Pauline Cuisenier

Soutenue These

A Publiquement

Faculte La

De Medecine De Grenoble

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Devant Le

Monsieur Le Professeur

Philippe Kahane

Membres Madame Le Professeur

Monica Baciu

Madame Le Professeur

Elena Moro

Madame Le Professeur

Agnès Trebuchon

Madame Le Docteur

Marcela Perrone-

COMPARISON OF INDUCED GAMMA BAND RESPONSES TO ELECTRO-CORTICAL STIMULATION AND FUNCTIONAL MRI DURING A LANGUAGE TASK: ARE THEY REDUNDANT OR COMPLEMENTARY TO ASSESS COGNITIVE POST-OPERATIVE OUTCOME IN EPILEPSY SURGERY ?

Apport des activités cérébrales gamma comme méthode de cartographie fonctionnelle et marqueur du devenir cognitif dans le bilan pré-chirurgie de l'épilepsie. Comparaison avec les stimulations électriques cérébrales et l'IRM fonctionnelle lors d'une tâche de langage.

A celles et ceux qui ont permis la réalisation de ce travail :

A Pierre Deman, un immense merci pour ton temps et ton aide sans lesquels ce travail n'aurait pas abouti. Merci également de ta patience face à mes ignorances informatiques. A IntrAnat Electrodes qui aura grandi en parallèle de ce travail.

A Bénédicte Testud, qui a rejoint ce projet en route. Merci de ton aide précieuse pour le traitement des données IRMf.

A Alexis Robin. Merci d'avoir lu avec moi 48956 cartes gamma, plutôt 5 fois qu'une, (soit 244 780 cartes…) Continue comme ça car on te veut dans l'équipe neurogrenoble ;-) A Lorella Minotti, pour son enseignement rigoureux de la neurologie et son hospitalité à l'italienne ainsi qu'à toute l'équipe du laboratoire d'Exploration et de Neurophysiopathologie de l'Epilepsie pour son accueil et son aide tout au long de ce projet mais également de mon internat : Marie-Pierre Noto et Patricia Boschetti pour leur soutien quasi maternel et Valérie Damon pour son organisation impeccable et bienveillante.

Au Professeur Alexandre Krainik. Merci de m'avoir donné accès aux données IMR. Merci de votre enseignement durant mon semestre à vos côtés en neuroradiologie.

Enfin, à tous les patients qui ont accepté de participer à ce projet.

A celles et ceux m'ont encadrée et entourée au cours de mon internat :

Aux équipes médicales : -De neurologie du CHU de Grenoble ; merci de m'avoir aidé au cours de ces quatre années d'internat, tout en partageant votre savoir et votre expérience clinique. Je suis heureuse de rejoindre vos équipes et de pouvoir continuer à apprendre à vos côtés. -De neuroradiologie du CHU de Grenoble : les Drs Grand, Tahon, Kastler et Heck ; vous m'avez beaucoup appris durant mon semestre à vos côtés. Au Dr Arnaud Attye, qui aura réussi à me faire aimer le scanner ORL (ok je n'ai pas tout compris). J'espère que notre projet commun aboutira.

A Anne Sophie Job-Chapron. Merci de ton soutient bienveillant et de tes conseils avisés, cette année, et tout au long de mon internat. Tu es notre exemple à tous ! A Mathieu Vaillant. Mon grand frère neurologue qui a guidé mon choix post ECN. Merci de m'avoir vendu du rêve, tu ne m'avais pas menti ! A ta petite famille en croissance que j'aime tant.

A Isabelle Favre, ma première assistante. Au cours de mon semestre à tes côtés, tu m'as appris à être une interne rigoureuse. Merci de m'avoir donné l'envie de continuer.

A Olivier Casez dit papa Casez. Tu es celui que l'on consulte pour ses connaissances neurologiques mais également oenologiques, pour ses bonnes adresses ou sa grande expérience culinaire. Merci d'avoir facilité mon quotidien à de nombreuses reprises ; du vélo de la grand-mère jusqu'à la recette de la tarte aux fraises-mascarpone en passant par les doublures de mes gardes ! Travailler avec vous est une chance, j'espère en profiter au maximum.

Aux équipes paramédicales, AS, IDE, MKDE, avec qui j'ai beaucoup partagé : tout particulièrement Sabrina, Lydie, Juliette et Emilie qui m'ont appris à gérer un patient à mes débuts, A maman Maryse et notre amour commun pour gwada. A l'équipe d'HDJ, meilleur service du monde pour petit-déjeuner, déjeuner, goûter, prendre le thé, diner (ah non c'est fermé à cette heure-là) mais aussi pour travailler ! A toute l'équipe de Neuro A, qui tremble, freeze, chante, et crise. Au manips de neuroradio, pour leur bonne humeur !

A Mes Co-Internes :

A Sébastien pour tes talents de craqueur de logiciels et tes cours improvisés de Word et Zotero. Ton oreille attentive et neutre a su guider mon chemin. Merci de ton soutient.

A Clémentine pour avoir STABILOté le terrain et les joysticks mais surtout pour ton amitié. Les rôles de Marco et Luigi, déboucheurs de tuyau nous ont liées à jamais, tellement que nous en inventions des thrombolyses. Merci d'avoir été là dans les moments difficiles.

A Jérémie, allias Anselme papapoussin. Nous avons formé le binôme qu'il ne fallait pas croiser en avis « elle a fait l'attaque ! », le binôme de choc en HDJ « nous voulons du fromage, et un peu de sucre en poudre », et formerons un binôme de choc en tant que CCA, je l'espère.

A Nastasia, qui m'a supportée et soutenue en période de thèse. Tu es l'amie sincère qu'il faut avoir, parfois brutale mais mais qui fait avancer. T'avoir à mes côtés ce semestre m'a été précieux.

A Marie qui me fait tant rire. Merci de m'apporter ton petit brin de légèreté et ton ouverture au monde extramédicale. Prochaines étapes ensemble : Saint-Egrève et le Mont Aiguille.

A Fanny, j'ai eu la chance de réviser le DIU de Neurophysiologie à tes côtés, avec succès. Merci d'avoir accepté mon cadeau empoisonné ! A Anne la voyageuse à bicyclette, spécialiste des bonnes attentions. A Giovanni merci pour la découverte de petit biscuit longuement écouté durant la rédaction de ce travail. A Sarah la souriante, Guillaume le voyageur, la belle Hélène, Thomas le taquin. Aux plus jeunes Lucie, Loïc et Hugo qui écriront la suite.

A Francesco Cavallieri, il mio professore d'italiano. Grazie per il suo regalo de un pocco della Dolce Vita.

A mes co-interne neuroradiologues, « la dream team » : Yann, avec qui j'ai découvert le TDM des rochers et surtout décrit le phénomène Pink Floyd en scanner. Corentin, le plus drôle, ne change rien ! Pierre le plus gentil et attentionné des co-interne ever.

A ceux qui ont facilité mon travail au quotidien :

Les ophtalmologues : Fréderic et Georges toujours partant pour une OCT rapide. Les cardiologues : Aure-Elise et Adrien qui m'ont dépanné plus d'une fois face à un ECG ou pour une ETT. Les psychiatres, membres du feu cercle des neuro-psy : Benoit Rumbach et Fabien Droux pour leur sens de l'humour et leurs connaissances toujours à la pointe. Anaïs Dartevel : une belle rencontre tardive de mon internat ;-). Aux heures passée ensemble à discuter jupon, étoilés, mais également anticorps anti PDC. A Sébastien Baillieul : ton optimisme et ta solidarité font de toi une personne à rencontrer absolument ! Et surtout les radio-imageurs : Amis qu'il fait bon retrouver en garde mais surtout en terrasse ou autour d'un d'une tarte citron-meringuée ; la mafia dijonnaise (Mathew et René dit Rooney), Perol, et enfin Moumoune, last but not least, à condition que tu ne me piques pas mon mec.

A mes maitres d'externat

Au Professeur Chavanet, qui m'a montré le bon chemin, et a marqué mes études de médecine. Au Professeur Giroud, qui a créé des vocations chez plusieurs générations d'externe dont la mienne. A JFM grâce à qui nous avions un mental de guerrier. A Pifu, qui nous a confié les clefs de son bureau pendant 2 ans, ce qui nous a permis d'atteindre nos objectifs ;

A Mes Amis

De Carnot, nos si belles années :

Ben et sa tchach, Garzai qui disparaît dès qu'on le retrouve, Nayef le bon conseiller qui vous veut du bien, Romblax le joyeux voyageur, la belle Morgane, Eric Hockety pockety wockety wock. Charlène, alias Charlou, du collège à la fac on en a partagé des moments ensemble ! Paul, avec qui la P1 fut adoucie par Plus belle la Vie. Vincent, notre pharmacien préféré au regard ravageur, membre de la bienveillante famille Vaillant.

A Pierre Emmanuel, Pilou, mon jumeau de P1, membre du cercle « auto-proclamé » du Jurançon. A nos samedi soir à Gallien à réviser la biocellulaire. Tu étais déjà le meilleur ! Alexia et toi êtes un couple que j'admire pour son courage. Qu'Alaska vous apporte beaucoup de bonheur…Et des nuits calmes.

A Louis, qui a été là de Carnot à la fac, en passant par l'Irlande, Paris et j'en passe. Merci pour ces séances intenses de révisions, tous les dimanches soir, avec ou sans macaron. Nabiha et toi m'avez beaucoup apportée.

