Agnès Trébuchon

F.-Xavier Alario

Catherine Liégeois-Chauvel

Functional topography of auditory areas derived from the combination of electrophysiological recordings and cortical electrical stimulation

Keywords: Cortical stimulation, auditory areas, functional mapping, Intracerebral recordings, Language

The posterior part of the superior temporal gyrus (STG) has long been known to be a crucial hub for auditory and language processing, at the crossroad of the functionally defined ventral and dorsal pathways. Anatomical studies have shown that this "auditory cortex" is composed of several cytoarchitectonic areas whose limits do not consistently match macro-anatomic landmarks like gyral and sulcal borders. The only method to record and accurately distinguish neuronal activity from the different auditory sub-fields of primary auditory cortex, located in the tip of Heschl and deeply buried in the Sylvian fissure, is to use stereotaxically implanted depth electrodes (Stereo-EEG) for pre-surgical evaluation of patients with epilepsy. In this prospective, we focused on how anatomo-functional delineation in Heschl's gyrus (HG), Planum Temporale (PT), the posterior part of the superior temporal gyrus anterior to HG, the posterior superior temporal sulcus (STS), and the region at the parietal-temporal boundary commonly labelled "SPT" can be achieved using data from electrical cortical stimulation combined with electrophysiological recordings during listening to to pure tones and syllables. We show the differences in functional roles between the primary and non-primary auditory areas, in the left and the right hemispheres. We discuss how these findings help understanding the auditory semiology of certain epileptic seizures and, more generally, the neural substrate of hemispheric specialization for language.

I. Introduction

Mapping cortical auditory functions in humans has provided valuable insights about inter-areal anatomo-physiological distinctions, or about left-right functional asymmetries. This approach has updated our vision of auditory cortex and of the hemispheric dominance for language. Here, we describe how electrical cortical stimulation can be combined with anatomy and electrophysiology to decipher the sensory and cognitive aspects of the auditory functions.

II. Anatomical description of the auditory cortex

The auditory cortex in humans is largely confined in the posterior part of the superior temporal gyrus (STG), including Heschl's gyrus (HG) and Planum Temporale (PT) (Figure 1A). The precise posterior and anterior boundaries of these structures within STG have not been clearly defined [START_REF] Berman | High Angular Resolution Diffusion Imaging Probabilistic Tractography of the Auditory Radiation[END_REF], but it is clearly established that this territory is composed of several anatomically and physiologically distinct sub areas [START_REF] Brodmann | Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues[END_REF][START_REF] Braak | Architectonics of the Human Telencephalic Cortex: With 43 fig[END_REF][START_REF] Rivier | Cytochrome Oxidase, Acetylcholinesterase, and NADPH-Diaphorase Staining in Human Supratemporal and Insular Cortex: Evidence for Multiple Auditory Areas[END_REF][START_REF] Morosan | Human Primary Auditory Cortex: Cytoarchitectonic Subdivisions and Mapping into a Spatial Reference System[END_REF]. Once these multiple subdivisions are identified, a consistent pattern can be discerned as follows

The core region labelled primary cortex (BA 41) is easily identified on the basis of its cytoarchitectonic structure [START_REF] Braak | Architectonics of the Human Telencephalic Cortex: With 43 fig[END_REF]. Macroscopically, it appears to be deeply buried in the sylvian fissure, confined to the postero-medial two thirds of HG, with substantial inter-hemispheric and inter-individual anatomical variations [START_REF] Rademacher | Topographical Variation of the Human Primary Cortices: Implications for Neuroimaging, Brain Mapping, and Neurobiology[END_REF][START_REF] Hackett | Chapter 2 -Anatomic organization of the auditory cortex[END_REF]. The primary auditory cortex is flanked by bands of secondary areas (BA 42) that extend in the lateral part of HG and, posteriorly, towards the PT. Anteriorly, on to the Planum Polare, lie associative areas (BA 22). Posteriorly, the ascendant segment of the PT has been distinguished from its horizontal segment based on where the Sylvian sulcus splits into ascending ramus and descending ramus, labelled as Sylvian-Parieto-temporal region (Spt) [START_REF] Witelson | Sylvian fissure morphology and asymmetry in men and women: Bilateral differences in relation to handedness in men[END_REF] [START_REF] Sweet | Mapping auditory core, lateral belt, and parabelt cortices in the human superior temporal gyrus[END_REF]). This simplified description provides a standard working hypothesis that disregards more elaborate accounts where up to 30 anatomical sub-areas may be distinguished [START_REF] Hackett | Chapter 2 -Anatomic organization of the auditory cortex[END_REF][START_REF] Galaburda | Cytoarchitectonic organization of the human auditory cortex[END_REF][START_REF] Wallace | Histochemical identification of cortical areas in the auditory region of the human brain[END_REF].

III. Anatomo-functional delineation of auditory areas

In vivo electrophysiological recordings and direct electrical stimulation are invasive experimental methods that can be used to advance our understanding of the human auditory cortex. This type of research is performed in patients with intractable epilepsy undergoing pre-surgical diagnostic investigations with a stereotactic method (stereo-electroencephalography, SEEG) involving depth electrodes [START_REF] Chauvel | Presurgical intracranial investigations in epilepsy surgery[END_REF], or with electro-corticographic (ECoG) electrodes apposed on the surface of the brain [START_REF] Hamberger | Brain stimulation reveals critical auditory naming cortex[END_REF]. The goal of the pre-surgical evaluation protocol is to define the organization of the epileptogenic zone as well as the functionally "eloquent" cortical regions. While ECoG recordings provide surface cortical maps of gyral activity, SEEG electrodes record activity from both gyri and sulci; importantly, SEEG access deep cortical structures, allowing to disentangle activity from sub-regions within auditory cortex (Figure 1B).

