Stefano Buccelli

Yannick Bornat

Ilaria Colombi

Matthieu Ambroise

Laura Martines

Valentina Pasquale

Marta Bisio

Jacopo Tessadori

Przemyslaw Nowak

Filippo Grassia

Przemysław Nowak

Alberto Averna

Mariateresa Tedesco

Paolo Bonifazi

Francesco Difato

Paolo Massobrio

PhD Timothée Levi
email: timothee.levi@u-bordeaux.fr

Dr Michela Chiappalone
email: michela.chiappalone@iit.it

Associate Prof

A Neuromorphic Prosthesis to Restore Communication in Neuronal Networks

Keywords: In vitro neuronal networks, micro-electrode arrays, real-time signal processing, closed-loop, neurobiohybrid, brain repair

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

Introduction

One of the greatest challenges of modern neuroscience is to find reliable and sustainable treatments for the disabling effects caused by many chronic and incurable brain conditions.

With the greatest impact carried by stroke [START_REF] Feigin | Global burden of stroke[END_REF]) and traumatic brain injury [START_REF] Maas | Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research[END_REF], brain disorders are among the leading causes of disabilities worldwide.

Due to recent advances in bioelectronics and in neural and neuromorphic engineering, direct interfacing of artificial circuits with large neuronal networks is possible to develop novel 'neurobiohybrid' systems (such as neuroprostheses [START_REF] Vassanelli | Trends and challenges in neuroengineering: toward "intelligent" Neuroprostheses through brain-"brain inspired systems" communication[END_REF]), which are envisaged as potentially interesting clinical applications for brain lesions [START_REF] Broccard | Neuromorphic neural interfaces: from neurophysiological inspiration to biohybrid coupling with nervous systems[END_REF]. In this paper, we introduce an innovative bioelectronic system acting as a neuroprosthesis which, thanks to a neuromorphic real-time hardware interface, can reestablish the communication between two disconnected neuronal populations.

Neural interfaces are promising solutions for brain repair [START_REF] Soekadar | Brain-machine interfaces in neurorehabilitation of stroke[END_REF].

Modern neural interfaces are mainly designed to restore lost motor functions in only one direction, i.e., from the brain to the body [START_REF] Abdulkader | Brain computer interfacing: applications and challenges[END_REF] or from the body to the brain [START_REF] Flesher | Intracortical microstimulation of human somatosensory cortex[END_REF]. Additionally, recent neuroprosthetic developments have shown the enormous potential of neural interfaces to aid and accelerate functional recovery [START_REF] Bouton | Restoring cortical control of functional movement in a human with quadriplegia[END_REF][START_REF] Rosin | Closed-loop deep brain stimulation is superior in ameliorating parkinsonism[END_REF]). However, a major obstacle in developing novel neuroprostheses for bidirectional communication with and within the brain is the complex nature of interactions among different brain areas, which in turn presents a challenge for the development of appropriate stimulation protocols as well as for testing such devices using in vivo models [START_REF] Kohler | Closed-loop interaction with the cerebral cortex: a review of wireless implant technology[END_REF].

Despite very recent technological progress [START_REF] Jun | Fully integrated silicon probes for high-density recording of neural activity[END_REF][START_REF] Steinmetz | Challenges and opportunities for largescale electrophysiology with Neuropixels probes[END_REF], in vivo models still have two main bottlenecks. The first bottleneck is the technical challenge to faithfully reproduce specific/focal network lesions (mainly due to their complexity) that the neuroprosthesis aims to treat, whereas the second is the difficulty in disentangling the actual effect of the adopted electrical therapy from the complex activity of a brain constantly processing sensory inputs and producing behaviour. Therefore, since in vivo models exhibit inherent complexity and low controllability, using in vitro reduced neuronal systems to model precise and reproducible neuronal network lesions and test neuroprosthetic devices for their treatment may be advantageous. This approach is also justified by a growing recognition that in vitro testing of both research and medical devices can be more effective in terms of cost, time consumption and ethical issues and much more reliable than in vivo testing [START_REF] Myers | From in vivo to in vitro: the medical device testing paradigm shift[END_REF].

