M Erostate

Stéphane Ghiotti

Frédéric Huneau
email: huneau_f@univ-corse.fr

D Jouffroy

E Garel

M Garrido

V Pasqualini

The challenge of assessing the proper functioning conditions of coastal lagoons to improve their future management

Keywords: Integrated water resources management, Multidisciplinary approach, Long-term trajectories of socio-hydrosystems, Coastal socio-hydrosystems, Groundwater dependent ecosystems, Corsica

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Coastal lagoons provide a large range of ecological, cultural and economic benefits, also known as ecosystem services, from which human societies take advantage [START_REF] Newton | Assessing, quantifying and valuing the ecosystem services of coastal lagoons[END_REF]. As a transitional environment, these complex coastline components are full part of large social-ecological hydrosystems [START_REF] Pérez-Ruzafa | Chapter 15 -Coastal Lagoons: Environmental Variability, Ecosystem Complexity, and Goods and Services Uniformity[END_REF], characterized by a highly dynamic biophysical environment continuously undergoing changes and considering human activities as an integrated part of their own ecology [START_REF] Clewell | Ecological Restoration: Principles, Values, and Structure of an Emerging Profession[END_REF]. Human activities influence the lagoons behavior and their watersheds since decennia and contribute to build present-day lagoons morphology and quality, leading to a rich, singular, eco-cultural heritage [START_REF] Corbau | Quantifying the impacts of the human activities on the evolution of Po delta territory during the last 120 years[END_REF][START_REF] El Mahrad | Social-Environmental Analysis for the Management of Coastal Lagoons in North Africa[END_REF].

Coastal lagoons have yet suffered severe environmental degradation because of human activities developed in coastal areas such as eutrophication, pollution or habitat destruction [START_REF] Newton | An overview of ecological status, vulnerability and future perspectives of European large shallow, semi-enclosed coastal systems, lagoons and transitional waters[END_REF][START_REF] Jones | Modelling interactive effects of multiple disturbances on a coastal lake ecosystem: Implications for management[END_REF][START_REF] Erostate | Groundwater dependent ecosystems in coastal Mediterranean regions: Characterization, challenges and management for their protection[END_REF]. Since the growing awareness of the importance of coastal lagoon ecosystems in the 1950s [START_REF] Kjerfve | Coastal Lagoons[END_REF][START_REF] Nixon | Coastal marine eutrophication: A definition, social causes, and future concerns[END_REF][START_REF] Basset | Estuarine and lagoon biodiversity and their natural goods and services[END_REF][START_REF] Newton | An overview of ecological status, vulnerability and future perspectives of European large shallow, semi-enclosed coastal systems, lagoons and transitional waters[END_REF][START_REF] Menció | Groundwater dependence of coastal lagoons: The case of La Pletera salt marshes (NE Catalonia)[END_REF][START_REF] Wit | Restoration ecology of coastal lagoons: new methods for the prediction of ecological trajectories and economic valuation[END_REF][START_REF] Newton | Assessing, quantifying and valuing the ecosystem services of coastal lagoons[END_REF], the protection, preservation and even restoration of these environments has become a major issue. However, management strategies are often focused on directly connected surface water and excludes other main fresh water contributors like the essential groundwater component although, in most cases, coastal lagoons are maintained by direct or indirect groundwater supplies and constitute therefore groundwater dependent ecosystems (GDEs; [START_REF] Krogulec | Hydrogeological study of groundwater-dependent ecosystems-an overview of selected methods[END_REF]. The importance of groundwater is further exacerbated in coastal Mediterranean regions where the lack of surface water is combined with a high anthropogenic pressure [START_REF] Malek | Global change effects on land management in the Mediterranean region[END_REF][START_REF] Erostate | Groundwater dependent ecosystems in coastal Mediterranean regions: Characterization, challenges and management for their protection[END_REF]. As for all Member States of the European Union (EU), the Mediterranean EU Member States have implemented measures for the protection of coastal lagoons under the Water Framework Directive (WFD, 2000/60/EC). These measures may involve human interventions (active restauration) to optimize and accelerate the restoration of coastal lagoon hydrosystems [START_REF] Wit | Restoration ecology of coastal lagoons: new methods for the prediction of ecological trajectories and economic valuation[END_REF]. However, a large majority of Mediterranean lagoons have still not achieved the ecological and chemical "good status" required by the WFD. Several questions thus arise: i) What was the evolution of the coastal lagoons in the past and how these systems can be restored?, ii) Did previous management measures always had the expected effect on the system? and finally, iii) How to pertinently evaluate the system's response to human actions and what will be required in the future?

To answer these questions, this study proposes an innovative, multidisciplinary, long-term approach that takes into account the evolution of lagoon ecosystems and their entire watershed (surface and ground water). The reconstitution of ecological, hydrological and socio-economic evolutions, also called "trajectories", allows to assess the influence of natural and anthropogenic events that have affected the hydrosystem. Proper functioning conditions of the hydrosystems, i.e. all the factors that contribute to the functioning of coastal lagoon hydrosystems and the connectivity with other biodiversity reservoirs, be they ecological, hydrological, social or political can thus be determined through this integrated approach. This approach has been applied to the hydrosystem of the Biguglia lagoon (Corsica, France) as a particularly relevant example of EU Mediterranean hydrosystems. First of all, it is representative of the management policies, as well as the regulatory and legislative tools implemented in the EU Member States under the WFD. The hydrosystem of the Biguglia lagoon also combines both the socio-economic development and the climatic and hydrological conditions characteristic of the Mediterranean coastal regions [START_REF] Erostate | Groundwater dependent ecosystems in coastal Mediterranean regions: Characterization, challenges and management for their protection[END_REF]. Finally, this hydrosystem is extremely well documented, with archives over the last 200 years. This wide range of historical data provides an ideal opportunity to understand the patterns of change in the hydrological and ecological functioning of this hydrosystem and the history of its management and governance. This learning from the past supports the implementation of hydrosystem-based management to ensure the future integrity of coastal lagoon hydrosystems [START_REF] Burt | Improving management of future coastal development in Qatar through ecosystem-based management approaches[END_REF][START_REF] Gross | Attributes of successful actions to restore lakes and estuaries degraded by nutrient pollution[END_REF][START_REF] Pasqualini | Spatiotemporal dynamics of submerged macrophyte status and watershed exploitation in a Mediterranean coastal lagoon: Understanding critical factors in ecosystem degradation and restoration[END_REF][START_REF] Derolez | Fifty years of ecological changes: Regime shifts and drivers in a coastal Mediterranean lagoon during oligotrophication[END_REF] as well as the development of a more relevant evaluation system for restoration measures.

Materials and methods

2.1.Study site

The Biguglia lagoon is a confined, shallow, brackish coastal lagoon (maximum depth of 1.8 m) located in the northern part of Corsica island (France), just south of Bastia city (Figure 1). Corsica island is characterized by a typical Mediterranean climate with marked inter-annual fluctuations in atmospheric temperature and precipitation amount [START_REF] Tagliapietra | Notes on coastal lagoon typology in the light of the EU Water Framework Directive: Italy as a case study[END_REF]. The mean annual temperature and precipitation measured at the Bastia Météo France Station are 15.8°C and 768 mm, respectively (average calculated from 1950 to 2016) [START_REF] Erostate | Coupling isotope hydrology, geochemical tracers and emerging compounds to evaluate mixing processes and groundwater dependence of a highly anthropized coastal hydrosystem[END_REF]. The lagoon is part of the largest wetland of Corsica covering 14.5 km². It is separated from the Mediterranean Sea by a long sand bar and seawater exchanges are controlled by only one narrow, shallow, natural channel to the North. Marine water inputs are limited because the sea channel tends to close naturally by sand accumulation and human intervention is regularly required to open it again. The lagoon receives fresh surface and ground water from a 182 km² watershed. One major river, the Bevincu River, at the North, flows continuously towards the lagoons, supplemented by several smaller ephemeral creeks (Figure 1).

