C.-G Bénar

J Velmurugan

V J López-Madrona

F Pizzo

J M Badier

Detection and localization of deep sources in magnetoencephalography: a review

Magnetoencephalography (MEG) is a non-invasive technique for exploring the spatio-temporal dynamics of brain networks with high temporal resolution as well as good spatial capacities thanks to relative insensitivity to low skull conductivity. It is a tool of choice both for neuroscience research and for clinical applications, and is used routinely in epilepsy for localizing the sources of epileptiform discharges.

Still, the capacity of capturing deep sources, such as hippocampus and amygdala that are key players in memory and emotion, has been for long a topic of debate. Thus, the fine characterization of deep structures has been up to now the reserved domain of intracerebral EEG, performed during presurgical evaluation of patients with epilepsy. We review here the evidence for the detection of deep sources in MEG, with emphasis on simultaneous recordings of MEG and intracerebral EEG.

In this review, we discuss how simultaneously recording depth and surface signals enables to investigate the correlation between MEG and invasive signals actually recorded in deep structures. We also discuss new venues in analysis and recording methods for reconstructing deep activities from MEG.

Introduction

Magnetoencephalography (MEG) measures neuronal activity in a non-invasive manner, with a temporal resolution of the order of the millisecond and weak dependence n the electrical conductivity of the underlying structures. This gives MEG a very good spatial discrimination power [START_REF] Gavaret | Meg and eeg sensitivity in a case of medial occipital epilepsy[END_REF], thanks in particular to its low sensitivity to skull conductivity. MEG is widely used to localize the brain regions underlying cognitive tasks, during functional mapping of eloquent and language regions before surgery, and is one of the key pre-surgical evaluation tools in patients with drug-resistant epilepsy [START_REF] Jayabal | Role of magnetoencephalography and stereo-electroencephalography in the presurgical evaluation in patients with drug-resistant epilepsy[END_REF]. Among all regions that can be investigated with MEG, deep brain structures such as hippocampus, amygdala and thalamus are of primary interest. Indeed, these structures are key players in memory, emotion, cognition, and in pathologies such as neurodegenerative disorders and epilepsy [e.g; [START_REF] Bartolomei | Neural networks involving the medial temporal structures in temporal lobe epilepsy[END_REF][START_REF] Barbeau | Spatio temporal dynamics of face recognition[END_REF]. They have however long been considered as difficult if not impossible to see from EEG/MEG surface sensors as signals attenuate rapidly as a function of the distance to sensors. Further attenuation arises from the fact that deep structures such as hippocampus, amygdala and thalamus are considered as the epitome of "closed fields" generators, i.e., producing little field outside the structure itself [START_REF] Lopes Da Silva | Biophysical aspects of eeg and magnetoencephalogram generation[END_REF]. To make things even more difficult, activity in deep "closed fields" structures propagate very fast to the nearby (neocortical) structures [START_REF] Alarcon | Intracerebral propagation of interictal activity in partial epilepsy: Implications for source localisation[END_REF], and what is visible on the surface signals could be in fact propagated activity or activity generated solely in lateral cortices [START_REF] Wennberg | Eeg and meg in mesial temporal lobe epilepsy: Where do the spikes really come from?[END_REF]. Finally, deep activity can be overshadowed by that of more superficial concurrent generators that have much higher signal to noise ratio at the surface [START_REF] Koessler | Catching the invisible: Mesial temporal source contribution to simultaneous eeg and seeg recordings[END_REF]. See Figure 1 for a schematic representation of these configurations.

A very important venue for better understanding deep activity arises from intracerebral recordings performed clinically during presurgical evaluation of epilepsy (stereo-electroencephalography, SEEG [START_REF] Talairach | Stereotaxic approach to epilepsy : Methodology of anatomofunctional stereotaxic investigations[END_REF]) as well as during deep brain stimulation. About 15 to 18 SEEG depth electrodes can be implanted, each electrode having between 5 and 15 contacts. They permit to obtain signals with exquisite spatial specificity, and to target directly deep brain structures. They are orthogonally or obliquely implanted through a small burr hole in the scalp, on sole clinical criteria. The number of electrodes required to insert depends on the underlying anatomo-electro-clinical hypotheses and on the hospital [START_REF] Balanescu | A personalized stereotactic fixture for implantation of depth electrodes in stereoelectroencephalography[END_REF][START_REF] Cossu | Stereoelectroencephalography in the presurgical evaluation of focal epilepsy in infancy and early childhood: Clinical article[END_REF][START_REF] Bartolomei | Defining epileptogenic networks: Contribution of seeg and signal analysis[END_REF][START_REF] Kahane | The bancaud and talairach view on the epileptogenic zone: A working hypothesis[END_REF]. Some centers use subdural grids with the advantage of higher spatial sampling, as they cover large areas of the brain. However, requirement of craniotomy, impracticality of bilateral monitoring, and inability to record from deeper cortical or subcortical sources are limitations of this approach.

Intracerebral recordings give a formidable opportunity for validating non-invasive results [START_REF] Bénar | Eeg-fmri of epileptic spikes: Concordance with eeg source localization and intracranial eeg[END_REF] and for ensuring the deep origin of signals. Importantly, for spontaneous activity such as interictal epileptic spikes, it is necessary to record simultaneously surface and deep signals in order to ensure that the exact same activity is captured at the two levels [START_REF] Koessler | Catching the invisible: Mesial temporal source contribution to simultaneous eeg and seeg recordings[END_REF][START_REF] Merlet | Reliability of dipole models of epileptic spikes[END_REF]. Indeed, the occurrence of epileptic discharges is unpredictable, and the frequency oand spatial distribution may flucturate depending on brain state and level of medication. Simultaneous recordings are also crucial if one wants to measure trial-to-trial coupling between deep structures and surface signals [START_REF] Williams | Dopamine-dependent changes in the functional connectivity between basal ganglia and cerebral cortex in humans[END_REF][START_REF] Dubarry | Simultaneous recording of meg, eeg and intracerebral eeg during visual stimulation: From feasibility to single-trial analysis[END_REF] or to trigger surface analysis based on activities marked in depth [START_REF] Gavaret | Simultaneous seeg-megeeg recordings overcome the seeg limited spatial sampling[END_REF][START_REF] Pizzo | Deep brain activities can be detected with magnetoencephalography[END_REF]. We review here studies that have performed simultaneous recordings of both deep structures and surface MEG signals, as well as new venues in analysis and recording methods for reconstructing deep activities from MEG. Previous reviews focussing on the hippocampus can be found in [START_REF] Ruzich | Characterizing hippocampal dynamics with meg: A systematic review and evidence-based guidelines[END_REF][START_REF] Pu | Non-invasive investigation of human hippocampal rhythms using magnetoencephalography: A review[END_REF].

Simultaneous MEG and intracerebral recordings

The first combined use of intracerebral electrodes and EEG/MEG was done by Cohen and Cuffin, who created artificial dipoles in the head by injecting current between consecutive electrodes [START_REF] Cohen | Meg versus eeg localization test using implanted sources in the human brain[END_REF]. They did not find a significantly better localization error for MEG than EEG, but it is to be noted that the injected dipoles were radial, which is the most unfavourable condition for MEG. Simultaneous recordings of MEG with intracranial signals were later performed with electrocorticography in patients during presurgical evaluation of epilepsy [START_REF] Mikuni | Simultaneous recording of epileptiform discharges by meg and subdural electrodes in temporal lobe epilepsy[END_REF][START_REF] Sutherling | Dipole localization of human induced focal afterdischarge seizure in simultaneous magnetoencephalography and electrocorticography[END_REF][START_REF] Shigeto | Feasibility and limitations of magnetoencephalographic detection of epileptic discharges: Simultaneous recording of magnetic fields and electrocorticography[END_REF][START_REF] Oishi | Epileptic spikes: Magnetoencephalography versus simultaneous electrocorticography[END_REF][START_REF] Rampp | Meg correlates of epileptic high gamma oscillations in invasive eeg[END_REF].