Auditory Evoked Potentials

The latencies of auditory evoked potentials (AEPs) elicited by clicks or pure tones reflect an anatomical segregation (Figure 1C) . The sources of the different components lie in HG along the medio-lateral axis. Primary components (latencies below 30 ms) are generated in the tip of HG allowing a physiological delineation of primary auditory cortex (BA 41) [START_REF] Liegeois-Chauvel | Localization of the primary auditory area in man[END_REF].Sources with intermediate latency components (50 ms to 80 ms) are distributed from the lateral part of BA 41 to BA 42. Late components (above 80 ms) are generated in BA 42, the lateral parts of HG and PT, and at the posterior part of STG (BA 22) [START_REF] Celesia | Organization of auditory cortical areas in man[END_REF][START_REF] Celesia | Auditory cortical areas of man[END_REF][START_REF] Liegeois-Chauvel | Evoked potentials recorded from the auditory cortex in man: Evaluation and topography of the middle latency com-ponents[END_REF][START_REF] Liégeois-Chauvel | Temporal Envelope Processing in the Human Left and Right Auditory Cortices[END_REF][START_REF] Howard | Auditory cortex on the human posterior superior temporal gyrus[END_REF][START_REF] Brugge | Functional localization of auditory cortical fields of human: Click-train stimulation[END_REF][START_REF] Brugge | Coding of Repetitive Transients by Auditory Cortex on Heschl's Gyrus[END_REF][START_REF] Liegeois-Chauvel | Auditory evoked potentials in the definition of eloquent cortical areas[END_REF].

Spectro-temporal analysis

Time Frequency analysis (TFA) has been important for revealing non phase locked cortical activity and allowed for distinguishing single-trial spatio temporal response patterns elicited across the auditory cortex by verbal and non-verbal stimulations [START_REF] Chang | Categorical speech representation in human superior temporal gyrus[END_REF]. These patterns provide evidence for the tuning properties of cortical sites [START_REF] Nourski | Spectral Organization of the Human Lateral Superior Temporal Gyrus Revealed by Intracranial Recordings[END_REF] and they are modulated by the repetition rate of the stimulation [START_REF] Nourski | Representation of temporal sound features in the human auditory cortex[END_REF]. All these patterns reveal the representation of stimulus features which can be used to predict responses to novel stimuli or reconstruct the presented stimuli from pattern of cortical activity [START_REF] Pasley | Reconstructing Speech from Human Auditory Cortex[END_REF]

Electrical stimulation of auditory areas

The functional properties of the human auditory cortex were first described by W. Penfield using electrical stimulation to perform functional mapping during awake craniotomy procedures. The primary goal was to generate seizures to localize their origin. The clinical effects of the stimulation of each site were documented, along with intraoperative photographs of the anatomic locations of the stimulated sites. In 1938, Penfield reported hallucinations of sounds previously heard or experienced, provoked by electrical stimulation of the temporal cortex. In subsequent seminal publications, Penfield and collaborators showed that the primary auditory area lied on the anterior part of HG within the sylvian fissure [START_REF] Penfield | The cerebral cortex of Man. A clinical study of localization of function[END_REF][START_REF] Penfield | Epilepsy and the functional anatomy of the human brain[END_REF][START_REF] Mullan | Illusions of Comparative Interpretation and Emotion: Production by Epileptic Discharge and by Electrical Stimulation in the Temporal Cortex[END_REF]. The stimulation of those locations resulted in an auditory sensation like a tone, a buzzing, or knocking sounds. This research thread is summarized in Penfield and Perot [START_REF] Penfield | The Brain's Record of Auditory and Visual Experience: A Final Summary and Discussion[END_REF].

An anatomo-functional dissociation was proposed between the sites from which electrical stimulation triggered elementary auditory hallucinations (i.e., crude auditory sensations) versus auditory illusions (i.e., altered interpretations of heard sounds: "sounds heard seemed louder or clearer, fainter or more distinct, nearer or farther"). The auditory hallucinations were triggered by the stimulation of the deep part of HG while the illusions were linked to the lateral part of HG, extending forward and back along the STG. More complex auditory "psychical responses" (e.g., relatives' voices, music, meaningful sounds) have been reported mostly after stimulation of the Planum Polare. They probably result from a complex and widely distributed activation, involving brain regions beyond the auditory cortex.

In de Graaf et al's [START_REF] Graaf | Electrical stimulation of the auditory cortex[END_REF] study, most of stimulation (62% of 180 stimulations) provoked auditory subjective symptoms. Among them, 32% consisted in simple hallucinations, mainly recorded in the postero-medial part of HG (BA 41). On the contrary, stimulation of the lateral part of HG provoked more illusions than hallucinations. More generally, there was a gradient in the subjective responses from area 41 to 42 in HG, changing from high frequency sounds to broadband noise, to illusions. In the Planum Temporale, auditory illusions and hallucinations were observed with equal frequency. Anteriorly to HG (BA 22), illusions were most often reported. They could be perceived contralateral to the stimulation or bilaterally. In summary, stimulation data consistently reveal two types of positive responses, with a clear-cut difference in the subjective auditory symptoms between the stimulation of BA 41 (primary cortex) eliciting mostly hallucinations and BA 42's (secondary cortex) provoking illusions. This is in line with the functional differences in electrophysiological responses (early vs mid latency evoked components respectively) recorded from these areas. The stimulation of the posterior lateral superior temporal area at the site of maximal potentials evoked by clicks elicited either hallucinations or illusions [START_REF] Howard | Auditory cortex on the human posterior superior temporal gyrus[END_REF].