Fresh water is also supplied by an artificial drainage network constructed in the 19 th century. The lagoon is directly connected at the south to the Golu River through an artificial channel, the "Fossone Canal" (Figure 1). Drainage channels on the west shore of the lagoon drain run-off and shallow groundwater from the Marana alluvial plain, which constitutes the largest aquifer system in the region.

Groundwater is then discharged towards the lagoons through five pumping stations, making the Biguglia lagoon a coastal GDE [START_REF] Erostate | Coupling isotope hydrology, geochemical tracers and emerging compounds to evaluate mixing processes and groundwater dependence of a highly anthropized coastal hydrosystem[END_REF]. Groundwater from this alluvial aquifer is also used for the drinking water supply of the Bastia's urban area (almost 72 000 inhabitants). The Biguglia lagoon watershed is subject to an important development since the end of the 20 th century (Département de la Haute-Corse, 2012). The Marana alluvial plain is currently largely anthropized since it constitutes the southern extension of the economic capital of Corsica. Urban sprawl and agricultural activities are currently the two main anthropogenic activities developed on the alluvial plain. This area is covered by an important transportation network associated with a dynamic economic context, including an airport, housing and several business parks. Four towns are extending in the immediate vicinity of the lagoon (Furiani, Biguglia, Borgo and Lucciana) with an increase in artificial areas about 3% per year between 2002 and 2011 [START_REF] Robert | Coastal Urbanization and Land Planning in Southern France[END_REF]. This urban sprawl has led to an important growth in the population living around the lagoon. In addition, tourism has become an important component of the local economy, especially during the summer period. The sand bar is particularly attractive and experiments a strong population growth in summer months.

The anthropogenic pressures have increasingly disturbed the lagoon's ecosystems through eutrophication over the past decades (Département de la Haute-Corse, 2012; [START_REF] Garrido | Water flux management and phytoplankton communities in a Mediterranean coastal lagoon. Part I: How to promote dinoflagellate dominance?[END_REF][START_REF] Pasqualini | Spatiotemporal dynamics of submerged macrophyte status and watershed exploitation in a Mediterranean coastal lagoon: Understanding critical factors in ecosystem degradation and restoration[END_REF]. Nutrient in this lagoon are higher than in most other Mediterranean lagoons [START_REF] Orsoni | Caractérisation de l'état d'eutrophisation des trois principaux étangs corses (Biguglia, Diana et Urbino), et proposition de renforcement de leur surveillance[END_REF][START_REF] Souchu | Patterns in nutrient limitation and chlorophyll a along an anthropogenic eutrophication gradient in French Mediterranean coastal lagoons[END_REF] due to the limited exchanges with seawater. Concerned about the vulnerability of the main wetland in Corsica, the Collectivity of Corsica voted the acquisition of the Biguglia lagoon in 1988 which belonged to a private owner. Since then, the Collectivity of Corsica has been managing the Nature Reserve to ensure its protection as well as its ecological and heritage enhancement. The Biguglia lagoon is classified as Ramsar site since 1991 and nature reserve in 1994 but also as sensitive natural area (ENS), natural zone of ecological interest for fauna and flora (ZNIEFF), Important Bird and Biodiversity Area (ZICO), Special Protection Area (ZPS), Area of Community Interest for Birds (SIC), Special Area of Conservation (ZSC). Access to the public is restricted to the hiking, educational paths along the lagoon and is prohibited on the water body. The professional fishing is the only authorized activity, in line with the historical exploitation of the lagoon.

Research of historical data

We used historical documents and maps to analyze the dynamics of the Biguglia lagoon hydrosystem and to identify the major anthropogenic pressures acting on the watershed on the long term. An extensive, multi historical-sourced data analysis gathering from 1800 to 2020 has been carried out through the consultation of regional and national archives as well as local stakeholders. These documents are extremely diverse, both in terms of nature (scientific reports, pictures, newspapers, administrative acts…) and subject matter (natural and human sciences, management, planning, law, etc.). Each information relating to the study area was collected in a database including: fauna, flora, quantity and nature of fisheries, salinity, any waters quality parameters, climate, water extraction, land use planning, human intervention on the lagoon… The main sources for the numerical and cartographic data are listed below. The number of inhabitants per town (4 towns in the watershed and the Bastia city) were available (i) from 1800 to 1999, at intervals of about five years (http://cassini.ehess.fr/cassini/fr/html/6_index.htm) and (ii) from 1999 to 2011 at intervals of seven to nine years (French National Statistics and Economic Studies Agency (INSEE). Historical land cover in the watershed was analyzed using two sources. The first modern and scientific cartography of Corsica based on new triangulation method "Plan Terrier", ordered in 1770 by Louis XV of France, provides an inventory of the natural resources of the island after its integration into the Kingdom of France (Caratini, 1995). This map is precise, at a scale of 1:10,000 (Source: Archives départementales de Corse du Sud). It was processed with ArcGis version 10.0 (ESRI ® ). The CORINE land-cover program established a precise land-cover map of the study site for 1990, 2006, 2012 (https://www.data.gouv.fr/fr/datasets/corine-land-cover-occupation-des-sols-en-france/). We considered three generic land-cover types, as defined by the CORINE land cover program: forests and shrublands, farmland, and urban areas. The surface areas corresponding to these three generic landcover types were calculated for the two maps. Detailed information on local meteorological and hydrological behavior started to be available from the 20 th century onwards. Since 1948, Météo-France ® has been recording cumulative rainfall in Bastia, at a station near to the lagoon. Historical records in local press and local monitoring network make it possible to reconstitute i) long time precipitation series at Bastia since 1880 (Figure 2) and ii) fishing volumes. Data on the mean summer salinity of the lagoon for the northern and southern basins were obtained from records published since 1930 (Frisoni et and Durieux, 1992;[START_REF] Orsoni | Caractérisation de l'état d'eutrophisation des trois principaux étangs corses (Biguglia, Diana et Urbino), et proposition de renforcement de leur surveillance[END_REF][START_REF] Pasqualini | Spatiotemporal dynamics of submerged macrophyte status and watershed exploitation in a Mediterranean coastal lagoon: Understanding critical factors in ecosystem degradation and restoration[END_REF]. Information on the extraction (drinking water supply, pumping stations) and quality of water resources (groundwater nitrate) has been collected from local operators and managers (Regional Health Agency (State health service), "Cullettività di Corsica" (regional assembly), "Acqua Publica" (water operator).