In order to confidently determine the deep origin of signals, it is useful to use the intracerebral technique that directly records within deep structures. The first simultaneous MEG and intracerebral recordings were performed at Centro Médico Teknon in Barcelona [START_REF] Santiuste | Simultaneous magnetoencephalography and intracranial eeg registration: Technical and clinical aspects[END_REF] and at the LENA laboratory at Pitié-Salpêtrière in Paris [START_REF] Godet | Concordance between distributed meg source localization dynamic, and simultaneous ieeg study of epileptic spikes[END_REF][START_REF] Dalal | Simultaneous meg and intracranial eeg recordings during attentive reading[END_REF]. Santiuste and colleagues recorded from a single depth electrode and showed that mesial spikes, despite their lower amplitude, can be detected on MEG (25 to 60% for deep spikes versus 95% for neocortical spikes); they considered signals to be concordant if they presented a delay less than 25 ms [START_REF] Santiuste | Simultaneous magnetoencephalography and intracranial eeg registration: Technical and clinical aspects[END_REF]. In another study, Dalal and colleagues showed a map of zero-lag correlation between the hippocampus and the MEG signals with a dipolar topography that strongly suggests a deep source [START_REF] Dalal | Simultaneous meg-intracranial eeg: New insights into the ability of meg to capture oscillatory modulations in the neocortex and the hippocampus[END_REF], even though no actual source reconstruction was performed on these signals. The superimposition of the intracerebral signal in the hippocampus and the most correlated MEG sensor shows clearly a theta oscillation with zero phase difference. This is in favour of a direct recording of hippocampus on MEG, even if zero-lag phase synchrony cannot be ruled out (see for example [START_REF] Gollo | Theta band zero-lag longrange cortical synchronization via hippocampal dynamical relaying[END_REF], noting however that in this latter study the hippocampus is the third-party driver leading to zero phase synchrony between neocortical structures).

We have shown in the MEG Centre of Marseille that it is possible to push the recording capacities in order to obtain signals from three modalities (MEG-EEG-SEEG) at the single trial level [START_REF] Dubarry | Simultaneous recording of meg, eeg and intracerebral eeg during visual stimulation: From feasibility to single-trial analysis[END_REF] and with high SEEG sampling [START_REF] Badier | Technical solutions for simultaneous meg and seeg recordings: Towards routine clinical use[END_REF]. Thanks to the high sampling (containing both mesial structures and surrounding neocortex) and to independent component analysis (ICA), we investigated the differential implication of subcortical structures and neocortex [START_REF] Pizzo | Deep brain activities can be detected with magnetoencephalography[END_REF]. Specifically, ICA allowed separating large-scale networks that correspond to propagated activity towards the neocortex from actual activity from deep structures, this latter being overshadowed by the former at the sensor level. Several tests were performed, including single-trial correlation between ICA components and SEEG, as well as source localization on the ICA components. Taken together, these results suggest that signals from deep structures can be captured on MEG -at least for epileptic activity. We are currently working on detectability of deep mesial structures in MEG within the context of a memory paradigm [START_REF] Vj | Detection of mesial networks with magnetoencephalography during cognition[END_REF].

Another important venue for simultaneously recording MEG and SEEG at deep structure arises from the possibility to record patients implanted with deep brain stimulation (DBS) electrodes [START_REF] Oswal | Analysis of simultaneous meg and intracranial lfp recordings during deep brain stimulation: A protocol and experimental validation[END_REF]. As DBS targets the thalamus, it will be possible to investigate the thalamic contribution to MEG signals, which has been suggested to be visible in MEG [START_REF] Pizzo | Deep brain activities can be detected with magnetoencephalography[END_REF][START_REF] Attal | Assessment of subcortical source localization using deep brain activity imaging model with minimum norm operators: A meg study[END_REF][START_REF] Krishnaswamy | Sparsity enables estimation of both subcortical and cortical activity from meg and eeg[END_REF]. To elucidate the therapeutic effects of DBS, simultaneous MEG-LFP recordings were carried out in patients with Parkinson's disease (PD). These studies were able to delineate two key networks between sub-thalamic nuclei and cortical structures (motor area and fronto-parietal regions) [START_REF] Litvak | Optimized beamforming for simultaneous meg and intracranial local field potential recordings in deep brain stimulation patients[END_REF][START_REF] Hirschmann | Distinct oscillatory stn-cortical loops revealed by simultaneous meg and local field potential recordings in patients with parkinson's disease[END_REF], where the cortico-sub-cortical coupling could be modulated by DBS [START_REF] Oswal | Analysis of simultaneous meg and intracranial lfp recordings during deep brain stimulation: A protocol and experimental validation[END_REF].

Source localization and forward modelling

Simultaneous recordings have shown that deep sources visible on SEEG can be reflected on the MEG signals. However, in most cases, only surface MEG signals are available, and one needs to ensure that deep activity can be recovered without the help of intracerebral recordings. Several difficulties arise. Generally, MEG recordings consist of signals with low signal to noise ratio, and this is especially true for deep sources. Moreover, there is a linear superposition of superficial sources at the channel level that may mask the activity from deep sources. One option to overcome these limitations is to use a source localization algorithm directly targeting deep sources [START_REF] Attal | Modeling and detecting deep brain activity with meg & eeg[END_REF].

To estimate brain sources based on MEG data, solution to both the forward and inverse problem must be addressed. The forward model is implemented by a gain matrix, which estimates the contribution of each dipole, i.e. each elementary source within the brain, to the sensors. The computation of the gain matrix is based on a volume conductor (head) model that defines the head geometry and tissue resistive properties. Depending on the topographical patterns computed using forward solution, the sources associated to the activity recorded with MEG are determined with inverse solution techniques. While constructing head model, it would be ideal to consider the electrical and geometrical features of subcortical structures. When a detailed head model is considered, the simulation study in [START_REF] Piastra | A comprehensive study on electroencephalography and magnetoencephalography sensitivity to cortical and subcortical sources[END_REF] showed that MEG is more sensitive than EEG for detecting tangential cortical sources and can also detect subcortical sources that are sufficiently tangential [START_REF] Piastra | A comprehensive study on electroencephalography and magnetoencephalography sensitivity to cortical and subcortical sources[END_REF].

One of the simplest ways to find the origin of the recorded activity of deep sources is by using one or a few equivalent current dipoles (ECD) that reproduce the magnetic field observed at the surface [START_REF] Shiraishi | Interictal and ictal magnetoencephalographic study in patients with medial frontal lobe epilepsy[END_REF]. The actual source configuration is likely to be non-dipolar (for example in the case of the convoluted fine structure of the hippocampus, see Fig. 1), but it is important to note that potential multi-dipolar contribution to signals attenuate very rapidly with distance. Dipolar localization has thus been used to identify hippocampal activations during memory tasks [START_REF] Martin | Brain regions and their dynamics in prospective memory retrieval: A meg study[END_REF][START_REF] Papanicolaou | The hippocampus and memory of verbal and pictorial material[END_REF]. Some researchers advocate to investigate also monopolar sources (see [START_REF] Riera | Pitfalls in the dipolar model for the neocortical eeg sources[END_REF] discussed in [START_REF] Destexhe | Do neurons generate monopolar current sources[END_REF]) Another approach consists in estimating sources distributed over the brain, for example the Minimum Norm Estimate (MNE) [START_REF] Hämäläinen | Interpreting magnetic fields of the brain: Minimum norm estimates[END_REF][START_REF] Baillet | Electromagnetic brain mapping[END_REF]. The distributed sources model does not require any prior on the number of actives sources, and can incorporate additional spatial information [START_REF] Attal | Modeling and detecting deep brain activity with meg & eeg[END_REF]. It also permits to consider the possibility of extended neocortical networks which activity can overlap in time with deep sources.

In distributed sources approaches, sources can be modelled as a very large number of dipolar sources located on a grid or constrained to lie on a mesh of the neocortex. Attal and colleagues have proposed to use additional compartments that model deep structures, in order to compensate for the bias introduced by the simultaneous activation of cortical and sub-cortical regions, specifically the hippocampus, amygdala and thalamus [START_REF] Attal | Assessment of subcortical source localization using deep brain activity imaging model with minimum norm operators: A meg study[END_REF][START_REF] Attal | Modeling and detecting deep brain activity with meg & eeg[END_REF]. Such framework was subsequently used to reconstruct amygdala time course [START_REF] Balderston | How to detect amygdala activity with magnetoencephalography using source imaging[END_REF][START_REF] Dumas | Meg evidence for dynamic amygdala modulations by gaze and facial emotions[END_REF]. The results indicate that hippocampus and amygdala can be localized with good accuracy when activated alone. However, regional specificity is reduced when there are simultaneous activations of cortical and subcortical sources, making it hard to differentiate deep regions without further assumptions. An additional difficulty arises from the fact that neocortical structures surrounding the hippocampal /amygdala can be activated and difficult to distinguish from the latter because of the proximity relative to the distance to sensors. Thus, it seems important to assess the volume of confidence of a given localization result [START_REF] Pizzo | Deep brain activities can be detected with magnetoencephalography[END_REF], and verify whether hippocampal, amygdala and neighbouring neocortex are included or not within the confidence interval. This confidence interval is more tractable for dipoles that for distributed sources [START_REF] Fuchs | Confidence limits of dipole source reconstruction results[END_REF][START_REF] Sorrentino | Bayesian multi-dipole modelling of a single topography in meg by adaptive sequential monte carlo samplers[END_REF] although solutions have been proposed for patches [START_REF] Schmidt | Bayesian inference applied to the electromagnetic inverse problem[END_REF].

