Laurent Michon
email: laurent.michon@univ-reunion.fr

The Volcanism of the Comoros Archipelago Integrated at a Regional Scale

Keywords: Comoros archipelago, Magmatism, Hotspot, Rift, Mozambique channel

The development of the Comoros archipelago in the Mozambique channel has been diversely interpreted since the 1970s. The two end-member causes are, on the one hand, a deep mantle plume that developed a hotspot track from the Seychelles Plateau to the Grande Comore, and, on the other hand, a lithospheric deformation that reactivated transform faults and controlled the magma path. The present work first surveys the sparse geological, geophysical and geochronological data available for this archipelago, re-evaluates the age of the magmatic activity and integrates this evolution at a regional scale. Combining realistic magma production rates, the volume of each edifice and the geochronological, it is showed that the magmatic activity started first in Mayotte about 20 Ma and second, almost simultaneously, in Anjouan, Mohéli and Grande Comore about 10 Ma ago. This magmatism, coeval with magmatic periods in areas surrounding the Mozambic channel, the southern East African rift and Madagascar, is organised in three periods since Late Oligocene. Magmatic provinces are now superimposed with seismic zones and graben structures. In consequence, the Comoros archipelago is tentatively interpreted as part of the East African rift rather than related to a distinct deep mantle plume.

Introduction

The origin of intraplate magmatism and the related volcanoes is a long-lasting debate [START_REF] Morgan | Deep mantle convection: plumes and plate motions[END_REF]Sleep 1990;[START_REF] Anderson | The thermal state of the upper mantle; no role for mantle plumes[END_REF][START_REF] Courtillot | Three distinct types of hotspots in the Earth's mantle[END_REF]). On the one hand, non-plate boundary magmatism results from deep mantle ascent rooted in the transition zone or at the core mantle boundary, producing flood basalts and/or linear chains of extinct volcanoes [START_REF] Morgan | Deep mantle convection: plumes and plate motions[END_REF][START_REF] Sleep | Onset of mantle plumes in the presence of preexisting convection[END_REF]). On the other hand, all intraplate volcanism is explained by shallow, plate-related stresses that fracture the lithosphere and cause volcanism along these fault zones [START_REF] Anderson | The thermal state of the upper mantle; no role for mantle plumes[END_REF]. A reconciling classification proposes that intraplate volcanoes stem from three mantle sources lying at different depths [START_REF] Courtillot | Three distinct types of hotspots in the Earth's mantle[END_REF]. Primary plumes (e.g. La Réunion and Hawaii) would originate at the core mantle boundary. Superswells in the lower mantle would feed secondary hotspots from the transition zone (e.g. Samoa and Tahiti). Finally, tertiary hotspots would result from asthenospheric convections caused by lithospheric deformation.

In such a scientific debate, the volcanoes of the Comoros archipelago were diversely interpreted in the past decades [START_REF] Morgan | Deep mantle convection: plumes and plate motions[END_REF][START_REF] Hajash | Paleomagnetic and radiometric evidence for the age of the Comores archipelago, west central Indian Ocean[END_REF][START_REF] Upton | The Comores archipelago[END_REF][START_REF] Emerick | Age progressive volcanism in the Comores Archipelago, western Indian Ocean and implications for Somali plate tectonics[END_REF][START_REF] Emerick | Age progressive volcanism in the Comores Archipelago and northern Madagascar[END_REF][START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF][START_REF] Späth | The Geochemistry of Lavas from the Gomores Archipelago, Western Indian Ocean: petrogenesis and Mantle Source Region Characteristics[END_REF][START_REF] Class | Plume-lithosphere interactions in the ocean basins: constraints from the source mineralogy[END_REF][START_REF] Class | The process of plume-lithosphere interactions in the ocean basins-the case of Grande Comore[END_REF][START_REF] Courtillot | Three distinct types of hotspots in the Earth's mantle[END_REF]. The aim of this paper is first to review the different interpretations, second to re-evaluate the age of the magmatism and third to integrate it at a regional scale.

Volcanoes of the Comoros Archipelago

The Comoros archipelago, located in the northern Mozambique channel between the northern tip of Madagascar and Mozambique, is composed of 4 volcanic islands aligned along a WNW-ESE direction (Fig. 21.1). From east to west, they correspond to Mayotte, Anjouan, Mohéli and Grande Comore. Including the Geiser and Leven Banks whose volcanic origin was confirmed by the volcanic rocks dredged on the submarine flanks [START_REF] Daniel | Relations Madagascar-Archipel des Comores (Nord-Est du Canal du Mozambique). Sur la nature volcanique du Banc de Leven[END_REF], the overall volcanic alignment remarkably displays the different erosion stages of hotspot volcanoes (Darwin 1842, Fig. 21.1c). Geochronological data seems to corroborate the diachronous magmatic activity, starting in Mayotte at least 10.58 Ma ago, in Mohéli and Anjouan around 3.9 and 5 Ma ago, respectively, and finally in Grande Comore since 0.13 Ma [START_REF] Hajash | Paleomagnetic and radiometric evidence for the age of the Comores archipelago, west central Indian Ocean[END_REF][START_REF] Emerick | Age progressive volcanism in the Comores Archipelago and northern Madagascar[END_REF]Duncan 1982, 1983;[START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF][START_REF] Debeuf | Etude de l'évolution volcano-structurale et magmatique de Mayotte (Archipel des Comores, Océan Indien): Approches structurale, pétrographique, géochimique et géochronologique[END_REF] [START_REF] Montaggioni | Les enclaves de roches détritiques dans les volcans d'Anjouan (archipel des Comores). Origine et interprétation dans le cadre de l'évolution du canal de Mozambique[END_REF][START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF]) suggests an early phase of magmatic activity coeval with the volcanism of Mayotte [START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF]. For Mayotte, a maximum age of 15 Ma was estimated for the onset of the magmatic activity on the seafloor (-3300 below sea level) [START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF].

Magmas emitted in the Comoros archipelago belong to the typical silica-undersaturated, alkaline series [START_REF] Strong | Petrology of the island of Moheli, western Indian Ocean[END_REF][START_REF] Flower | Petrology of volcanic rocks from Anjouan, ComoreArchipelago[END_REF][START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF]). Their isotopic composition indicates a mixing between the Indian Ocean lithosphere and deep mantle sources showing affinities with the HIMU and EM1 components (Emercik 1985;[START_REF] Späth | The Geochemistry of Lavas from the Gomores Archipelago, Western Indian Ocean: petrogenesis and Mantle Source Region Characteristics[END_REF][START_REF] Class | Plume-lithosphere interactions in the ocean basins: constraints from the source mineralogy[END_REF][START_REF] Class | The process of plume-lithosphere interactions in the ocean basins-the case of Grande Comore[END_REF][START_REF] Deniel | Geochemical and isotopic (Sr, Nd, Pb) evidence for plume-lithosphere interactions in the genesis of Grande Comore magmas (Indian Ocean)[END_REF][START_REF] Debeuf | Etude de l'évolution volcano-structurale et magmatique de Mayotte (Archipel des Comores, Océan Indien): Approches structurale, pétrographique, géochimique et géochronologique[END_REF]. At the scale of the archipelago, lavas from the active Karthala volcano (Grande Comore), which are the less undersaturated and have a distinct isotopic signature (EM1), would result from a higher degree of mantle partial melting than for the other volcanoes [START_REF] Späth | The Geochemistry of Lavas from the Gomores Archipelago, Western Indian Ocean: petrogenesis and Mantle Source Region Characteristics[END_REF][START_REF] Class | The process of plume-lithosphere interactions in the ocean basins-the case of Grande Comore[END_REF].