Results and discussion

Evolution of the territory

Wetland remediation

Tracing back the dynamics of land use planning is a necessary first step to understand the historical hydrosystem behavior and how it has been influenced by human activities and land cover changes [START_REF] Erostate | Delayed nitrate dispersion within a coastal aquifer provides constraints on land-use evolution and nitrate contamination in the past[END_REF][START_REF] Corbau | Quantifying the impacts of the human activities on the evolution of Po delta territory during the last 120 years[END_REF][START_REF] Tănăsescu | The human ecology of the Danube Delta: A historical and cartographic perspective[END_REF]. When Corsica was incorporated to France in 1768, the government was committed to the problem of land remediation in Corsica (Jaujou, 1954). The objectives were therefore to combat malaria and to increase the amount of arable land, including the Biguglia watershed [START_REF] Letteron | Causerie sur l'étang de Biguglia[END_REF]Jaujou, 1954). To this end, several remediation programs based on surface water flows were carried out. However, like many other wetlands, the Biguglia lagoon results from shallow groundwater and surface water contributions [START_REF] Sánchez-Martos | Groundwater-wetlands interaction in coastal lagoon of Almería (SE Spain)[END_REF][START_REF] David | Groundwater discharge to coastal streams -A significant pathway for nitrogen inputs to a hypertrophic Mediterranean coastal lagoon[END_REF][START_REF] Erostate | Groundwater dependent ecosystems in coastal Mediterranean regions: Characterization, challenges and management for their protection[END_REF]. At the time, the groundwater component was still unknown and remediation programs followed one after another without meaningful good results. The first draining measures were implemented in 1774 with the digging of channels to favor cultivation and periodical openings of the lagoon to the sea, to ensure efficient emptying of the lagoon (Figure 3.a; Jaujou, 1954; Département de la Haute-Corse, 2012). A few years later, the "Fossone" channel at the South of the lagoon was created between the Golu River and the lagoon (Figure 1), with no significant improvement in water drainage. A new remediation program began in 1855 with the establishment of new drainage channels surrounding the lagoon to eliminate the adjacent marsh (Figure 3.a). This new drainage system was accompanied by complementary measures, such as the planting of hydrophilic tree species or the diking of the river (Figure 3.b). It was quickly found that drainage channels were not sufficient to dry out the plain. Indeed, in addition to collecting some surface water, the drainage channels mostly drain shallow groundwater and represent a specified head boundary condition which exacerbates the natural hydraulic flow of the alluvial aquifer. The total water collected by the channels was therefore well in excess of their capacity and these channels could not ensure the drying up of the plain. Without really understanding the origin of the water saturating the drainage network, five pumping stations were set up between 1925 and 1935 to complete the dewatering (Figure 3.a). This system was functional before the World War 2 (WW2) and first effects were quickly visible. Located on the west coast of the lagoon, these stations pump the water in the channels when the levels are too high (0.8m below the ground) and reject it towards the lagoon. As a result, the natural discharge of groundwater toward the lagoon has become marginal.

Currently, after more than 70 years of pumping, the huge water volumes withdrawn are ranged between 23 Mm 3 /y and 39 Mm 3 /y. Given the past water saturation of the plain, the volumes of water withdrawn were probably much higher in the past. Destroyed during the WW2, pumping stations were repaired between 1946 and 1948 (Figure 3.a). Despite the land reclamation program, the surface and the configuration of the lagoon basin remained almost identical since the 18 th century. A main natural channel connects the lagoon to the sea at the north (Figure 1). Yet, the creation of Fossone Canal in 1774 (Figure 1) has modified the freshwater/salt water balance. This channel also constitutes a source of contention with the fishermen of the lagoon, who regularly block this communication with the Golu River to prevent the escape of fish. Finally, the punctual opening of a second natural channel (Figure 1) due to extreme flood events, has also been identified in 1774, 1870, 1901and 1937 (Figure 3.c) (Figure 3.c). Unlike its neighbor, this channel has never been subject to human intervention to keep it open and is definitively closed since the urbanization of the sand bar in the 1960s. This channel is still visible as it is the thinnest part of the sandbar (Figure 1).

Human settlement

Considered as an inhospitable, disease-causing area mainly because of malarial issues, the alluvial During the 18 th and the 19 th centuries, the Biguglia lagoon was characterized by a high biological productivity. Large quantities of mules and eels were exported to supply Corsica, French East coast (cities of Nice and Marseille) and Italy [START_REF] Letteron | Causerie sur l'étang de Biguglia[END_REF]. The manual opening of the main natural channel (Figure 1) as early as the 1870s, the opening of a secondary punctual channel due to flood events and the occurrence of Trachinus draco (sea weeverfish) at the North of the lagoon indicate a good communication between the lagoon and the sea and suggest a relatively high salinity. The first salinity measurement (30g/L and 12g/L in the northern and the southern basin respectively) was recorded in 1917 (Figure 2). In barely 15 years, salinity decreased significantly (20g/L and 10g/L in the northern and the southern basins respectively) (Figure 3.c) due to the important inflow of fresh surface and groundwater drained and rejected towards the lagoon. This period also coincides with changes in the management of the main natural channel which is voluntarily kept closed since the beginning of the 20 th century in order to prevent fish escapes from the lagoon. In 1954, salinity reaches its highest value (32g/L and 21g/L in the northern and the southern basins respectively). This is consistent with 3 major events: i) the destruction of the pumping stations, ii) the regular re-opening of the main natural channel and iii) the exceptional floods of 1938 (Figure 3). The destruction of the pumping stations considerably reduced the freshwater inflow towards the lagoon and the regular dredging of the channel allows exchanges with the sea. Finally, the exceptional rains of 1938 allowed the reopening of the second natural channel and contribute to increase interactions with the sea. These high salinity values are supported by the occurrence of mollusks species particularly adapted to the saline environment (Mytalister minimus, Ruditapes decussatus and Venerupis geographica) (Figure 3).

Then, the pumping network was re-established in 1948 and the second natural channel never opened again. Salinity started to steadily fall, as confirmed by the progressive disappearance of Mytalister minimus, Ruditapes decussatus and Venerupis geographica. This disappearance testifies of an evolution of the ecosystem that has become unfavorable to their subsistence but the fishing volumes are still relatively high (Figure 5). In the early 1970s, four aquatic angiosperms were well developed in Biguglia lagoon: Zostera noltei, Ruppia cirrhosa, Stuckenia pectinata and Najas marina. These aquatic angiosperms are indicators of water quality. Their presence then suggests the good qualitative status of the lagoon water [START_REF] Pasqualini | Spatiotemporal dynamics of submerged macrophyte status and watershed exploitation in a Mediterranean coastal lagoon: Understanding critical factors in ecosystem degradation and restoration[END_REF] (Figure 5). So far, the lagoon ecosystem has therefore been able to adapt to the physico-chemical variations of the waters. However, in the 1990s, the ecosystem reached a tipping point. The predominance of angiosperms gave way to a variable dominance of phytoplankton and opportunistic macroalgae (Figure 5) [START_REF] Pasqualini | Spatiotemporal dynamics of submerged macrophyte status and watershed exploitation in a Mediterranean coastal lagoon: Understanding critical factors in ecosystem degradation and restoration[END_REF]. The volumes of fish caught were constantly decreasing (Figure 5). Nitrate concentrations increased significantly into the aquifer (Figure 5) and urbanization was developing rapidly. A first dystrophic crisis has affected the lagoon in 1991 when the salinity was particularly low (12g/L and 9g/L in the northern and the southern basins respectively). After a slight increase, the salinity continued to decrease from 1999 (18g/L and 13g/L in the northern and the southern basins respectively) to 2012 (15g/L and 5g/L). A second major crisis has affected the lagoon in the summer of 2007 (salinity about 14g/L and 9g/L) (Figure 3.c) with the proliferation of a toxic cyanobacterium, Anabaenopsis circularis. The concentrations of total nitrogen reached 470 µM (Figure 5). These ecosystem modifications and the dynamics of total nitrogen concentrations observed in the lagoon raise questions about the nitrogen origin (especially NO3 -). The groundwater flow toward the lagoon, the low NO3 - concentrations in river water and the good correlation between NO3 -concentrations in groundwater and in the lagoon suggests that groundwater has a predominant impact on the NO3 -supply to the lagoon (Figure 5) [START_REF] Erostate | Delayed nitrate dispersion within a coastal aquifer provides constraints on land-use evolution and nitrate contamination in the past[END_REF]. Since 2010, barely three years after the dystrophic crisis, macroalgae and phytoplankton are decreasing in favor of the development of aquatic angiosperms.