In this work, we bidirectionally interfaced in real-time a neuroprosthetic system with an in vitro culture constituted by interconnected 'neuronal assemblies' [START_REF] Hebb | A neuro-inspired model-based closed-loop neuroprosthesis for the substitution of a cerebellar learning function in anesthetized rats[END_REF]. Therefore, our first objective was to create a simplified yet plausible in vitro model of a focal brain lesion by using bimodular cultures grown onto micro-electrode arrays (MEAs) [START_REF] Bisio | Emergence of bursting activity in connected neuronal sub-populations[END_REF][START_REF] Bonifazi | In vitro large-scale experimental and theoretical studies for the realization of bidirectional brain-prostheses[END_REF][START_REF] Shein-Idelson | Engineered neuronal circuits: a new platform for studying the role of modular topology[END_REF]) with reciprocal connections cut by a custom-made laser setup [START_REF] Difato | Combined optical tweezers and laser dissector for controlled ablation of functional connections in neural networks[END_REF] to mimic the pathological effect of a traumatic brain injury [START_REF] Hayes | Traumatic brain injury as a disorder of brain connectivity[END_REF]. We created a neurobiohybrid system connecting the biological element (the bimodular culture) following the lesion with a neuroprosthetic prototype. Our hardware neuroprosthesis could perform low-power computations in hard real-time [START_REF] Pirog | Multimed: an integrated, multi-application platform for the real-time recording and sub-millisecond processing of biosignals[END_REF], collecting the inputs coming from neural recordings, processing those signals and generating suitable electrical stimulation triggers as an output. With this experimental setup, we tested two specific applications, namely, bidirectional bridging (BB) to artificially reconnect two disconnected neuronal modules and hybrid bidirectional bridging in which a real-time spiking neural network (SNN) replaced the activity of one of the two modules in real-time while implementing bidirectional connectivity with the remaining neuronal module.

The motivation of our research is to provide a new technological instrument as a novel form of neuroprosthesis aimed at treating disabling brain pathologies. The hardware choice (field-programmable gate array, FPGA) maximise the real-time performances of the system and allows for a faster development of a future implantable biolectronic device for biomedical applications. The adoption of bidirectional communication allows the development of a generalized non-specific approach that is applicable to the central nervous system (CNS) or peripheral nervous system. In particular, prostheses for the CNS should restore the communication between two or more neuronal assemblies whose functional and anatomical path could be distributed and sparse and not necessarily known a priori. Indeed, our idea to develop a generalized approach comes from the future perspective of creating a cerebral neuroprosthesis for direct implantation in the brain that could be used by patients affected by stroke or brain injury. Our proof-of-principle results are the first for a next-generation neurobiohybrid system to restore brain functions [START_REF] Broccard | Neuromorphic neural interfaces: from neurophysiological inspiration to biohybrid coupling with nervous systems[END_REF][START_REF] Vassanelli | Trends and challenges in neuroengineering: toward "intelligent" Neuroprostheses through brain-"brain inspired systems" communication[END_REF].

Results

Neuroprosthetic architecture

To create bimodular in vitro systems, we developed PDMS masks with two connecting compartments that constrained the growth of neuronal cells in two precise areas over 60electrode MEAs (Figure S1). The obtained bimodular neuronal culture constitutes the biological neuronal network (BNN) of our system (Figure 1A). The signal from the BNN was amplified by a commercial system and acquired by a custom-developed FPGA-based neuromorphic board (Figure S2) previously configured by a custom-made MATLAB code (MathWorks, Natick, MA, USA) running on a general purpose personal computer. The neuromorphic board triggered a commercial stimulator to close the loop with the BNN. The general protocol designed for this study involved three steps. First, spontaneous activity in both neuronal modules was recorded ('pre-lesion condition'). Then, laser ablation of the biological connections between the two modules was performed (see Transparent Methods), followed by recording of spontaneous activity in both modules ('post-lesion condition') to assess the viability of the networks. Finally, we tested our neuroprosthetic device using two experimental frameworks. In the first case, we applied a reconnection strategy using a bidirectional activity-dependent stimulation ('bidirectional bridging', BB), whereas in the second case, we interfaced a hardware-implemented biomimetic SNN with one of the two neuronal modules ('hybrid bidirectional bridging', HBB) to simulate a 'replacement' strategy that utilizes the bidirectional interaction between the biological system and its artificial counterpart (Figure 1B). The sequence of algorithms (e.g., spike detection, network burst detection) implemented on the board to realize both experimental approaches (BB or HBB) is schematically depicted in Figure 1C.