More rarely, hearing suppression was observed, for example following the stimulation of the "posterolateral aspect of the STG" or the "anterior part of HG" (29) see also [START_REF] Sinha | Transient unilateral hearing loss induced by electrocortical stimulation[END_REF] and [START_REF] Fenoy | Hearing suppression induced by electrical stimulation of human auditory cortex[END_REF]. Those hearing suppressions were not lateralized and they outlasted the duration of the stimulation. They could be accompanied by an altered perception of the timing in series of acoustic stimuli, or by a temporal dissociation between the experimenter's lips movements and the speech sounds they uttered.

Effects on language processing

Besides inducing auditory sensations, electrical cortical stimulations can impair language perception and production when they are delivered during behavioral tasks [START_REF] Trébuchon | Electrical Stimulation for Seizure Induction and Functional Mapping in Stereoelectroencephalography[END_REF]. Figure 1D shows the outcome of 117 stimulations of 39 electrodes from 26 patients, sorted according to the different sub-regions of posterior STG. On the left hemisphere, during a word repetition task. hallucinations or illusions are observed when HG was stimulated without any language deficit, while the stimulation of the PT induced auditory symptoms along with comprehension deficit. Articulatory or phonological errors are elicited by the stimulation of Spt during word or pseudo word repetition, presumably due to a difficulty to maintain task-relevant representations in a phonological loop (in keeping with [START_REF] Hickok | Computational neuroanatomy of speech production[END_REF][START_REF] Buchsbaum | Conduction aphasia, sensory-motor integration, and phonological short-term memory -An aggregate analysis of lesion and fMRI data[END_REF]). Lastly, the posterior part of left STS seems involved in more high-level language processes required in naming and reading tasks, because its stimulation did not induce positive auditory symptoms but naming or reading deficits (e.g. delayed responses, phonological errors or semantics errors). The reading deficit included grapheme decoding, comprehension deficit and grapheme to phoneme deficit.

The contrastive consequences HG and PT electrical stimulations have been replicated in a recent study where stimulations were applied at the onset or the offset of a sentence the patient was asked to repeat [START_REF] Forseth | Language prediction mechanisms in human auditory cortex[END_REF]. Speech comprehension was disrupted by the stimulation of HG at the onset of the sentence while the disruption of speech production was observed when the stimulation of PT was applied at the end of the sentence, about the time when the patient must start to repeat. Performance impairments were observed specifically in the left hemisphere in cases of typical language organization. When we compared left/right HG and PT stimulations during a repetition task we did not observe comprehension deficits on the right side (Figure 1D, bottom panel). The fact that comprehension deficits are selectively observed in the language specialized hemisphere is consistent with the hypothesis that the hemispheric dominance would result from the asymmetry of auditory cortical tuning [START_REF] Liégeois-Chauvel | Specialization of Left Auditory Cortex for Speech Perception in Man Depends on Temporal Coding[END_REF][START_REF] Kell | Lateralization of Speech Production Starts in Sensory Cortices-A Possible Sensory Origin of Cerebral Left Dominance for Speech[END_REF].

IV. Functional asymmetry between the right and left auditory cortices

There is suggestive neuroanatomical evidence for structural differences between the left and right auditory cortices in humans. The primary auditory cortex (BA41) is larger in the left hemisphere, with a higher density of gray and white matter, irrespective of handedness [START_REF] Penhune | Interhemispheric Anatomical Differences in Human Primary Auditory Cortex: Probabilistic Mapping and Volume Measurement from Magnetic Resonance Scans[END_REF][START_REF] Dorsaint-Pierre | Asymmetries of the planum temporale and Heschl's gyrus: relationship to language lateralization[END_REF]. The left auditory cortex (HG and PT) contains larger cortical columns than its right counterpart, with a higher number of large pyramidal cells in cortical layer III [START_REF] Hutsler | Hemispheric asymmetries in cerebral cortical networks[END_REF]. The Planum Temporale, or secondary auditory cortex, is also larger in the left hemisphere in the majority of individuals, and this structural asymmetry is related with the hemispheric dominance for language [START_REF] Shapleske | The planum temporale: a systematic, quantitative review of its structural, functional and clinical significance[END_REF]. Such differences in cytoarchitectonic organization coincide with electrophysiological and functional differences between auditory regions.

Building on these observations, D. Poeppel [START_REF] Poeppel | The analysis of speech in different temporal integration windows: cerebral lateralization as 'asymmetric sampling in time[END_REF] hypothesized that two endogenous oscillations, in the low-gamma (25-45 Hz) and in the theta (4-8 Hz) bands, underlie asymmetric sampling in time (AST) of auditory signals. These two rhythms are asymmetric at rest in HG, with theta dominating in right and gamma in left auditory cortex [START_REF] Sinha | Transient unilateral hearing loss induced by electrocortical stimulation[END_REF][START_REF] Fenoy | Hearing suppression induced by electrical stimulation of human auditory cortex[END_REF]. This observation is compatible with distinct integration properties in right and left auditory cortices underlying the chunking of continuous speech into phonemic and syllabic segments, respectively [START_REF] Poeppel | The analysis of speech in different temporal integration windows: cerebral lateralization as 'asymmetric sampling in time[END_REF][START_REF] Giraud | Cortical oscillations and speech processing: emerging computational principles and operations[END_REF]. This functional asymmetry is a plausible neurophysiological substrate of the greater sensitivity of the left auditory cortex to short sound segments and brief speech features [START_REF] Jamison | Hemispheric Specialization for Processing Auditory Nonspeech Stimuli[END_REF][START_REF] Obleser | Bilateral Speech Comprehension Reflects Differential Sensitivity to Spectral and Temporal Features[END_REF] and of the greater sensitivity of the right auditory cortex to slower acoustic fluctuations and longer steady speech signals such as vowels and syllables [START_REF] Boemio | Hierarchical and asymmetric temporal sensitivity in human auditory cortices[END_REF][START_REF] Abrams | Right-Hemisphere Auditory Cortex Is Dominant for Coding Syllable Patterns in Speech[END_REF]).