The resettlement by aquatic angiosperms suggests then a significant improvement in water quality within a few years. This relatively short period of time highlights the reactivity of the lagoon ecosystem. The major disruptions caused by the dystrophic crisis of 2007 do not appear to have exceeded the threshold beyond which the lagoon could no longer recover its ecological potential [START_REF] Pasqualini | Spatiotemporal dynamics of submerged macrophyte status and watershed exploitation in a Mediterranean coastal lagoon: Understanding critical factors in ecosystem degradation and restoration[END_REF]. However, the progressive desalination hugely impacts the ecosystem with the marked development of freshwater angiosperms (Najas marina) and the expansion of the common carp (Cyprinus carpio), never reported before in the Biguglia lagoon. As a GDE, the ecological state of the lagoon need to be related to the status of the groundwater. Nitrate concentrations in groundwater appear to be increasing over the last 10 years (Figure 5). Since 2012, focusing efforts to keep the channel open leads to sudden marine inflow resulting in marked salinity variations into the lagoon (Figure 5). Tracing back land development and ecological and hydrological conditions make it possible to define past socio-ecological conditions of the hydrosystems. However, these conditions do not constitute a natural, pristine or preferable state of the hydrosystem that should be achieved as a matter of urgency.

Rather, it is a historical link between the ecological conditions of the lagoon and human activities (fishing especially), before a recent change due to the land development (drainage network, urbanization, agriculture). Above all, this long-term approach allows us to understand the evolution of the system and thus to take a critical look at the established management strategies in order to better define future relevant ones.

Management deadlock

Complementary information from historical and modern data provides relevant information to assess the efficiency of the Biguglia lagoon protection. In addition to the classification of the lagoon as nature reserve, the lagoon and its wetlands currently benefit from 8 classifications implemented between 1985 and 2011 (ENS, ZNIEFF, ZICO, ZPS, SIC, ZSC) (Figure 6.f). However, over the same period, two major dystrophic crises affected the ecosystem highlighting the ineffectiveness of protective statutes. The classification as a nature reserve was sometimes perceived by local populations as an expropriation by politicians. The stakeholders as well as population then found it very difficult to find their place and to get involved in the implementation of integrated management.

The major dystrophic crisis of the summer 2007 constituted yet a trigger. Active management measures in order to improve the situation were implemented trough several strategic planning programs and management tools (PAGD, SAGE, lagoon contract, MAEC) (Figure 6.f). Substantial efforts have been made to improve sewage treatment, to develop sustainable agricultural practices over the watershed and to reduce the confinement of the lagoon. Artificial opening of the current channel and/or cleaning of drainage channels have been regularly carried out. These active restoration measures seem to be beneficial to the lagoon ecosystem on the medium-term and to highlight the resilience capacity of the lagoon. Conversely, the progressive nitrate accumulation into the groundwater indicates the poor self-remediating capacity of aquifers [START_REF] Erostate | Delayed nitrate dispersion within a coastal aquifer provides constraints on land-use evolution and nitrate contamination in the past[END_REF]. Historic nitrate legacies therefore continue to degrade current groundwater quality [START_REF] Jaunat | Combinations of geoenvironmental data underline coastal aquifer anthropogenic nitrate legacy through groundwater vulnerability mapping methods[END_REF]. In addition, the occurrence of human-made organic pollutants in groundwater is an indicator of an ongoing groundwater degradation related to wastewater infiltration [START_REF] Erostate | Coupling isotope hydrology, geochemical tracers and emerging compounds to evaluate mixing processes and groundwater dependence of a highly anthropized coastal hydrosystem[END_REF]. At present, all the improvements made in the hydrosystem's management have still not allowed the lagoon to reach the "good qualitative status" required by the WFD. On-going degradation quality of groundwater due to legacy and current pollution threaten the resilience and long-term protection of the whole hydrosystem.

Towards a really sustainable management of coastal lagoon hydrosystems

A sectorial management approach

The recognition of wetlands as specific natural areas came about as a result of the Ramsar Convention, the Birds Directive and, above all, the Rio process in 1992 (Figure 6.a, 6.b). From this date, the standard-setting or regulatory activities has intensified (Figure 6.b, 6.c). At the same time, the attractiveness of coastal areas is increasing, particularly in the Mediterranean context [START_REF] Erostate | Groundwater dependent ecosystems in coastal Mediterranean regions: Characterization, challenges and management for their protection[END_REF]. With the greening process, priorities changed and were given to the protection of natural coastal areas considered remarkable and vulnerable. Since the WFD was established, restoration measures are most often implemented in order to achieve the "good status". Restoration should allow the ecosystem to return to a previous, more "natural" state, called the "reference state". According to the WFD, achieving this ideal state should then allow to preserve and improve, if necessary, the ecological status of aquatic systems in order to promote their sustainable use and ensure water supply.

In the case of coastal lagoon hydrosystems, this concept of past, undisturbed state is irrelevant. Human modifications of lagoons environment have been significant for several millennia. As many others lagoons, the Biguglia lagoon is used and managed since centuries, especially for fisheries. Human activities -especially artificial opening -both influence the natural evolution of the system, i.e. the closure and filling up, and the biological communities as well as the dynamics of the ecosystems [START_REF] Conde | Solutions for sustainable coastal lagoon management: from conflict to the implementation of a consensual decision tree for artificial opening[END_REF]. Natural and social characteristics of coastal hydrosystems are inseparable and human-nature interactions play a central role in the construction of lagoon landscapes and dynamics.

Human activity is not an external factor that does not fit well into natural processes, but rather a full part of those processes. Present-day system is resulting from both natural and human influences since decades or centuries. The presence of man cannot therefore be reduced to an external degradation.

Moreover, events currently considered to be ecosystem dysfunctions, such as dystrophic crises, are not necessarily the result of human actions. Most coastal lagoons have always been very nutrient-rich environments, potentially affected by anoxic episodes long before human eutrophication [START_REF] Kjerfve | Coastal Lagoons[END_REF][START_REF] Nixon | Coastal marine eutrophication: A definition, social causes, and future concerns[END_REF][START_REF] Newton | An overview of ecological status, vulnerability and future perspectives of European large shallow, semi-enclosed coastal systems, lagoons and transitional waters[END_REF]. In the case of the Biguglia lagoon, the archives describe frequent events of anoxia: "when the rainy season has passed, when the temperature rises, when the water in the marshes recedes and leaves enormous quantity of rotting plants and animals" (Newspaper "Le Petit Bastais" of July 14, 1882). Local newspapers even mention a major crisis during the summer of 1884 that led to the putrefaction of huge quantities of plants and eels on the shores (Figure 3.e). In addition to the near-impossibility of defining a relevant period for the reference state, it may not correspond to "good ecological conditions" according to the current WFD indicators. All these specificities make coastal lagoons very complex to apprehend and to manage efficiently and sustainably.

Ensure resilience capacity of coastal lagoon hydrosystems

One of the principles behind restoration operations is that the restoration of past conditions and associated disturbance patterns lead to a recovery of previously predominant ecological conditions.