<FIGURE 1 ABOUT HERE>

Control experiments

To evaluate the stability and effect of the focal lesion on bimodular BNN activity, we first performed two sets of control experiments. In the first set defined as 'experiments with no lesion' (Figure 2A1), we recorded 4 consecutive hours of spontaneous activity (S1-S4, n=9 cultures). In the second set defined as 'experiments with a lesion' (Figure 2A2), we recorded one hour of spontaneous activity (S1), followed by laser ablation of the connections between the two modules, which usually took less than 20 minutes. Next, we recorded 3 hours of spontaneous activity post lesion (SPL1-SPL3) to quantify the effects of laser ablation (n=4 cultures). As depicted in the raster plot of one representative experiment (Figure 2B1), bimodular neuronal networks exhibited spontaneous, synchronized, multi-unit activity composed of network-wide bursts (NBs) spreading over the two modules. Following laser ablation, the propagation between compartments was disrupted, as shown in Figure 2B2.

With no lesion, the percentage of active channels with respect to the first hour of recording (S1) was higher than 98% and was maintained for the entire duration of the experiment (Figure 2D1, light blue bars). The mean firing rate (MFR) was stable for all control experiments with no lesion (from S1 to S4, Figure S3 A). Alternatively, control experiments with lesions showed a reduced number of active channels (close to 73%) during the first hour after ablation (SPL1). During the following two hours (SPL2-SPL3), this value increased and reached 93% at the end of the recording (Figure 2C1, dark grey bars). No significant differences were found. The MFR was quite stable for all control experiments with lesions except between S1 and SPL1 (Figure S4 A). The activity level with respect to the S1 phase, expressed by the MFR ratio with respect to S1, was stable during the control experiments without lesions (Figure 2D2, light blue bars). The lesion produced a clear decrease in activity in most cultures, especially during the first two hours (SPL1-SPL2, Figure 2D2). We found a significant difference between the two experimental sets during the first two hours after S1 but not during the last hour. This result suggests that two hours after a lesion, almost complete spontaneous recovery occurred in terms of the firing rate for the two neuronal modules.

To evaluate changes in the synchronicity between the two modules, we performed cross-correlation (CC) analysis between the collapsed spike trains of each module. The shape of the CC function was stable throughout the entire recordings in experiments without lesions, as reported in Figure 2C1 for a representative experiment. After a lesion, the CC function collapsed to zero and did not recover during the experiment (Figure 2C2: representative experiment). To quantify this difference, we integrated the CC function in a range of ±500 ms to obtain the CC area. We did not find any significant change in the CC area values for all experiments with no lesion (Figure S3B). By contrast, the CC area values showed a marked decrease following the lesion (SPL1). This decrease was due to the lack of anatomical connections between the compartments and did not recover by itself (Figure S4B). Comparing the CC area ratio between later phases and S1 resulted in a significant difference between matching periods in 'lesion' and 'no lesion' experiments (Figure 2E1).

We also computed the correlation coefficient (i.e. Pearson Correlation, PC) among all the active channels both intra module and inter module (Figure 2E2). The intra-module PC was constant across experimental phases for controls with no lesion (light blue bars). On the other hand, for controls with lesion (dark grey bars) there was a drop in the intra-module PC, related to the reduced firing rate following the lesion, but no statistical difference was found (Figure 2E2, left panel). The inter-module CC was stable for controls with no lesion. On the other hand, following the lesion the inter-module PC collapsed and never recovered by itself (Figure 2E2, right panel) as already demonstrated with the previous analysis.