Whether the volcanic activity developed on an oceanic or continental crust remains unclear. The presence of sandstone xenoliths in lavas of Mayotte, Anjouan, Mohéli and Grande Comore was first interpreted as evidencing a continental nature of the underlying crust [START_REF] Lacroix | La constitution lithologique de l'archipel des Comores[END_REF][START_REF] Flower | The significance of sandstone inclusions in lavas of the Comores archipelago[END_REF]. However, magnetic b The archipelago is composed from east to west of Mayotte, Anjouan, Mohéli and Grande Comore. Geiser and Leven banks are submarine reliefs of volcanic origin [START_REF] Daniel | Relations Madagascar-Archipel des Comores (Nord-Est du Canal du Mozambique). Sur la nature volcanique du Banc de Leven[END_REF]. Saint Lazare (StL) and Paisley seamounts also correspond to submarine volcanoes related to the Kerimba and Lacerda basins [START_REF] Mougenot | Structure et volcanisme d'un rift sous-marin: le fossé des Kérimbas (marge nord-mozambique)[END_REF]. Black lines account for Miocene to Quaternary faults related to the Kerimba and Lacerda basins (after [START_REF] Mougenot | Structure et volcanisme d'un rift sous-marin: le fossé des Kérimbas (marge nord-mozambique)[END_REF]. NB Nosy Be. c Topography along the volcanic track [START_REF] Emerick | Age progressive volcanism in the Comores Archipelago, western Indian Ocean and implications for Somali plate tectonics[END_REF], 1983), d Hajash and Amstrong (1972) data suggest that the Comoros archipelago lie on a Late Jurassic to Early Cretaceous oceanic lithosphere resulting from the North-South opening of the Somali Basin [START_REF] Rabinowitz | The separation of Madagascar and Africa[END_REF][START_REF] Coffin | Reconstruction of Madagascar and Africa: evidence from the Davie fracture zone and western Somali basin[END_REF]. The sedimentary rocks could then correspond to xenoliths of sedimentary rocks resulting from erosion of continental units stemming from either the Davie Ridge [START_REF] Leclaire | La ride de Davie dans le Canal de Mozambique: approche stratigraphique et géodynamique[END_REF] or the Karoo formations cropping out on the eastern or western coasts of Africa or Madagascar, respectively. In such a plausible scenario, the occurrence of the 0.175 km 2 sandstone massif cropping out in the subaerial central part of Anjouan [START_REF] Debeuf | Etude de l'évolution volcano-structurale et magmatique de Mayotte (Archipel des Comores, Océan Indien): Approches structurale, pétrographique, géochimique et géochronologique[END_REF], about 3500 m above the sea floor, requires additional processes than upward magma transport to be uplifted to its present structural level. Whatever the nature of the crust, seismological data clearly show that the volcanic edifices stand on a seismically active zone connecting the northern extremity of Madagascar in the east to the African coast in the west [START_REF] Bertil | Seismotectonics of Madagascar[END_REF]Rindraharisaona et al. 2013) (Fig. 21.1b). This seismicity develops in a regional E-W extensive setting [START_REF] Grimison | Earthquakes in the Davie Ridge-Madagascar region and the southern Nubian-Somalian Plate boundary[END_REF][START_REF] Foster | Source parameters of large African earthquakes: implications for crustal rheology and regional kinematics[END_REF][START_REF] Heidbach | Active tectonics of the Alaotra-Ankay Graben System, Madagascar: possible extension of Somalian-African diffusive plate boundary?[END_REF].

3 Hotspot and Rift-Related Interpretations of the Magmatism of the Comoros Archipelago Three main interpretations have been put forward to explain the magmatism of the Comoros archipelago. Their main difference stands on the source of the magmatism. First, the intraplate volcanism together with the island alignment was interpreted as arising from a deep mantle plume [START_REF] Morgan | Deep mantle convection: plumes and plate motions[END_REF]. The hotspotimpingement, about 40-50 Ma ago below the Seychelles Plateau, would have produced a NNE-SSW volcanic alignment formed by the Amirantes arc, the Farquhar isles and the Comoros archipelago [START_REF] Emerick | Age progressive volcanism in the Comores Archipelago, western Indian Ocean and implications for Somali plate tectonics[END_REF]Emercik 1985). The plume hypothesis would be supported by the lack of "any significant zone of seismicity" (pp. 417 in [START_REF] Emerick | Age progressive volcanism in the Comores Archipelago, western Indian Ocean and implications for Somali plate tectonics[END_REF] and the EM1 and HIMU signatures of the volcanic rocks [START_REF] Emerick | Age progressive volcanism in the Comores Archipelago and northern Madagascar[END_REF][START_REF] Späth | The Geochemistry of Lavas from the Gomores Archipelago, Western Indian Ocean: petrogenesis and Mantle Source Region Characteristics[END_REF][START_REF] Class | The process of plume-lithosphere interactions in the ocean basins-the case of Grande Comore[END_REF]. However, in such a model the northwest orientation of the volcanic alignment is hardly compatible with the migration of the African plate toward the NNE [START_REF] Müller | Revised plate motions relative to the hotspots from combined Atlantic and Indian Ocean hotspot tracks[END_REF]). Thus, opposite views, involving lithospheric processes instead of deep plumes, have been invoked to explain the development of the magmatism. The Comoros archipelago would represent the surface expression of either a very slowly spreading ridge, similar to the tholeiite and alkali olivine basalt islands at the southern end of the Red Sea [START_REF] Upton | The Comores archipelago[END_REF], or the reactivation of lithospheric transform zones [START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF]). Whatever the lithosphere dynamics, the magmatism could be linked to the asthenosphere and be a passive response to forms of lithospheric breakup [START_REF] Courtillot | Three distinct types of hotspots in the Earth's mantle[END_REF].

I showed that several lines of evidences can be used to support the hotspot or tectonic origins of the Comoros archipelago. Instead of proposing an additional interpretation, I present a re-evaluation of the age of the magmatism, I compare it to the surrounding volcanic areas and integrate it in the regional geodynamic setting. [START_REF] Hajash | Paleomagnetic and radiometric evidence for the age of the Comores archipelago, west central Indian Ocean[END_REF], [START_REF] Emerick | Age progressive volcanism in the Comores Archipelago and northern Madagascar[END_REF]Duncan (1982, 1983), [START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF], [START_REF] Debeuf | Etude de l'évolution volcano-structurale et magmatique de Mayotte (Archipel des Comores, Océan Indien): Approches structurale, pétrographique, géochimique et géochronologique[END_REF]

Onset of the Volcanism of the Comoros Archipelago

The age of 15 Ma proposed for the beginning of the magmatism in Mayotte has been inferred for a magma production rate of 0.5 m 3 s -1 [START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF], which corresponds to a mean value determined for some of the most active volcanoes worldwide (between 0.26 and 0.69 m 3 s -1 ; [START_REF] Wadge | Output rate of magma from active central volcanoes[END_REF]). Yet, this value is one order of magnitude larger than the magma emission rate defined for the current shield building stage of Karthala volcano (Grande Comore), between 0.04 and 0.06 m 3 s -1 , from the activity of the last two centuries [START_REF] Bachèlery | Le fonctionnement des volcans boucliers. Exemples des volcans de La Réunion et de la Grande Comore[END_REF]). Such production rates for Karthala correspond to intermediate values; between those of moderately active hotspot volcanoes like La Gomera, Terceira, Santo Antao or Sao Miguel (production rates around 1-7 × 10 -3 m 3 s -1 ) and those related to active to very active hotspots like Kilauea, Mauna Loa and Piton de la Fournaise (production rates between 0.3 and 1.6 m 3 s -1 ; [START_REF] Crisp | Rates of magma emplacement and volcanic output[END_REF][START_REF] Gerlach | Eruption rates and isotopic systematics of ocean islands: further evidence for small-scale heterogeneity in the upper mantle[END_REF][START_REF] White | Long-term volumetric eruption rates and magma budgets[END_REF].

Assuming an average long-term production rate of the Comoros archipelago in the same range as the current magma emission rate of Karthala, 0.05 m 3 s -1 , and considering the total volume of each edifice from the sea floor, I determined a duration of the magmatic activity of around 10, 3.5, 5.5 and 9 Ma for Mayotte, Anjouan, Mohéli and Grande Comore, respectively. Added to the oldest subaerial geochronological ages of each edifice [START_REF] Emerick | Age progressive volcanism in the Comores Archipelago, western Indian Ocean and implications for Somali plate tectonics[END_REF][START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF][START_REF] Debeuf | Etude de l'évolution volcano-structurale et magmatique de Mayotte (Archipel des Comores, Océan Indien): Approches structurale, pétrographique, géochimique et géochronologique[END_REF]), these results suggest a beginning of the magmatic activity in Mayotte, Anjouan, Mohéli and Grande Comore around 20, 7, 10.5 and 9.1 Ma ago, respectively. Thus the magmatism of the Comoros archipelago probably initiated 5 Ma earlier than initially proposed. Furthermore, as mentioned above, an early activity of Anjouan likely started as early as 11.1 Ma [START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF]. In consequence, I propose that the magmatic activity begun first in Mayotte about 20 Ma ago and second, almost simultaneously, in Anjouan, Mohéli and Grande Comore between 9 and 11 Ma (Fig. 21.3).

Regional Distribution of the Volcanism

Integrated at a regional scale, the magmatism of the Comoros archipelago shows strong petrological and geochemical similarities with the undersaturated alkaline basalt and basanite series emplaced in northern Madagascar and along the Kerimba and Lacerda basins [START_REF] Daniel | Relations Madagascar-Archipel des Comores (Nord-Est du Canal du Mozambique). Sur la nature volcanique du Banc de Leven[END_REF][START_REF] Mougenot | Structure et volcanisme d'un rift sous-marin: le fossé des Kérimbas (marge nord-mozambique)[END_REF][START_REF] Melluso | Petrogenesis of Late Cenozoic mafic alkaline rocks of the Nosy Be archipelago (northern Madagascar): relationships with the Comorean magmatism[END_REF]. Conversely, they present distinct chemical and isotopic compositions than the Neogene magmas emitted in central Madagascar around the Alaotra graben, which are explained by smaller degrees of partial melting of an heterogeneous mantle lithosphere (Melluso et al. 2011)Fig. 21.4).