The aim is to achieve sustainable use by returning to a previous "better" state, whereas the coastal hydrosystem is, by definition, in perpetual evolution. This approach does not fit with the complexity, evolving and unpredictable nature of coastal lagoon hydrosystems. Defining precise restoration objectives is then almost impossible when they are supposed to return to a previous state that is poorly known and/or irrelevant with the uses and the complexity of coastal lagoon hydrosystems. As a result, restoration effects are often unpredictable, as is the response time of the hydrosystems [START_REF] Facca | Natural recovery and planned intervention in coastal wetlands: venice lagoon (northern adriatic sea, italy) as a case study[END_REF][START_REF] Wit | Restoration ecology of coastal lagoons: new methods for the prediction of ecological trajectories and economic valuation[END_REF]. Rather than returning to a reference state, restoration should aim at achieving a new state of ecological and hydrological equilibrium, which would allow the maintenance of ecosystem functions and the sustainable development of their use. It is therefore necessary to set up a participative reflection between all stakeholders (scientists, managers, operators, local population...) in order to predetermine the uses and ecosystem functions that are considered as priorities and then to define restoration objectives in line with the territory's development objectives [START_REF] Eriksson | An ecosystem approach to small-scale fisheries through participatory diagnosis in four tropical countries[END_REF][START_REF] Sy | Identifying Consensus on Coastal Lagoons Ecosystem Services and Conservation Priorities for an Effective Decision Making: A Q Approach[END_REF]. Evaluation of the success of restoration measures must be linked to what a restoration project is designed to do, by whom and when [START_REF] Baker | Ecological restoration success: a policy analysis understanding[END_REF]. The involvement of stakeholders and the perception of populations for example are also essential parameters that reflect the effectiveness of sustainable management. Moreover, the indicators used by the WFD are often based on defined and non-dynamic reference states. The current indicators support a normative and simplified approach of coastal lagoon hydrosystems, which are in fact as unique as they are complex.

Their mandatory use then became a means of assessing managers and the effectiveness of management policies even if they do not make it possible to achieve sustainable restoration. Finally, restoration strategies must take into account the entire proper functioning conditions of the coastal lagoon hydrosystems. Perceptions of hydrologic interactions are often restricted to lateral and longitudinal flows and connectivity with groundwater is still under-documented. Widely used, manipulation of natural dynamics represents an inadequate short-term solution to address a long-term complex socio-economic problem [START_REF] Conde | Solutions for sustainable coastal lagoon management: from conflict to the implementation of a consensual decision tree for artificial opening[END_REF]. This approach leads to strong and rapid changes in physico-chemical conditions which can strongly affect communities and processes. In order to reduce sudden disturbances due to artificial openings and to make progress toward sustainable physico-chemical conditions improvement, upstream management of freshwater and nutrient flows appears as essential. The often neglected role of groundwater in water and nutrient inputs needs to be better understood. Defining and managing groundwater flows is the only way to achieve sustainable management of coastal lagoon hydrosystems and stabilization of physico-chemical conditions in lagoon waters.

Integrating global change into management strategies

Conservation management plans are often the result of short or medium-term planning. They assume regular species distributions in the absence of human-induced disturbance. Sustainable management plans must incorporate future changes in species distribution due to climate change. Although difficult to quantify, future changes in precipitation, temperature and evaporation patterns foreshadowed by the climatic data of the last century (visible at local level on Figure 2) could significantly affect future populations (IPCC, 2018). Changes in species distribution, population size, timing of reproduction or migratory events are already observable. The current species loss and the establishment of invasive species could be significantly facilitated. Invasive species cause changes, often irreversible or difficult to control, in biodiversity and the ecosystem services it provides. It is therefore essential that policy makers and management strategies take into account the need for adaptation. This involves understanding how invasive species adapt to new environments and how other species adapt to invasions, but more importantly how humans adapt to invasive species, and how this adaptation could affect ecosystems and human well-being [START_REF] Howard | Human adaptation to invasive species: A conceptual framework based on a case study metasynthesis[END_REF].

Many coastlines are projected to be impacted by rising sea levels. While the risk of marine flooding is often mentioned first -and need to be assessed, the risk of groundwater flooding would probably be the first to impact coastal areas [START_REF] Rotzoll | Assessment of groundwater inundation as a consequence of sealevel rise[END_REF]. For aquifers with a groundwater level very close to the surface, the rise in sea level will lead to a simultaneous rise of the groundwater level, which may exceed the topographic elevation surface [START_REF] Rotzoll | Assessment of groundwater inundation as a consequence of sealevel rise[END_REF]. This process could then lead to significant and costly problems related to water management and infrastructure (salinization, flood…). It could increase the mobilization of salts and soil pollutants currently trapped in the unsaturated zone and threaten groundwater quality and hydraulically connected ecosystems.

Long-term storage and restitution capacity of soil pollutants thus need to be assessed. Finally, the increasing coastlines development induces a strong pressure on water resources, both for human and environmental needs. With water withdrawals expected to increase in a drier climate, the outflow toward the coastal GDEs could be strongly reduced by the end of the century which could accelerate their drying up [START_REF] Erostate | Groundwater dependent ecosystems in coastal Mediterranean regions: Characterization, challenges and management for their protection[END_REF]. In response to these treats, an appropriate management of groundwater appears as essential to ensure the preservation and sustainability of coastal GDEs.

Conclusion

Given the coastline development and climate change effects, the sustainable management and governance of coastal lagoon hydrosystems is a key issue for the socio-economic and environmental development of many coastal areas worldwide. The innovative multidisciplinary long-term approach developed in this study allows to better assess the influence of past management actions and supports the implementation of future relevant hydrosystem-based management plans which have to be coordinated and politically driven. It supports the establishment of integrated water resources management by considering the lagoons and all its hydrological, ecological and societal proper functioning conditions. Taking into account the dynamic nature of the coastal lagoon hydrosystems is essential to defined relevant restoration and management objectives. The stable conditions of the WFD reference values isolate the system in a past, static state, disconnected from the land development and climate change impacts, considering human as the major disturbing element. Restoration objectives should ensure that ecological functions are maintained based on current and future ecosystem benefits and uses. The state of an ecosystem should not only be evaluated on ecological criteria but also take into account socio-economic and political indicators. In any case, considering the highly unpredictable nature of coastal lagoon hydrosystems, restoration measures may lead to unexpected results that do not constitute a failure of management measures. The implementation of the 3 rd river basin management plan of the WFD as soon as 2022 could be the appropriate occasion to reassess the restoration objectives towards more realistic goals and to give more significance to the definition of the "resilience capacity" of water bodies in place of inappropriate restricted restauration objectives.

Figure 1 :

 1 Figure 1: Localization map of the watershed of the Biguglia lagoon and land use on the alluvial plain

Figure 2 :

 2 Figure 2: Mean annual rainfall reconstructed from archive data, from 1880 to 1919 and rainfall and

Figure 3 :

 3 Figure 3: Multi-parameter timelines for a cross-comprehension of the hydraulic behavior of the

  plain remained underdeveloped since the 18 th century. Only the mountainous inland regions of the watershed supported a subsistence pastoral economy and community-based social structures. Drinking water supply works started in 1916 but above all the remediation completed at the end of the 1940s boosted the development of the plain. The watershed of the Biguglia Lagoon gradually became conducive to human settlement, reflecting a new human/space relationship (Figure4). With the changes in land use in the Mediterranean mountains and the development of urban coastal hubs[START_REF] Roman Sanz | Long-Term Forest Dynamics and Land-Use Abandonment in the Mediterranean Mountains, Corsica, France[END_REF], populations left the mountainous, inland areas of the watershed in favor of the suburban area of the Bastia city. These migration movements were complemented by the installation of the population repatriated from Algeria in 1962 (Figure4) after the independence of this country. If the population of Bastia seems relatively constant from the 1970s onwards, the population of the 4 cities of the plain has increased considerably (Figure4). The plain turned into a residential area. The sand bar that separates the lagoon from the sea, mainly developed by vineyard, was rapidly urbanized right after the construction of the first sturdy bridge to cross the lagoon to the North in 1969.An important agricultural development program started in 1965 in order to develop mainly viticulture and citrus growing on the plain. From 1980 to 2020, the land use is mainly characterized by a conversion of the agricultural areas into urbanized areas (Figure4) and natural areas were relatively constant over the past 40 years. Shrinking of the agricultural area was accompanied by a modification of agricultural practices. Over the last decades, orchards and vineyards were progressively replaced by cattle breeding and vegetables production. Massive soil remodeling due to culture type changes and urban construction have led to significant soil nitrogen mobilization resulting in high nitrate inputs accumulated into the aquifer[START_REF] Erostate | Delayed nitrate dispersion within a coastal aquifer provides constraints on land-use evolution and nitrate contamination in the past[END_REF].