A Jean Baptiste, « Rien ne vaut le trésor de tant de souvenirs communs, de tant de brouilles, de réconciliations, de mouvements du coeur. On ne reconstruit pas ces amitiés-là. » A. de St Ex.

A Victor, mon binôme de choc de toujours. Merci de ton amitié sans faille qui m'est si précieuse. A ta Mathilde.

A Ma Famille

A mes parents, Je vous remercie pour votre soutien permanent, et votre amour et pour tout ce que vous m'avez transmis ; la curiosité, l'amour des voyages, la culture des belles choses, l'envie d'apprendre. Papa, puis-je espérer un jour être aussi admirée et respectée de mes patients que toi. Maman, merci de m'avoir transmis ta sensibilité et ton sourire.

A ma grand-mère, pour son amour Au Pad. Tu souhaitais que tes petits enfants sachent encore utiliser un BIC, rassures toi ! J'espère que tu es fier de nous. Et à ceux parti trop tôt sans qui je n'aurais pas été là.

A ma famille, aux Lugnier et Curie ainsi qu'aux Elnécavé et Hubert qui dans mon coeur en font partie. A ma filleule Lucie. Vous êtes venu de loin pour me soutenir. Merci de toutes vos attentions.

To my Australian family, Kathy and Eric. I am very grateful for your help on this work and for your love.

Aux Maillot, ma deuxième famille. A Anne et Bernard, je vous remercie de votre accueil si chaleureux que ce soit à Dijon, à la mer ou à la montagne. A Clémence, Maud et Nicolas, avec qui je vais apprendre ce que c'est que d'avoir des frères et soeurs. J'espère que je serai à la hauteur.

A Olivier

A nous deux toujours plus, toujours plus vite, les pieds sur terre, la tête dans les nuages, cela promet…Les clefs n'ont qu'à bien se tenir. Merci d'être aussi joyeux, de déborder de projets et d'idées en tout genre, et surtout de me faire autant rire. A tes cotés tout est possible. Merci de t'être battu. Je t'aime.

Table of contents

Abstract

Rationale: Like any brain surgery, epilepsy surgery can have various negative effects on cognition and behaviour. The best way to anticipate post-operative deficits is to test, before surgery, the 'functional integrity' of the brain. Different methods can be used for that purpose, including neuropsychological testing, functional neuroimaging (fMRI), and Electro-Cortical Stimulation (ECS). None of these approaches, however, has been proved accurate enough to reliably anticipate the risks of postoperative cognitive deficits.

Study aims: This last decade, intracranially recorded task-related Gamma Band Responses (GBR) has emerged as a putative biomarker of various cognitive processes. The present study aimed at comparing the GBR method with the classical fMRI and ECS procedures for localizing language functions, and at evaluating whether the removal of brain tissue exhibiting GBR might have significant consequences on language processing. Methods: Fourteen epileptic patients who underwent stereotactic intracerebral EEG (SEEG) recordings and who were subsequently operated on were included in the study. SEEG signals were recorded while the patients performed a language task involving two different language processes: semantic and phonologic. Language-related GBR (50-150 Hz) were analysed at every recording site, and compared with the results of ECS-elicited clinical responses. These findings were also compared with the results of fMRI language assessment in a sub-group of 6 patients. Post-operative language outcome was evaluated in patients in whom at least one GBR+ site was resected versus those in whom no GBR+ site was resected.

Results: GBR predicted ECS language interference with a high specificity (92.4%) and negative predictive value (NPV, 95.5%), but with a low sensitivity (11.7%) and positive predictive value (PPV, 7.4%). Similar findings, although a little bit weaker, were found when comparing GBR and fMRI (specificity: 89.2%, NPV: 84.7%, sensitivity: 8.4%, PPV: 12.2%). Resections that included GBR+ sites, as compared with resections that spared GBR+ sites, did not show any significant language decline both in semantic and phonological conditions. Only a few patients, however, had a resection that included GBR+ sites (n=2 for semantic condition, n=2 for phonological condition).

Conclusion:

GBR mapping appears as a useful tool for pre-surgical evaluation of language functions, complimentary to ECS, that might be used to build a preliminary functional map to reduce the duration of ECS sessions. Although preliminary, these findings emphasise the benefit of a multimodal screening for language features before epilepsy surgery. Keywords: epilepsy surgery; stereo-electroencephalography; gamma band response; brain functional mapping; language 1. Introduction Resective surgery is the only treatment able to suppress drug-resistant seizures in epileptic patients. This therapeutic surgery is possible only if the Epileptogenic Zone (EZ) is focal, clearly identified, and can be safely removed [START_REF] Kahane | La zone épileptogène[END_REF] for a review of EZ definition). The identification of the EZ, and the evaluation of its functional integrity is a difficult process which requires intracranial EEG (iEEG) recordings in 25-50% of the cases. However, even when using such iEEG information, epilepsy surgery still fails in a substantial ratio of patient (Téllez-Zenteno, 2010), and post-operative cognitive/psychiatric deficits still exist in a significant number of the cases [START_REF] Baxendale | Predicting memory decline following epilepsy surgery: a multivariate approach[END_REF][START_REF] Helmstaedter | Neuropsychological aspects of epilepsy surgery[END_REF], especially for language processes [START_REF] Sherman | Neuropsychological outcomes after epilepsy surgery: Systematic review and pooled estimates[END_REF].

Language is a high-level and non-monolithic cognitive function supported by an extended network of brain regions and by several complex dynamic processes [START_REF] Price | A review and synthesis of the first 20 years of PET and fMRI studies of heard speech, spoken language and reading[END_REF] such as lexico-semantic, phonological and motor commands. Brain structures which support such processes are relatively well described in literature. For instance, the semantic network involves mainly the pars orbitalis and triangularis of the inferior frontal gyrus [START_REF] Bookheimer | Functional MRI of language: new approaches to understanding the cortical organization of semantic processing[END_REF] and the left mid and inferior temporal gyri [START_REF] Binder | Where is the semantic system? A critical review and meta-analysis of 120 functional neuroimaging studies[END_REF], while the phonological network is mostly supported by the pars opercularis of the left inferior frontal gyrus [START_REF] Vigneau | Metaanalyzing left hemisphere language areas: phonology, semantics, and sentence processing[END_REF] and the left posterior and superior temporal regions [START_REF] Démonet | The anatomy of phonological and semantic processing in normal subjects[END_REF].

Nevertheless, an important inter-subjects variability exists on brain language representation and this variability is more important in epileptic patients [START_REF] Baciu | What do patients with epilepsy tell us about language dynamics? A review of fMRI studies[END_REF] for a review). Hence, preoperative language mapping should delineate eloquent areas at the individual level.

Currently, many tools and methods are available for pre-surgical evaluation of cognitive anf language processes, of which none has been proved accurate enough to reliably anticipate the risks of postoperative deficits. These exams include neuropsychological testing, functional neuroimaging, chemical inactivation (Wada test), and Electro-Cortical Stimulation (ECS).

ECS, as performed during iEEG, is classically considered as the 'gold standard' method for the identification of the cortical regions that have to be spared during surgery [START_REF] David | Studying network mechanisms using intracranial stimulation in epileptic patients[END_REF][START_REF] Penfield | Epilepsy and the Functional Anatomy of the Human Brain[END_REF][START_REF] Lesser | Electrical stimulation and language[END_REF][START_REF] Ojemann | Electrocorticographic (ECoG) correlates of language. I. Desynchronization in temporal language cortex during object naming[END_REF]. It is an invasive method, the clinical validity of which to assess post-operative outcome has been reported [START_REF] Haglund | Cortical localization of temporal lobe language sites in patients with gliomas[END_REF][START_REF] Hermann | Effects of anterior temporal lobectomy on language function: A controlled study[END_REF]. However, ECS mapping has several limitations: (i) ECS has a limited spatial sampling, since it can be applied only at the sites where the intracranial electrodes are implanted; (ii) ECS is a time-consuming method, that may occasionally lead to seizures [START_REF] Lesser | Cortical afterdischarge and functional response thresholds: results of extraoperative testing[END_REF] and therefore limitates the repetition of ECS and subsequently reduces inter-subject reproducibility; (iii) ECS does not always trigger objective clinical signs, especially in associative cortices such as language areas; (iv) elicited signs can be subtle, especially in the language domain (e.g., a specific lexico-semantic deficit), and they may be therefore difficult to detect or interpret; (v) patient's subjective experience can be misleading, or may add difficulties for ECS interpretation; (v) it is currently not clear whether ECS trigger inhibition or activation of neuronal networks [START_REF] David | Studying network mechanisms using intracranial stimulation in epileptic patients[END_REF]. For all these reasons, ECS may fail to reveal the functionality of a given brain region, revealing only the "tip of the iceberg" of functional cortical networks.

Functional Magnetic Resonance Imaging (fMRI), by comparison, is a non-invasive method which has an excellent spatial coverage and can be routinely used for brain mapping, notably language [START_REF] Price | The anatomy of language: a review of 100 fMRI studies published in 2009[END_REF], including pre-operative mapping in patients [START_REF] Perrone-Bertolotti | How silent is silent reading? Intracerebral evidence for top-down activation of temporal voice areas during reading[END_REF][START_REF] Baciu | Functional MRI assessment of the hemispheric predominance for language in epileptic patients using a simple rhyme detection task[END_REF]Baciu et al., 2005). Nevertheless, it has limitations in terms of temporal resolution, relationships to neural processing and statistical quantification. Functional activity assessed by fMRI depends on the statistical threshold used, which is most important during single brain mapping (Baciu et al., 2005 ;[START_REF] Baciu | What do patients with epilepsy tell us about language dynamics? A review of fMRI studies[END_REF] for a review). Still, fMRI shows widely distributed networks that are mainly relevant to lateralize language processing before surgery, rather than to precisely delineate those of language areas that should be spared during surgery.