As a paradigmatic example, consider Voice Onset Time (VOT), which is the primary phonetic cue for the phonological distinction between voiced and voiceless stop consonants in a large variety of languages [START_REF] Cho | Variation and universals in VOT: evidence from 18 languages[END_REF][START_REF] Serniclaes | Etude expérimentale de la perception du trait de voisement des occlusives du français[END_REF]. VOT is the time lag between the release of the oral constriction for the consonant and the onset of the vibration of the vocal folds (i.e., the voicing:(52))

Several studies have reported VOT discrimination deficits in patients with damage to the left hemisphere [START_REF] Blumstein | The perception and production of Voice-Onset Time in aphasia[END_REF]. Liégeois-Chauvel and collaborators [START_REF] Liégeois-Chauvel | Specialization of Left Auditory Cortex for Speech Perception in Man Depends on Temporal Coding[END_REF] showed lateralized processing of acoustic elements of the French voiced stops (e.g., /ba/) by time locking neural signals in the left dominant auditory cortex to the consonant onset or the release burst. These findings have been replicated and used as an electrophysiological marker of the hemispheric dominance for language (54). Figure 2 (A&C) illustrates the asymmetry between left and right auditory cortices in the case of a typical left organization for language. Conversely, Figure 2 (D-bottom frame) shows one patient with an atypical language organization. These temporal processing patterns are a function of the specific features of the syllables, with different electrophysiological patterns across languages (e.g., English vs. French). However, regardless the native language of the patients, the enhanced sensitivity to the temporal acoustic characteristics of sounds that is only present in BA41 and BA 42 reflects information processes needed for tagging further phonetic processing which likely take place in BA 22 [START_REF] Morillon | Asymmetric Function of Theta and Gamma Activity in Syllable Processing: An Intra-Cortical Study[END_REF][START_REF] Giroud | Asymmetric sampling in human auditory cortex reveals spectral processing hierarchy[END_REF].

Following spectro temporal analysis of the acoustic signal in the auditory cortex which is the first stage of the speech processing, the phonetic and phonological processes take place in posterior part of STG [START_REF] Morillon | Asymmetric Function of Theta and Gamma Activity in Syllable Processing: An Intra-Cortical Study[END_REF][START_REF] Hickok | The cortical organization of speech processing[END_REF]. High gamma frequency band has been correlated with phonetic and categorical features (23) More recently, decoding algorithms have been developed , synthetizing acoustic features from parameters predicted from the brain activity. These studies showed successful decoding of spectro-temporal features of speech in the STG ( for review see, ( 58))

Ictal auditory symptomatology

Auditory auras reported by patients during spontaneous seizures include a spectrum of phenomena ranging from simple auditory hallucinations to complex hallucinations or illusions. Simple auditory, when they occur as a first ictal sign, are reliable signs to localize the epileptogenic zone (EZ) in the lateral posterior temporal regions ( [START_REF] Maillard | Semiologic and Electrophysiologic Correlations in Temporal Lobe Seizure Subtypes[END_REF][START_REF] Barba | Ictal clinical and scalp-EEG findings differentiating temporal lobe epilepsies from temporal "plus" epilepsies[END_REF]. Auditory hallucinations are most often heard contra-laterally to the EZ, which is largely consistent with what is observed during electrical cortical stimulations. Retrospective studies including a large number of patients show that the prevalence is weak (~ 2% of the temporal lobe patients) [START_REF] Balgetir | Epileptic auditory illusions as reliable findings in the determination of the lateralization and localization of epileptogenic zone[END_REF][START_REF] Florindo | Lateralizing value of the auditory aura in partial seizures[END_REF]. The localization value of illusion is less consistent and suggest a more large and complex organization of the EZ , for instance in case of temporal plus epilepsy ((60). Auditory auras has been also report in context of autosomal dominant partial epilepsy characterized by auditory features [START_REF] Ottman | Localization of a gene for partial epilepsy to chromosome 10q[END_REF] for which the responsible gene LGI1 has been defined [START_REF]Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy[END_REF] There are only a few case reports of ictal verbal and musical hallucinations. Verbal hallucinations appear to be linked to EZs in the dominant hemisphere [START_REF] Florindo | Lateralizing value of the auditory aura in partial seizures[END_REF] while musical hallucinations are linked to the right temporal lobe regardless of dominance (65-67) (reviewed in [START_REF] Kaplan | Musicogenic epilepsy and epileptic music: a seizure's song[END_REF][START_REF] Wieser | Musicogenic epilepsy: review of the literature and case report with ictal single photon emission computed tomography[END_REF]). As was argued for stimulation-induced hallucinations of similar content, hallucinatory perceptions may be construed as re-experiencing stored perceptual experiences, presumably involving a broad network.

Finally, ictal illusions or post-ictal palinacousis (i.e., auditory illusions consisting of the perseveration or echoing of an external auditory stimulus after it has ceased) are rarely reported in patients with temporo-parietal seizures (for a review, (70)).

V. Applications to tinnitus

Auditory hallucinations evoked by electrical cortical stimulation share features with tinnitus, commonly defined as the perception of sound in the absence of an external auditory source. The rare observations of hearing suppression after cortical stimulation have opened new perspectives to treat tinnitus. It has been postulated in tinnitus patients that networks connecting the primary sensory cortices to other cortical areas and the periphery exhibit hyperexcitability leading to hallucinations [START_REF] De Ridder | The Bayesian brain: Phantom percepts resolve sensory uncertainty[END_REF].