Figure 4 :

 4 Figure 4: Evolution of developed, agricultural and natural areas on the alluvial plain and demography

Figure 5 :

 5 Figure 5: Compilation of reconstructed key parameter data in order to trace back the social (drinking water supply), hydrological (pumping stations, groundwater NO₃ -) and ecological (lagoon water total

Figure 6 :

 6 Figure 6: Timeline of key dates relating to the development and management of the lagoon from 1807

Acknowledgement

Funding: This work was supported by a grant from the "Fondation de France" and was also (co)funded by the Labex DRIIHM, French program "Investissements d'Avenir" (ANR-11-LABX-0010) which is managed by the French ANR. This research action is also, for a part, financially supported by the "Culletività di Corsica" through the GERHYCO interdisciplinary project dedicated to water management, ecology and hydro-ecosystem services in insular context.

Supplementary materials

Table 1 : Main archive sources consulted using a keyword search referring to the study site, including "Corse", "Marana", "Biguglia", "Chiurlinu", "étang", "lagune", "Bastia".

Documents type


Eric Guedj

Françoise Lazarini

Silvia Morbelli

Mathieu Ceccaldi

Charlotte Hautefort

Aurélie Kas

Thomas Radulesco

Dominique Salmon-Ceron

Carole Eldin

Jacob Bani

Emina Arsovic

Marion Montava

Nicolas Fakhry

Jean-Pierre Lavieille

Karel Pacak

David Taïeb

Arthur Varoquaux
email: arthur.varoquaux@ap-hm.fr

Quantitative biomarkers allow the diagnosis of head and neck paraganglioma on multiparametric MRI

Keywords: paragangliomas, neck tumors, MRA, DWI, biomarkers, multiparametric imaging

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors, and represent a subset of pheochromocytoma/paraganglioma (PPGL) neoplasms. HNPGLs are specifically associated with the parasympathetic nervous system, and arise from paraganglia which are derived from multifated Schwann Cell Precursors (SCP) [START_REF] Espinosa-Medina | Parasympathetic ganglia derive from Schwann cell precursors[END_REF][START_REF] Kastriti | Schwann Cell Precursors Generate the Majority of Chromaffin Cells in Zuckerkandl Organ and Some Sympathetic Neurons in Paraganglia[END_REF]. HNPGLs are located close to great vessels and parasympathetic ganglia [START_REF] Varoquaux | Retrostyloid parapharyngeal space tumors: A clinician and imaging perspective[END_REF] in middle ear (tympanomastoid PGL), jugular formamen (tympanojugular PGL), retrostyloid parpharyngeal space (vagal PGL), and carotid artery bifurcation (carotid body PGL). HNPGLs have a hereditary background in up to 40% of cases [START_REF] Taïeb | Current Approaches and Recent Developments in the Management of Head and Neck Paragangliomas[END_REF]. Of all the known genetic mutations (collectively named SDHx), SDHD mutations are currently the leading cause of hereditary HNPGLs [START_REF] Taïeb | Current Approaches and Recent Developments in the Management of Head and Neck Paragangliomas[END_REF].

Surgical biopsy of lesions at the base of the skull (e.g. tympanojugular PGL) or located in the vascular space (e.g. vagal PGL) requires complex surgical approaches. Percutaneous biopsy under CT is considered risky because of the proximity of the internal carotid artery and the hypervascular nature of these lesions. Computed tomography (CT) and magnetic resonance angiography (MRA) are conventional tools to depict PGL in the neck with the socalled "salt and pepper" appareance on T2-weighted imaging and tumor hypervascularity on angio-CT imaging. The diagnostic sensitivity of these techniques is relatively low, ranging from 75 to 89% [START_REF] Archier | Prospective comparison of 68 Ga-DOTATATE and 18 F-FDOPA PET/CT in patients with various pheochromocytomas and paragangliomas with emphasis on sporadic cases[END_REF][START_REF] Gravel | The value of a rapid contrast-enhanced angio-MRI protocol in the detection of head and neck paragangliomas in SDHx mutations carriers: a retrospective study on behalf of the PGL.EVA investigators*[END_REF]. Diffusion-weighted imaging (DWI), which is dependent on tissue cellularity, and DCE witch explores tumors enhancement patterne has both gained a potential role in tumor in differentiating PGL from other deep soft-tissue tumours of the neck [START_REF] Aschenbach | Diffusion-Weighted Imaging and ADC Mapping of Head-and-Neck Paragangliomas[END_REF][START_REF] Gaddikeri | Dynamic Contrast-Enhanced MRI in the Evaluation of Carotid Space Paraganglioma versus Schwannoma[END_REF].

The aim of the present study was to identify and to combine quantitative MR biomarkers that allow distinction between paragangliomas and other deep soft-tissue tumours of the neck on DCE and DWI.

Materials and methods

Study population

A comprehensive retrospective automatic search in our database was performed in order to identify all patients evaluated by neck DCE MR imaging and DWI for a presumed PGL from January 2009 to January 2019. A control group evaluated during the same time period was included and comprised of parapharyngeal space squamous cell carcinoma (NSCC) metastatic nodes (n=18 lesions, in 15 patients) and nerve sheath tumors (NSTs, n=12, in 12 patients). Pathological examination was considered the gold standard (level 1 of evidence, n=41). In cases where no surgical resection was performed, the diagnosis of PGL was made by presence of tumor uptake on 18 F-DOPA PET (specific radiopharmaceutical). In the remaining cases, the consensus between experienced radiologists and surgeons warranted a diagnosis, where all clinical information, imaging studies and follow-up was taken into account (level 3 of evidence, n=14). The search for SDHx mutations was performed in all PGL, and recorded for further analysis.

MR imaging

Multiparametric MR imaging data were obtained at 1.5 Tesla (Amira Siemens, Erlangen, Germany) with a 16-channel phased array head and neck coil. DWI and DCE imaging parameters are described in Table 2. Patients first underwent unenhanced DWI, axial T1 weighted sequence without fat suppression, and T2-weighted fast spin-echo. A DCE sequence was then acquired before and during a 0.2 mL/kg gadolinium injection (Dotarem® gadotrial acid, Guerbet France) at 3 ml/sec. An axial and coronal T1WI with fat suppression was performed after gadolinium injection. Three different DCE sequences (gradient-recall-DCE/GRE, spin-echo-DCE/SE or time resolved 4D-MRA/4D) were used in this study, depending mainly on the indication and inclusion period. GRE, SE and 4D sequences were performed in 26, 24, and 38 lesions, respectively.

Image analysis

Regions of interest (ROIs) centered on the lesions were manually drawn on DCE images, with exclusion of areas of necrosis. A 10 mm2 OI was placed in consensus by radiologists (E.A. and A.V. with 6 and 20 year of experience in ENT radiology), blinded to clinical report information. Time-intensity parameters were generated for each ROI using the plugin DCE tool (v2.2) on Horos software (Pixmeo, Bernex, Switzerland, v1.1.17). The following semiquantitative parameters of enhancement were automatically extracted from time-intensity curves (TICs) for each lesion: basal signal intensity (SIpre), signal intensity at signal peak (SImax), time to peak (TTP), and signal intensity 20 seconds after peak (SI20). Wash in ratio (WIR) and wash out ratio (WOR) were obtained by linear regression of signal intensity, from SIpre to SImax for WIR, and from SImax to SIt20 for WOR.