In order to overcome ECS and fMRI limitations, High Frequency Activities (HFAs > 40Hz) elicited by various cognitive tasks, as recorded in patients submitted to iEEG exploration, have been proposed as putative biomarkers of cognitive processes, especially for language functions, (e.g., [START_REF] Mainy | Cortical dynamics of word recognition[END_REF][START_REF] Vidal | Localizing cognitive function in epilepsy with intracranial gamma-band dynamic responses[END_REF] HFAs induced by cognitive tasks were first described in animal studies which reported that primary visual cortex neurons fired jointly at 40Hz during a visual task [START_REF] Gray | Oscillatory responses in cat visual cortex exhibit intercolumnar synchronization which reflects global stimulus properties[END_REF]. A more recent micro-electrodes recordings study in the human cortex showed that broadband HFAs (40Hz-150HZ) could reflect summed local population of neurone spiking and thus allowed the evaluation of direct neural activity [START_REF] Manning | Broadband shifts in local field potential power spectra are correlated with single-neuron spiking in humans[END_REF]. Two decades ago, two studies showed that cognitive information processing generated transient activities in a high frequency range between 40 and 150 Hz in motor [START_REF] Crone | Functional mapping of human sensorimotor cortex with electrocorticographic spectral analysis. II. Event-related synchronization in the gamma band[END_REF] and sensory [START_REF] Lachaux | A quantitative study of gamma-band activity in human intracranial recordings triggered by visual stimuli[END_REF] cortices. These HFAs, called Gamma Band Responses (GBR), are currently considered as a proxy of population level spiking activity while patients perform a cognitive task. Since then, an increasing number of studies have reported GBR in specific brain regions related to the task performed [START_REF] Lachaux | High-frequency neural activity and human cognition: past, present and possible future of intracranial EEG research[END_REF]. GBR are not visible in raw intracerebral iEEG traces, but are revealed by simple signal processing techniques involving time-frequency analysis [START_REF] Jerbi | Task-related gamma-band dynamics from an intracerebral perspective: review and implications for surface EEG and MEG[END_REF]. These studies have revealed the functional role of GBR in almost every sensory modality and its subserving cortical regions, as well as in various high-level cognitive processes such as visual selective attention [START_REF] Ossandón | Transient Suppression of Broadband Gamma Power in the Default-Mode Network Is Correlated with Task Complexity and Subject Performance[END_REF], auditory perception [START_REF] Bidet-Caulet | Neural substrate of concurrent sound perception: direct electrophysiological recordings from human auditory cortex[END_REF], language processing (Perrone-Bertolotti, 2012; [START_REF] Mainy | Cortical dynamics of word recognition[END_REF][START_REF] Lachaux | Relationship between task-related gamma oscillations and BOLD signal: new insights from combined fMRI and intracranial EEG[END_REF] and many others.

Brain mapping using GBR evaluation offers many advantages. It provides an exquisite anatomical, functional and temporal specificity, and GBR can be compared with an estimate of the intensity of any given neuronal population's engagement in a specific task processing [START_REF] Lachaux | A quantitative study of gamma-band activity in human intracranial recordings triggered by visual stimuli[END_REF]. Thus, it can distinguish neural activity increases and decreases, i.e., activations and deactivations, which is interesting in terms of cognition as cognitive processes, mainly attention, are mediated not only by distributed cerebral activations, but also by concurrent suppressions [START_REF] Ossandón | Transient Suppression of Broadband Gamma Power in the Default-Mode Network Is Correlated with Task Complexity and Subject Performance[END_REF]. Moreover, this method offers high signal-to-noise ratio and low sensitivity to artifacts that are not offered by surface EEG, for instance. As GBR are elicited during cognitive tasks, high level processes, namely those supported by associative cortices, can be explored in each subject depending on specific tasks availability. Furthermore, functional networks revealed by GBR assessment have been proven to be complementary to those revealed by fMRI activation studies [START_REF] Lachaux | Relationship between task-related gamma oscillations and BOLD signal: new insights from combined fMRI and intracranial EEG[END_REF][START_REF] Conner | Variability of the Relationship between Electrophysiology and BOLD-fMRI across Cortical Regions in Humans[END_REF].

GBR studies in the language domain has been showed as a reliable method [START_REF] Llorens | Intra-Cranial Recordings of Brain Activity During Language Production[END_REF], that combines a high temporal and spatial resolution with a low sensitivity to artifacts. It provides highly specific results which depend on the functions that are tested, and allows the study of specific language processes, including their neural mechanisms and time courses. This has been showed, as an example, for word recognition [START_REF] Mainy | Cortical dynamics of word recognition[END_REF], sentence comprehension, reading (Perrone-Bertolotti, 2012), and naming [START_REF] Crone | Electrocorticographic gamma activity during word production in spoken and sign language[END_REF]. Therefore, GBR recording during cognitive tasks seems to be an efficient method to perform brain mapping and, more specifically, to perform language mapping. Nevertheless, few studies have compared this method with the classical methods (ECS and fMRI) used to perform pre-surgical functional mapping [START_REF] Sinai | Electrocorticographic high gamma activity versus electrical cortical stimulation mapping of naming[END_REF], and only a few have evaluated the value of GBR assessment to predict post-operative cognitive outcome [START_REF] Towle | ECoG gamma activity during a language task: differentiating expressive and receptive speech areas[END_REF].

The present study aimed at evaluating the clinical relevance of induced GBR as a functional mapping method for pre-operative assessment of cognitive functions before epilepsy surgery. Attention was focused on language-induced GBR, since language is one of the most frequently impaired functions following epilepsy surgery. Also, language is classically mapped, in our clinical environment, by ECS and fMRI, allowing direct comparison of results of the three methods. We firstly evaluated the reliability of the GBR as compared with ECS and fMRI. In a second step, we evaluated the value of GBR to predict post-operative language outcome.

Materials and Methods

Patients selection and characteristics

Fourteen patients were included in this study, based on the following inclusion criteria: (i) aged over 12 years, native French speakers; (ii) having undergone SEEG recordings with stereotactically implanted multilead depth electrodes at the Epilepsy Department of Grenoble University Hospital (France); (iii) in whom the cognitive brain mapping assessment, as performed during SEEG procedure (ISD-SEEG project, DRCI Grenoble, 2009), included at least a language task allowing the assessment of behavioural performance and related gamma band responses; (iv) who were subsequently operated, after the SEEG study, between January 1, 2013 and July 1, 2016.

The 14 patients (6 men, 8 women, mean age: 30 years) were all suffering from drug-resistant partial epilepsy. The operability of this epilepsy could not be decided on the basis of a non-invasive screening including scalp-video-EEG monitoring, and neuropsychological tests. See Figure 2

Electrode implantation and localization

The number and placement of intracerebral electrodes was defined according to the prior hypothesis regarding the localization of the epileptogenic tissue, based on seizure semiology and on the results of the non-invasive investigations. A total number of 199 semi-rigid, multi-lead electrodes were stereotactically implanted in the 14 patients (mean: 12-18/patient), which allowed a good coverage of mesial and lateral brain structures as well as deep-seated areas (e.g., insula). Every SEEG electrode had a diameter of 0.8mm and comprised 8 to 18 contact leads 2mm wide and 1.5mm apart, depending on the target structure (DIXI Medical, Besançon, France). Every electrode contact was identified on a post-implantation MRI. The MNI (Montreal Neurological Institute) coordinates for every electrode contact were extracted using SPM (http://www.fil.ion.ucl.ac.uk/spm/).

Stereotactic intracerebral EEG (SEEG) recordings

Intracranial recordings were conducted using a video-SEEG monitoring system (Micromed®, Treviso, Italy), which allowed the simultaneous recording from up to 128 depth-EEG electrode sites. Data was bandpass filtered online from 0.1 to 20Hz and sampled at 512 Hz in all patients. At the time of acquisition, data was recorded using a reference electrode located in the white matter, and each electrode trace was subsequently re-referenced with respect to its direct neighbour (bipolar derivations). This bipolar montage has a number of advantages over common referencing. Notably, it helps eliminate signal artifacts common to adjacent electrode contacts and allows an accurate focal recording. The spatial resolution achieved by bipolar SEEG recordings was in the order of 3mm [START_REF] Jerbi | Task-related gamma-band dynamics from an intracerebral perspective: review and implications for surface EEG and MEG[END_REF]; [START_REF] Lachaux | Intracranial EEG and human brain mapping[END_REF]. The localization of epileptogenic brain tissue was based on the visual analysis of interictal and ictal SEEG activity.

Electrical cortical stimulations (ECS)

As part of our routine procedure, ECS were performed during the SEEG monitoring, during sessions that lasted 1-3 hours. The aim was to reproduce part or the totality of the ictal clinical symptomatology, and to localize functionally eloquent areas that had to be spared during surgery. Bipolar ES were performed using a constant current rectangular pulse generator, and applied at 1 Hz (pulse width: 1 msec; ES duration: 40 sec) and 50 Hz (pulse width: 1 ms; ES duration: 5 sec) between contiguous contacts at various levels of the electrode axis, with stepwise increasing intensities ranging from 0,2 to 3 mA and until clinical subjective or objective responses or after-discharges were obtained. ECS were performed after checking that the electrode site to be stimulated exhibited its baseline activity. Patients were asked to perform different simple tasks, depending on the stimulated region. More specifically, for language assessment, patients were asked to perform several speech tasks audibly including counting, naming pictures or listing series of words. ECS were performed immediately after every speech task onset. ECS findings were classified by the examiner (neurologist) into different categories (motor, sensitive, sensory, vegetative, language, emotional, etc...) and documented in the patients' files.

