multimodal therapeutic strategies not only to the nature and course of the lesion, but also to the instability of the connectome and the constant re-adaptation of the large-scale distributed cortico-subcortical networks. To this end, it is time to reinforce the synapse between clinical neurology and basic neurosciences.

Figure legends

Figure 1: The meta-networking approach of complex cerebral functionsfrom [START_REF] Mandonnet | Electrically induced verbal perseveration: A striatal deafferentation model[END_REF] Basic sensory inputs are processed 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 are 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. -at the cortical level, 1, 2 and 3 marked the left ventral premotor cortex (lateral part of the precentral gyrus), which elicited speech arrest during IEM; of note, the rest of the cortical mapping performed before resection was negative, including over the left inferior gyrus, allowing its removal; -in addition to the critical cortical areas, IEM of white matter tracts allowed the detection of the following subcortical neural networks:

. 50, evoking articulatory disorders during IEM, corresponding to the anterior part of the layer III of the SLF, running to the ventral premotor cortex;

. 49, generating semantic paraphasias during IEM, corresponding to the frontal part of the IFOF, running to the dorsolateral prefrontal cortex;

. 48, eliciting language initiation disturbances during IEM, corresponding to the FAT, running to the SMA (surgically preserved since not invaded by the glioma).

  naming and repetition[101,102]. Nonetheless, these non-invasive stimulations induce changes of the FC in a larger network, by playing with complex interactions across the ipsilesional, contralesional and interhemispheric connectivity [103]: as a consequence, inhibitory low-frequency rTMS has also been achieved over contralateral homotopic language regions to potentiate poststroke recovery[104,105].As future prospects, by applying the concept of metaplasticity (that is, changes in the ability to induce subsequent synaptic plasticity) based upon the principle that the current state of the neuron depends on past states induced by separate prior events [106], use of rTMS or tDCS could be considered during a first period to achieve a priming effect [107] before a subsequent period of neuro-stimulation. The first series demonstrated that the tDCS/TMS priming protocol improved functional results compared to protocols without priming[108]. Furthermore, combining rTMS and constraint-induced cognitive rehabilitation may potentiate the recruitment of compensatory circuits and subsequently enhance functional outcomes, in particular in aphasia[109]. To sum up, neuromodulation of between-network coordination by non-invasive stimulation, based on a better understanding of mechanisms underlying IEM and its behavioral consequences on the neural connectivity[110], might be helpful to improve recovery following brain injury.

Figure 2 :

 2 Figure 2: Awake resection of a left frontal DLGG involving Broca's area

Fig 1B :

 1B Fig 1B: Intraoperative view after resection in awake patient. The anterior part of the

  Small arrow = precentral sulcus; long arrow = central sulcus; yellow circle = previous location of the pars opercularis which has been removed; yellow triangle = previous location of the pars triangularis which has been removed.

Fig 1C :

 1C Fig 1C: Postoperative sagittal enhanced T1-weighted MRI (left) and axial enhanced

Funding

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Disclosure of interest

The author declares that he has no competing interest.