Apparent diffusion coefficient (ADC) maps were calculated with linear regression analysis of the function ln(S/S0) = -b.ADC, where S is the signal intensity after application of the diffusion gradient, S0 is the signal intensity when the b value was 0 sec/mm2 , and b is the b1000 value. The corresponding DCE lesion ROIs were automatically reported on ADC maps.

Statistical analysis

Statistical analysis and post-processing was performed using the statistical software R (version 3.3.3; R Foundation for Statistical Computing, Vienna, Austria). Univariate analysis consisted of the comparison of quantitative features in each group. Continuous variables were expressed as mean and standard deviation. Comparison of mean values between the two groups were performed using a Student's t-test. ANOVA was used to analyze the differences among groups in the multivariate analysis. Clusters were obtained by multivariate unsupervised analysis by principal component analysis (PCA) and compared with variables of interest to analyse their relevance. Logistic regression was used in order to build regression diagnostic trees (CART).

Results

Patients, tumors and technical characteristics

A total of 90 tumors (in 77 patients) were evaluated, of which included 60 HNPGLs (10 carotid body PGLs, 16 vagus nerve PGLs, and 34 jugular PGLs), 12 NSTs (11 schwannomas and 1 neurofibroma), and 18 metastatic lymph nodes from squamous cell carcinomas or UCNT. Table 1 describes characteristics of the lesions, including the gold standard and DCE MRI method that were used across all tumor types. PGLs were histologically proven in 28%.

In the remaining cases, PGL diagnosis was based on tumor 18 F-DOPA uptake. 48% of HNPGLs were related to a germline mutation in one of the SDH genes (SDHB, n=4 in 4 patients; SDHC, n=3 in 3 patients; SDHD, n= 22 in 13 patients). For NSCC, histological proof was obtained in 33%. Table 2 describes the imaging parameters of DCE-MRI protocols.

Dynamic contrast enhancement pattern

All PGLs exhibited early and intense enhancement following gadolinium administration (with a rapid wash-out) on time intensity curves. In contrast, NSTs and NSCCs showed a more progressive enhancement, with a plateau phase. Figure 1 shows typical timeintensity curves for PGL, NST, and NSCC.

Univariate analysis

Figure 2 depicts the values of all biomarkers for each tumor type. Table 3 shows the results of the univariate analysis. All biomarkers were different across the 3 histological tumor types on univariate analysis, with a p-value <0.001. PGLs showed a shorter time-topeak intensity (TTP) compared to other groups, measured at 25.0 +/-29 sec. The WIR and WOR were also significantly higher for PGLs (p<0.001). NSTs showed a more delayed enhancement (TTP value: 233 ms). On DWI sequences, the mean ADC value for PGLs (1.17 ± 0.19 10^-3 mm2/s) was significantly different than the other tumor groups (p<0.001). The mean ADC was higher in NSTs (1.81 ± 0.28 10^-3 mm2/sec) (p<0.001). NSCC exhibited a lower ADC (0.95 ± 0.2 10^-3 mm2/s) compared to PGLs. No differences in DCE-derived indices or ADC were observed between sporadic versus SDHx-mutated PGLs.

Discrimination of HNPGL with multivariate modeling

A distinct PGL group without overlap from other tumors was observed on principal component analysis using WIR, WOR, TTP and ADC (Figure 3). NSTs and NSCCs were also separated from both each other and PGLs using the same criteria. A multiparametric classification and CART approach was used to determine optimal cut-off values to differentiate tumor groups. This method permitted to draw a decision tree (Figure 4). The analysis of DWI and pooled DCE MRI sequences resulted in a model (Table 4).

Discussion

Multiparametric MRI is known to be an added value in the diagnostic strategy of soft tissue tumors (e.g. parotid space tumors). Until now, very few studies with limited cases have evaluated quantitative parameters of DCE MR imaging in the diagnosis of parapharyngeal tumors.

Paragangliomas are rare tumours with a unique metabolism leading to neovascularisation, particularly rich in arterioles. SDHx mutations are found in up approximately 50% of HNPGL and are associated with metabolic changes that constitute an emerging metabolic hallmark of these tumors. These mutations lead to a disruption of Tricarboxylic Acid (TCA) cycle (also called Krebs cycle) with subsequent accumulation of succinate that alter various cellular and extra-cellular functions. Succinate acts as an oncometabolite an influences a broad spectrum of pathways such as the hypoxic response.

Thus, the major outcome of elevated succinate levels is HIF stabilization despite normal oxygen supply (e.g., pseudohypoxia) that promotes tumor angiogenesis [START_REF] Nölting | Personalized management of pheochromocytoma and paraganglioma[END_REF].

During the past 15 years, MRA has shown excellent results for localizing PGLs [START_REF] Gravel | The value of a rapid contrast-enhanced angio-MRI protocol in the detection of head and neck paragangliomas in SDHx mutations carriers: a retrospective study on behalf of the PGL.EVA investigators*[END_REF][START_REF] Ferré | Optimized time-resolved 3D contrast-enhanced MRA at 3T: Appreciating the feasibility of assessing cervical paragangliomas[END_REF][11][START_REF] Van Den Berg | The value of MR angiography techniques in the detection of head and neck paragangliomas[END_REF][START_REF] Arnold | Dynamic contrast enhancement of paragangliomas of the head and neck: evaluation with time-resolved 2D MR projection angiography[END_REF][14]. Overall, CE-MRA and T1-weighted sequence proved to be excellent in the detection HNPGLs with a sensitivity of 88.7 % and a specificity of 93.7 %. DWI has also shown high sensitivity for identifying PGL in the setting SDHB-related syndromes [START_REF] Tufton | Diffusion-weighted imaging (DWI) highlights SDHB -related tumours: A pilot study[END_REF].

Beyond its detection and localization value, MR is also more likely to provide better characterization of tumors. Previous studies evaluating multiparametric MR imaging have focused on the use of either DCE or DWI imaging features alone. Furukawa et al., evaluated the diagnostic efficacy of a time intensity curve analysis on DCE MRI for characterization of head and neck tumors (including a single case of PGL) in a cohort of 20 patients [START_REF] Furukawa | Dynamic contrast-enhanced MR perfusion imaging of head and neck tumors at 3 Tesla[END_REF]. They found that metastatic tumors had a significantly lower relative maximum enhancement and prolonged time to peak with lower relative WOR compared to benign lesions. Gaddikeri et al., compared the imaging features of DCE-MRI in 2 PGLs and 4 schwannomas [START_REF] Gaddikeri | Dynamic Contrast-Enhanced MRI in the Evaluation of Carotid Space Paraganglioma versus Schwannoma[END_REF]. PGLs were characterized by a high peak enhancement and signal-enhancement ratio (equivalent to WIR in our study) and less time for maximum enhancement, whereas schwannomas had a lower peak enhancement and signal-enhancement ratio with more time for maximum enhancement. Yuan et al., studied the features of HNPGLs on DWI and DCE-MRI [START_REF] Gaddikeri | Dynamic Contrast-Enhanced MRI in the Evaluation of Carotid Space Paraganglioma versus Schwannoma[END_REF]. The mean maximum enhancement ratio (equivalent to WIR) and TTP were estimated to be 193.79+/-67.18 and 8.16+/-3.29, respectively. DCE MRI was obtained with a fast spoiled gradient echo (FSPGR) acquisition technique. The better temporal resolution of this technique could explain the lowest TTP values compared to our findings. Sakai et al., evaluated the value of non-contrast-enhanced 4D-MRA in head and neck tumors in comparison with contrast-enhanced 4D MRA. Time intensity curves were obtained for 3 PGLs, with the same patterns observed-a distinct peak followed by wash out. In our study, PGLs were characterized by a shorter time-to-peak intensity (TTP), and higher WIR and WOR compared to other groups [START_REF] Sakai | Feasibility of non-contrast-enhanced four dimensional (4D) MRA in head and neck tumors, comparison with contrast-enhanced 4D MRA[END_REF].