2.5 Functional mapping using task-related gamma-band responses (GBR)

During the SEEG procedure, patients were asked to participate to an experimental protocol screening various cognitive processes (ISD and SEEG project, DRCI Grenoble, 2009) to extract task-related GBR.

This experimental protocol was approved by the local Ethical Committee (CPP Sud-Est V n° 09-CHUG-12), and all participants provided their written informed consent before entering the project.

For the purpose of the present study, attention was focused on one these cognitive tasks, namely a behavioural language task (abbrev. LEC1) that involved two different language processes (visual input), phonology and semantic, and three different experimental conditions (phonological, semantic and visual control). During the phonological condition, patients were asked to judge whether or not a presented pseudo-word was composed of two syllables (e.g., scrout; fruzon). During the semantic condition, participants were instructed to perform a semantic categorisation on words. They also were instructed to judge whether a presented word was a living being (e.g., dog or dove) or not (e.g., table or car). In the visual control condition, patients were asked to judge whether a randomly arranged consonants string had capital or lower case letters (e.g., XTVNXD or xbxnbd). In all conditions, patients were instructed to answer as rapidly and accurately as possible. The three conditions (semantic, phonological and control) were presented randomly in a block dressing of 5 consecutive trials per condition. A total of 60 stimuli per condition was presented. Stimuli were presented in a fixed 2 s duration with an interstimulus interval of 3.5 s (see Figure 1). Visual stimulation was delivered using Presentation stimulus delivery software (Neurobehavioral systems Inc.) and was displayed on a 19-inch computer screen located 60cm away from the subject. Participants were instructed to respond by pressing a key with the index finger of their left hand for a yes response and of their right hand for a no response. Responses were recorded in order to assess behavioural performances in terms of response exactitude (accuracy) and rapidity (reaction times).

Patients performed this task twice: during the pre-operative assessment conjointly with the iEEG recordings in order to obtain both behavioural performances and language-related GBR and then after surgery to evaluate behavioural performances only (see Figure 2). All participants went through a short training session with different items from those presented during the pre-and post-operative evaluation.

Furthermore, to reduce a possible learning effect induced by task repetition, stimuli used during the pre-and post-operative evaluations were different. 2.6 Functional mapping using functional MRI (fMRI) for language Among our group of 14 patients, all underwent a fMRI scan prior to surgery in order to lateralize language functions, either before or after the SEEG study. Nevertheless, only 6 of them had available fMRI data (P1, 2,[START_REF]Conclusion[END_REF]7,13,14). These six language fMRI were performed at the Grenoble University Hospital (Grenoble, France) in a whole-body 3T Philips scanner (Achieva 3.0T TX Philips-Philips Medical systems, Best, NL)

with an 8-channel head coil. For functional scans, the manufacturer-provided gradient-echo/T2*-weighted EPI method was used. Forty-one adjacent axial slices parallel to the bicommissural plane were acquired in sequential mode. Slice thickness was 4 mm. The in-plane voxel size was 4 × 4 mm (256 × 256 × 168 mm field of view acquired with a 64 × 64 pixels data matrix). For the two functional runs, the main sequence parameters were: TR = 3 s, TE = 35 ms, and flip angle = 90°. Finally, a T1-weighted high-resolution threedimensional anatomical volume was acquired, by using a T1 TFE sequence (field of view = 256 × 256 × 160 mm; resolution: 1 × 1 × 1 mm; acquisition matrix: 256 × 256 pixels).

One task composed of two identical sessions was carried out during MRI acquisition. The two sessions were block design-alternating task periods consisting of a pseudorandomized presentation of auditory stimuli and baseline periods (rest). Auditory stimuli were names (e.g., ball). A total of 24 stimuli were presented in four blocks per fMRI sessions. Patients were instructed to mentally perform a sentence including the word that they have just heard. Auditory stimuli were presented via the Presentation stimulus delivery software (Neurobehavioral systems Inc.).

Surgery and post-operative follow-up

Surgery was performed according to SEEG results (Table 1). It concerned the dominant hemisphere for language in 10 patients, and consisted in frontal (n=7), temporal (n=3), parietal (n=2) and multilobar (n=2)

resections. The extent of the resection was assessed on a 3D-T1 post-operative MRI usually performed 3 months after surgery. Volume of resection (in mm 3 ) was computed through voxels number into the resected area and MRI acquisition characteristics. The volume of the resection was not computed for Patient 9 since he presented a post-traumatic subdural haemorrhage 3 months after surgery which underestimated the extent of resection on the post-operative MRI.

Patients were usually followed up at three months, six months, and then once a year. Final post-operative outcome in terms of seizure was evaluated at the last follow-up visit, according to Engel's Classification [START_REF] Engel | Outcome with respect to epileptic seizures[END_REF] 10 patients became seizure-free (Engel's class I) after surgery, 2 were improved and 2 did not show any seizure frequency changes.

Data analysis

ECS analysis

The clinical effect of ECS delivered over sites were retrospectively reviewed from patient's video-SEEG files. Only speech disturbances, labelled as absent, incorrect or delayed responses or paraphasia, were taken into account. Other elicited clinical signs were not considered in this work. Thus, stimulated sites were binary classified into sites which showed language symptoms (ECS+) and those which did not (ECS-). As bipolar ECS were performed between two contiguous sites, each electrode was counted separately to allow comparison with GBR mapping. Any site that was common to two tested pairs, was regarded as ECS+ only when it exhibited positive response in both paired stimulations that included the site. If the site was tested only in a single pair, it was labelled the same as the including pair. Next, for each bandpass filtered signal we computed the envelope using a standard Hilbert Transform. The obtained envelope is down sampled to a sampling rate of 64Hz (i.e., one-time sample every 15,625ms). For each frequency interval, the time-varying amplitude was divided by its mean across the entire recording period of the experiment and multiplied by 100. This yields instantaneous amplitude envelope values as percentage-of-the-mean. Finally, the envelope signals computed for each consecutive band were averaged to provide one single time series (the GBR) across the entire recording session. The obtained envelopes had a sampling rate of 64 Hz. We also performed single trials GBR maps for each electrode contact. These single-trial maps were screened visually one-by-one. Hence, we determined electrodes sites which showed statistically significant GBR, labelled as GBR+, and those which did not show any statistically significant GBR, labelled as GBR-. Gamma band deactivations were not taken into account in this study.

Language-related GBR

The visual method used in this work was previously evaluated by two independent observers of our team:

inter-rater agreement on detecting gamma activation was estimated on 17 666 single-trial maps using a

Cohen's kappa coefficient, which showed a substantial agreement [START_REF] Cuisenier | Reproductibilité de l'analyse visuelle de cartes d'activité à hautes fréquences (HFA) évaluant les réseaux fonctionnels cognitifs en SEEG[END_REF].

Language-fMRI BOLD responses

Data analysis was based on the general linear model [START_REF] Friston | Stochastic designs in event-related fMRI[END_REF] in SPM12 (Welcome Department of Imaging Neuroscience, London, UK) implemented in MATLAB (MathworksInc., Sherborn, MA, USA).

Each condition, language and rest, was modelled using a canonical hemodynamic function model. Data analysis started with the spatial pre-processing steps. The T1-weighted anatomical volume was coregistered to mean images created by the realignment procedure and was normalized to the MNI space using a trilinear interpolation. The anatomical normalization parameters were subsequently used for the normalization of functional volumes. Finally, to be able to compare fMRI results with the SEEG data, each functional volume was smoothed by a 3-mm FWHM Gaussian kernel. Time-series for each voxel were highpass filtered (1/128 Hz cut-off) to remove low frequency noise and signal drift. Pre-processed data were then statistically processed and included into one design matrix including both sessions. Movement parameters derived from the realignment corrections (3 translations and 3 rotations) were also included in the design matrix as additional factors using ART toolbox for Matlab available on the Web at https://www.nitrc.org/projects/artifact_detect/. The block presentation allowed us to analyse data performing average response for all items, task vs control. Statistical parametric maps were generated from linear contrasts between the HRF parameter estimates for the different experimental conditions. Whole brain statistical analyses were first performed at an individual level in order to evaluate the language effect (K = 5; p value< .001 uncorrected, T = 3.55). Statistical analyses were subsequently performed at a group level (one sample t-test, k=5, p < .001 uncorrected; T=3.55). Finally, in order to compare fMRI results with GBR maps, we performed Region of Interest (ROI) analysis on fMRI data. We defined a sphere-type 3mm-radius ROI on each electrode contact from their MNI coordinates using SPM. We extracted the BOLD signal change for each of the ROI per patients. According to the statistical significance of the signal change on each site (p < .001, T = 3.55), we classified sites into two labels : fMRI + or fMRI -.