The most remarkable point is the timing of the magmatic activity in and around the Mozambique channel. Geochronological data suggest the occurrence of three periods of magmatic activity since the Upper Oligocene (Fig. 21.3). The first period, which developed in late Oligocene, is documented in the Rungwe volcanic province, the southernmost volcanic occurrence related to the East African rift (Roberts et al. 2012b), and in Central Madagascar [START_REF] Piqué | The geological evolution of Madagascar: an introduction[END_REF][START_REF] Bardintzeff | Madagascar volcanic provinces linked to the Gondwana break-up: geochemical and isotopic evidences for contrasting mantle sources[END_REF]. Only a few volcanic manifestations can be linked to this event. The second period of activity started around 20 Ma ago and lasted about 3-4 Ma. The magmatism resumed in the Rungwe volcanic province [START_REF] Rasskazov | A magmatic episode in the western rift of East Africa (19-17 Ma)[END_REF] and in Central Madagascar [START_REF] Piqué | The geological evolution of Madagascar: an introduction[END_REF][START_REF] Bardintzeff | Madagascar volcanic provinces linked to the Gondwana break-up: geochemical and isotopic evidences for contrasting mantle sources[END_REF]. It also probably initiated in Mayotte as estimated above from the magma production rates. After a lull of 4-6 Ma, the activity drastically spread over the Mozambique channel and the surrounding areas, forming the third, largest period of activity (Fig. 21.3). The former Rungwe and Central Madagascar provinces were reactivated [START_REF] Ebinger | Chronology of volcanism and rift basin propagation: Rungwe volcanic province, East Africa[END_REF][START_REF] Ebinger | Tectonic controls on rift basin morphology: evolution of the Northern Malawi (Nyasa) Rift[END_REF][START_REF] Bardintzeff | Madagascar volcanic provinces linked to the Gondwana break-up: geochemical and isotopic evidences for contrasting mantle sources[END_REF]. Moreover, volcanic activity appeared almost simultaneously in the southwest and north parts of Madagascar and in the Anjouan, Mohéli and Grande Cormore [START_REF] Emerick | Age progressive volcanism in the Comores Archipelago and northern Madagascar[END_REF]Duncan 1982, 1983;[START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF][START_REF] Rasamimanana | Les épisodes magmatiques du Sud-Ouest de Madagascar (bassin de Morondava), marqueurs des phénomènes de rifting crétacé et néogène[END_REF][START_REF] Debeuf | Etude de l'évolution volcano-structurale et magmatique de Mayotte (Archipel des Comores, Océan Indien): Approches structurale, pétrographique, géochimique et géochronologique[END_REF][START_REF] Bardintzeff | Madagascar volcanic provinces linked to the Gondwana break-up: geochemical and isotopic evidences for contrasting mantle sources[END_REF][START_REF] Cucciniello | New Ar ages and petrogenesis of the Massif d'Ambre volcano, northern Madagascar[END_REF]. Additionally, oceanographic data indicate magmatic occurrences in the Kerimba and Lacerda basins since the middle Miocene (Mougenot et al. 1986a[START_REF] Mougenot | Structure et volcanisme d'un rift sous-marin: le fossé des Kérimbas (marge nord-mozambique)[END_REF].

To sum up, the temporal distribution of volcanism of the Comoros archipelago shows striking similarities with the adjacent volcanic provinces, suggesting a narrow genetic link at regional scale.

The Magmatism of the Comoros

Archipelago Integrated in the Regional Geodynamics

The Neogene magmatism that developed in the Kerimba and Lacerda basins, in the East African rift and in Madagascar is spatially superimposed to an active seismicity linked to an overall E-W extension [START_REF] Grimison | Earthquakes in the Davie Ridge-Madagascar region and the southern Nubian-Somalian Plate boundary[END_REF][START_REF] Bertil | Seismotectonics of Madagascar[END_REF][START_REF] Foster | Source parameters of large African earthquakes: implications for crustal rheology and regional kinematics[END_REF]; Geochronological dating from [START_REF] Hajash | Paleomagnetic and radiometric evidence for the age of the Comores archipelago, west central Indian Ocean[END_REF], [START_REF] Emerick | Age progressive volcanism in the Comores Archipelago and northern Madagascar[END_REF]Duncan (1982, 1983), [START_REF] Montaggioni | Les enclaves de roches détritiques dans les volcans d'Anjouan (archipel des Comores). Origine et interprétation dans le cadre de l'évolution du canal de Mozambique[END_REF], [START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF], [START_REF] Ebinger | Chronology of volcanism and rift basin propagation: Rungwe volcanic province, East Africa[END_REF][START_REF] Ebinger | Tectonic controls on rift basin morphology: evolution of the Northern Malawi (Nyasa) Rift[END_REF], [START_REF] Rasamimanana | Les épisodes magmatiques du Sud-Ouest de Madagascar (bassin de Morondava), marqueurs des phénomènes de rifting crétacé et néogène[END_REF], [START_REF] Piqué | The geological evolution of Madagascar: an introduction[END_REF]; Bardintzeff et al. (2001[START_REF] Bardintzeff | Madagascar volcanic provinces linked to the Gondwana break-up: geochemical and isotopic evidences for contrasting mantle sources[END_REF], [START_REF] Rasskazov | A magmatic episode in the western rift of East Africa (19-17 Ma)[END_REF], [START_REF] Debeuf | Etude de l'évolution volcano-structurale et magmatique de Mayotte (Archipel des Comores, Océan Indien): Approches structurale, pétrographique, géochimique et géochronologique[END_REF], [START_REF] Cucciniello | New Ar ages and petrogenesis of the Massif d'Ambre volcano, northern Madagascar[END_REF]), Roberts et al. (2012a). White bars account for the newly estimated activity for the different edifices of the Comoros archipelago. 1, 2 and 3 identify the different periods of volcanism that developed at a regional scale. Rifting of the Kerimba and Lacerda basins is dated by Mougenot et al. (1986a). The uplift of Madagascar is determined from river profile analysis (Roberts et al. 2012b). See text for explanation [START_REF] Delvaux | African stress pattern from formal inversion of focal mechanism data[END_REF][START_REF] Rindraharisaona | Earth structure and instrumental of Madagascar: implications on the seismotectonics[END_REF] (Madagascar;[START_REF] Laville | Le fossé méridien d'Ankay-Alaotra, témoin d"une extension crustale récente et actuelle à Madagascar[END_REF]Kusky et al. 2010). This entire system of grabens would correspond to the southeastward continuity of the East African rift (Mougenot et al. 1986b;[START_REF] Piqué | The geological evolution of Madagascar: an introduction[END_REF][START_REF] Stamps | A kinematic model for the East African Rift[END_REF]. The Comoros archipelago is also located in an active seismic zone. However, very few data allow a precise determination of the stress regime that affected this seismic band. No obvious tectonic structures have been identified and only rare focal mechanisms suggest a present strike slip stress regime [START_REF] Delvaux | African stress pattern from formal inversion of focal mechanism data[END_REF]. It is worth noting that this stress field is consistent with the Plio-Quaternary transpression described along the N150 trending faults of the Kerimba basin (Mougenot et al. 1986a[START_REF] Mougenot | Structure et volcanisme d'un rift sous-marin: le fossé des Kérimbas (marge nord-mozambique)[END_REF]. Strike slip and transpression, if any, could explain the occurrence of uplifted blocks like the sandstone one in Anjouan and extension along NE-SW faults [START_REF] Debeuf | Etude de l'évolution volcano-structurale et magmatique de Mayotte (Archipel des Comores, Océan Indien): Approches structurale, pétrographique, géochimique et géochronologique[END_REF]). In consequence, considering the spatial and temporal distribution of the seismic activity, the magmatism and the tectonic structures, I propose that the volcanism of the Comoro Islands do not result from a distinct deep hotspot but instead primarily stems from lithospheric deformation in the general context of the East African rift.

Conclusion

The main points of this review can be summarized as follows:

1. The magmatism of the Comoros archipelago has been diversely interpreted in the past decades as the result of a deep mantle plume or lithospheric deformation. It is thus a classical example that fed the debate on the origin of intraplate ocean volcanoes. 2. The age of Comoros archipelago is very likely older than previously considered and did not migrated linearly. Magmatism in Mayotte probably started about 20 Ma ago whereas Anjouan, Mohéli and Grande Comore may develop almost simultaneously about 10 Ma ago. 3. The magmatic activity was coeval with that developed in Madagascar and in the Rungwe volcanic province. At a regional scale, three different periods of activity can be distinguished. All these provinces are spatially superimposed to a current seismic activity. 4. The Comoros archipelago is consequently interpreted as the result of a lithospheric deformation in the general context of the East African rift rather than the surface expression of a deep mantle plume.