Another extensively used method in source reconstructions is adaptive spatial filtering (or "beamforming") [START_REF] Sekihara | Reconstructing spatio-temporal activities of neural sources from magnetoencephalographic data using a vector beamformer[END_REF]. This method is based on a spatial filter computed for each source location independently and can reconstruct the time series throughout the brain, including the hippocampus or amygdala [START_REF] Cornwell | Evoked amygdala responses to negative faces revealed by adaptive meg beamformers[END_REF]. Beamforming estimates the activity recorded at a given location, incorporating biophysical constraints (typically a regional basis of dipoles). When the activity is temporally overlapping with cortical fields, leakage originating from the inverse problem [START_REF] Brookes | Measuring functional connectivity in meg: A multivariate approach insensitive to linear source leakage[END_REF] may obscure the signal originating from deep sources. Subtraction of several conditions with different activities may be used to mitigate this effect [START_REF] Quraan | Detection and localization of hippocampal activity using beamformers with meg: A detailed investigation using simulations and empirical data[END_REF]. On the other hand, beamforming reconstructs the activity at the desired location, instead of finding the point that better reproduces the recorded field. Therefore, this approach is complementary to the other methods for source localization. Different source localization algorithms could reconstruct deeper subcortical sources from MEG data by suppressing the high SNR signals from the neocortex. In general, source reconstruction from beamformer seems to be more focal and localized to hippocampus, compared to MNE images, but this requires further investigation as estimation of source extent is a difficult task [START_REF] Maksymenko | Strategies for statistical thresholding of source localization maps in magnetoencephalography and estimating source extent[END_REF].

Krishnaswamy and colleagues proposed a method based on sparse representations for recovering deep sources. Based on the analysis of the forward field, they show that in the presence of largely distributed cortical sources (full cortical space) it is impossible to unambiguously estimate simultaneously active subcortical sources. On the contrary, if cortical generators are sparse, then it is possible to recover separately cortical and sub-cortical activities [START_REF] Krishnaswamy | Sparsity enables estimation of both subcortical and cortical activity from meg and eeg[END_REF], which they do based on a subspace pursuit greedy algorithm. Sparse source localization is in general difficult, but is certainly a promising path for source localization and mitigation of source leakage effects [START_REF] Grova | Evaluation of eeg localization methods using realistic simulations of interictal spikes[END_REF] (review in [START_REF] Krishnaswamy | Sparsity enables estimation of both subcortical and cortical activity from meg and eeg[END_REF]).

Beyond source localization biophysical/mathematical models, one can use computational models in order to infer hidden variables. In other words, one can perform an inverse problem on a variable that is in the computational model but not directly visible from the data, as done for example in dynamic causal modeling [START_REF] David | Dynamic causal modeling of evoked responses in eeg and meg[END_REF], or in the 'virtual epileptic patient' [START_REF] Jirsa | The virtual epileptic patient: Individualized whole-brain models of epilepsy spread[END_REF]. This was done in the context of distant subcortical-cortical networks where effective connectivity based on DCM allowed inferring subcortical activity [START_REF] David | Dynamic causal modeling of subcortical connectivity of language[END_REF].

Blind source separation

One option for disentangling deep and cortical sources mixed on sensors is ICA, performed on the continuous signals [START_REF] Pizzo | Deep brain activities can be detected with magnetoencephalography[END_REF]. ICA was successfully applied to EEG and MEG in order to separate different processes mixed on the signals, either in cognition [START_REF] Jung | Analysis and visualization of single-trial event-related potentials[END_REF]or in epilepsy [START_REF] Ossadtchi | Automated interictal spike detection and source localization in magnetoencephalography using independent components analysis and spatio-temporal clustering[END_REF][START_REF] Sohrabpour | Noninvasive electromagnetic source imaging of spatiotemporally distributed epileptogenic brain sources[END_REF][START_REF] Malinowska | Interictal networks in magnetoencephalography[END_REF].This was the strategy used in the study of Pizzo and colleagues in order to separate deep activity from that of superficial networks, then comparing it to simultaneously acquired SEEG [START_REF] Pizzo | Deep brain activities can be detected with magnetoencephalography[END_REF] (Figure 2). ICA aims at separating the activity of N sources mixed on M sensors (where N ≤ M), assuming that the sources have different spatial distributions and that their time-series are independent [START_REF] Comon | Handbook of blind source separation, independent component analysis and applications[END_REF]. After reconstructing the time-course of the sources, their origin can be inferred using ECDs to reproduce the ICA topography of each source. As pointed earlier, one difficulty that arises when solving the inverse problem is that activities from deep sources can be mixed with neocortical sources [START_REF] Pizzo | Deep brain activities can be detected with magnetoencephalography[END_REF]. If the ICA manages to fully disentangle the sources, then one component can actually correspond to a single brain region [START_REF] Delorme | Independent eeg sources are dipolar[END_REF] and thus be reasonably modelled with a single dipole (assuming the activity is not too extended, which is not guaranteed). In some cases, two symmetric sources can be observed that correspond to homologous brain regions, and can be modelled by symmetric dipoles [START_REF] Piazza | Eeg effective source projections are more bilaterally symmetric in infants than in adults[END_REF]. Bayesian source localization is also an interesting path to explore [START_REF] Sorrentino | Bayesian multi-dipole modelling of a single topography in meg by adaptive sequential monte carlo samplers[END_REF], as well as sparse methods such as L1 on the spatial gradient of the sources (total variation) [START_REF] Sohrabpour | Noninvasive electromagnetic source imaging of spatiotemporally distributed epileptogenic brain sources[END_REF]. For more complex source configurations and in particular for extended brain areas, distributed sources including patch modelling can be considered; a difficulty to overcome is that the definition of noise covariance for ICA topography is not straightforward (there is not temporal dimension one which to estimate covariance, only one data vector). Moreover, the ICA approach has been challenged recently, showing that source localization of single ICA components does not improve the localization results in MEG (and can on the contrary be detrimental) [START_REF] Pellegrino | Effects of independent component analysis on magnetoencephalography source localization in pre-surgical frontal lobe epilepsy patients[END_REF], a potential explanation for these results is the above-mentioned difficulty for modelling the source of a single topography when it is not purely dipolar, and also in the fact in some cases several ICs may need to be taken in to account [START_REF] Malinowska | Interictal networks in magnetoencephalography[END_REF].

We noted above the importance of sparsity constraints in source localization. It is interesting to note that ICA can be seen as another way to obtain sparse representations [START_REF] Daubechies | Independent component analysis for brain fmri does not select for independence[END_REF]. Potentially, the patterns seen on ICA topographies could be used in order to gain information on the underlying sources, as was done on EEG patterns in epilepsy [START_REF] Ebersole | Spike voltage topography identifies two types of frontotemporal epileptic foci[END_REF].

The computation of ICA or covariance matrices that are used in source localization require large amount of time samples which increases with the square of number of channels. To be noted, there are signal space separation (SSS) [START_REF] Özkurt | Decomposition of magnetoencephalographic data into components corresponding to deep and superficial sources[END_REF] and beamspace dual signal space projection (bDSSP) [START_REF] Sekihara | Beamspace dual signal space projection (bdssp): A method for selective detection of deep sources in meg measurements[END_REF] algorithms where dimensionality reduction is obtained by projecting the data into a low dimensional subspace. Moreover, these methods decompose the MEG signals into superficial and deep source components and suppress the stronger interference from superficial sources, as performed in the cortical signal space suppression (CSS) method [START_REF] Samuelsson | Cortical signal suppression (css) for detection of subcortical activity using meg and eeg[END_REF] that preserves the subcortical signals while suppressing the cortical contributions. This latter method is completely data-driven and does not require forward modelling or inverse solutions.