Functional data fusion

Visualization and fusion of data was assessed using a home-made software (IntrAnat Electrodes, GIN INSERM U1216, Grenoble) available on the WEB at https://f-tract.eu/index.php/softwares/. This software allows co-registration (using ANTs or SPM12) of the different imaging modalities (pre-implantation anatomical 3DT1 MRI, per-implantation 3DT1 MRI, post-operative 3DT1 MRI, fMRI) and visualization of respective surgery, electrode implantation and functional maps. 3-D modelized intracerebral electrodes were inserted on post-implantation MRI using IntrAnat Electrodes®. Cortex parcellation was achieved with Mars Atlas® (Brainvisa toolbox, UMR 7289, Marseille [START_REF] Auzias | MarsAtlas: A cortical parcellation atlas for functional mapping[END_REF]). Through this procedure, each electrode site was labelled according to i) its parcel in MarsAtlas, ii) its MNI (Montreal Neurological Institute)

coordinates iii) its relation with resection mask (computed by subtracting post-operative 3D-T1 brain segmentation from the pre-implantation one) iv) fMRI ROI results v) clinical responses to ECS vi) languagerelated GBR. This allowed comparison between ECS, GBR and fMRI maps, as well as comparison of ECS and GBR maps with the extent of the resection.

Comparison between GBR, ECS and fMRI maps

As ECS is classically considered as the gold standard for localization of language, only anatomical sites where ECS were applied were taken into account.

GBR were first compared to ECS results, according to the methodology proposed by [START_REF] Sinai | Electrocorticographic high gamma activity versus electrical cortical stimulation mapping of naming[END_REF]. We thus determined the i) sensitivity, ii) specificity, and iii) positive and negative predictive values (PPV and NPV) of GBR maps in relation to ECS maps. GBR sensitivity was defined by the percentage of electrode sites that were positive for both methods (GBR+ and ECS+) among all ECS+ sites. GBR specificity was calculated as the percentage of electrode sites that were negative for both methods (GBR-and ECS-) among all ECS-sites. The PPV was defined by the probability that a GBR+ site showed language interference after ECS (ECS+) and was calculated as the percentage of sites that were both GBR+ and ECS+ among all GBR+ sites. Finally, the NPV was defined by the probability that a GBR-site did not exhibit any language interference by ECS (ECS-) and was computed as the percentage of sites that were both GBR-and ECS-among all GBR-sites.

Then, GBR were compared with fMRI in the 6 patients in whom fMRI data was available. The sensitivity, specificity, PPV and NPV were determined according to the same methodology as described above.

Finally, to test the relation or agreement between GBR and the other two functional mapping methods (i.e., ECS and fMRI), a tetrachoric correlation (rt) was performed (see for instance [START_REF] Divgi | Calculation of the tetrachoric correlation coefficient[END_REF]. The rt allowed the evaluation of the correlation on binary data, thus the rt coefficient (ρˆ * ) showed the strength of the relationship or association between ratings for two raters (i.e., a "0" indicates no agreement and a "1" represents a perfect agreement between the measures). Thus, tetrachoric correlation coefficients (ρˆ * ) were computed.

Effect of surgery

Pre and post-operative behavioural performances during LEC1, in both phonological and semantic conditions, were compared using an analysis of variance (ANOVA) in terms of accuracy (percentage of correct responses) and reaction times (in ms).

Whether language post-operative outcome was related to the extent of the resection was evaluated using a Bravais-Pearson correlation (r) between the Delta performance (difference between pre-minus postoperative behavioural performances) and the volume of resection (in mm 3 ).

Finally, to evaluate the prognostic value of removing brain regions displaying significant language-related GBR, we compared the Delta performance, for each experimental condition, between patients in whom at least one GBR + site was resected with the group of patients in whom none of the GBR+ site was resected (called control group). This comparison was performed using a Crawford and Howell's modified t-test [START_REF] Crawford | Payne and Jones revisited: estimating the abnormality of test score differences using a modified paired samples t test[END_REF], with a significance level set at p <0.05. A similar analysis was performed to compare post-operative language outcome of patients in whom at least one ECS+ site was resected with the group of patients in which no ECS+ site was resected. As the language task performed during ECS was a picture naming, close to the semantic condition of LEC1, only the performances obtained during the semantic condition were used to perform this latter comparison.

Results

Functional Maps

Among all 14 patients, 979 electrodes sites were explored through ECS and GBR (662 left, 317 right; mean: 70 sites/patient) and were thus considered in this study. This represented 58% of the total number of intracranial sites. The other 42% of intracranial sites (n=715; 360 left, 355 right) provided information only for GBR but were not stimulated, so that they were excluded from the analysis.

All patients exhibited GBR during the LEC1 task regardless of the experimental condition, at 81 of the 979 relevant sites (8%; mean: 6 GBR+ sites/patient). Twenty-five (30%) of the 81 GBR+ sites showed a selective activation for the semantic condition (n=12) or the phonological condition (n=13). ECS showed language interference in 9/14 patients at 51 of the 979 investigated sites (5 %, mean: 4 ECS+ sites/patient).

BOLD signal changes were observed in all the 6 patients in whom language fMRI data was available: 59 of the 393 explored sites (as only sites where ECS were applied were considered) showed significant BOLD signal changes (15%, mean: 10 sites/patient). Figure 3 illustrates the cortical distribution of all investigated sites and sites that were positive for each method (ECS+, GBRs and fMRI+ sites).

Comparison between GBR and ECS

Six of the 979 relevant sites were GBR+ECS+ and 857 GBR-ECS-as shown in Table 2. GBR+ECS+ sites were all located on the left (and language dominant) hemisphere. Specifically, they were localised in the superior parietal, dorsolateral somatosensory, medial visual, dorsomedial premotor and dorsomedial motor cortices. These sites showed GBR during LEC1 in both semantic and phonological conditions, except for one site located in the medial superior parietal cortex that showed GBR for the semantic condition only (see Sensitivity and specificity of GBR for language mapping relative to ECS were respectively 11.7% and 92.4%, with a PPV and NPV of 7.4% and 95.5%, respectively.

Comparison of GBR maps with fMRI activations

Only 6 patients had available data from a fMRI for language mapping, in whom a total of 393 sites were stimulated and were thus considered in this study. Five of these 393 sites were GBR+fMRI+ and 298 were GBR-fMRI-(see Table 4), and none were positive for the three methods (GBR+fMRI+ECS+). GBR+fMRI+ sites were all located on the left hemisphere, except one which was located on the right mid temporal gyrus (See Sensitivity and specificity of GBR for language mapping relative to fMRI were respectively 8.4% and 89.2%, with a PPV and NPV of 12.2% and 84.7%, respectively.

Correlation between functional mapping methods

The tetrachoric correlation showed low correlation between GBR and fMRI, and between GBR and ECS as well, both for semantic and phonological conditions (see Table 6 for correlations values). The best correlation -although low -was observed between GBR and ECS for the semantic condition (ρˆ * = -.343). Table 7 : Functional outcome of surgery and resection features: statistical significance of the behavioural outcome of patients as assessed by LEC1 (including semantic and phonological condition), pre-and postoperative denomination score (DO80) assessed by speech therapist, resection details (relationship with GBR and volume in mm 3 ) and time between surgery and post-operative assessment (S/A). Abbreviation: RT: Reaction Time; Acc: Accuracy; ++: indicates a significant improvement in behavioural performances after surgery; --: indicates a significant decrement in performances after surgery; ns: no statistical difference between before and after surgery; GRB+R: indicates the resection of an GBR+ site or no; Y: yes, N: no; Vlm: volume.

GBR -ECS GBR -fMRI

Effect of GBR resection on behavioural performances

Two patients underwent a resection including at least one GBR+ site during the semantic condition (P1 and P13). P1 did not demonstrate any significant change after surgery, and its Delta performance did not statistically differ from the Delta performance of the control group (i.e., without GBR+ sites resected). P13 significantly improved after surgery for reaction times, but its Delta performance did not show any statistical difference with the Delta performance of the control group (see Table 8 in appendix)

Two patients underwent a resection including at least one GBR+ site during the phonological condition (P10 and P13). Both exhibited a significant post-operative improvement for reaction times but not for accuracy.

The Delta performance of these 2 patients was not statistically different from the Delta performance of the control group (See Table 9 in Appendix).

By comparison, 4 patients had a resection upon ECS+ sites (P4, P6, P12, P13), of whom 3 (P4, P12, P13)

showed a significant decrease of accuracy after surgery as compared to the control group, and one (P6)

showed a significant improvement of both accuracy and reaction times as compared to the control group (see Table 8 iin appendix for statistical details).

Discussion

The aim of this study was to assess whether task-related GBR might be used to anticipate cognitive deficits after surgery, and whether they might complement the classical methods for language mapping, namely ECS and fMRI. Indeed, GBR have been described as a putative biomarker of cognitive functions for almost 20 years [START_REF] Lachaux | High-frequency neural activity and human cognition: past, present and possible future of intracranial EEG research[END_REF] but their clinical relevance in predicting post-operative language outcome has never been formally assessed. To do so, we choose a language task that have the advantage to be compared with other modalities (ECS, fMRI) and provide quantitative features of behavioural performances to evaluate possible changes after surgery. The main results of the study, as well as its methodological limitations, are described in the followings sections.