Fig

  Fig. 21.1 a Location of the Comoros archipelago, between the northern tip of Madagascar and Africa. b The archipelago is composed from east to west of Mayotte, Anjouan, Mohéli and Grande Comore. Geiser and Leven banks are submarine reliefs of volcanic origin (Daniel et al. 1972). Saint Lazare (StL) and Paisley

  Fig. 21.2 Age of the volcanism in the Comoros archipelago. Geochronological dating from[START_REF] Hajash | Paleomagnetic and radiometric evidence for the age of the Comores archipelago, west central Indian Ocean[END_REF],[START_REF] Emerick | Age progressive volcanism in the Comores Archipelago and northern Madagascar[END_REF] Duncan (1982, 1983),[START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF],[START_REF] Debeuf | Etude de l'évolution volcano-structurale et magmatique de Mayotte (Archipel des Comores, Océan Indien): Approches structurale, pétrographique, géochimique et géochronologique[END_REF]

Fig. 21 . 3

 213 Fig. 21.3 Synthesis of the age of the volcanism (black bars) in the Comoros archipelago and the surrounding volcanic provinces. See Fig. 21.4 for location.Geochronological dating from[START_REF] Hajash | Paleomagnetic and radiometric evidence for the age of the Comores archipelago, west central Indian Ocean[END_REF],[START_REF] Emerick | Age progressive volcanism in the Comores Archipelago and northern Madagascar[END_REF] Duncan (1982, 1983),[START_REF] Montaggioni | Les enclaves de roches détritiques dans les volcans d'Anjouan (archipel des Comores). Origine et interprétation dans le cadre de l'évolution du canal de Mozambique[END_REF],[START_REF] Nougier | The Comores Archipelago in the western Indian Ocean: volcanology geochronology and geodynamic setting[END_REF],[START_REF] Ebinger | Chronology of volcanism and rift basin propagation: Rungwe volcanic province, East Africa[END_REF][START_REF] Ebinger | Tectonic controls on rift basin morphology: evolution of the Northern Malawi (Nyasa) Rift[END_REF],[START_REF] Rasamimanana | Les épisodes magmatiques du Sud-Ouest de Madagascar (bassin de Morondava), marqueurs des phénomènes de rifting crétacé et néogène[END_REF],[START_REF] Piqué | The geological evolution of Madagascar: an introduction[END_REF];Bardintzeff et al. (2001[START_REF] Bardintzeff | Madagascar volcanic provinces linked to the Gondwana break-up: geochemical and isotopic evidences for contrasting mantle sources[END_REF],[START_REF] Rasskazov | A magmatic episode in the western rift of East Africa (19-17 Ma)[END_REF],[START_REF] Debeuf | Etude de l'évolution volcano-structurale et magmatique de Mayotte (Archipel des Comores, Océan Indien): Approches structurale, pétrographique, géochimique et géochronologique[END_REF],Cucciniello et al. (2011), Roberts et al.

  Fig. 21.4 a Distribution of seismic activity, volcanism and normal faults active from the Miocene to the actual. Earthquakes from the Institut et Observatoire de Géophysique d'Antananarivo (IOGA) (Bertil and Reignoult 1998). A.G. Alaotra graben

  Table 21.1; Fig. 21.2). It is worth noting that a syenite xenolith dated at 11.1 Ma in Anjouan

Table 21

 21

	.1 Geochronological dating of the volcanic rocks of the Comoros archipelago
	Location	Latitude	Longitude	Age (Ma)	Sample name	Reference
	Mayotte	-12.9	45.133	10.58	M41	a
	Mayotte	-12.75	45.08	7.7	samp. 16	b
	Mayotte	-12.75	45.08	7.7	samp. 92	b
	Mayotte	-12.75	45.08	7.1	samp. 110	b
	Mayotte	-12.75	45.08	6.9	samp. 31	b
	Mayotte	-12.989	45.151	6.11	M140	a
	Mayotte	-12.75	45.08	5.9	samp. 12	b
	Mayotte	-12.71	45.1	5.28	samp. MA-29	c
	Mayotte	-12.71	45.1	5.26	samp. MA-30	c
	Mayotte	-12.75	45.08	5	samp. 22	b
	Mayotte	-12.999	45.142	4.98	M137	a
	Mayotte	-12.75	45.08	4.9	samp. 116	b
	Mayotte	-12.67	45.0567	4.41	M112	a
	Mayotte	-12.649	45.0385	4.36	M104	a
	Mayotte	-12.673	45.05	4.2	M109	a
	Mayotte	-12.75	45.08	4.03	samp. 46	b
	Mayotte	-12.98	45.113	3.97	M132	a
	Mayotte	-12.949	45.162	3.95	M39a	a
	Mayotte	-12.881	45.214	3.91	M38	a
	Mayotte	-12.647	45.022	3.79	M108	a
	Mayotte	-12.94	45.1	3.75	samp. MA-81	c
	Mayotte	-12.86	45.1	3.65	samp. MY13-1	d
	Mayotte	-12.84	45.107	3.64	M55	a
	Mayotte	-12.94	45.1	3.41	samp. MA-82	c
	Mayotte	-12.74	45.23	3.4	samp. MY1-1	d
	Mayotte	-12.975	45.202	3.4	M93	a
	Mayotte	-12.75	45.08	3.3	samp. 149	b
	Mayotte	-12.75	45.08	3.3	samp. 147	b
	Mayotte	-12.75	45.08	3.3	samp. 112	b
	Mayotte	-12.77	45.1	3.27	samp. MA-68	c
	Mayotte	-12.72	45.08	3.25	samp. MA-25	c
	Mayotte	-12.91	45.1	3.24	samp. MA-73	c
	Mayotte	-12.75	45.08	3.23	samp. 03	b
	Mayotte	-12.75	45.08	3.1	samp. 117	b
	Mayotte	-12.75	45.08	2.7	samp. 126	b
	Mayotte	-12.94	45.175	2.55	M87	a
	Mayotte	-12.944	45.124	2.52	M95	a
	Mayotte	-12.75	45.08	2.5	samp. 93	b
	Mayotte	-12.9	45.084	2.43	M46	a
	Mayotte	-12.75	45.08	2.4	samp. 138	b
						(continued)

Table 21

 21

	.1 (continued)
	Location	Latitude	Longitude	Age (Ma)	Sample name	Reference
	Mayotte	-12.737	45.144	2.39	M97	a
	Mayotte	-12.777	45.23	2.32	M4	a
	Mayotte	-12.77	45.18	2.31	samp. MA-37	c
	Mayotte	-12.75	45.08	2.2	samp. 83	b
	Mayotte	-12.75	45.08	2.15	samp. 85	b
	Mayotte	-12.841	45.125	2.13	M82	a
	Mayotte	-12.75	45.08	2	samp. 87	b
	Mayotte	-12.67	45.09	2	M25	a
	Mayotte	-12.991	45.109	1.95	M115	a
	Mayotte	-12.75	45.08	1.85	samp. 06	b
	Mayotte	-12.75	45.2	1.59	samp. MA-59	c
	Mayotte	-12.76	45.1	1.49	samp. MA-38	c
	Mayotte	-12.75	45.08	1.49	samp. 144	b
	Mayotte	-12.72	45.2	1.42	samp. MY3-1	d
	Mayotte	-12.809	45.189	1.41	M56	a
	Mayotte	-12.736	45.19	1.3	M123	a
	Mayotte	-12.804	45.193	0.8	M58	a
	Mayotte	-12.762	45.099	0.78	M59	a
	Mayotte	-12.783	45.234	0.15	M53	a
	Anjouan	-12.15	44.3	11.1	samp. AN14	b
	Anjouan	-12.15	44.3	3.9	samp. AN08	b
	Anjouan	-12.24	44.32	1.52	samp. AJ-28-1	d
	Anjouan	-12.15	44.3	1.5	samp. AN02	b
	Anjouan	-12.17	44.41	1.18	samp. AN-11	c
	Anjouan	-12.17	44.38	0.39	samp. AJ-21-1	d
	Anjouan	-12.15	44.3	0.36	samp. AN01	b
	Anjouan	-12.15	44.3	0.36	samp. AN04	b
	Mohéli	-12.25	43.66	5	samp. MO12	b
	Mohéli	-12.25	43.66	3.2	samp. MO10	b
	Mohéli	-12.25	43.66	2.75	samp. RH-32	c
	Mohéli	-12.33	43.84	1.89	samp. RH-22	c
	Mohéli	-12.33	43.84	1.53	samp. RH-21	c
	Mohéli	-12.28	43.71	1.14	samp. RH-42	c
	Mohéli	-12.25	43.66	0.71	samp. RH-33	c
	Mohéli	-12.29	43.77	0.62	samp. RH-36	c
	Mohéli	-12.25	43.66	0.56	samp. MO04	b
	Mohéli	-12.25	43.66	0.48	samp. MO05	b
	Grande Comore	-11.85	43.49	0.13	samp. 35G	c
	Grande Comore	-11.62	43.27	0.01	samp. GC1-1	d

a Debeuf (2004), b Nougier et al. (1986), c Emerick and Duncan


PhD Olivier Colliot

Neda Bernasconi

Najmeh Khalili

MSc Samson B Antel

Véronique Naessens

MD Andrea Bernasconi
email: andrea@bic.mni.mcgill.ca

MD ; N Bernasconi

PhD ; N Khalili

PhD ; V Naessens

MD ; A Bernasconi

Individual voxel-based analysis of gray matter in

Keywords: epilepsy, focal cortical dysplasia, voxel-based morphometry, magnetic resonance imaging, image analysis