The network bursting rate (NBR) was stable during all experiments with no lesions (Figure S3C). For the experiments with lesions, this parameter was less stable but with no significant differences between phases (Figure S4C). When comparing the two experimental protocols with the NBR ratio with respect to S1, we found significant differences during the first and the second hour post lesion (Figure 2F1). The mean probability to have NBs composed of spikes belonging to a single module (i.e. Prob smNB, see Transparent Methods) was close to 0.2 in the experiments without lesions (Figure S3D), meaning that the majority of NBs in an intact bimodular network involved both modules. Alternatively, following the lesion, the probability became close to 1 (Figure S4D), meaning a total loss of functional communication between the two compartments. Using the Prob smNB ratio with respect to S1 (Figure 2F2), we found significant differences between the two experimental groups during all phases post lesion (Mann-Whitney test; p < 0.05). Thus, for the no lesion experiment, the Prob smNB remained very similar to the initial values, while for the lesion experiments, it changed abruptly due to the lesion. This result further confirmed that the lesion was effective in functionally disconnecting the two modules.

< FIGURE 2 ABOUT HERE > Experiment 1: Bidirectional Bridging (BB)

The goal of this experiment is to restore communication between two neuronal assemblies after lesion-induced separation. To achieve this goal, we designed and implemented a stimulation reactive paradigm inspired by the 'activity-dependent stimulation' (ADS) described in [START_REF] Guggenmos | Restoration of function after brain damage using a neural prosthesis[END_REF] in our neuromorphic board. In contrast to the control experiments, the general protocol (Figure 3A) included 20 minute recordings of spontaneous activity before the lesion (S1). Upon the lesion execution, we waited for two hours to reach stable activity in both modules, as shown by the results of control experiments (see Figure 2).

Then, we recorded 20 minutes of spontaneous activity (SPL3). The raster plot of a representative experiment is reported in Figure 3b. Before the lesion (S1), the bursting activity involved both modules (Figure 3B1), whereas after the lesion (SPL3), the activity was characterized by single-module NBs (Figure 3B2). To choose the best parameters (threshold and window time, see Transparent Methods) that allowed us to reliably detect NBs in both modules, we performed offline NB detection. After the FPGA was updated with these parameters, a 20 minute session of BB was conducted. (see, Figure 1B and C for the description of the BB protocol). The BB approach implemented a reactive paradigm: every time an NB was detected in one module, a stimulation pulse was delivered to an electrode in the other module (see Transparent Methods) in both directions. During the BB phase, the bursting activity involved both modules similar to the intact condition due to the bidirectional stimulation pulses (Figure 3B3, blue and red lines represent electrical stimulation pulses delivered from module 1 to module 2 and vice versa). The last phase of the protocol involved 20 additional minutes of spontaneous activity (SPL4), which showed the same activity as SPL3 (Figure 3B4). We did not observe significant changes in spiking activity (i.e., MFR) throughout the recordings (Figure 3c).

Next, we evaluated the effect of this configuration in terms of CC (Figure 3d1and 2).

During spontaneous activity before the lesion (S1), the CC peak was high and stable due to the functional and anatomical connections between the two modules, which was also reported for the control experiments. After the lesion (SPL3), there was a decrease in CC that was not expected to recover without external intervention, as we demonstrated before (see, Figure 2D). The bidirectional stimulation at least partially recovered the CC area and consequently the communication between modules (Figure 3D2), as demonstrated by statistical analysis.

Regarding the number of NBs, we did not find any significant difference between the experimental phases (Figure 3E1). However, the probability of isolated NBs was not uniform; it reached the maximum value after the lesion, as we previously observed in the control experiments with lesions (see, Figure 2D2). During bidirectional stimulation, these values became closer to the spontaneous recording (Figure 3E2), meaning that NBs mainly involved both modules. This finding further confirmed that the BB protocol could reconnect two disconnected modules though a real-time ADS acting in both directions (from module 1 to module 2 and from module 2 to module 1).