Detectability of deep sources according to MEG configuration

The significance of MEG sensor design on the depth sensitivity of MEG is still under investigation. Conventional MEG systems have either any of the three types of pickup coil configurations: magnetometers (with single loop of wire), axial, and planar gradiometers (two or more loops spaced at a distance with opposite orientation). Overall, axial gradiometers were able to deliver optimal brain SNRs compared to magnetometers, while planar gradiometer is sensitive to superficial sources by suppressing environmental noise. Although axial gradiometers have an added advantage, any sensor type can measure subcortical activity relative to the square of the distance and the amount of noise in the background of other brain activity [START_REF] Vrba | Signal processing in magnetoencephalography[END_REF].

In another (complementary) line of research, Tzovara and colleagues have identified the difficulty of localizing deep sources, and propose to use a head cast to ensure minimal head movement and therefore optimal localization precision [START_REF] Tzovara | High-precision magnetoencephalography for reconstructing amygdalar and hippocampal oscillations during prediction of safety and threat[END_REF] -which should be useful for both deep and superficial sources.

Conclusion and New venues

There is now several converging evidence that deep signals can be recorded in MEG, in line with EEG findings [START_REF] Koessler | Source localization of ictal epileptic activity investigated by high resolution eeg and validated by seeg[END_REF][START_REF] Seeber | Subcortical electrophysiological activity is detectable with high-density eeg source imaging[END_REF], thus opening new exciting new venues for the non-invasive investigation of brain networks in physiology and pathology, a fast growing field in neuroscience [START_REF] He | Electrophysiological brain connectivity: Theory and implementation[END_REF].

Simultaneous recordings of intracerebral EEG and MEG recordings provide perhaps the strongest evidence that MEG can reliably measure deep activity in patients [START_REF] Pizzo | Deep brain activities can be detected with magnetoencephalography[END_REF][START_REF] Dalal | Simultaneous meg and intracranial eeg recordings during attentive reading[END_REF][START_REF] Crespo-Garcia | Slowtheta power decreases during item-place encoding predict spatial accuracy of subsequent context recall[END_REF]. Reliability of deep sources detection with source localization and source separation methods (ICA/bDSSP/CSS) can be assessed if simultaneous ground truth such as SEEG electrode recordings are available. More progress is thus expected from such simultaneous acquisitions.

An important future path is the advent of a new generation of MEG sensors. As opposed to conventional SQUID system, optically pumped magnetometers (OPMs; [START_REF] Boto | A new generation of magnetoencephalography: Room temperature measurements using optically-pumped magnetometers[END_REF]) does not require liquid helium. They have lower sensitivity, but a four-fold increase in SNR could be achieved as OPMs can be brought closer to scalp surface and allow head movements [START_REF] Boto | Moving magnetoencephalography towards real-world applications with a wearable system[END_REF]. A question that still remains to be investigated is whether being close to the surface does not 'blind' the OPM to the deeper sources by being overwhelmed by the strong activity of superficial sources [START_REF] Krishnaswamy | Sparsity enables estimation of both subcortical and cortical activity from meg and eeg[END_REF][START_REF] Samuelsson | Cortical signal suppression (css) for detection of subcortical activity using meg and eeg[END_REF]. As OPM sensors are mobile, it has been proposed to record directly within the mouth in order to obtain a recording of hippocampal activity dorsally from within the mouth [START_REF] Tierney | Mouth magnetoencephalography: A unique perspective on the human hippocampus[END_REF]. This could help in more accurately to determine the actual deep origin of the signals.

Another interesting possibility is to use simultaneous recording of surface and depth signals as a combined "meta-modality", i.e. to fuse them into a joint analysis [START_REF] Gavaret | Simultaneous seeg-megeeg recordings overcome the seeg limited spatial sampling[END_REF][START_REF] Litvak | Optimized beamforming for simultaneous meg and intracranial local field potential recordings in deep brain stimulation patients[END_REF][START_REF] Crespo-Garcia | Slowtheta power decreases during item-place encoding predict spatial accuracy of subsequent context recall[END_REF]. In any case, the continuous or single trial analysis is crucial in order to extract the covariation between depth and surface signals, either at zero lag (reflecting the same activity) or at different lags (network analysis) [START_REF] Dubarry | Simultaneous recording of meg, eeg and intracerebral eeg during visual stimulation: From feasibility to single-trial analysis[END_REF][START_REF] Zhang | Dynamic analysis on simultaneous ieeg-meg data via hidden markov model[END_REF].

Future progress in simultaneous recordings (number of modalities, type of sensors) and in the inverse problem of both MEG and intracerebral EEG [START_REF] Hosseini | Electromagnetic source imaging using simultaneous scalp eeg and intracranial eeg: An emerging tool for interacting with pathological brain networks[END_REF][START_REF] Caune | Evaluating dipolar source localization feasibility from intracerebral seeg recordings[END_REF][START_REF] Chang | Dipole localization using simulated intracerebral eeg[END_REF] should also allow refining the definition of the links between surface measures and cerebral activity. signal is recorded from the surface. b) Activity from hippocampus propagates to nearby neocortex, which has a structured source geometry (open field) and can be seen as a signal at the surface (small because of the depth). c) only subparts of hippocampus and amygdala are active, producing an open field and small signal at the surface. d) The activity from deep structures is overshadowed by activity from the superficial neocortex that has a higher amplitude due to shorter distance to the sensors. This is the first attempt to record hippocampus from within the mouth, which is now possible thanks to the new generation of OPM MEG sensors that are mobile. This gives the opportunity to improve the sampling of the topography deep activity, by providing a measure from below. This is very relevant for deep sources that can have a widespread topography, and in which surface sensors may miss important parts of the fields. This should in turn improve the localization of deep sources and help disantangling them from superficial measures * Sekihara K, Adachi Y, Kubota HK, Cai C, Nagarajan SS. Beamspace dual signal space projection (bDSSP): A method for selective detection of deep sources in MEG measurements. Journal of Neural Engineering 2018;15(3). This study adresses the difficult challenge of separating deep and superfical sources from surface measures, as the former can be overwhelmed by the activity of the latter on non-invasive sensors.

Here, the approach is based on the beamformer signal processing technique, a spatial filter that suppresses the activity of sources other than the source of interest. The authors show that by using a signal subspace approach specific to deep sources, they can obtain better suppression of the superficial contribution to the recorded signals than with a classical method. * Seeber M, Cantonas LM, Hoevels M, Sesia T, Visser-Vandewalle V, Michel CM. Subcortical electrophysiological activity is detectable with high-density EEG source imaging. Nature Communications 2019;10.

This study uses for the first time simultaneously recorded DBS electrodes and surface EEG for assessing the detectability of thalamus on EEG. The authors have correlated the time courses of source reconstructed signals and that of DBS electrodes, and found highest correlation for sources close to the DBS electrodes recording the thalamus. This suggests that thalamic activity can indeed be reconstructed from the surface signals. This study investigates the possibility of retrieving deep brain sources in MEG (magnetometers), thanks to simultaneously recorded intracerebral EEG (stereoelectroencephalography, SEEG). Epileptiform events were marked on SEEG, and independent component analysis was used in order to disentangle deep sources from superficial (propagated) sources. Importantly, there was a high spatial sampling iof depth electrodes that allowed probing nearby neocortex. The origin of the putative deep components was assessed by several methods in order to strengthen confidence in the results: (i) the deep aspect of the MEG topography ("wide" field) (ii) correlation of MEG-ICA and SEEG across time along trials (testing for general ressembalnce of the time courses) or at a given time point across trials (testing whether tria-to-trial fluctuations correlate in depth and surface), as well as (iii) dipolar source reconstruction with a confidence interval (which is expected to be large for deep sources). This study applied ICA on MEG during a memory task to explore the signature of the hippocampal formation on MEG. They found a common ICA-MEG component across subjects, with the same "deep" topography. Using simultaneous SEEG recordings and partial correlation, they confirmed the origin of the ICA-MEG as a network composed solely by the hippocampus and rhinal cortex. These results confirmed that hippocampal activity can be seen on MEG in cognition. Importantly, they identified a specific fingerprint of this network on MEG recordings, facilitating future studies based on this activity without an intracranial confirmation of its origin.