Abstract

High-resolution MRI of the brain has made it possible to identify focal cortical dysplasia (FCD) in an increasing number of patients. There is evidence for structural abnormalities extending beyond the visually identified FCD lesion. Voxel-based morphometry (VBM) has the potential of detecting both lesions and extra-lesional abnormalities because it performs a whole brain voxel-wise comparison. However, on T1-weighted MRI, FCD lesions are characterized by a wide spectrum of signal hyperintensity that may compromise the results of the segmentation step in VBM. Our purpose was to investigate grey matter (GM) changes in individual FCD patients using voxel-based morphometry (VBM). In addition, we sought to assess the performance of this technique for FCD detection with respect to lesion intensity using an operator designed to emphasize areas of hyperintense T1 signal. We studied 27 patients with known FCD and focal epilepsy, and 39 healthy controls. We compared the GM map of each subject (controls and patients) with the average GM map of all controls and obtained a GM z-score map for each individual. The protocol being designed to achieve a maximal specificity, no differences in GM concentration were found in the control group. The z-score maps showed an increase in GM that coincided with the lesion in 21/27 (78%) patients. Five of the six remaining patients whose lesions were not detected by VBM, presented with a strong lesion hyperintensity and a significant part of their lesion was misclassified as white matter. In 16/27 (59%) patients, there were additional areas of GM increase distant from the primary lesion. Areas of GM decrease were found in 8/27 (30%) patients. In conclusion, individual voxel-based analysis was able to detect FCD in a majority of patients. Moreover, FCD was often associated with widespread GM changes extending beyond the visible lesion. In its current form, however, individual VBM may be unable to detect lesions characterized by strong signal intensity abnormalities.

Introduction

Malformations caused by abnormalities of cortical development (MCD) [START_REF] Barkovich | Classification system for malformations of cortical development: update 2001[END_REF] have been increasingly recognized as an important cause of intractable focal epilepsy. Taylor-type focal cortical dysplasia (FCD) [START_REF] Taylor | Focal dysplasia of the cerebral cortex in epilepsy[END_REF], a pathology due to abnormal neuroglial proliferation, is the most frequent MCD in patients referred for presurgical evaluation [START_REF] Frater | Surgical pathologic findings of extratemporal-based intractable epilepsy: a study of 133 consecutive resections[END_REF][START_REF] Sisodiya | Surgery for malformations of cortical development causing epilepsy[END_REF]. The pathologic spectrum of FCD includes various degrees of cortical thickening, indistinctness ("blurring") of the gray matter (GM)-white matter (WM) transition, abnormal sulcal pattern, abnormal neuroglial elements in the underlying WM, and disruption of the normal cortical lamination associated with an excess of large, aberrant neurons [START_REF] Prayson | Pathologic characteristics of the cortical dysplasias[END_REF].

On T1-weighted MRI, FCD is mainly characterized by variable degrees of GM thickening, a poorly defined transition between GM and WM, and hyperintense signal within the dysplastic lesion relative to normal cortex (Barkovich andKuzniecky, 1996, Lee et al., 1998). High-resolution MRI of the brain has made it possible to identify FCD in an increasing number of patients (Barkovich andKuzniecky, 1996, Grant et al., 1998) . However, in many patients, lesions of FCD are characterized by minor structural abnormalities that go unrecognized or are too subtle to be detected by standard radiological analysis.

In FCD, there is evidence for structural abnormalities extending beyond the visually identified lesion. Histological abnormalities may be disseminated rather than confined to a single patch or even be multifocal [START_REF] Frater | Surgical pathologic findings of extratemporal-based intractable epilepsy: a study of 133 consecutive resections[END_REF][START_REF] Gomez-Anson | Imaging and radiological-pathological correlation in histologically proven cases of focal cortical dysplasia and other glial and neuronoglial malformative lesions in adults[END_REF][START_REF] Prayson | Pathologic characteristics of the cortical dysplasias[END_REF][START_REF] Taylor | Focal dysplasia of the cerebral cortex in epilepsy[END_REF]. Electrophysiological studies in animal models of MCD [START_REF] Jacobs | Focal epileptogenesis in a rat model of polymicrogyria[END_REF][START_REF] Kraemer | Metabolic and electrophysiological alterations in an animal model of neocortical neuronal migration disorder[END_REF][START_REF] Redecker | Longterm evolution of excitotoxic cortical dysgenesis induced in the developing rat brain[END_REF] and humans have also shown that the epileptogenic region frequently exceeds the boundaries of the obvious lesion [START_REF] Palmini | Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results[END_REF][START_REF] Raymond | EEG features of focal malformations of cortical development[END_REF][START_REF] Tassi | Cortical dysplasia: electroclinical, imaging, and neuropathologic study of 13 patients[END_REF]. The presence of these widespread structural abnormalities may be an important factor explaining the relatively poor outcome of surgery in MCD patients [START_REF] Sisodiya | Surgery for malformations of cortical development causing epilepsy[END_REF] when compared to patients with other causes of epilepsy such as hippocampal sclerosis [START_REF] Engel | Surgery for seizures[END_REF].

To date only few studies have been dedicated to the automatic detection of FCD and to the evaluation of structural changes distant to the primary lesion using quantitative methods that can potentially capture structural changes too subtle to be detected by visual inspection [START_REF] Sisodiya | Widespread cerebral structural changes in patients with cortical dysgenesis and epilepsy[END_REF][START_REF] Sisodiya | Disproportion of cerebral surface areas and volumes in cerebral dysgenesis. MRI-based evidence for connectional abnormalities[END_REF]. We previously showed that computational models based on known MRI features of FCD and texture analysis improve the sensitivity of detection of FCD relative to the standard MRI evaluation [START_REF] Antel | Computational models of MRI characteristics of focal cortical dysplasia improve lesion detection[END_REF][START_REF] Antel | Automated detection of focal cortical dysplasia lesions using computational models of their MRI characteristics and texture analysis[END_REF][START_REF] Bernasconi | Texture analysis and morphological processing of magnetic resonance imaging assist detection of focal cortical dysplasia in extratemporal partial epilepsy[END_REF].

Voxel-based morphometry (VBM) is a fully automated technique allowing identification of regional differences in the amount of GM and WM in spatially standardized structural MR images, enabling an objective analysis between groups of subjects [START_REF] Ashburner | Voxel-based morphometry--the methods[END_REF]. While originally developed for group comparison, VBM has also been used to assess morphological changes in individual brains compared to a control group [START_REF] Mehta | Evaluation of voxel-based morphometry for focal lesion detection in individuals[END_REF][START_REF] Mummery | A voxel-based morphometry study of semantic dementia: relationship between temporal lobe atrophy and semantic memory[END_REF][START_REF] Wilke | Automated detection of gray matter malformations using optimized voxel-based morphometry: a systematic approach[END_REF][START_REF] Woermann | Voxel-byvoxel comparison of automatically segmented cerebral gray matter--A raterindependent comparison of structural MRI in patients with epilepsy[END_REF]. As VBM involves a whole brain voxel-wise comparison, it has the potential of detecting both the FCD lesion and structural abnormalities that would extend beyond the lesion itself. However, accuracy and sensitivity of VBM analysis depend upon the quality of the underlying preprocessing steps, namely segmentation and spatial normalization. When dealing with brain pathologies, a major source of error could arise when abnormal voxel intensities are present [START_REF] Mehta | Evaluation of voxel-based morphometry for focal lesion detection in individuals[END_REF]. In our previous studies, we developed a computational operator to model the hyperintense signal within the FCD lesion [START_REF] Antel | Computational models of MRI characteristics of focal cortical dysplasia improve lesion detection[END_REF][START_REF] Bernasconi | Texture analysis and morphological processing of magnetic resonance imaging assist detection of focal cortical dysplasia in extratemporal partial epilepsy[END_REF] and proved that FCD lesions are characterized by a wide spectrum of hyperintense voxels with respect to normal cortex [START_REF] Colliot | Quantitative MRI profiling of cortical dysplasia[END_REF]). Thus, it is possible that FCD may be misclassified as WM instead of GM, and therefore be undetected by VBM.