<FIGURE 3 ABOUT HERE> Experiment 2: hybrid bidirectional bridging (HBB)

With an injury causing damage to an entire neuronal subnetwork, a reconnection strategy such as the BB illustrated above would not be feasible. For this reason, we developed a second reconnection strategy based on the use of a hardware SNN that can interact in realtime with its biological counterpart, HBB (see Figure 1). We created a set of SNNs (i.e., SNN library) by tuning the mean value of the synaptic weight distributions of our models to cover the variability of the BNNs (i.e., BNN library, Figure 4A). The biomimetic SNN (see Figure S5), working in hardware real-time to allow bidirectional communication with living neurons, was modelled as a network of 100 Izhikevich (IZH) neurons [START_REF] Izhikevich | Simple model of spiking neurons[END_REF], with 80 excitatory and 20 inhibitory neurons (see Transparent Methods), according to the biological composition of dissociated cultures [START_REF] Bonifazi | Statistical properties of information processing in neuronal networks[END_REF][START_REF] Hayashi | Inhibitory neurons from fetal rat cerebral cortex exert delayed axon formation and active migration in vitro[END_REF].

Synaptic noise [START_REF] Grassia | Digital hardware implementation of a stochastic twodimensional neuron model[END_REF], inhibitory and excitatory synapses [START_REF] Izhikevich | Which model to use for cortical spiking neurons?[END_REF]), short-term plasticity [START_REF] Izhikevich | Large-scale model of mammalian thalamocortical systems[END_REF] and axonal delays were included in the model to recreate the network dynamics (see Transparent Methods and Figure S6 A1 andA2). Regarding the connectivity rules, we set the outdegree (i.e., the number of post-synaptic neurons) to 25 for all neurons in the network, while the indegree (i.e., the number of presynaptic neurons) followed a normal distribution with a mean value of 25 and a standard deviation of 4.3 (Figure S6, R-Square=0.806). The goal of creating an SNN library was to cover a wide range of NBRs because NB was chosen as the triggering event for our reconnection paradigm, as explained above. To this end, we tuned only the mean value of the normal distribution of synaptic weights (the standard deviation was kept constant at the value of 0.3). By increasing or decreasing the mean synaptic weights, we tuned the NBR. For excitatory synapses, the mean value ranged from 0.99 to 1.34 (Figure 4C left), while that for inhibitory synapses ranged from -2.02 to -1.02 (Figure 4C right and Table S1). As previously stated, our goal was to cover the NBR variability and not the MFR. The MFR variability in our BNN library was higher than that obtained with our SNN library (Figure 4E andF1).

Nevertheless, the BNN variability in terms of NBR was completely covered by our SNN library, which also contains networks with a much higher NBR than that in the BNN library (Figure 4F2).

<FIGURE 4 ABOUT HERE>

The general HBB protocol (Figure 5A) is similar to the BB protocol. The HBB procedure included a 20 minute recording of spontaneous activity before the lesion. This recording was used to quantify activity in terms of the NB rate of the network. This feature was used to choose one SNN from the SNN library that had an NB rate closer to its biological counterpart. We waited two hours after the lesion to allow activity in both modules to stabilize, as shown by the results of control experiments (e.g., Figure 2). Then, we recorded 20 minutes of spontaneous activity. After setting FPGA detection parameters, we performed a 20 minute HBB session (see, Figure 1B and C for the description of the HBB protocol). As anticipated, the HBB approach also implemented an ADS paradigm; every time an NB was detected on the 'surviving' module (i.e., when one of the two modules was completely damaged), a stimulation pulse was delivered to the SNN. The board implemented the corresponding paradigm in the opposite direction. Detection of NBs occurred in the SNN, while stimulation was delivered to the 'surviving' module, thus avoiding the imposition of any predefined unidirectional communication. Next, we recorded 20 additional minutes of spontaneous activity.

We did not observe significant changes in terms of spiking activity (i.e., MFR) throughout the recordings (Figure 5C). Then, we evaluated the effect of this configuration in terms of CC (Figure 5D1 and2). During spontaneous activity before the lesion (S1), the CC peak was high and stable due to the functional and anatomical connections between the two modules, which was also reported for the control experiments. As expected, with no external intervention, CC decreased sharply after the lesion (SPL3), as we previously observed. One of the two modules was damaged, while the correlation was evaluated between the SNN and the surviving module during the HBB phase. The bidirectional stimulation created a relevant correlation area between SNN and the surviving module, as demonstrated by statistical analysis. Regarding the number of NBs, we did not find a significant difference between the S1 and HBB phases (Figure 5E1). However, the probability of isolated NBs was not uniform; it reached the maximum value after the lesion, as we previously observed in the control experiments with lesions (see, Figure 3E2). During the hybrid bidirectional stimulation, these values became closer to the spontaneous recording (Figure 5E2), meaning that NBs mainly involved both modules. This finding further confirmed that the HBB protocol created a hybrid system with the surviving biological module though real-time ADS acting in both directions (from BNN to SNN and from SNN to the BNN).