Hippocampus

Figure 1 :

 1 Figure 1: Schematic view of different source configurations and their reflection on MEG. a) only deep sources are active (hippocampus and amygdala). As activation is of a 'closed field' type, no visible

Figure 2 :

 2 Figure 2: Results of simultaneous MEG/intracerebral recordings (methods in [19]. a) Example of an ICA component corresponding to a deep source (note the "wide" topography), found on data triggered on spikes visible in mesial temporal SEEG contacts b) Source localization performed on the topography (confidence interval of equivalent dipole), within right mesial temporal regions c) SEEG implantation (only left side is shown) d) Superimposition of average ICA time course (in color, based on SEEG triggers) and SEEG contacts for which there is significant correlation (in black). Contacts are located in left amygdala (Ap), left hippocampus (Bp) and left basal temporal regions (TBp) and are shown on the right of the panel, with the same color convention as the traces.

*

  Pizzo F, Roehri N, Medina Villalon S, Trebuchon A, Chen S, S, Carron R, Gavaret M, Giusiano B, McGonigal A, Bartolomei F et al: Deep brain activities can be detected with magnetoencephalography. Nat Commun (2019) 10(1):971.

*

  Samuelsson JG, Khan S, Sundaram P, Peled N, Hämäläinen MS. Cortical Signal Suppression (CSS) for Detection of Subcortical Activity Using MEG and EEG. Brain Topography 2019;32(2):215-28. Tailoring of the source reconstruction for specifically targeting deep sources.This article presents a signal subspace approach that is tailored for suppressing neocortical signals and emphasizing the deep contribution to the surface sensors. It takes advantage of the presence of both gradiometers and magnetometers, using the (more short-sighted) gradiometers for the estimation of superficial activity. * López-Madrona VJ, Medina Villalon S, Jayabal V, Trébuchon A, Alario FX, Bartolomei F, et al. Detection of mesial networks with magnetoencephalography during cognition. LiveMEG 2020: a cutting EEG event2020.

ACKNOWLEDGEMENTS

This work was partially supported by the RHU EPINOV, A*MIDEX project (ANR-17-RHUS-0004) funded by the 'Investissements d'Avenir' French Government and by a FLAG ERA/HBP grant from Agence Nationale de la recherche "SCALES" ANR-17-HBPR-0005, by France Life Imaging network (grant ANR-11-INBS-0006), and ILCB convergence institute ANR-16-CONV-0002.


Alice Mignot1

Karelle De Luca3

Gérard Leboucher2

Véronique Servais1

MSc in Clinical psychology, Ph.D student Alice Mignot
email: alice.mignot@parisnanterre.fr

French handlers' perspectives on Animal-Assisted Interventions

Background: Animal-Assisted Interventions (AAI) are well implemented in human healthcare, in France as elsewhere; yet there are still difficulties in characterizing these practices and misconceptions about their mechanisms -little is known about the French practice of AAI and about the human-animal team.

Objectives: This study aims to characterize AAI by exploring their specificities through French handlers' perspectives.

Material and method: An online survey addressed to French handlers working in AAI with mainly one dog was carried out. This research included questions about their practice in AAI (registration status, beneficiaries, and animals) and their background (training in AAI, training in the medico-social field, training in animal behavior). We then examined a phenomenological understanding of handlers' definitions of their practice in AAI, their motivations to work with these approaches, and the expectations of the human-animal team.

We used an open coding strategy and created major themes from their answers.

) the shared role of mediator, and (5) handlers' beliefs about the human-animal relationship related to their personal experiences. This survey allowed us to understand how the French use AAI and its role in the care system.

Conclusion:

The benefits of AAI are numerous both for care settings and for the caregivers mainly by making the care more humane. AAI seem to put the wellbeing of beneficiaries and the relationship with the caregiver at the center of the care. The complementarity of the human-animal team is the common feature of these practices and is critical to their success.

Future interdisciplinary studies are required to explore the particularities of these interspecific approaches and the differences between countries.

Introduction

Practices utilizing the human-animal bond in healthcare settings are commonly designated by the term Animal-Assisted Interventions (AAI). They are defined as "a goal oriented and structured intervention that intentionally includes or incorporates animals in health, education and human services (e.g., social work) for the purpose of therapeutic gains in humans. It involves people with knowledge of the people and animals involved" [START_REF] Iahaio | The IAHAIO Definitions for Animal Assisted Intervention and Guidelines for Wellness of Animals Involved in AAI[END_REF]. AAI include several sub categories such as Animal-Assisted Therapies (AAT), Animal-Assisted Activities (AAA), Animal-Assisted Education (AAE) and Animal-Assisted Coaching (AAC) [START_REF] Iahaio | The IAHAIO Definitions for Animal Assisted Intervention and Guidelines for Wellness of Animals Involved in AAI[END_REF]. These methods are receiving increased attention within the medical and paramedical fields because of their benefits on a large range of health-related problems [START_REF] Cirulli | Animal-assisted interventions as innovative tools for mental health[END_REF]. The interactions with animals in care settings have positive impacts on human health such as the decrease of anxiety [START_REF] Barker | The effects of animal-assisted therapy on anxiety ratings of hospitalized psychiatric patients[END_REF][START_REF] Cole | Animal-assisted therapy in patients hospitalized with heart failure[END_REF][START_REF] Waite | A meta-analysis of animal assisted interventions targeting pain, anxiety and distress in medical settings[END_REF] and depression [START_REF] Koukourikos | Benefits of Animal Assisted Therapy in Mental Health[END_REF][START_REF] Ambrosi | Randomized controlled study on the effectiveness of animal-assisted therapy on depression, anxiety, and illness perception in institutionalized elderly[END_REF] as well as the improvement of social skills [START_REF] King | Effect of a time-out session with working animalassisted therapy dogs[END_REF][START_REF] Becker | Animal-assisted social skills training for children with autism spectrum disorders[END_REF][START_REF] Hediger | Effects of animalassisted therapy on social behaviour in patients with acquired brain injury: a randomised controlled trial[END_REF] and self-esteem [11,[START_REF] Schuck | The role of animal assisted intervention on improving self-esteem in children with attention deficit/hyperactivity disorder[END_REF]. As a result, the benefits of animals on human health represent a significant scientific research field that continues to grow [START_REF] Fine | The State of Animal-Assisted Interventions: Addressing the Contemporary Issues that will Shape the Future[END_REF]; yet there is still difficulty to characterize AAI. Even if there is a professionalization of the field, there is still a lack of standards and inconsistencies about the terms and definitions of AAI [START_REF] Parish-Plass | Order Out of Chaos Revised: A Call for Clear and Agreed-Upon Definitions Differentiating Between Animal-Assisted Interventions[END_REF][START_REF] Santaniello | Methodological and Terminological Issues in Animal-Assisted Interventions: An Umbrella Review of Systematic Reviews[END_REF][START_REF] Enders-Slegers | Animal-assisted interventions with in an international perspective: Trends, research, and practices[END_REF][START_REF] López-Cepero | Current Status of Animal-Assisted Interventions in Scientific Literature: A Critical Comment on Their Internal Validity[END_REF], specifically, regarding the French AAI where there is a lack of data about these seemingly heterogeneous practices [START_REF] Michalon | Panser avec les animaux: Sociologie du soin par le contact animalier[END_REF]. It could be linked to the absence of governmental regulation and mandatory training to practice AAI [START_REF] Enders-Slegers | Animal-assisted interventions with in an international perspective: Trends, research, and practices[END_REF][START_REF] Boizeau | [END_REF]. Furthermore, most research on AAI has been focused on proving the efficiency of animals on the beneficiaries [START_REF] Servais | Du surnaturel au malentendu Pour une approche interactionnelle des systèmes de communication homme/animal[END_REF]. However, the complementarity of the human-animal dyad is central in AAI for the influence and mutual benefits it has during sessions [START_REF] Payne | Current perspectives on attachment and bonding in the dog–human dyad[END_REF][START_REF] Menna | The Human-Animal Relationship as the Focus of Animal-Assisted Interventions: A One Health Approach[END_REF][START_REF] Kuzara | Exploring the Handler-Dog Connection within a University-Based Animal-Assisted Activity[END_REF]. Handlers are regularly excluded from studies and little is known about their perspectives and their roles [START_REF] Firmin | Qualitative Perspectives of an Animal-Assisted Therapy Program[END_REF][START_REF] Grandgeorge | Human-animal relationships: from daily life to animalassisted therapies[END_REF]. There are still misconceptions about AAI, such as the thinking that petting the animals is sufficient to get the reward [START_REF] Parish-Plass | Order Out of Chaos Revised: A Call for Clear and Agreed-Upon Definitions Differentiating Between Animal-Assisted Interventions[END_REF].