In this context, a treatment strategy which seems to generate long and robust tinnitus suppression is to stimulate the auditory cortex using epidural electrodes [START_REF] De Ridder | Primary and Secondary Auditory Cortex Stimulation for Intractable Tinnitus[END_REF][START_REF] De Ridder | Transcranial magnetic stimulation and extradural electrodes implanted on secondary auditory cortex for tinnitus suppression: Clinical article[END_REF].

The seemingly contradictory behavioral effects of suppression in tinnitus vs. hallucinationsillusions in epileptic patients could depend on the stimulation parameters and on the individual state of the cortical sites. In tinnitus, the peripheral deafferentation (hair cell deterioration) changes the spontaneous rate, synchrony and entails a cortical reorganization; the electrical stimulation might induce a decorrelation of the spontaneous activity. On the healthy auditory cortex, stimulations excite all neurons and elicit hallucinations (as noted above, only in rare cases does it result in temporary deafness).

VI. Discussion: Interpreting the symptomatology elicited by electrical stimulation for clinical and research purposes

It is important to remember that electrical stimulation during SEEG explorations is performed primarily for eliciting seizures. The electrophysiological mapping of sensory and associative areas involved in cognitive networks should be conducted alongside, to answer the fundamental question of whether there is a spatio-temporal overlap between the epileptogenic and the functional networks. The identification of cortical structures that are essential to cognitive or perceptual functions is challenging because the human brain is a complex system in which a vast range of function arises from coordinated neural activity across diverse spatial and temporal scales [START_REF] Sporns | Modular Brain Networks[END_REF][START_REF] Bassett | Small-World Brain Networks Revisited[END_REF].

Effects arising from the stimulation of the primary sensory cortices are more localizing than that of associative cortices which involves the activation of a network or networks that underpins the functional emergence of language impairments. Trebuchon [START_REF] Trébuchon | Electrical Stimulation for Functional Mapping During Stereo EEG Exploration[END_REF] described the procedure to follow, including stimulation parameters such as duration and timing, to avoid pitfalls such as "false negative stimulation". They also described how to interpret the symptoms in relation with collateral electrophysiological changes such as after-discharges. It is especially important to interpret the role of the Planum Temporale and the posterior part of the superior temporal sulcus in language perception and production. Choosing the task according to the stimulated sub-region is particularly crucial (Figure 1A). HG and PT should be tested with a repetition or repetition and designation task; Spt should be tested with repetition and repetitive motor tasks, STS should be preferentially tested with naming and reading tasks

The relationship between phenomena induced by cortical electrical stimulation and normal brain physiology is also a fair question to ask, given that the epilepsy condition may result in the functional alterations of the networks it affects. The auditory manifestations following the stimulation of auditory cortex could result from a perturbation of the efferent pathway between the cortex and the periphery (cochlea), that would lead to abnormal auditory processing.

A stimulation induced deficit could result from an inhibitory effect of the stimulation due to the temporary inactivation of a local population of neurons, either pyramidal cells or interneurons. However, we are far from a perfect understanding of the functional or physiological effects of pulse or train stimulations. It is very common that the stimulation of the same region with the same parameters leads to various effects. One explanation could be that the "inhibitory effect" of the stimulation induces a rapid plasticity of the system that lasts for at least a few minutes following the trial [START_REF] Trébuchon | Electrical Stimulation for Functional Mapping During Stereo EEG Exploration[END_REF].

Overall, the available data favor the view that a positive response is evidence of an activation of the stimulated cortical neurons while a negative response could be interpreted as an inhibition of behavior attributed to neuronal inactivation [START_REF] Borchers | Direct electrical stimulation of human cortex -the gold standard for mapping brain functions?[END_REF]. The stimulation of auditory cortex at the base of the cortical hierarchy of networks involved in auditory perception elicited frequent and simple effects and allows a reliable assessment of sensory function. But these effects become increasingly rare, heterogeneous and complex in heteromodal networks making the evaluation of speech perception and production functions more uncertain [START_REF] Fox | Intrinsic network architecture predicts the effects elicited by intracranial electrical stimulation of the human brain[END_REF].

The use of single pulse electrical stimulation could help to resolve how adjacent and remote areas are inter-connected by measuring the cortico-cortical evoked potentials and identify the role of the auditory cortex in the language network ((79,80), for review see ( 81)).

In our view, solid physiological foundations underlying the effect of electrical stimulation need to be established, and the labelling of direct electrical stimulation as the "gold standard for mapping brain function" remains the matter of an interesting debate ((82) The several subparts according to the anatomical landmark are showed on (1) MRI axial view of auditory cortex; (2) 3D lateral brain representation and (3) on a schematic representation of auditory regions described above.

B Example of electrode position along the auditory cortex.

The 3 electrodes cross the two main sulci. The medial contacts of T electrode (yellow dots), explore the planum polare and the lateral contacts (blue dots) after crossing the transverse sulcus (yellow line) record the anterior part of HG (BA 42). H explore the medial part of HG (green dots, BA 41), then after crossing HS (green line) explore PT. The electrode contacts of P explore the medial part of HG (green dots, BA 41), then after crossing HS (green) explore PT.

C Example of AEPS in the several sub-part of the auditory cortices in response of tone burstsound. Note the difference of the latency of the first component, around 30ms for primary auditory cortex (BA41) and 60 ms for secondary auditory cortex.

D Stimulation of auditory cortex according to the subpart of the auditory cortices during language task (original data).

The Y-axis corresponds to the number of stimulations performed, and the color codes for the different type of errors. Each bars graph corresponds to a sub-region (HG, PT, STS and Spt). Each panel corresponds to repetition on left or right hemisphere (1&2), motor (3) and reading and naming (4) tasks.