<FIGURE 5 ABOUT HERE>

Discussion

We presented an innovative neuromorphic prosthesis based on a FPGA board and demonstrated two successful reconnection paradigms for a lesion interrupting the communication between two neuronal populations in vitro.

According to previous reports, in vitro systems constitute a successful experimental model of neuronal dynamics [START_REF] Javier | Noise focusing and the emergence of coherent activity in neuronal cultures[END_REF][START_REF] Johnson | Neural dynamics of in vitro cortical networks reflects experienced temporal patterns[END_REF], thus providing an excellent test bed for adaptive closed-loop neural interfaces [START_REF] Potter | Closing the loop between neurons and neurotechnology[END_REF]. Starting from our recently developed methodology [START_REF] Kanner | Design, surface treatment, cellular plating, and culturing of modular neuronal networks composed of functionally inter-connected circuits[END_REF], we created custom bimodular cultures with the goal of reproducing two interacting neuronal populations, thus mimicking the intrinsic modularity of the brain [START_REF] Bonifazi | In vitro large-scale experimental and theoretical studies for the realization of bidirectional brain-prostheses[END_REF]. Our bimodular cultures were highly temporally stable in terms of firing properties at the whole network level as the activity between the two populations remained highly correlated for the entire duration of the recording. A lesion produced via laser ablation was employed to physically cut the connections between the two modules. This methodology was proven to be safe because it produced localized damage by selectively ablating subcellular compartments without damaging adjacent structures [START_REF] Difato | Combined optical tweezers and laser dissector for controlled ablation of functional connections in neural networks[END_REF][START_REF] Habibey | A microchannel device tailored to laser axotomy and long-term microelectrode array electrophysiology of functional regeneration[END_REF][START_REF] Soloperto | Modulation of neural network activity through single cell ablation: an in vitro model of minimally invasive neurosurgery[END_REF].

We assume that such a focal damage, allowing to specifically cut few connections among those available in the network, together with possible intrinsic compensatory mechanisms of synaptic scaling [START_REF] Le Feber | Loss and recovery of functional connectivity in cultured cortical networks exposed to hypoxia[END_REF][START_REF] Turrigiano | The self-tuning neuron: synaptic scaling of excitatory synapses[END_REF], were responsible of the spontaneous recovery of the firing rate on a timescale of two-three hours. This demonstrates the effectiveness of our technique in preserving the functionality of the two modules while decoupling their activity, as proven by the loss of correlation of bursting behaviour.

Two different applications of our neuroprosthesis, BB and HBB, were tested. Our neuromorphic prosthesis, independently of the stimulation paradigm, works according to a closed-loop reactive policy as follows: each time a condition is met (i.e., an 'event' is detected), a stimulus is delivered. The hardware architecture was designed to be flexible enough to allow the implementation of different experimental paradigms and the definition of different triggering events. In our study, we chose 'NBs' as trigger events (see Transparent Methods). The choice to deliver a stimulation depending on a network-wide event has two main advantages as follows: first, NB frequency is low enough to avoid inducing plasticity phenomena by electrical stimulation in our cultures [START_REF] Wagenaar | Searching for plasticity in dissociated cortical cultures on multi-electrode arrays[END_REF], which could confound the final results and effectiveness of neuroprosthetic reconnection. The second point is anticipation of the following major issue that will emerge during in vivo recordings: monitoring single neurons presents problems at both theoretical [START_REF] Guggenmos | Restoration of function after brain damage using a neural prosthesis[END_REF]) and practical levels. Namely, how much information on complex functions can be obtained by single-neuron observation remains unclear [START_REF] Luczak | Packet-based communication in the cortex[END_REF][START_REF] Panzeri | Cracking the Neural Code for Sensory Perception by Combining Statistics, Intervention, and Behavior[END_REF], while tracking the activity of the same neuron for extended periods of time is problematic [START_REF] Kozai | Brain tissue responses to neural implants impact signal sensitivity and intervention strategies[END_REF]. Taking multiple input sources into account was also used in the work of Berger [START_REF] Berger | A hippocampal cognitive prosthesis: multi-input, multi-output nonlinear modeling and VLSI implementation[END_REF]), but they employed a neuroprosthetic strategy different from ours. In particular, these authors used a generalized linear model to predict the CA1 activity from spikes in CA3 of the hippocampal circuit. Our system is considered more flexible and adaptable to networks with different connectivity, not just feedforward similar to that in the hippocampus. Moreover, we were interested in mimicking the overall spiking activity of the network and not mapping an input-output transformation only.