Our purpose was to investigate GM changes in individual FCD patients using VBM. In addition, we sought to assess the performance of this technique for FCD detection with respect to lesion intensity.

Methods

Subjects

We studied 27 adult patients (11 males, mean age ± [standard deviation (SD)] =25 ± 7 years) who had been investigated at the Montreal Neurological Institute for partial epilepsy related to FCD and had high-resolution MRI, including curvilinear reformatting [START_REF] Bastos | Diagnosis of subtle focal dysplastic lesions: curvilinear reformatting from three-dimensional magnetic resonance imaging[END_REF]. The FCD lesion was seen on MRI in all of them. Patients were compared to 39 sex-and age-matched healthy controls (18 males, mean age 29 ± 8). The Ethics Board of the Montreal Neurological Institute and Hospital approved the study and written informed consent was obtained from all participants.

Eighteen patients (18/27=67%) underwent surgery and FCD was confirmed by histopathology in all of them. Mean post-operative follow-up was 4.7 years (median = 4.5 years). Ten patients (10/18=56%) became completely seizure free after surgery (Engel's classification IA) [START_REF] Engel | Outcome with respect to epileptic seizures[END_REF], while eight others did not achieve complete seizure freedom (five had rare disabling seizures -Engel's classification II-, two had a worthwhile improvement -Engel's classification III-and one had no worthwhile improvement -Engel's classification IV-).

Three patients refused the surgical intervention and another patient with normal neurological examination was not operated because the FCD lesion encroached the sensorimotor hand area. In five patients, seizures were controlled with antiepileptic medication.

The FCD lesions were located in the frontal lobe in 17/27 (63%) patients and in the parietal lobe in 10/27 (37%) patients.

MRI scanning

In all patients and healthy controls MRI volumetric images were acquired on a 1.5 T Gyroscan (Philips Medical System, Best, The Netherlands) using a T1-fast field echo sequence (TR=18, TE=10, 1 acquisition average pulse sequence, flip angle=30 o , matrix size=256x256, FOV=256, thickness=1mm).

Image processing

Voxel-wise processing of the MRI included the following steps (Figure 1). Images were automatically registered into a standard, stereotaxic space to adjust for differences in total brain volume and brain orientation [START_REF] Collins | Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space[END_REF]. Each image underwent automated correction for intensity non-uniformity and intensity standardization [START_REF] Sled | A nonparametric method for automatic correction of intensity nonuniformity in MRI data[END_REF]. This correction produces consistent relative gray matter (GM), white matter (WM) and cerebro-spinal fluid (CSF) intensities. Classification of brain tissue in GM, WM and CSF was performed using the INSECT algorithm [START_REF] Zijdenbos | Automatic quantification of ms lesions in 3D MRI brain data sets: validation of INSECT[END_REF], which relies on an artificial neural network classifier. GM masks were then blurred with an isotropic Gaussian kernel of 12 mm FWHM to generate 3D-maps of GM "concentration". The validity of a 12 mm smoothing kernel in unbalanced designs has been shown previously [START_REF] Salmond | Distributional assumptions in voxel-based morphometry[END_REF]. All GM concentration maps from the control group were then averaged to produce mean and standard deviation (SD) maps.

We compared the GM concentration map of each subject (controls and patients) with the average GM map of all controls (Figure 1A) and obtained a GM z-score map for each individual (Figure 1B).

Assessment of FCD hyperintensity

To assess whether the hyperintensity of FCD lesions (i.e. the fact that they are characterized by higher signal intensity than the normal cortex) has a significant impact on the automatic tissue segmentation and on the results of individual voxel-based analysis, we used our previously developed model of relative intensity [START_REF] Bernasconi | Texture analysis and morphological processing of magnetic resonance imaging assist detection of focal cortical dysplasia in extratemporal partial epilepsy[END_REF]. Relative intensity is defined for a particular voxel as 100*[Bg-|Bg-g(i,j,k)|]/Bg , where Bg is the intensity at the boundary between GM and WM, and g(i,j,k) represents the intensity at a given voxel (Figure 2A). Using the relative difference enables the analysis of voxels located within cortical GM in which the intensity is higher than normal and may even overlap that of the WM.

The primary FCD lesions were segmented manually on the high-resolution T1weighted MRI by a trained rater (V.N.). The proportion of FCD lesion label classified as GM and WM was calculated. We then computed the mean relative intensity within the segmented FCD (Figure 2).

Analysis

To detect significant differences in GM concentration, a voxel was considered abnormal if its value fell outside the mean of the controls ±4.5 SD. This threshold was chosen to exceed the maximum GM increase or decrease seen in any control subject.

The voxel-based analysis was considered to successfully detect the FCD lesion when a GM increase greater than 4.5 was present at the lesion location. To quantify the fraction of the lesion correctly identified by the method, we computed a lesion coverage ratio, which is equal to the percentage of voxels in the lesion label having a GM z-score greater than 4.5. Association between the ratio of lesion coverage and the size of the FCD lesion, as determined by manual segmentation, was assessed using Pearson correlation coefficient (r).

To assess the influence of the chosen threshold (4.5 SD) on the detection results, we computed the sensitivity [percentage of positives correctly identified = true-positives / (true-positives + false-negatives)] and specificity [percentage of negatives correctly identified = true-negative / (true-negatives + false-positives)] for different threshold values (i.e., 5 SD, 4.5 SD, 4 SD, 3.5 SD, 3 SD, 2.5 SD, 2 SD). True positives are patients that had an increase in GM concentration higher than the threshold and coinciding with the lesion. False positives are healthy controls that had a GM increase larger than the threshold.

To assess the influence of the size of the healthy control group on the results, we randomly sub-sampled the control population into two groups of 20 and 25 subjects.

We considered as extra-lesional GM increase any GM increase greater than our 4.5 threshold and not coinciding with the lesion. Conversely, we considered as GM decreases, regions of GM decrease smaller than -4.5 SD that did not coincide with the lesion.

We assessed using χ 2 test whether the presence of extra-lesional GM increases as well as extra-lesional GM decreases differed between patients who became seizure free after surgery compared to those who did not.

Results

Lesional GM increase

The z-score maps showed an increase in GM that coincided with the primary FCD lesion in 21/27 (78%) patients. Examples of individual patients are presented in Figure 3. In 6/27 (22%) patients, no GM increase was found at the FCD location.

FCD lesions volumes ranged from 773mm 3 to 88726mm 3 (mean=10803mm 3 ± 16037). For the 21 patients in whom the lesion was detected, the mean lesion coverage ratio was 21% (SD=17%, range=0.1%-63%). There was no correlation between FCD volume and the coverage ratio. Results of FCD lesion detection corresponding to various coverage ratios are presented in Figure 3.

The results for sensitivity and specificity obtained for different threshold values are presented in Figure 4.

Using a randomly sub-sampled group of 20 controls and our chosen threshold of 4.5 SD, 22/27 (81%) lesions were detected and no GM increase above 4.5 was found in the controls. When using 25 controls and the same threshold, 21/27 (78%) lesions were detected and no increase was found in the controls.

Extra-lesional GM increase

Sixteen (16/27=59%) patients had extra-lesional areas of GM increase. This was the case for 13/21 (62%) of those who presented a GM increase at the location of the lesion and for three (3/6=50%) of those whose lesion was not detected by VBM. For the 16 patients with extra-lesional GM increase, the mean number of areas of increase was 2 (range=1-4). There was no difference in extra-lesional GM increases between patients who became seizure free after surgery and those who did not (50% vs. 50%).

Four (4/16=25%) patients had extra-lesional GM increases in the same hemisphere as the lesion; four (4/16=25%) had GM increases in the hemisphere contralateral to the FCD lesion; and eight (8/16=50%) had bilateral GM increases. The areas of GM increase were predominantly found in the frontal lobe (10 patients). Other locations included: temporal (5), occipital (5), parietal (3) lobes, and the insula (3).

Examples of FCD patients with extra-lesional GM increases are presented in Figure 5.

Extra-lesional GM decrease

Areas of GM decrease were found in eight (8/27=30%) patients. There was no difference in extra-lesional GM decrease between patients who became seizure free after surgery and those who did not (3/10=30% vs 4/8=50% χ 2 =0.75, df=1, p=0.38).

Five patients (5/8=63%) had GM decrease in the same hemisphere as the FCD lesion; one patient (1/8=13%) had GM decrease in the hemisphere contralateral to the lesion; and two (2/8=25%) had bilateral GM decrease. The majority of patients (6/8=75%) had GM decrease in the temporal lobe neocortex. Other areas included: frontal (3), occipital (2), and the insula (2). Examples of patients with extra-lesional GM decrease are presented in Figure 6.