Theoretical framework

We aimed to apply the recommendations of changes in AAI research suggested by Delfour & Servais [START_REF] Delfour | L'animal dans le soin : entre théories et pratiques[END_REF] that are: "the consideration of the animal as a subject; the restitution of their speech to handlers; and the development of attentive and creative methods of observation and investigation". Consequently, the qualitative perspective respects these criteria since it "facilitates better understanding of factors that may influence the intervention implementation" [START_REF] López-Cepero | Current Status of Animal-Assisted Interventions in Scientific Literature: A Critical Comment on Their Internal Validity[END_REF]. As highlighted in the Shen et al. [START_REF] Shen | We need them as much as they need us": A systematic review of the qualitative evidence for possible mechanisms of effectiveness of animal-assisted intervention (AAI)[END_REF] review of qualitative studies, these studies can be a way to reveal possible mechanisms of AAI. However, they focused on the beneficiaries point of view [START_REF] Lange | Is Counseling Going to the Dogs? An Exploratory Study Related to the Inclusion of an Animal in Group Counseling with Adolescents[END_REF][START_REF] Schmitz | Animal-assisted therapy at a University Centre for Palliative Medicine -a qualitative content analysis of patient records[END_REF][START_REF] Lubbe | The application of animal-assisted therapy in the South African context: A case study[END_REF]. Only a few of the studies were interested in handlers' opinions about their practices in AAI [START_REF] Firmin | Qualitative Perspectives of an Animal-Assisted Therapy Program[END_REF][START_REF] Abrahamson | Perceptions of a hospitalbased animal assisted intervention program: An exploratory study[END_REF][START_REF] Berget | Animal-Assisted Interventions and Psychiatric Disorders: Knowledge and Attitudes among General Practitioners, Psychiatrists, and Psychologists[END_REF][START_REF] Bibbo | Staff Members' Perceptions of an Animal-Assisted Activity[END_REF][START_REF] Black | Australian psychologists' knowledge of and attitudes towards animal-assisted therapy: Psychologists and animal-assisted therapy[END_REF][START_REF] Crowley-Robinson | A long-term study of elderly people in nursing homes with visiting and resident dogs[END_REF] and were principally focused on their knowledge and attitudes regarding specific practice [START_REF] Abate | Nurse Leaders' Perspectives on Animal-Assisted Interventions[END_REF]. This makes it essential to interview handlers with different backgrounds and considerations towards the relationship between themselves and their animals to get a better understanding of AAI.

The aim of the present research is to contribute to increasing the body of knowledge surrounding AAI by integrating handlers' opinions.

To this end, we focused on two axes through handlers' answers to four questions. The first axis concerned the main features of AAI that we obtained through interviewing handlers about their definition of their own practice in AAI. In addition, we assumed that handlers' professional backgrounds and motivations to work in AAI enabled them to understand the characteristics of these practices. The second axis concerned the interspecific complementarity of the human-animal team that we investigated through their views on their dedicated roles and the roles of their animals in AAI.

Materials & Method

Participants & recruitment

Our cohort was composed of 111 French handlers in AAI. Our inclusion criteria were to be active in AAI and to work with at least one dog because dogs constitute the most represented species in AAI [START_REF] Hatch | The View from All Fours: A Look at an Animal-Assisted Activity Program from the Animals' Perspective[END_REF][START_REF] Maurer | Analyse de dix recherches sur la thérapie assistée par l'animal : quelle méthodologie pour quels effets ?[END_REF][START_REF] Nimer | Animal-Assisted Therapy: A Meta-Analysis[END_REF][START_REF] Ng | Describing the Use of Animals in Animal-Assisted Intervention Research[END_REF]. Handlers were all volunteers and we had no selection criteria based on their professional backgrounds. We constructed an online questionnaire that was posted on AAI-specialized social media accounts and sent by email from April 2018 to May 2019. It was important for us to develop an online questionnaire for ease of use and timesaving reasons. Moreover, contrary to other qualitative research that focuses on small samples and/or specific groups, we aimed to interview a large panel of handlers.

Ethics

Before accessing the questionnaire, handlers were required to complete a consent form that included an explanation of the study framework, objectives and the research ethics features.

Signing this consent form guaranteed the confidentiality of their responses, the possibility of interrupting the research, respect for their integrity and their rights in accordance with the research ethics. The collection, processing and storage of personal data complied with the rules laid down by the European General Data Protection Regulation [START_REF] Voigt | The eu general data protection regulation (gdpr)[END_REF].

Data collection

The questionnaire was built based on a literature review [START_REF] Iahaio | The IAHAIO Definitions for Animal Assisted Intervention and Guidelines for Wellness of Animals Involved in AAI[END_REF][START_REF] King | Effect of a time-out session with working animalassisted therapy dogs[END_REF][START_REF] Firmin | Qualitative Perspectives of an Animal-Assisted Therapy Program[END_REF][START_REF] Delfour | L'animal dans le soin : entre théories et pratiques[END_REF][START_REF] Berget | Animal-Assisted Interventions and Psychiatric Disorders: Knowledge and Attitudes among General Practitioners, Psychiatrists, and Psychologists[END_REF][START_REF] Society | Standards of practice for animal assisted activities and animal assisted therapy[END_REF][START_REF] Boizeau | La médiation animaleproblématiques règlementaires et enjeux professionnels[END_REF][START_REF] Budahn | Effectiveness of Animal-Assisted Therapy: Therapists' Perspectives[END_REF] and informal interviews of handlers and scientific experts in the field. It was entirely written in French and was composed of four unequal sections for approximatively 20 minutes in total. We used a mixed method; therefore, some data was obtained through closed questions while other data was obtained through open questions. We chose to separate our data into specific articles; therefore, this one presents only data about the characteristics of AAI through handlers' perceptions.

Analysis

The data presented below are based on sociodemographic and open questions. Quantitative data were treated with the Software GraphPad Prism 8. These data concerned sociodemographic questions (gender, age), followed by questions about their current practice in AAI (their registration status, the populations and the animal species they work with) and questions about their professional background (their training in AAI and their education institution, their training in the medico-social field and their training in animal behavior). Descriptive characteristics of the cohort were calculated and presented as means averages for continuous variables and percentages for categorical variables.

The qualitative method was selected for four open questions: We used a phenomenological method because it "describes the meaning for several individuals of their lived experiences of a concept or a phenomenon; describing what all participants have in common as they experience a phenomenon" [START_REF] Creswell | Qualitative inquiry and research design: Choosing among five approaches[END_REF]. Like Firmin et al. [START_REF] Firmin | Qualitative Perspectives of an Animal-Assisted Therapy Program[END_REF],

we used an open coding strategy with a line-by-line analysis approach and developed clusters of meaning into themes. We wrote a description of the significant themes that emerged from our data [START_REF] Creswell | Qualitative inquiry and research design: Choosing among five approaches[END_REF] and illustrated them with citations (translated from French to English) of subjects with their anonymity number.

Results

Demographic characteristics of our sample

Our sample was composed of 111 handlers in AAI. They were mostly women (94.59%; N=105) with a mean age of 41 years (min 20 years; max 68 years). Handlers worked with a broad range of populations; based on the two first pathologies cited we analyzed data on 166 answers. Beneficiaries were mostly elderly with dementia (30.12%; N=50), followed by people with mental and/or motor disability (22.29%; N=37), followed by Pervasive Developmental Disorders (13.85%; N=23) and people with various mental health problems (13.25%; N=22). Also, 47.75% (N=53) of the handlers in our sample only worked with dogs, the rest worked with two species on average (range 1 to 7), mainly small pets such as guinea pigs and rabbits (45.04%; N=50). Handlers' professional backgrounds were different. 83.78%

(N=93) of our sample were trained in AAI from different institutions that included both university training centers and private structures. 71.17% (N=79) of interviewed handlers had training in the medico-social field that represented various types of care professions. They were mostly psychologists (24/05%;N=19), caseworkers (16.46%;N=13), nurses (13.92%;N=11) and psychomotor therapists and occupational therapists (12.66%;N=10). In addition, some of them had a background in the animal field (37.84%: N=42) which concerned mostly dog trainer (50%; N=21) and veterinary/assistant veterinary (19.05%; N=8).