Another important novelty of our system regards directionality. To our best knowledge, this neuroprosthetic system is the first to implement a truly bidirectional interaction with a SNN through a hard real-time interface. We recorded activity from the first module (via multiple sources); when a criterion was met, the device stimulated the second module (this is how a 'typical' closed-loop in neuroscience works, for a review see [START_REF] Greenwald | Implantable neurotechnologies: bidirectional neural interfaces--applications and VLSI circuit implementations[END_REF]). The novelty is simultaneously monitoring multiple sources from another module and delivering the stimulation when the triggering event is detected. To date and as far as we are aware of, only Jung and colleagues [START_REF] Jung | Real-time interaction between a neuromorphic electronic circuit and the spinal cord[END_REF]) have performed a bidirectional interface to a neuromorphic device, but their models were not precise at the spike level (modelling neuron populations) and they used non configurable analogue electronics, which resulted in an experiment-specific setup. The other neuroprosthetic devices that have been proposed in the literature can implement a 'unidirectional' artificial link only from one area to another (or maybe the same) but not doubling it. Here, we are not imposing any preferred directionality to the communication; networks are self-organizing on the basis of their intrinsic natural relationship (we are not imposing who is driving whom). This approach has the main advantage of informing both brain regions (i.e., neuronal modules, in our case) that an event occurred in the other region, given that interaction in the brain is intrinsically bidirectional [START_REF] Roelfsema | Control of synaptic plasticity in deep cortical networks[END_REF]. For example, in the sensorimotor system, sensory simulation can help motor recovery [START_REF] Cuppone | Consolidation of human somatosensory memory during motor learning[END_REF], and motor learning can enhance sensory functions [START_REF] Ostry | Somatosensory plasticity and motor learning[END_REF][START_REF] Takeuchi | Rehabilitation with poststroke motor recovery: a review with a focus on neural plasticity[END_REF].

Applications of our neuroprosthetic systems to conditions where the sensorimotor interaction is impaired would allow restoration of both communication channels, suggesting improvements in current rehabilitation therapies. Moreover, although tested on a bimodular system, the neuromorphic FPGA board can be easily upgraded to play the bridging role on an arbitrary number (within reason) of different neuronal circuits. A recent work [START_REF] Forró | Modular microstructure design to build neuronal networks of defined functional connectivity[END_REF]) developed directional networks of primary hippocampal neurons on MEA and compared the information flow of these networks with respect to bidirectional networks (similar to our bimodular preparations). They found that without physically imposing a unidirectional configuration, there is a continuous back and forth communication between nodes thus suggesting the importance of a bidirectional communication in a healthy network.