Performance of VBM with respect to FCD hyperintensity

Relative intensity values for FCD patients are presented in Table 1. The relative intensity computed over the whole lesion label ranged between 72 and 93 in our patients with a mean of 85±4.6 (arbitrary units).

In 5/6 patients in whom VBM was unable to identify the primary lesion, the FCD was strongly hyperintense (relative intensity values ranging from 87 to 93). In fact, four of them presented with the four highest hyperintensity values in the patient group. These five patients also had a lower portion of the lesion classified as GM (from 37% to 80%). Representative examples are presented in Figure 7.

Discussion

Using individual voxel-based analysis, we were able to reliably and automatically detect the FCD lesion in more than three-quarter of our patients.

Comparison with previous quantitative methods

Our VBM approach provided average lesion coverage of 21% compared to expert tracing. This was slightly higher than that of our previously implemented automatic classifier based on computational models of FCD and texture analysis, which attained 13% lesion coverage [START_REF] Antel | Automated detection of focal cortical dysplasia lesions using computational models of their MRI characteristics and texture analysis[END_REF]. The sensitivity of the individual VBM analysis presented here was 78%. In a previous work based on individual VBM analysis of FCD lesions, the sensitivity for lesion detection was similar to our results [START_REF] Wilke | Automated detection of gray matter malformations using optimized voxel-based morphometry: a systematic approach[END_REF]. In that study, the authors chose an arbitrary threshold of 2 SD above the mean GM concentration in normal controls as indicative of abnormality. Therefore, they did not fully evaluate the specificity of their methodology. Indeed, at a threshold of 2 SD, we found numerous areas of false positives in our control population. To detect reliably abnormal GM, we selected a higher threshold, so that no areas of GM changes (increase or decrease) could be found in any of our healthy control subjects. Our protocol was thus designed to limit as much as possible the detection of false positives, particularly in patients who undergo presurgical evaluation for medically refractory seizures.

Statistical threshold

Choosing a threshold value of 4.5 that exceeded the maximum GM change in controls allows taking multiple comparisons into account in an empirical manner. Indeed, the number of voxels, and thus the number of comparisons, are the same when analyzing GM maps in individual patients and controls. Thus, the proportion of voxels that will be found abnormal by chance is also the same in patients and controls. Since no false positives are found in controls at this threshold, the probability of finding a false positive in the patients is very low. Our threshold selection, therefore, constitutes a significant improvement over existing individual VBM analyses that use a 2SD threshold and do not take into account multiple comparisons [START_REF] Wilke | Automated detection of gray matter malformations using optimized voxel-based morphometry: a systematic approach[END_REF].

A threshold of 4.5 SD was the minimal value to avoid false positives in healthy controls. A slightly lower value of 4 SD would allow the detection of one additional lesion while decreasing the specificity from 100% to 90%. Thresholds of 4 SD and 4.5 SD lead to high sensitivity and specificity and are thus both equally acceptable when using individual VBM for FCD detection in a clinical context. On the contrary, with lower threshold values, the number of false positives would increase rapidly as shown in Figure 4. In a clinical setting, it is conceivable to explore different thresholds below 4.0 SD, provided that the output of VBM converges with the information given by independent exams such as EEG, clinical semiology and other imaging methods.

Influence of the control group

The choice of the healthy control sample did not have a significant impact on the results. The only difference was that using 20 controls, one additional lesion could be detected at a threshold of 4.5 SD. However, in spite of this, it is preferable to use a larger group of healthy controls to better cover the spectrum of normal anatomical variability.

Performance of VBM with respect to FCD hyperintensity

Our VBM method failed to detect the FCD lesion in six patients. With a threshold of 4 SD, one of these six lesions would be detected by VBM. To identify additional lesions, the threshold should be lowered to at least 3 SD, leading to a specificity of only 31%.

Even though there was no significant correlation between lesion size and coverage, we failed to detect the two FCD lesions with the smallest volume in the group. It is likely that a very small lesion will correspond to a small focal area of GM increase, which may not exceed the order of magnitude of the normal variability of GM "concentration" in that region. The second plausible factor that can explain the ineffectiveness of VBM is FCD hyperintensity. In five of the undetected FCDs, a relatively small portion of the lesion was classified as GM by the automated segmentation algorithm, even though three of these lesions had a medium to large size compared to the others. In all five cases the FCD lesion was strongly hyperintense relative to the rest of the neocortex. Therefore a large proportion of lesional voxels were misclassified as WM. These findings emphasize the need for caution when using VBM alone to detect pathologies characterized by intensity abnormalities. They also demonstrate that VBM and our computational model of FCD hyperintensity convey complementary information.

Alternative and complementary approaches

Image analysis approaches other than VBM have the potential to detect lesions by modeling the abnormal characteristics of FCD. We previously developed a classifier that integrates computational models of the main FCD features, such as focal thickening of the cortex computed directly in the 3D image space [START_REF] Antel | Automated detection of focal cortical dysplasia lesions using computational models of their MRI characteristics and texture analysis[END_REF]. Other approaches relying on surface-based analysis of cortical thickness [START_REF] Lerch | Focal Decline of Cortical Thickness in Alzheimer's Disease Identified by Computational Neuroanatomy[END_REF][START_REF] Sailer | Focal thinning of the cerebral cortex in multiple sclerosis[END_REF] would allow a more direct comparison of cortical areas between subjects. By providing an evaluation of cortical thickness compared to similar regions in healthy controls these methods could improve FCD detection. Furthermore, automatic methods for sulci extraction and analysis have been recently developed [START_REF] Riviere | Automatic recognition of cortical sulci of the human brain using a congregation of neural networks[END_REF]. These techniques have the potential to identify abnormal sulcal patterns that may also be associated with FCD (Usui et al., 2001a[START_REF] Yagishita | Focal cortical dysplasia: appearance on MR images[END_REF]. Overall, these advanced techniques could be used in conjunction with our individual VBM approach. It is however important to keep in mind that GM/WM segmentation constitutes a crucial common pre-processing step in all these approaches. It can thus be expected that signal hyperintensity associated with FCD might still compromise the end results, similarly to what was demonstrated here. To this purpose, future effort should be dedicated to the development of segmentation algorithms that take into account FCD hyperintensity, possibly relying on region-growing techniques [START_REF] Mangin | From 3D magnetic resonance images to structural representations of the cortex topography using topology preserving deformations[END_REF] and computational models of hyperintensity [START_REF] Bernasconi | Texture analysis and morphological processing of magnetic resonance imaging assist detection of focal cortical dysplasia in extratemporal partial epilepsy[END_REF].

In our experience, T1-weighted 3-D gradient-echo technique with a voxel size of 1x1x1 mm 3 on a 1.5 Tesla scanner provides good anatomic details for digital image processing. High-field magnets are increasingly available in research and clinical facilities. Higher magnetic field-strength provides high signal-to-noise ratio due to higher signal intensity, which allows for increased spatial resolution or faster imaging. However, other unwanted effects such as the sensitivity to magnetic field inhomogeneities and changes in relaxation times increase with higher field strength, which lead to changes in image contrast. High-field imaging has the potential to improve lesion detection, provided that appropriate intensity correction methods become available.

Extra-lesional GM changes in FCD

Focal areas of extra-lesional GM decrease were found in approximately one third of the patients, the majority of them being located within the hemisphere ipsilateral to the primary FCD lesion and in the temporal lobe neocortex. Similar findings were reported in a previous study of 10 patients with various MCD, mostly heterotopias [START_REF] Woermann | Voxel-byvoxel comparison of automatically segmented cerebral gray matter--A raterindependent comparison of structural MRI in patients with epilepsy[END_REF]. Although the exact nature of GM decrease remains unclear, its location in the temporal lobe ipsilateral to the primary FCD lesion, that was frontal in most patients, could indicate GM atrophy secondary to alteration of fronto-temporal neuronal circuits. This hypothesis is supported by previous observations showing decreased metabolic function in the temporal lobe of patients with extra-temporal lesions, including FCD [START_REF] Miller | Medial temporal lobe neuronal damage in temporal and extratemporal lesional epilepsy[END_REF].