GBR mapping may help to choose the sites that have to be stimulated

Our results, though preliminary and extracted from a small cohort of patients, suggest first that GBR assessment can be a realistic complementary tool to ECS as part of iEEG recordings. Language-related GBR predicted ECS language interference with a high specificity (92.4%) and NPV (95.5%), meaning that if language tasks did not induce GBR on a cortical site, the likelihood of language impairment by stimulating the same site was very low. This highlights the possibility to first perform a functional map with GBR before starting the ECS procedure, and therefore save time and avoid stimulating sites that are a priori not relevant. These results compare favourably with the only two other studies having evaluated GBR and ECS during naming (n=13, [START_REF] Sinai | Electrocorticographic high gamma activity versus electrical cortical stimulation mapping of naming[END_REF]) and word repetition (n=12, [START_REF] Towle | ECoG gamma activity during a language task: differentiating expressive and receptive speech areas[END_REF]) tasks, and which showed a specificity of 78% and 63%, respectively. These two studies, however, reported a much higher sensitivity (38% and 57%, respectively) than the one we found in our series (11.7%, with a PPV of 7.4%), a finding which can be related to the differences between the iEEG methods used. [START_REF] Sinai | Electrocorticographic high gamma activity versus electrical cortical stimulation mapping of naming[END_REF] and [START_REF] Towle | ECoG gamma activity during a language task: differentiating expressive and receptive speech areas[END_REF] performed ECS and recorded GBR through subdural grids, that offered a broad coverage of neocortical areas. Compared with grids, SEEG electrodes provide narrower neocortical coverage resulting in a restricted mapped of cortical regions, which is particularly true for language areas. Also, ECS using SEEG electrodes is very focal, since stimulation is applied bipolarily between contacts that are only distant from 2.5mm (center to center). Still, the current intensity used for functional mapping with grids is usually much higher (up to 15mA) than with SEEG electrodes (up to 3-4 mA), a difference which is related to the fact that subdural electrodes record the cortical surface while SEEG electrodes are intracortical. Previous studies suggested that ECS effects depend on several factors, such as the intensity of stimulation [START_REF] Kahane | Intracerebral depth electrodes electroencephalography[END_REF][START_REF] Trébuchon | Electrical Stimulation for Seizure Induction and Functional Mapping in Stereoelectroencephalography[END_REF]. Hence, it remains uncertain whether the ECS intensity applied in our study (ranging from 0,2 to 3mA) was sufficient enough to show obvious language disturbances. In any cases, there do not exist any studies having evaluated the 'optimal' ECS parameters to perform cognitive mapping.

GBR, ECS and fMRI do not reveal similar functional maps

Our results indicate that GBR and ECS were weakly correlated (R = -.22), suggesting a lack of concordance between GBR and ECS maps. A potential explanation for this result is related to the method itself. Indeed, ECS is a technique that disrupts functions (and therefore reveals key structures for a given cognitive process), while GBR is an activation method (which thus reveals the whole cortical network subserving a cognitive process). Still, subtle language dysfunctions triggered by ECS can be easily missed, leading to an underestimation of functional tissue. Consequently, language regions revealed by GBR are broader than -and partly overlap with -those defined with ECS [START_REF] Brown | In vivo animation of auditory-language-induced gamma-oscillations in children with intractable focal epilepsy[END_REF]. This is in line with the results of the present study, which showed that 81 GBR+ sites were identified, as compared with only 51 ECS+ sites. Furthermore, ECS may produce effects that are distant from the stimulated area, as the current may spread through axons or fibres to distant sites [START_REF] Lesser | Cortical afterdischarge and functional response thresholds: results of extraoperative testing[END_REF][START_REF] Blume | Properties of after-discharges from cortical electrical stimulation in focal epilepsies[END_REF].

Indeed, current density models have showed that focal current application similar to ECS can interfere not only with cell body activity but also with axons transmission, thus influencing distant areas [START_REF] Ranck | Which elements are excited in electrical stimulation of mammalian central nervous system: a review[END_REF].

Our results also indicated that GBR and fMRI were even less correlated than GBR and ECS. This was an unexpected result, because previous studies have showed that GBR and BOLD signal assessed with fMRI demonstrated significant functional relationships [START_REF] Lachaux | Relationship between task-related gamma oscillations and BOLD signal: new insights from combined fMRI and intracranial EEG[END_REF]There exists, however, several methodological limitations that might explain these findings, including first the small number of patients assessed throughout both methods (n=6). Also, we deliberately choose small-sized (3mm-radius) ROI to compute comparisons between BOLD and GBR, this choice being motivated by the spatial resolution achieved by depth electrodes (3mm). In previous studies comparing GBR and BOLD activity [START_REF] Conner | Variability of the Relationship between Electrophysiology and BOLD-fMRI across Cortical Regions in Humans[END_REF][START_REF] Esposito | Cortex-based inter-subject analysis of iEEG and fMRI data sets: application to sustained task-related BOLD and gamma responses[END_REF][START_REF] Conner | Variability of the Relationship between Electrophysiology and BOLD-fMRI across Cortical Regions in Humans[END_REF], greater ROI sizes were used (10mm) that guaranteed stronger correlation but reduced accuracy. Still, the restricted number of relevant cortical sites (i.e. only those sites where ECS were applied) represented another limitation, and a a better relationship between GBR and BOLD signal might have been obtained if consideration had been given to all implanted sites. A final limitation, detailed below, is related to the difference between the language tasks used during fMRI (speech production) and SEEG (visual presentation of single words for language comprehension).

Are GBR maps more accurate than ECS or fMRI maps?

The language system involves several linguistic processes and in clinical settings it may be important to discriminate and precisely localise these processes (see, for instance, [START_REF] Perrone-Bertolotti | How silent is silent reading? Intracerebral evidence for top-down activation of temporal voice areas during reading[END_REF]. Our results pinpointed one site among GBR+ECS+ sites, which illustrates nicely the capacity of GBR to specify language processing: C'11 (P 4) located in the medial superior parietal cortex. Indeed, this electrode site exhibited specific GBR induced only during the semantic condition, while ECS triggered a non-specific aphasia. This is in line with intracranial studies which established that GBR provided a powerful means to detect task-specific activations [START_REF] Crone | Electrocorticographic gamma activity during word production in spoken and sign language[END_REF][START_REF] Towle | ECoG gamma activity during a language task: differentiating expressive and receptive speech areas[END_REF]. Language mapping through ECS is based only on disruption of language and provides only rough "yes'' or ''no" responses. Stimulation therefore may appear as a less specific and as a less subtle mapping tool than GBR. Moreover, the slow time course of haemodynamic imaging technique (fMRI) makes it difficult to distinguish different linguistic processes [START_REF] Towle | ECoG gamma activity during a language task: differentiating expressive and receptive speech areas[END_REF]. As neural activity during language occurs on a millisecond time scale, it appears to be better explored by intracranial EEG signal analysis than using fMRI.

and even if we adopted a validated statistical method in clinical practice and in single-case research [START_REF] Crawford | Payne and Jones revisited: estimating the abnormality of test score differences using a modified paired samples t test[END_REF], our results should be considered preliminary and further studies with larger population are needed; (ii) the differences in tasks used across the three methods evaluated (LEC1 during iEEG recordings, picture naming during ECS, and overt speech production during fMRI), that may explain the weak concordance that we found between the methods; cerebral regions involved in every task may differ, since different linguistic processes are used to trigger the response (see for a review [START_REF] Baciu | What do patients with epilepsy tell us about language dynamics? A review of fMRI studies[END_REF][START_REF] Perrone-Bertolotti | Organisation et réorganisation cérébrale du langage: approche pluridisciplinaire[END_REF]; studies using a common task should be encouraged in the future to better evaluate relationship between GBR and other functional mapping techniques; (iii) the very small number of patients with available a fMRI examination, the realization of which was decided on the basis of clinical needs. Despite these limitations, our study can be viewed as a proof of concept.

Conclusion

This study is the first, to our knowledge, to have assessed post epilepsy surgery language outcomes through functional data obtained from a behavioural task combined with iEEG recordings, and compared with ECS and fMRI data. It mainly shows that GBR elicited by a controlled language task may predict ECS language interference with a strong specificity, but with a weak sensitivity. This therefore suggests to use GBR mapping as a preliminary tool to adapt ECS sessions. The ability of GBR mapping to detect specific linguistic processes could make it also a useful complement to ECS that can be thus applied during specific tasks accordingly. The present study, however, must be considered as a proof of concept and deserves further studies.

D

  'ici et d'ailleurs Anaïs, Charles, Philippe et Hortense #miglietouzetoujoursautop #bitofaction, je vous adore. Merci également à T O U C A N T O C O d'avoir participé à ce projet.

  Remerciements ..................................................................................................................................

Figure 1 .

 1 Figure 1. Language task paradigm. Example of arrays for control, semantic and phonologic conditions. Every condition stimuli were presented during 2000 ms and after 3500 ms. The semantic stimuli were presented on the top, phonologic stimuli in the middle and visual control stimuli on the bottom of the screen. The patient was instructed and trained to perform every condition in a block of 5 consecutive trials.

Figure 2 .

 2 Figure 2. Schematic illustration of the experimental design. Left: pre-operative assessment (time 1 -t1-) including iEEG evaluation including electro-cortical stimulation (ECS) and gamma band activity screening (GBR) through behavioural language task (LEC1), neuropsychological, anatomical (MRI) and functional MRI (fMRI). Right: post-operative assessment (time 2 -t2-) including LEC1, neuropsychological assessment and anatomical MRI (resection characteristics). Arrows represent the different comparison computed in the study.

Figure 3 :

 3 Figure 3 : Spatial distributions of the investigated sites, and positive responses during each method from all 14 patients (P1-14) in common coordinates. Distributions are presented on axial and lateral views of MNI brain template. A. All electrode sites studied, where both ECS and GBR were performed (n=979) B. sites where ECS interfered with language. C. Electrode sites with significant GBR during Lec1. Different colours of the sites indicate the two different language processes: semantic (blue) and phonology (green). Red areas indicate sites which exhibited GBR in both conditions. D. Results from fMRI group analysis: Activated regions during the speech production task displayed on a 3D anatomical template and a 2D axial slice. k=5, p < .001 uncorrected; T=3.55, n=6. See Figure 6 in appendix for more details. LH: Left hemisphere, RH: Right hemisphere.