Solely hallucinations or illusions are predominantly induced in HG and PT and, specifically in the left hemisphere, sometimes accompanied by comprehension deficit. Stimulation of Spt induced phonological errors. The deficit in Naming and reading task is mainly observed in the posterior part of the STS.

Figure 1

 1 Figure 1 Functional heterogeneity of auditory cortices A Anatomical subpart of Auditory CorticesThe subparts of auditory cortices are delimited according to the different sulcus of the posterior part of the temporal Gyrus. Heschl's Gyrus (HG) by the transverse sulcus (yellow line) and posteriorly by Heschl sulcus (HS, green line). The Planum temporale (PT)) is limited anteriorly by the HS and posteriorly the horizontal PT is limited where the Sylvian sulcus splits into ascending ramus and descending ramus (red line). The Sylvian-Parieto-temporal region (Spt in red) lies between PDRLS and the posterior ascendant ramus of the sylvian sulcus.

Acknowledgments

We would like to thank Manuel Mercier for his contribution to the figures and for providing valuable feedback on this manuscript.

Funding

Research supported by grant ANR-16-CONV-0002 (ILCB) and the Excellence Initiative of Aix-Marseille University (A*MIDEX).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author Contributions

These authors have contributed equally to the writing of this review A&C Illustration of example of AEP in response to voice /ba/ and /pa/ of two patients with typical language organization (according to handedness: RH, fMRI-activation in the left hemisphere during language task, stimulation, and ictal speech disturbance in the left hemisphere).

A The temporal auditory coding of VOT took place specifically in the left HG and PT (A). The /ba/ (black curve) elicited a first complex N1/P2 at the onset of voicing and a second component [marked by *] time-locked to release whereas the /pa/(red curve) elicited only one complex N1/P2.

C On the right PT and HG no difference between /pa/ and /ba/ is observed. B Voiced stop consonants /ba/ and voiceless stop consonants /pa/. The VOT refers to the time between a phonetically relevant supra-laryngeal event, such as release, and glottal paulsing. In French, VOT it is a long negative value (~ -110 ms) for voiced stop consonants (/ba/) and a short positive value (~ +20 ms) for voiceless syllable (/pa/). D AEP in response to voice /ba/ and /pa/ and stimulations results of one patient with atypical language organization (left handed; no language deficit during seizure and stimulation of the left temporal regions whereas stimulation of the right temporal region induced language deficit). AEP and stimulations results are presented together to underline their complementarity. Left hemisphere/AEP: the temporal auditory coding of VOT took place in the left HG. Left hemisphere/ Stimulation: typical hallucination and illusion are elicited in two parts of HG Right hemisphere/AEP: the temporal auditory coding of VOT has been recorded on the HG and the PT. Right hemisphere/ Stimulation: the stimulation of the right HG induced auditory hallucinations associated to a comprehension deficit.


Olivia Savatier Sjöholm

AN AMBITOUS, NEWLY DISCOVERED DRAWING BY HENDRICK GOLTZIUS

Hendrick Goltzius (1558-1617) "is a rare Proteus, or Vertumnus, who can assume all possible guises in his art, and can truly inhabit every style

An ambitious composition

The composition is not mentioned in any archival source, nor is there any known related drawn, engraved, or painted work that can be directly connected with it. The Virgin, with the Child, is seated on clouds with her feet resting on a large crescent moon. She is about to be crowned by two angels whose flowing draperies flutter in the air. She ascends toward heaven, escorted by cherubs who support the clouds. They are flanked on both sides by angels and cherubs praying, playing the trumpet, or bearing symbols of the Song of Songs (roses, lilies, palm tree). In the lower register, St. Cecilia is playing the organ with the help of an angel who operates the bellows. On either side are music-making angels, divided into two groups of three; their stringed instruments accompany the song of the angels shown in the background. That the sheet was once larger and has been significantly trimmed is evident from the cropped figures at upper right, on both sides, and especially on the bottom edge, where fragements of two cherubs' heads can be seen.

Elements of the new Louvre drawing can be compared to other works by the artist. The motif of St. Cecilia playing the organ with the help of an assistant, accompanied by a choir of three angels gathered around a song book, is similar to the iconography of a drawing of St. Cecilia in the Teylers Museum, Haarlem (Fig. 2),4 executed by Goltzius c. 1593, a variant of which was later engraved by his stepson Jacob Matham (1571-1631).5 That red and black chalk drawing already betrays the strong influence of Federico Barocci in its technique and in the rendering of the saint's face. Goltzius also tackled the theme of the Virgin with the Child as Queen of Angels, in a black and red chalk drawing, touched with red wash, a work once again highly reminiscent of the art of Barocci--the Virgin and Child with Two Angels, now in the Anhaltischen Gemäldegalerie, Dessau (Fig. 3),6 which is datable c. 1605-6. The drawing recently acquired by the Louvre stands apart from the other two sheets by virtue of its size and the complexity of its subject matter, making it one of the rare chalk drawings by Goltzius from after 1600 to feature multiple figures. Today only three other examples are known: the Mars and Venus of c. 1602-5 in the Herzog Anton Ulrich-Museum, Braunschweig,7 the Diana and Callisto of after 1600 in a Swiss private collection,8 and the drawing that offers by far the best comparison with the sheet introduced here: the Mystic Marriage of St. Catherine of c. 1600-1602 in the Kupferstichkabinett, Berlin (Fig. 4).9

Analogies with the Mystic Marriage of St. Catherine in Berlin

The Virgin and Child in Glory with St. Cecilia and Music-making Angels offers striking stylistic and technical analogies with the Berlin drawing. The compositions feature many comparable motifs, such as the Virgin holding the Child on her lap, the angels playing stringed instruments, the pair of angels bearing a crown, and the cherubs in the clouds. The figures' faces are very much alike, especially that of the Virgin-almond-shaped, with puffy eyelids, and enlivened by a delicate, little smile-which owes much to the art of Barocci. The technique is also comparable with both drawings executed in black and red chalk, with opaque white highlights and colored washes (brown and red for the Paris drawing, gray and red for the one in Berlin). In the Louvre drawing, Goltzius also added a hint of yellow chalk for the hair of the angel playing the viol at bottom right, further recalling the work of Barocci.