Fifty-nine percent of our patients exhibited extra-lesional areas of GM increase, which were present in equal proportions in the hemisphere ipsi-and contralateral to the FCD lesion. Areas of GM increase were located mainly within the frontal lobe. Interestingly, the majority of FCD lesions were also located in the frontal lobe. This might indicate that a similar developmental process is the source of both primary FCD lesions and extra-lesional GM increase. Retrospective visual analysis of the areas of GM increase in individual z-score maps and on conventional MRI of these patients was not suggestive of FCD pathology. Moreover, scalp EEG data from these regions did not exhibit any epileptic abnormality nor patterns found to be associated with FCD such as polyspike activity [START_REF] Gambardella | Usefulness of focal rhythmic discharges on scalp EEG of patients with focal cortical dysplasia and intractable epilepsy[END_REF]. These findings are in agreement with our previous work on automatic classification of FCD, where we found extra-lesional clusters exhibiting a pattern of features similar to FCD lesions in one third of patients [START_REF] Antel | Automated detection of focal cortical dysplasia lesions using computational models of their MRI characteristics and texture analysis[END_REF]. The absence of any false positives in our control subjects combined with pathological [START_REF] Prayson | Pathologic characteristics of the cortical dysplasias[END_REF][START_REF] Taylor | Focal dysplasia of the cerebral cortex in epilepsy[END_REF] and MRI reports [START_REF] Sisodiya | Surgery for malformations of cortical development causing epilepsy[END_REF][START_REF] Sisodiya | Malformations of cortical development: burdens and insights from important causes of human epilepsy[END_REF], Sisodiya et al., 1995[START_REF] Sisodiya | Disproportion of cerebral surface areas and volumes in cerebral dysgenesis. MRI-based evidence for connectional abnormalities[END_REF] of diffuse cortical involvement in FCD suggests that these clusters may indeed indicate abnormal regions that are otherwise undetectable via conventional means.

Areas of GM increase detected by VBM in FCD patients could represent abnormalities of gyration rather than true increase in GM or cortical thickening. On visual analysis of conventional MRI, sulcal and gyral abnormalities are sometimes noted in patients with MCD. These abnormalities are thought to represent an underlying pathological cortical cytoarchitecture [START_REF] Barth | Disorders of neuronal migration[END_REF][START_REF] Rakic | Defects of neuronal migration and the pathogenesis of cortical malformations[END_REF] and have been described in the proximity of the MRI visible lesion, but also distant from it. Sulcal and gyral abnormalities are characterized by a large spectrum of changes ranging from clefts of various depth [START_REF] Bronen | Cerebrospinal fluid cleft with cortical dimple: MR imaging marker for focal cortical dysgenesis[END_REF] to minor changes such as slight shape asymmetry, broad gyri, shallow or deep sulci, altered gyral or sulcal orientation or location (displacement) [START_REF] Muntaner | MRI of a family with focal abnormalities of gyration[END_REF][START_REF] Raymond | Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumor and dysgenesis of archicortex in epilepsy. Clinical, EEG and neuroimaging features in 100 adult patients[END_REF], Usui et al., 2001b[START_REF] Yagishita | Focal cortical dysplasia: appearance on MR images[END_REF]. The fact that sulcal and gyral abnormalities have been rarely reported is not surprising since the cerebral cortex is a convoluted 3D structure and abnormalities in its surface gyration may not be appreciated when it is viewed on 2D MRI slices. Our VBM procedure involved a linear spatial normalization of images, and thus did not attempt to match exactly every gyrus in the brain. Therefore, an abnormality of gyral pattern such as deeper gyri would appear on the VBM maps as an increase in GM. Ultimately, correlative pathological studies would be required to shed more light on the nature of extra-lesional GM abnormalities in FCD.

Clinical considerations

Previous studies have suggested that a less favorable post-surgical outcome in MCD patients might be linked to the presence of extra-lesional pathology [START_REF] Sisodiya | Surgery for malformations of cortical development causing epilepsy[END_REF]. Although there have been numerous studies on post-surgical outcome in MCD [START_REF] Cohen-Gadol | Longterm outcome after epilepsy surgery for focal cortical dysplasia[END_REF], Colombo et al., 2003[START_REF] Fauser | Focal cortical dysplasias: surgical outcome in 67 patients in relation to histological subtypes and dual pathology[END_REF][START_REF] Francione | Surgery for drug resistant partial epilepsy in children with focal cortical dysplasia: anatomical-clinical correlations and neurophysiological data in 10 patients[END_REF][START_REF] Frater | Surgical pathologic findings of extratemporal-based intractable epilepsy: a study of 133 consecutive resections[END_REF][START_REF] Kral | Outcome of epilepsy surgery in focal cortical dysplasia[END_REF][START_REF] Prayson | Cortical dysplasia in extratemporal lobe intractable epilepsy: a study of 52 cases[END_REF], Russo et al., 2003[START_REF] Sisodiya | Surgery for malformations of cortical development causing epilepsy[END_REF][START_REF] Tassi | Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome[END_REF], none of them included a detailed MRI assessment of extralesional brain. Therefore, the above hypothesis has not yet been tested adequately. In our study, we found no influence of extra-lesional GM increase on surgical outcome. However, this findings need to be confirmed in a larger population of surgically treated FCD patients.

In conclusion, using individual voxel-based analysis of GM, we identified the primary FCD lesion in the majority of our patients. We also showed that brain pathology in FCD extends beyond the visible lesion and is associated with widespread GM changes. While VBM has the potential to detect the increase in GM associated with FCD, lesions presenting with signal intensity different from normal GM might be misclassified as WM, and thus not be detected. It can be expected that the combination of VBM with other computational models of FCD could enhance both sensitivity and lesion coverage. Table 1. Mean and standard deviation of FCD relative intensity, percent classified as GM, lesion volume and maximum increase in GM concentration that coincided with the lesion. Mean values are presented for all FCD patients. Individual values are presented for those six whose lesions were not identified using VBM. 1.

Tables

  Figure 1. Voxel-wise processing of MR images. (A) Processing steps for the healthy controls group. First, T1-weighted MRI are registered into a standard, stereotaxic space and corrected for intensity non-uniformity. Images are then segmented into GM (green), WM (yellow) and CSF (blue). A GM "concentration" map is then generated (see text for details). All GM concentration maps are then averaged to produce mean and standard deviation maps for the control group. (B) The processing steps used for the analysis of a single individual healthy control or a single FCD patient. A representative patient with FCD is presented. Registration, intensity correction, segmentation and creation of a GM concentration map are done as described in Panel A. Finally, a GM concentration z-score map is computed by subtracting the GM mean of the healthy controls from the GM concentration map of each individual and dividing the result by the GM SD of the healthy controls.

Figure 2 .

 2 Figure 2. Computation of relative intensity. (A) To model the hyperintense signalwithin the FCD lesion on T1-weighted MRI, the normalized absolute difference between the intensity at a given voxel and the intensity at the GM/WM boundary (Bg), as defined by the image histogram, is calculated (see text for details). Using the relative difference allows analysis of voxels located within the GM in which the intensity is higher than normal and overlaps that of the WM. GM at higher intensity is closer to the GM-WM boundary. (B) Computation of relative intensity within the manually segmented FCD. The relative intensity map is presented alone (a) and superimposed on the T1-weighed MRI (b). On the relative intensity map, hyperintense voxels appear brighter. The manual lesion label (c) in which relative intensity is calculated is superimposed on the segmented MRI (d). This allows calculating the proportion of FCD lesion label classified as GM and WM. The arrow shows the FCD lesion.

Figure 3 .

 3 Figure 3. Four examples (A-D) of FCD lesion detection using individual voxel-based analysis of GM. Top panels show the T1-weighted MRI in which the FCD lesion is indicated by an arrow. Bottom panels show the thresholded GM concentration z-score map superimposed on the MRI. The lesion coverage produced by the automated VBM method is indicated for each case (see text for details).

Figure 4 .

 4 Figure 4. Sensitivity and specificity obtained for different thresholds.

Figure 5 .

 5 Figure 5. Extra-lesional GM increase in three (A-C) FCD patients. Panel on the left shows the primary FCD lesion on the T1-weighted MRI indicated by an arrow. The middle panel shows the area of extra-lesional GM increase on the GM concentration zscore map superimposed on the MRI, and the right panel shows the T1-weighted MRI at that level.

Figure 6 .

 6 Figure 6. Extra-lesional GM decrease in four FCD patients (A-D). Areas of extralesional GM decrease are shown on the GM concentration z-score maps superimposed on the MRI.

Figure 7 .

 7 Figure 7. Four cases of undetected FCD due to lesion hyperintensity are presented (A-D).For each patient, from top to bottom: T1-weighted MRI, the manual lesion label (blue) superimposed on the automatic MRI segmented map (GM in red, WM in white), and the relative intensity map (where brighter voxels correspond to higher relative intensity values). As shown on the segmented MRI map (middle panel), a large proportion of lesional voxels are misclassified as WM instead of GM. The mean relative intensity and the percentage of the lesion classified as GM in these patients are presented in Table1.

This work was supported by a grant of the Canadian Institutes of Health research (CIHR-grant #203707-MOP 57840) and by the Scottish Rite Charitable Foundation of Canada. O.C. is recipient of the Epilepsy Canada Clinical Sciences fellowship. The authors are grateful to Dr F. Andermann and F. Dubeau for referring patients to the study.