Qualitative analysis

Five themes were identified as important characteristics of AAI: (1) AAI as additional approaches in care settings, (2) the person-centered approach, (3) the complementarity between handler and their animal(s), ( 4) the shared role of mediator and (5) handlers' beliefs about the human-animal relationship related to their personal experiences. A brief description of each theme supported with illustrative citation of participant data is presented for every result of the study.

AAI as additional approaches in care settings

Handlers alluded that AAI bring benefits to various care settings. They mentioned objectives that concern a diverse set of domains (therapeutic, educative, social, pedagogical etc.). Most of them referred to the introduction of AAI to mitigate the limits of conventional care. More specifically, care professionals referred to AAI as additional approaches to support their work and some of them distinguished themselves from other handlers by the therapeutic value of their AAI. Regardless of their initial training, handlers mentioned the benefits that AAI brought to themselves, such as being able to specialize in a new approach or even a career change.

s1: "The inadequacies of "conventional" approaches" s32: "It is a practice with a therapeutic aim (by virtue of my function)" s46: "It is a "way" to achieve an objective that cannot be achieved with conventional tools" s70: "Another string to my bow" s109: "Doing the work for which he [the handler] was trained, for me as a psychologist, with an additional tool that is the dog"

Person-centered approaches

The construction of the objectives seemed to be flexible and adapted to each patient.

Therefore, the beneficiary appeared to regain an active role in his or her care. The most frequently cited objectives concerned the well-being of beneficiaries and the creation of bonds between beneficiary and caregiver. When handlers described their relationship with beneficiaries, they used words associated with positivity and warmth (i.e. "link," "alliance,"

"trust," "affection," "tenderness," and "empathy"). For most handlers, their animals were seen as assistants that take an immersive role in these relationships.

s5: "My practice is created according to my patients: they are the ones who initiate the process and propose activities around the dog most often" s50: "[…] sometimes there is also a therapeutic interest, but this is not the primary goal" s73: "humane and playful" s99: "The goal is to increase interactions with humans through interactions with animals"

Complementarity of the human-animal team

Handlers pointed out the central role of animals into enriching the actual care. They spoke about the common intrinsic attributes of animals such as their absence of judgement, their neutral attitude toward human pathologies, and the absence of verbal communication.

Handlers referred to their main role as optimizing the effects of the animal and to guarantee safety. That implies a work upstream to construct the project, downstream to evaluate objectives and adapt the next sessions and the adjustment of what is emerging during sessions. They also mentioned a major responsibility in their animals' welfare by observing their behavior such as their signs of fatigue and stress. Finally, they highlighted a teamwork with their animals.

s14: "He can be himself! Not being programmed. To offer with one's naturalness a well-being to people, as well as efforts without realizing it" s39: "a partnership relationship with my dog" s48: "I am the guarantor of the framework and safety during the session" s61:" Define, organize, adjust, readjust, guide, evaluate the sessions […]" s79: "Create situations to enrich patient/animal exchanges, frame the work" s83: "Protecting your animal and listening to them to see when they have had enough" s97: "The animal is a precious help for the handler, they offer them/us a multitude of possibilities to enter into a relationship, to consolidate a relationship, to make people work on so many different objectives"

The shared role of mediators

Handlers seem to not make any difference between the animal species involved, however dogs seemed to be considered more proactive in the interactions. The most common term used to talk about the animal's role is "mediator", acting as a link between handler and beneficiary, but also between objectives and beneficiary. Some handlers went beyond this, suggesting that the animal is the intermediary that allows the establishment and/or reinforcement of the care relation. Handlers were also referring to themselves as mediators between the animal-beneficiary interactions and objectives. It was their duty to intervene in specific ways in order to influence the behavior of the animal offering support so as to guide the interactions and reach the objectives. Then, they can stimulate or calm beneficiaries according to what is happening during the interactions.

s38: "An added value to the relationship of committed help and a precious mediator because it is alive and offers a diversity of emotions" s39: "It depends, sometimes I am the mediator of the meeting with the animal, sometimes it is him who allows the patient to access the care and to come to meet me" s48: "It is the use of the animal presence as a media in the caring relationship" s73: "Accompany the patient-dog pairing to work on the patient's own objectives"

Beliefs about the human-animal relationship related to their personal experiences

Handlers directed themselves to AAI because they had beliefs about the benefits of the human-animal relationship. Their beliefs were mostly linked to their personal experiences with animals more than the theory around the human-animal bond. They believed that the introduction of animals into care would benefit other humans. In addition, they had a passion for animals and the care of other humans. AAI were therefore a good compromise to work with both humans and animals.

Discussion

The purpose of this study was to gain insight into the representations of handlers in AAI, focusing on their definitions of their practices, their motivations to work in AAI and the roles of the human-animal team. Our research suggests that AAI include numerous methods because of the variety of handlers' professional backgrounds and the possibility of adding AAI to various settings. Even though there is a wide heterogeneity of practices, we found common features to all handlers. Some characteristics concur on the more "humane" care, the convictions of handlers based on their personal experiences with animals and the complementarity of the human-animal team.

The goal of the present research was to contribute to the body of knowledge surrounding AAI and representations of handlers via two axes. The first one concerned the main features of AAI. The second one concerned the interspecific complementarity of the human-animal team.

The characteristics of the French practice of AAI

Our first aim was to highlight the main features of the French practice of AAI. Handlers defined AAI as holistic approaches that allow a wide cross-section of applications in human health (psychological, motor, speech, cognitive, social). Therefore, handlers reported to work in AAI with various populations and animal species. This is consistent with the common French application of AAI that is defined as a set of heterogeneous practice [START_REF] Michalon | Panser avec les animaux: Sociologie du soin par le contact animalier[END_REF], contrary to the US model that is more categorized. To underline the main features of AAI, we assumed that the interview about handlers' professional backgrounds would give us information.

Indeed, it highlights various profiles in handlers that correspond to a variety of settings.

Furthermore, handlers were trained in various fields and in various institutions. As mentioned before by Kruger et al. [11], it could explain the heterogeneity of AAI because handlers will practice AAI according to their initial professions. The variety of their professional backgrounds can be explained by their motivations to work in AAI, which were mostly based on their personal positive experiences with animals. Handlers introduced AAI because of their convictions that AAI brought something new to care, which is consistent with Michalon [START_REF] Michalon | Les relations anthropozoologiques à l'épreuve du travail scientifique[END_REF].

AAI can therefore concern people with various professional backgrounds who have the willingness of compromise between care work and love for animals in common. In this sense, AAI are chosen because of handlers' intrinsic convictions more than their theoretical knowledge of the human-animal bond. Another feature that we can underline about handlers' professional backgrounds is a distinction between handlers that were care professionals and others who were not. Care professionals incorporated their initial training first to define their practices in AAI, which is consistent with another recent French report [START_REF] Boizeau | [END_REF]. Consequently, most participants of our sample can be considered as AAT handlers because they are care professionals working within the scope of their professions [START_REF] Iahaio | The IAHAIO Definitions for Animal Assisted Intervention and Guidelines for Wellness of Animals Involved in AAI[END_REF][START_REF] Black | Australian psychologists' knowledge of and attitudes towards animal-assisted therapy: Psychologists and animal-assisted therapy[END_REF]. However, it seems that the common US model can hardly be applied to the French practice of AAI because the French practice is more heterogeneous than a distinction between care professionals and the non-care professionals. This is consistent with previous studies that highlighted the difficulty in exporting the US model to other countries [START_REF] Black | Australian psychologists' knowledge of and attitudes towards animal-assisted therapy: Psychologists and animal-assisted therapy[END_REF][START_REF] Haubenhofer | Austrian and American approaches to animal-based health care services[END_REF]. Finally, we wanted to underline that some handlers work in AAI without any training, which can expose the practice to certain abuses.

This diversity of handlers' backgrounds points out the need of standards to ensure: i) the quality of sessions, ii) the welfare of animals and iii) the welfare of beneficiaries as proposed by the Italian model [START_REF] Simonato | The Italian Agreement between the Government and the Regional Authorities: National Guidelines for AAI and Institutional Context[END_REF]. Efforts should be made on the regulation of these practices in France mostly concerning the necessary minimal training of handlers to ensure quality and safety within AAI sessions.