Another common feature of the drawings in Paris and Berlin-one shared by The Crucifixion, also in the Teylers Museum, Haarlem (see Fig. 7 below)10--is the method of incorporating cut and pasted paper corrections: the Child, the head of the Virgin, and the host of angels in the Berlin drawing; and the fragmentary putto's head at the bottom right of the Paris drawing. These revisions reflect the care taken by Goltzius when preparing his compositions. Unlike The Crucifixion in Haarlem, all the contours of which are indented with a stylus, the drawings in Berlin and Paris show only a few slight indentations here and there, as if the result of Goltzius having used highly sharpened pieces of chalk.11 On the Louvre drawing, these indentations are mainly evident in the central motif of the Virgin and Child borne aloft by angels.

The principal technical difference between the Berlin and Paris drawings is the support: the Louvre drawing was originally executed on nine pieces of paper joined together, to which Goltzius added a tenth fragment in the course of correcting the figure of the putto at the bottom right (Fig. 5).12 Whereas Goltzius would often add narrow strips of paper to extend his compositions on one side (as, for example, on the lower edge of The Crucifixion in Haarlem; see Fig. 7), only in exceptional cases--and only at the end of his career--did he draw the composition on sheets assembled beforehand. The Mars and Venus of c. 1602-5 in Brunswick is drawn on three fragments, and a drawing of the Fall of Man in the Royal Library, Windsor Castle, dated 1606, consists of just two. [START_REF] Inv | RCIN 904758. Pen and dark brown ink, with pink and gray wash, and white heightening[END_REF] The close similarity of the Berlin and Paris drawings raises the question of the purpose of the Louvre's recent acquisition. The Berlin drawing is probably a preparatory sketch for a painting (now lost), which was described by Van Mander in his Schilder-Boeck as a "large panel made for his traveling companion Jan Mathijssen" that may "be interpreted as the marriage of St. Catherine."14 The painting can be accurately situated c. 1600-1602, since its description appears just after The Crucifixion of 1600 in Karlsruhe (see Fig. 8) and before that of two paintings dated 1602 and 1603. The hypothesis that the Berlin drawing is a preparatory sketch for this painting, first suggested by W. Waterschoot, is corroborated by Lawrence W. Nichols's observation that the portraits on the right are those of Jan Matthijsz. Ban (c. 1566-1624), his brother-in-law Cornelis Gerritsz. Vlasman (c. 1565-after May 1629), and their respective wives. [START_REF] Lawrence | 1558-1617[END_REF] Modelli for paintings from the early 1600s

The Berlin and Paris drawings belong to a series of carefully executed modelli in black and red chalk made by Goltzius beginning around 1600, when he switched from printmaking to painting. According to Van Mander, Goltzius, then aged forty-two and at the peak of his career as an engraver, suddenly chose to abandon the burin to take up the brush. This shift, as Van Mander further noted, was heralded by Goltzius's growing fondness for the use of color and "cryons" (i.e., crayons or chalks) in his drawings. [START_REF] Van Mander | Van Mander's "cryons" consist of dry chalks made by hand, with pigments that are bound with glue[END_REF] Goltzius began to adopt black and red chalk more often after his time spent in Italy in 1590 and 1591. The example of Federico Zuccaro, whom Goltzius met in Rome in the summer of 1591, inspired in particular his use of black chalk for draperies and red chalk for flesh tones. He visited Zuccaro's workshop, and it was perhaps then that he drew his portrait, now in Berlin.17 He studied Zuccaro's drawings and perhaps brought one of them back to Haarlem to be engraved by Jacob Matham. [START_REF] Zuccaro | Dutch and Flemish Printmakers in Rome, 1565-1600[END_REF] The handling of a host of music-making angels among the clouds in the upper register of the Virgin and Child in Glory owes much to The Annunciation frescoed by Federico Zuccaro in the church of S. Maria Annunziata, Rome. [START_REF] Zuccaro | The New Hollstein: Dutch & Flemish Etchings, Engravings, and Woodcuts[END_REF] If Goltzius was already familiar with the fresco scheme through a reproductive engraving by Cornelis Cort (c. 1533-1577/78) made in 1571,20 he may also have encounterd preparatory drawings during his stay in Rome (e.g., Fig. 6).21 It was also in Italy, in his celebrated series of large portraits of artists, that Goltzius first combined the use of both black and red chalk with colored wash. This highly pictorial approach, with the occasional additional of yellow or brown chalk, as on the sheet under discussion here, is reminiscent of the graphic technique of Federico Barocci. That artist became a focus of interest for Goltzius during his Italian sojourn, as is testified by the account he gave to Van Mander on his return to Haarlem for the latter's biography of Barocci in the Schilder-Boeck.22 Alongside Goltzius's pen drawings (the famous Federkunststücke) made from c. 1600 onward, E.K.J. Reznicek and Lawrence Nichols have identified a group of nine large modelli in black and red chalk, often with added wash and/or colored chalk. 23 The new Louvre drawing now makes a tenth. These colored modelli reflect works that Goltzius admired during his sojourn in Italy. The earliest, Sine Cerere et Libero friget Venus (Without Ceres and Bacchus, Venus Would Freeze) in the Musées Royaux des Beaux-Arts de Belgique, Brussels, is not a preparatory drawing for a painting but an incised study for a grisaille oil on paper and the print after it engraved by Goltzius in 1600,24 thus highlighting the need for caution against assuming that all such chalk compositions were preparatory studies for paintings. The Crucifixion in Haarlem (Fig. 7), whose contours are also carefully incised, the drawing served as a full-scale cartoon for a small painting on copper of the subject now in the Staatliche Kunsthalle, Karlsruhe (Fig. 8).25 This is the only known instance of the survival of both the preparatory modello and its related painting, but Nichols mentioned a fragmentary drawing of Venus and Adonis, destroyed during World War ii, which was a preliminary study for an extant painting of the subject in a private collection, datable c. 1600.26 He also noted an indented cartoon--the Allegory of Hearing in the Albertina, Vienna--which was used for a painting that is now lost, but whose appearance is known from a copy.27 Only some of these modelli--definitely or hypothetically identifiable as preparatory works for paintings or grisailles--are incised.