Figure 6

 6 Figure 6 Brain activation during the speech production task projected onto 2D slices. For each activated site, MNI coordinates are showed. MNI, Montreal Neurological Institute.

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biathlètes sans limite à la martin F. avec qu'il fait si bon partir. Ne quittez pas Grenoble, sinon nous serions obligés de vous suivre ! De l'Externat :

A Christophe B., allias Toff, le meilleur des co-externes, qui gère dans TOUTES les situations ! Les patients ont de la chance de t'avoir ! A Kevin C., ton mental de tueur a été précieux pour moi en D4. A Louise M. merci pour ta joie et ton accueil nantais et à Pierre F. pour ta bonne humeur, j'espère que nous ferons enfin cette traversée de la Chartreuse ensemble. A la douce Sarah S. A Noé L., retrouvée dans les méandres de la recherche clinique, pour son cache-cache C 1 . A Eloïse F., la plus jolie, ma bonne copine que je ne vois pas assez.

De Grenoble

A Bleuenn. Ta bonne humeur permanente fait de toi une amie très précieuse. Ces quelques mois de colocation furent heureux ! A Thomas, le capitaine exemplaire et surtout à ma belle filleule Alice. A Hélène qui a réussi à me transformer en CAFiste et me faire aimer le ski de rando. A Aurélien. Les Feuillu-Flesch, à qui rien ne fait peur pas même les kms en voiture, (ou pour des chaussures de ski). Vous êtes des amis en or. A Marie et Max, rois des pentes et de la tarte flambée. Votre calme cache une énergie débordante dont j'espère profiter plus. A Irina, Ira. Merci pour la poésie et les rêveries que tu as apporté à mon internat et à notre année recherche.

Ce travail est aussi dédié aux lanceuses de patates… A Mathieu et Anna.

Table of

 of contents .............................................................................................................................. Abstract ............................................................................................................................................

Table 1 .

 1 for experimental paradigm. A summary of the patients' characteristics is given in Table1. Patients

	P	Age	Gender	VIQ/PIQ	HL	HDL	EZ location	MRI	Resection	Pathology	E outcome
	1	38	F	NA	R	L	L temp	NL	L Temporo-basal	FCD	Engel IV
	2	23	F	99/76	L	L	L temp	NL	L-Cingulo-parietal	NS	Engel I
	3	23	F	79/76	R	L	R front	MG	R-Fronto-opercular	FCD	Engel III
	4	20	F	102/92	R	L	L temp	HS	L-Temporo-mesial	HS	Engel I
	5	37	M	100/115	R	L	L front	NL	L-Frontal-polar and orbital	FCD	Engel I
	6	13	F	90/105	R	L	R front	NL	L-Prefrontal	FCD	Engel I
	7	15	F	NA	R	L	R temp	NL	R-Temporo insulo-opercular	FCD + HS	Engel IV
	8	23	F	96/60	L	L	L pariet	NL	L-Mesio parietal	NS	Engel III
	9	59	M	112/104	R	L	L temp	NL	L-Fronto-basal	NS	Engel I
	10	29	M	131/116	R	L	R front	DNET	R-Fronto orbital and anterior insula	DNET	Engel I
	11	28	M	106/112	R	L	R front	POG	R-Pre motor frontal	ODG	Engel I
	12	41	M	98/106	R	L	L front	FCD	L-Frontal superior	FCD	Engel I
	13	27	F	104/90	R	L	L front	NL	L-Frontal superior	NS	Engel I
	14	48	M	112/106	L	R	R temp	NL	R-Temporo-mesial	FCD	Engel I

' (P) characteristics: Age, Gender, Pre-operative neuropsychological scores on Verbal and nonverbal performances (VIQ/PIQ; Handedness lateralization as assessed by Edinburgh Handedness inventory (HL)

[START_REF] Oldfield | The assessment and analysis of handedness : The Edinburgh inventory[END_REF]

; Hemispheric dominance for Language (HDL) as assessed by fMRI; epilepsy characteristic (epileptic zone -EZ-location and MRI findings); anatomical resection location (Resection); pathology, seizure outcome

[START_REF] Engel | Outcome with respect to epileptic seizures[END_REF]

. Abbreviations: NA: not available; L: Left handed R: Right handed; NL: Non Lesional; MG: Micropolygyria; FCD: Focal Cortical Dysplasia; HS: Hippocampal sclerosis; DNET: Dysembryoplastic neuroepithelial tumour; POG: post-operative gliosis; NS: Nonspecific; ODG: Oligodendroglioma.

Table 3 and

 3 Figure 4 in Appendix for details).

		ECS+	ECS -	Total
	GBR +	6	75	81
	GBR -	40	858	898
	Total	46	933	979

Table 2 :

 2 Electrode sites distribution depending on ECS and GBR results.

	Patient	Site	x	y	z	Label	GBR results
	4	C'11	-59	-35	-13.3	LSPC	Sem + Phono -
	8	C'8	-31	-46	43	LSdl	Sem + Phono +
	8	F'6	-37	-56	-7	LSPC	Sem + Phono +
	9	D'5	-41	-47	-13	LVCm	Sem + Phono +
	12	L'6	-23	1	50	LPMdm	Sem + Phono +
	13	M'1	4	3	53	LMdm	Sem + Phono +

Table 3 :

 3 GBR+ and ECS+ sites. Including the name of the site (site), MNI coordinates (x, y, z) and the anatomical label (Label). Results of GBR analyses for the two experimental conditions are presented.

Abbreviations: LSPC: Left Superior Parietal Cortex; LSdl: Left Dorsolateral Somatosensory Cortex; LVCm: Left Medial Visual Cortex; LPMdm: Left Dorsomedial Premotor Cortex; LMdm: Dorsomedial Motor Cortex; Sem: semantic task; Phono: phonological task.

Table 5 and

 5 Figure 5 in Appendix for details).

		fMRI+	fMRI -	Total
	GBR +	5	36	41
	GBR -	54	298	352
	Total	59	334	393

Table 4 :

 4 Electrode sites distribution depending on fMRI and GBR results.

	Patient Site	X	Y	Z	Location	GBR results
	1	G'9	-55	-50	-15	L SPC	Sem + Phono +
	4	Q'1	-38	24	15	L VCm	Sem + Phono +
	4	X'5	-31	20	0	L VCm	Sem + Phono +
	7	D3	44	-52	5	R MTC	Sem + Phono +
	13	X'5	-28	19	-1	L ICC	Sem + Phono +

Table 5 :

 5 MNI coordinates for the GBR+ IRMf+ sites. x, y, and z refer to the MNI coordinates of the sites, in millimetres.

L SPC: Left Superior Parietal Cortex; L VCm: Left Medial Visual Cortex; R MTC: Right Middle Temporal Cortex; L ICC: Left Isthmus Cingulate Cortex.

Table 6 :

 6 Correlation between GBR and both ECS and fMRI results for the sub-group of patients who performed fMRI exploration.

	Language condition	Phonological	Semantic	Phonological and Semantic	Phonological	Semantic	Phonological and Semantic
	ρˆ *	-.285	-.343	-.217	-.053	.025	.104

Table 8 :

 8 Semantic task results from all 14 patients in pre and post-operative. 1 Mean and Standard deviation,

	Response Time

2

difference between preoperative features (mean) minus post-operative features (mean),* 2x2 ANOVA,• Crawford and Howell's modified t-test for patient with GBR+ site resected,Ψ Crawford and Howell's modified t-test for patient with ECS+ site resected; †P9 Vlm non available ( see 2.7 for details).

Table 9 :

 9 Phonological task results from all 14 patients in pre and post-operative. 1 Mean and Standard deviation, 2 difference between preoperative features (mean) minus post-operative features (mean),* 2x2 ANOVA,• Crawford and Howell's modified t-test for patient with GBR+ site resected, †P9 Vlm non available (see 2.7 for details).

Table 10 :