Reintroducing some care in the cure

The most common trait of AAI mentioned by handlers was that its practices contrast with classical approaches. The differences cited by handlers are consistent with previous studies, though more research is needed to increase our understanding of the mechanisms. Contrary to conventional medicine, the objectives cited mostly focus on the well-being of beneficiaries during sessions, which is consistent with the theme "mood improvement" found in 6

qualitative studies about AAI in the review of Shen et al. [START_REF] Shen | We need them as much as they need us": A systematic review of the qualitative evidence for possible mechanisms of effectiveness of animal-assisted intervention (AAI)[END_REF]. More specifically, handlers referred to AAI as a moment where the disease is no longer central in the care, which is consistent with the theme "fostering feeling of normalcy" highlighted in the review of Shen et al. [START_REF] Shen | We need them as much as they need us": A systematic review of the qualitative evidence for possible mechanisms of effectiveness of animal-assisted intervention (AAI)[END_REF]. Therefore, the relationship between caregiver and patient was central and handlers gave importance to creating an alliance, almost an affectionate relationship with beneficiaries, which was redundant in other qualitative researches [START_REF] Firmin | Qualitative Perspectives of an Animal-Assisted Therapy Program[END_REF][START_REF] Lubbe | The application of animal-assisted therapy in the South African context: A case study[END_REF][START_REF] Black | Australian psychologists' knowledge of and attitudes towards animal-assisted therapy: Psychologists and animal-assisted therapy[END_REF]. This was first highlighted by Levinson [37] who reported AAI as allowing the change from "patient" to individual. We can assume that AAI are close to "person-centered approaches" that are defined as "putting the person with the human's worth and uniqueness, as well as the person's interests and lived experience, at the center of the caring process" [START_REF] Edvardsson | Implementing national guidelines for personcentered care of people with dementia in residential aged care: effects on perceived person-centeredness, staff strain, and stress of conscience[END_REF]. It is interesting also to note that AAI give some benefits to handlers, too, with the positive emotions of the beneficiaries giving them joy and a sense of usefulness [START_REF] Black | Australian psychologists' knowledge of and attitudes towards animal-assisted therapy: Psychologists and animal-assisted therapy[END_REF][START_REF] Gundersen | What motivates arrangements of dog visits in nursing homes? Experiences by dog handlers and nurses[END_REF]. Handlers also mentioned that AAI help them to overcome the impasse with traditional tools and the possibility of spending time with their animals [START_REF] Abrahamson | Perceptions of a hospitalbased animal assisted intervention program: An exploratory study[END_REF].

Therefore, the benefits of AAI seem to be due to their differences with classical medicine that focuses on curing the patient first. The introduction of animals in care settings could allow another form of care work, a more humane care regarding the objectives but also the consideration of patients as individuals. Further investigations need to focus on limits of the current care and the fact that animals bring more humanity.

The complementarity of the human-animal dyad

Our second goal was to question separately the roles of handlers and animals to understand the specificity of the interspecific teamwork. The centrality of animals in these practices are indeed recognized since they are critical to the identity of AAI [START_REF] Marino | Construct Validity of Animal-Assisted Therapy and Activities: How Important Is the Animal in AAT?[END_REF]. Though, the interviews of the handlers highlight the importance of the interspecific collaboration in AAI [START_REF] Black | Australian psychologists' knowledge of and attitudes towards animal-assisted therapy: Psychologists and animal-assisted therapy[END_REF]. Handlers mentioned the intrinsic qualities of animals, such as their absence of judgment and their unconditional love [START_REF] Wry Aanderson | Alberta, Alberta Children's Services, Chimo Project, Paws on purpose: implementing an animal-assisted aherapy program for children and youth, including those with FASD and developmental disabilities, Chimo Project[END_REF]. However, animals are also actors in the therapeutic setting that facilitate contact between humans and facilitate the establishment of a therapeutic relationship [START_REF] Nimer | Animal-Assisted Therapy: A Meta-Analysis[END_REF][START_REF] Beetz | The Effect of a Real Dog, Toy Dog and Friendly Person on Insecurely Attached Children During a Stressful Task: An Exploratory Study[END_REF][START_REF] Glenk | A Dog's Perspective on Animal-Assisted Interventions[END_REF][START_REF] Joye | Biophilia in Animal-Assisted Interventions-Fad or Fact?[END_REF][START_REF] Beetz | Theories and possible processes of action in animal assisted interventions[END_REF][START_REF] Villers | La médiation animale : un concept fourre-tout?[END_REF]. Still, it is important to highlight that the relationship between beneficiary and animal is not a substitute to the relationship between handler and beneficiary [START_REF] Chandler | Animal Assisted Therapy in Counseling[END_REF]. Handlers referred to their roles as mediators and as "good" caregivers who succeed in creating a positive relationship with beneficiaries. They are also the spokesperson for their animals and need to ensure their well-being and appropriate interactions [START_REF] Michalon | Panser avec les animaux: Sociologie du soin par le contact animalier[END_REF][START_REF] Ng | Our Ethical and Moral Responsibility[END_REF]. Therefore, handlers and their skills are necessary to build the framework around AAI, such as ensuring the good conditions of interactions and the evaluation of objectives. This data clarifies the fact that studies must take in account both handlers and animals to understand the mechanisms of AAI, whereas most research is focused on proving the benefits of animals [START_REF] Servais | Du surnaturel au malentendu Pour une approche interactionnelle des systèmes de communication homme/animal[END_REF]. Moreover, it would be interesting to clarify the aspects related to the different modalities of interspecific relationships based on the animal species involved. Indeed, dogs are the most common species in AAI because they are well adapted to therapeutic settings because of their availability, trainability and predictability [START_REF] Glenk | Current Perspectives on Therapy Dog Welfare in Animal-Assisted Interventions[END_REF]. Some authors point out that dogs allow for a more therapeutic work with more reciprocity than other species [START_REF] Menna | The Human-Animal Relationship as the Focus of Animal-Assisted Interventions: A One Health Approach[END_REF][START_REF] Beetz | Theories and possible processes of action in animal assisted interventions[END_REF]. It may be due to their outstanding skills to communicate and their ability to create relationships with humans [START_REF] Beck | Romantic Partners and Four-Legged Friends: An Extension of Attachment Theory to Relationships with Pets[END_REF].

They are also easier to train for therapy [START_REF] Bert | Animal assisted intervention: A systematic review of benefits and risks[END_REF]. Other species, such as small pets, are increasingly introduced in AAI on the other hand because of their small size and toy-like appearance that can allow for the development of other forms of relationships [START_REF] Loukaki | Animal welfare issues on the use of rabbits in an animal assisted therapy program for children[END_REF].

Limits

This research presents some limits that can be palliated in further studies. First, our sample was mostly composed of handlers that were initially care professionals, which can be a bias for the representativeness of our study. Further studies can focus on handlers without a background in the medico-social field to observe the pertinence of their answers vis-à-vis of those with a medical professional background. Secondly, our cohort concerned handlers that worked with dogs and other species, but we focused on dogs. Other specific studies on other animal species introduced into AAI could bolster the knowledge. Finally, our study concerned the French practice of AAI; other studies in various European countries can be useful to understand the importation of the US model to France.

Conclusion

The aim of this study was to underline handlers' perspectives on Animal-Assisted Interventions in order to contribute to the body of knowledge surrounding AAI. To this end, we focused on the main features of AAI and the interspecific complementarity of the humananimal team that we interviewed. Our study underlined that AAI in France are heterogeneous because they are complementary approaches to various care settings. This is also linked to the fact that handlers will work in accordance to their initial training, which represent a wide scope of fields. Moreover, handlers' profiles are heterogeneous because these practices concern people who want to include their passion of animals in their work. It seems that AAI allow a more "humane" care through the presence of animals. This point needs more consideration to question the actual care and its limits for both patients and caregivers.

Finally, the human-animal dyad must be considered as a teamwork. The animal is here to "be himself" and the handler to bear the benefits of the beneficiary-animal relationship to fulfil the objectives. Consequently, this exploratory study highlights the heterogeneity of AAI and the need to focus on individual considerations [START_REF] Cirulli | Animal-assisted interventions as innovative tools for mental health[END_REF][START_REF] Serpell | The Human-Animal Bond[END_REF][START_REF] Beetz | Theories and possible processes of action in animal assisted interventions[END_REF][START_REF] Colussi | Variations of salivary cortisol in dogs exposed to different cognitive and physical activities[END_REF].

  s8: "Combining my passion for dogs with my job" s85: "It's natural because I've always shared my life with dogs […]" s108: "The conviction that the animal can bring things to humans"

Acknowledgments

The researchers would like to thank the handlers who took the time to answer the questionnaires.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. grant from funding agencies in the public, commercial, or not-for-profit sectors.