Our study identifies a multiparametric MRI signature of HNPGLs in a large cohort of patients based on a combination of both DWI and DCE characteristics. We have deliberately chosen semi-quantitative parameters derived from the analysis of the time intensity curve. Such an approach is free of complex post-processing (e.g. arterial deconvolution) which allows it to be applicable in a multicentric setup.

Results from DWI-MRI are less common in the literature. The study from Yuan et al.

found a mean ADC of 1.12 E-3 mm 2 /s in a sample of 10 PGLs [START_REF] Gravel | The value of a rapid contrast-enhanced angio-MRI protocol in the detection of head and neck paragangliomas in SDHx mutations carriers: a retrospective study on behalf of the PGL.EVA investigators*[END_REF], which is concordant with our results. A recent meta-analysis that included 1,227 lesions from 22 studies showed that ADC plays a limited role in distinguishing malignant from benign lesions in the head and neck region. The authors conclude that a mean ADC value greater than 1.75 E-3 mm2/s is in favour of a benign lesion [START_REF] Surov | Apparent Diffusion Coefficient for Distinguishing Between Malignant and Benign Lesions in the Head and Neck Region: A Systematic Review and Meta-Analysis[END_REF]. However, this study is hampered by mixing a wide diversity of neoplasms located in various anatomical deep cervical spaces, and must be interpreted with caution. Indeed, miscellaneous lesions can frequently develop in parotid space where benign neoplasms (such as Whartin tumors) classically demonstrate diffusion restriction with low ADC values (usually below 1 E-3 mm 2 /s). Furthemore, only 12 PGLs were included in this meta-analysis (10 without topographic specification and 2 glomus jugulare PGLs) and different DWI MR-techniques were performed. Therefore, the heterogeneity in tumor origin and DWI sequences along with the absence of anatomical-space based analyses are a potential sources of overlap between ADC-values that must be considered.

This study has some limitations. First, it is retrospective in nature. Different types of DCE sequences were used to assess quantitative parameters. GRE and 4D-DCE sequences have a better temporal resolution than SE-DCE, which explains the wide range in TTP values.

An additional limitation is the lack of pathological confirmation (level 1 of evidence gold standard) for all tumors. However, the diagnosis of PGL can be made by 18 F-FDOPA PET/CT and can serve as so-called "in vivo" immunohistochemistry [START_REF] Taïeb | European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma[END_REF]. False positive results have been reported in only a few anecdotal case reports including solid pseudopapillary tumors of the pancreas, thyroid neoplasms of follicular origin (oncocytoma), squamous cell carcinomas (cervix, epiglottis), poorly differentiated adenocarcinomas and melanomas.

To our best knowledge, no previous study has examined the combination of DWI and DCE MR imaging in a large cohort of vascular space tumors. Our study shows that multiparametric MR plays an important role for tumor subtyping. Accurate characterization of these tumors by reliable imaging biomarkers could help to avoid unnecessary biopsies and guide further investigation. Our results would need to be validated in the setting of a prospective study. After confirmation, the validated quantitative values could be implemented in softwares to allow for automated detection and classification of vascular space tumors.

Conclusion

This study identifies a multiparametric MRI signature of paragangliomas that provides a strong impetus for switching from qualitative to quantitative analysis of deep soft-tissue tumors of the neck. MR features may serve as biomarkers for HNPGL diagnosis which could prevent unnecessary biopsy sampling and guide further investigation.

Ethical approval

The study was approved by an institutional Ethics Advisory Committee for using anonymous personal data extracted from institutional medical datafiles for research purposes. Written informed consent was waived by the Institutional Review Board. The author(s) declare that this manuscript has not been published previously and not under consideration for publication elsewhere.

Funding statement

The author(s) received no financial support for the research, authorship, and/or publication of this article. A, E, I : DCE imaging enhancement time-intensity curves (x-axis represents time in seconds, y-axis signal intensity). PGL (A) demonstrates a peak initial enhancement with a short timeto-peak, and a rapid wash-out. Schwannoma (E) and NSCC (I) demonstrate a more progressive enhancement with a plateau phase (without wash out). B, F, J : T2-weighted images in axial (B, F) and coronal (J) planes. PGL (B) demonstrates a typical heterogenous signal. Here the 'Salt and pepper' appearance is not obvious. Schwannoma (F) demonstrates a heterogenous appearance with hyperintense portions.

Metastatic lymphadenopathy (J) demonstrates a lower signal compared to schwannoma. C, G, K : Apparent diffusion coefficient map. PGL (C) and schwannoma (G) are moderately cellular lesions with ADC values of 1.2 and 1.3 x 10^-3 mm2/s respectively. NSCC (K) exhibits a lower ADC value (0.9 x 10^-3 mm2/s) compared to other tumors. D, H, L : 4D-MRA acquisition at early (arterial) time. PGL (D) exihibits an intense enhancement whereas schwannoma (H) and lymphadenopathy (L) are not enhanced at early phase.

Figure 2: Box plots of quantitative perfusion and diffusion parameters

On the univariate analysis, all parameters are significantly different between NSCC, NST and PGL with a p-value < 0.001 for each parameter. ADC is significantly higher in NST compared to PGL and NSCC. PGL exhibits significantly shorter TTP values, greater WIRs and WORs compared to NSCC and NST. The first predictor was ADC, which allows for the identification of NST when the value is higher than 1.65 (x 10^-3mm2/s). When the ADC-value is lower than 1.65, TTP is the second discriminating criteria. PGLs are eliminated with a high accuracy when the TTP is higher than 75.8 s. A short TTP (< 75.8 s) and an ADC-value that is higher than 0.97 are predictive of a PGL. When the TTP is short and the ADC < 0.97, the lesion can be either a PGL or NSCC.

Tables

8 . 3 :Figure 1 :

 831 Figure 1: Representative time intensity curves and images of paraganglioma (A, B, C,

Figure 3 :

 3 Figure 3: Clusters of quantitative variables constituting histological patterns

Figure 4 :

 4 Figure 4: Regression trees

Table 1 .

 1

		PGL	NSCC	NST
	Number of patients	50	15	12
	Number of lesions	60	18	12
	Age (year)	58 ± 17	59 ± 16	77± 17
	Gold standard
	Histology	28%	100%	33%
	PET using a specific tracer	72%	0%	0%
	Follow-up and consensus	0%	0%	67%
	DCE-MRI methods
	SE	5%	94%	33%
	GRE	40%	6%	50%
	4D-ARM	55%	0%	17%

Table 3 .

 3

		PGL	SCC	NST
		Mean ± SD	Mean ± SD	Mean ± SD	p
	ADC	1.17 ± 0.19	0.95 ± 0.2	1.80 ± 0.29	<0.001
	TTP	25.9 ± 29.30	160 ± 125	233.3 ± 145.3	<0.001
	WIR	5.34 ± 2.99	0.72 ± 0.79	0.39 ± 0.28	<0.001
	WOR	1.24 ± 0.80	0.27 ± 0.4	0.05 ± 0.06	<0.001

Table 4 .

 4

		n	CART	Se	Sp	PPV	NPV	Balanced Accuracy	p
	PGL	60	ADC ≤ 1.65 & TTP ≤ 75.8 95% 90% 95%	90%	93%	p < 0.001
	SCC	18	ADC ≤ 1.65 & TTP >75.8 83% 92% 71%	96%	88%	p < 0.001
	NST	12	ADC > 1.65	75% 100% 100% 96%	88%	P < 0.001