 10 Correlation between the extend of the resection and behavioural performances in the semantic and phonological tasks in terms of response time and accuracy. R = Pearson correlation coefficient value Contexte : La chirurgie de l'épilepsie offre aux patients épileptiques pharmaco-résistants l'opportunité d'être libérés de leurs crises. Elle les expose néanmoins à un risque de déficits cognitifs post-opératoires, notamment à des troubles du langage. L'anticipation de ces déficits nécessite la réalisation d'une cartographie cérébrale pré-opératoire afin de localiser les régions cérébrales fonctionnelles à préserver durant la chirurgie. Il existe actuellement plusieurs méthodes de cartographie fonctionnelle cérébrale dont l'IRM fonctionnelle (IRMf) et les stimulations corticales électriques (SCE) réalisées au cours d'une exploration électroencéphalographique invasive par électrodes intracérébrales (Stéréo-EEG, SEEG). Les SCE constituent actuellement le « gold standard » en terme de cartographie fonctionnelle. Néanmoins, cette technique, comme l'IRMf, présente des limites.Objectifs : Depuis une quinzaine d'années, l'étude des activités cérébrales haute fréquence dans la bande gamma (ou gamma band responses, GBRs) connait un véritable essor. Ces activités constituent un marqueur robuste de l'activité neuronale pouvant être utilisé comme outil « localisateur » des régions corticales fonctionnelles. Les GBRs apparaissent ainsi comme une alternative aux autres méthodes de cartographie fonctionnelle. Cette étude vise à comparer l'analyse des GBRs, comme outil localisateur des régions qui sous-tendent le langage, avec les SCE et l'IRMf. Elle vise également à évaluer la capacité des GBRs à prédire le devenir cognitif post-chirurgicale en déterminant si la résection d'une région ayant présenté des GBRs est à l'origine de plus de déficits post-opératoires que si ces régions sont préservées.Méthodes : Quatorze patients épileptiques ayant bénéficié d'une exploration SEEG et subi une cortectomie au CHU de Grenoble ont été sélectionnés. Le signal EEG intracrânien était enregistré durant la réalisation d'une tâche informatisée de langage (Lec1) incluant deux conditions langagières (sémantique et phonologique). Des GBRs langage induites (50-150 Hz) ont été recherchées au niveau de chaque site exploré et comparées aux résultats obtenus lors des SCE. De plus, l'analyse des GBRs était comparée aux données de l'IRMf dans un sous-groupe de 6 patients ayant bénéficié d'une cartographie pré-opératoire du langage par IRMf. Une évaluation post-opératoire par Lec1 était réalisée. Ainsi le devenir post-opératoire du langage des patients ayant subi une résection comportant un site ayant GBRs + était comparé à celui des patients dont les sites GBR+ étaient épargnés (groupe contrôle).Résultats : Les GBRs langage-induites ont prédit les résultats des SCE avec une forte spécificité (92.4%) et une forte valeur prédictive négative (VPN, 95.5%) mais une faible sensibilité (11.7%) et une faible valeur prédictive positive (VPP, 7.4%). Les résultats étaient similaires lors de la comparaison avec l'IRMf (spécificité : 89.2%, VPN : 84.7%, sensibilité : 8.4%, VPP : 12.2%). Les avantages des GBRs ont été soulignés, notamment leurs capacités à préciser le processus cognitif impliqué, spécifiquement linguistique. Les performances post-opératoires en langage des patients ayant subi une résection comportant un site ayant GBRs + n'étaient pas significativement différentes de celles du groupe contrôle. Seul un faible effectif de patients ont subi une résection comportant un site GBRs+ (n= 2 en condition sémantique et n=2 en condition phonologique).Conclusion: Nos résultats confirment la faisabilité des GBRs induites lors d'une tâche comportementale dans le bilan pré-chirurgical de l'épilepsie pharmaco-résistante. Les GBRs complètent les données obtenues en SCE et IRMf et guident la réalisation des SCE. L'intérêt d'une cartographie pré-chirurgicale multimodale est ainsi souligné.

			Response Time					Accuracy
												GBR+	ECS+
	P	Pre op 1	Post op 1	Delta 2	P-value *	P value•	Pre op 1	Post op 1	Delta	P-value *	P value•
												R	R
		1936 402,2	1746 573	190	0,10		93	91,6	1,4	0,87
		989 360,3	964 300,5	25	0,99		95	91.7	3,3	0,98
		1569 458,6	1420 396,1	149	0,28		83.3	95	-11,7	>0,99
		1548 403,6	1419 489,6	129	0,48		91.7	95	-3,3	0,98			x
		1942 413	1434 417,6	508	< 0,0001		46.7	40	6,7	< 0,0001
		2084 669,8	1534 471,4	550	< 0,0001		46.7	75	-28,3	0,005			x
		1356 622,5	1002 344,3	354	< 0,001		85	98.3	-13,3	< 0,001
		1910 732,9	1103 358,6	807	< 0,0001		3.3	95	-91,7	< 0,0001
		1107 281,7	1198 401,6	-91	0,52		100	98.3	1,7	0,99
	10	1032 228	854 191,5	178	0,004	0,36	98.3	100	-1,7	0,99	0,32	x
	11	1378 456,4	1097 360,9	281	<0,0001		51.7	96.7	-45	< 0,0001
	12	1316 476,2	1207 386,1	109	0,41		93.3	90	3,3	0,96			x
	13	1243 1044	898 471	345	<0,0001	0,39	93.3	98.3	-5	0,17	0,25	x	x
	14	1518 441	1419 915	98,75	0,29		91.6	75	16.6	0,04
			Condition		Response Time		Accuracy
			Semantic
			R			0,27		0,304
			p value			0,36		0,31
			Phonological
			R		-0,07		0,34
			p value			0,59		0,13

Mots-clés : Chirurgie de l'épilepsie ; Stéréo-électroencéphalographie ; Activités gamma ; cartographie fonctionnelle ; Langage ;

Remerciements

A Monsieur le Professeur Philippe Kahane, Merci de me faire l'honneur de présider cette thèse. Votre disponibilité et votre expérience m'ont été particulièrement précieuses tout au long de mon internat et pour la réalisation et enfin la relecture rigoureuse de ce travail. Vous savez éveiller en nous la joie de travailler et de connaître. Merci de votre chaleureux soutien.

SERMENT D'HIPPOCRATE En présence des Maîtres de cette Faculté, de mes chers condisciples et devant l'effigie d'HIPPOCRATE,

Je promets et je jure d'être fidèle aux lois de l'honneur et de la probité dans l'exercice de la Médecine.

Je donnerai mes soins gratuitement à l'indigent et n'exigerai jamais un salaire au-dessus de mon travail. Je ne participerai à aucun partage clandestin d'honoraires.

Admis dans l'intimité des maisons, mes yeux n'y verront pas ce qui s'y passe ; ma langue taira les secrets qui me seront confiés et mon état ne servira pas à corrompre les moeurs, ni à favoriser le crime.

Je ne permettrai pas que des considérations de religion, de nation, de race, de parti ou de classe sociale viennent s'interposer entre mon devoir et mon patient.

Je garderai le respect absolu de la vie humaine.

Même sous la menace, je n'admettrai pas de faire usage de mes connaissances médicales contre les lois de l'humanité.

Respectueux et reconnaissant envers mes Maîtres, je rendrai à leurs enfants l'instruction que j'ai reçue de leurs pères.

Que les hommes m'accordent leur estime si je suis fidèle à mes promesses.

Que je sois couvert d'opprobre et méprisé de mes confrères si j'y manque.

Effects of surgery

Behavioural performances were considered as impaired post-surgery when they showed, as compared with pre-operative data, a statistically significant decrease of accuracy and/or statistically increase of reaction time. By opposition, Behavioural performances were defined as improved when they showed, as compared with pre-operative data, a statistically significant better accuracy and/or statistically shorter reaction time.

Effects of surgery on behavioural performances

Seven patients showed language changes in the semantic domain after surgery (see Table 7 and Table 8 in appendix for statistical details): 2 patients exhibited a significant impairment, one for reaction times (P11) and one for both accuracy and reaction times (P5), while 5 patients demonstrated a significant improvement, 3 in terms of accuracy (P7, P8 and P14) and 2 for reaction times. Behavioural comparison revealed no change in the other patients.

Seven patients showed language changes in the phonological condition after surgery (see Table 7 and Table 11 in appendix for statistical details): 2 patients (P5, P14) had a significant impairment of behavioural in terms of accuracy, while 5 patients were improved, 4 (P6, P7, P8, P11) in terms of accuracy and one (P13) in terms of reaction times.

No correlation was found between the Delta Performance (difference between pre-and post-operative behavioural performances) and the extent of the resections for both semantic and phonological conditions (see details in Table 10 in appendix).

Brain resection does not necessarily mean loss of function

In the present study, the assumption was made that the extent of resections could affect cognitive/language post-operative outcome as there is evidence now from different sources that more restrictive tailored or selective resections have better cognitive outcomes [START_REF] Helmstaedter | Neuropsychological aspects of epilepsy surgery[END_REF][START_REF] Clusmann | Prognostic factors and outcome after different types of resection for temporal lobe epilepsy[END_REF][START_REF] Pauli | Neuropsychologic findings depending on the type of the resection in temporal lobe epilepsy[END_REF]. Our results were not consistent with this assumption and we even showed that 5 of the 14 patients exhibited post-operative language improvements in the phonological domain well as in the semantic domain. These results, in line with the current literature which shows that cognitive improvement after epilepsy surgery can be observed in up to 30% of patients [START_REF] Helmstaedter | Neuropsychological aspects of epilepsy surgery[END_REF], underlines the benefit of epilepsy surgery not only in terms of rendering the patient seizure-free, but also in terms of neuropsychological and behavioural abilities. Improving behavioural performance suggest that the suppression of epileptic activity allows efficient cerebral reorganisation and functional restoration.

We also hypothesized that surgical resection would be associated with language decline if the resection included a region activated (GBR+) during the language tasks. This was not confirmed by our results, probably due to the limited number of patient, and above all of patient with GBR+ sites resection (n=2 for phonological and n=2 for semantic condition). Furthermore, it seems likely that the small number of GBR+ sites resected (which represented only 5% of the GBR sites in each patient) was insufficiently important to provoke any deficit. Still, task-related GBR, as fMRI activation, reveals large networks involved in a given function, but not necessary critical for the task performance [START_REF] Lachaux | High-frequency neural activity and human cognition: past, present and possible future of intracranial EEG research[END_REF][START_REF] Crone | High-frequency gamma oscillations and human brain mapping with electrocorticography[END_REF].

Methodological concerns

Using a unique set of tools combining both behavioural performances, electrophysiological findings and functional data, our study demonstrates the feasibility of language mapping through GBR during SEEG recording and the assessment of pre-and post-operative behavioural performances as an objective measure of cognitive outcomes. Some limitations, however, must be acknowledged, including: (i) the small sample of our patients population, that did not allow for statistical analyses at group level; consequently, Appendix