A cartoon for a Catholic devotional painting

The new Louvre drawing is most probably preparatory for a devotional painting. Is it--like the Berlin study--a modello for a large-format painting by Goltzius on panel or canvas? A large altarpiece on panel from 1609, The Annunciation in the Pushkin State Museum of Fine, Arts, Moscow (Fig. 9),28 shows similar compositional elements, such as the hosts of angels among clouds and the figure of the Virgin with her almond-shaped visage, bowed head, swollen eyelids, and the smile playing on her small mouth, and particularly the foreshortened and open position of her right hand. This painting may have been commissioned by one of Haarlem's many clandestine Catholic churches. With Utrecht and Amsterdam, the city was one of the bastions of Catholicism in the post-Reformation Northern Netherlands.29 The iconography would be appropriate for the Haarlem beguinage, the Begijnhof, which professed great devotion to St. Cecilia.30

The drawing's size-thought to have originally measured c. 800 x c. 600 mm-would suggest that it was a same-size cartoon for a smaller private devotional painting on wood or canvas, rather than for a large-scale altarpiece.31 Yet since it is not squared and only partially indented (like the Berlin drawing), it clearly was not used to transfer the composition onto another support. Goltzius must therefore have employed a second cartoon, unless the project was ultimately abandoned.

The theme of the glorification of the Virgin, Queen of Angels, was common in the late sixteenth century and early seventeenth, both for altarpieces and for small private devotional paintings. These were found not only in Italy, but also in the heartlands of the Counter Reformation, such as the Bavaria of William v, the dedicatee of Goltzius's Life of the Virgin series. The extensive and explicitly Catholic iconography of this Virgin and Child in Glory with St. Cecilia and Music-making Angels celebrates the Virgin Mary simultaneously as the Queen of Heaven and the Mother of the Savior. It also exalts the highly controversial belief in the Immaculate Conception-as alluded to by the crescent moon and the symbols of the Song of Songs (rose, lilies, and palm tree)-which was fervently defended by the Jesuits, who led the Counter Reformation in the Northern Netherlands. In 1607 Jacob Matham engraved after Abraham Bloemaert (1566-1651) a Virgin crowned with stars, surrounded by a host of angels, her feet resting on a crescent moon, adoring the Infant Christ.32 Jacob Matham, to whom the Louvre drawing was long attributed, and his mother, Goltzius's wife, were both Catholics. While Goltzius's own denominational affiliation cannot be established with any certainty, he is known to have had many close friends who were Catholics outside his own family circle. They include Jan Matthijsz. Ban and Tobias Henrixsz. van Swartsenburgh (d. 1607/8), for both of whom he produced paintings.33 Perhaps this devotional painting was intended for or commissioned by someone in Goltzius's Catholic network in Haarlem.

The stylistic proximity of the Louvre drawing to the Mystic Marriage of St. Catherine suggests a date of c. 1601-2. It is surprising, however, that Van Mander made no mention of a painting with the subject of the Virgin and Child in Glory with St. Cecilia and Music-making Angels, even though he described all of Goltzius's other paintings up until the publication of the Schilder-Boeck in 1604.34 Should we therefore assign the Louvre drawing to c. 1605, like the Virgin and Child with Two Angels in Dessau? Or was the painting never realized? The latter hypothesis would explain the lack of any trace of this composition prior to the drawing's rediscovery.

Figure 1 Figure 2 Figure 4 Figure 5

 1245 Figure 1 HENDRICK GOLTZIUS Virgin and Child in Glory with St. Cecilia and Musicmaking Angels Paris, Musée du Louvre, Département des Arts Graphiques Figure 2 HENDRICK GOLTZIUS St. Cecilia Haarlem, Teylers Museum Figure 3 HENDRICK GOLTZIUS Virgin and Child with Two Angels Dessau, Anhaltischen Gemäldegalerie Figure 4 HENDRICK GOLTZIUS Mystic Marriage of St. Catherine Berlin, Kupferstichkabinett Figure 5 Diagram of the fragments that make up Figure 1

Figure 6 FEDERICOFigure 7 Figure 8 Figure 9

 6789 Figure 6 FEDERICO ZUCCARO Study for the Apse of S. Maria Annunziata, Rome Washington, DC, National Gallery of Art Figure 7 HENDRICK GOLTZIUS The Crucifixion Haarlem, Teylers Museum Figure 8 HENDRICK GOLTZIUS The Crucifixion, 1600 Karlsruhe, Staatliche Kunsthalle Figure 9 HENDRICK GOLTZIUS The Annunciation Moscow, Pushkin State Museum of Fine Arts