The second paradigm we tested was based on the use of a biomimetic SNN to 'substitute' a missing/damaged neuronal population. Currently, SNN applications span different fields, including computational neuroscience [START_REF] Markram | The human brain project[END_REF][START_REF] Melozzi | The virtual mouse brain: a computational neuroinformatics platform to study whole mouse brain dynamics[END_REF], and very recently, they were used for sensory encoding in hand prosthesis for amputees [START_REF] Osborn | Prosthesis with neuromorphic multilayered e-dermis perceives touch and pain[END_REF][START_REF] Valle | Biomimetic intraneural sensory feedback enhances sensation naturalness, tactile sensitivity, and manual dexterity in a bidirectional prosthesis[END_REF]. SNNs can be simulated in software [START_REF] Goodman | The brian simulator[END_REF] and/or neuromorphic hardware [START_REF] Thakur | Large-scale neuromorphic spiking array processors: A quest to mimic the brain[END_REF]. As time and energy consumption are fundamental in neuroprosthetic applications for translational purposes, the use of hardware-based computing systems becomes mandatory.

In general, hybrid systems composed of in vitro BNNs coupled to SNNs are rare. In one approach, the SNN served as a self-organizing classifier of activity patterns exhibited by the BNN, with output of the SNN being subsequently used to control the behaviour of a robot [START_REF] Pizzi | A cultured human neural network operates a robotic actuator[END_REF]. Other studies focused on the unidirectional or bidirectional influence of the two networks, investigating the dynamics of the interaction between the BNN and SNN in which the SNN played a role of an artificial counterpart of its biological original [START_REF] Bruzzone | Interfacing in silico and in vitro neuronal networks[END_REF][START_REF] Chou | Bidirectional neural interface: closed-loop feedback control for hybrid neural systems[END_REF]. However, closed-loop effects in those hybrid networks were not thoroughly determined. In one of these studies, only unidirectional connectivity was considered with input from the SNN to the BNN, which was also simulated beforehand [START_REF] Bruzzone | Interfacing in silico and in vitro neuronal networks[END_REF]. In this study, we established hybrid communication in the case of an entire neuronal population that needed substitution.

A study by [START_REF] Chou | Bidirectional neural interface: closed-loop feedback control for hybrid neural systems[END_REF] implemented a bidirectional interface between an SNN and a retinal slice obtained from an adult rat and recorded by an MEA. This system is quite interesting, but there is a 1 s delay between the BNN and SNN interactions.

Therefore, this delay in Chou's setup is 3 orders of magnitude larger than that in our work in which the sampling of biological activity is never interrupted, and the step size of the SNN is 1 ms. The difference between the two systems is radical; bidirectional communication in real-time allows actual clinical application, whereas delays in the range of seconds prevent (or at least seriously reduce) the possibility of meaningful control of a biological system.

A recent study, inspired by a previous work [START_REF] Hebb | A neuro-inspired model-based closed-loop neuroprosthesis for the substitution of a cerebellar learning function in anesthetized rats[END_REF], implemented a hybrid interaction [START_REF] Xu | Real-time cerebellar neuroprosthetic system based on a spiking neural network model of motor learning[END_REF] between the cerebellum of a rat and an SNN implemented on FPGA. Their model involved 10k leaky integrate and fire (LIF) neurons and did not integrate other biomimetic behaviours, such as axonal delay, short-term plasticity and synaptic noise, unlike the IZH neurons implemented in our system. Both the hard real-time processing and simplified neuronal model (which allow mimicking the richness of the electrophysiological patterns in vivo) are mandatory for reproducing the biological dynamics of living neural networks and for performing useful real-time hybrid experiments.

In this work, we demonstrated the possibility to design a neuromorphic all-hardware prosthesis capable of artificially reconnect two disconnected neuronal networks or artificially replacing one entire neuronal sub-network.

The use of a fully integrated hardware computing system allowed hard real-time performances and low power consumption, which are crucial for translational purposes related to therapeutic applications in humans [START_REF] Kipke | Advanced neurotechnologies for chronic neural interfaces: new horizons and clinical opportunities[END_REF][START_REF] Wang | Neural interface technology for rehabilitation: exploiting and promoting neuroplasticity[END_REF].

Limitations of the study

A limitation of the present work is that we deliberately chose to downsample both the number of biological neurons recorded through a low density MEA and the number of artificial neurons implemented on the FPGA. For the purpose of detecting network-wide activity, this oversimplification of biological complexity can be acceptable to test the functionality of the device and the feasibility of the approach, but if the goal is to functionally replace a biological network, a higher resolution would be preferable. It is worth underlying that this hardware implementation is not exploiting the full resources of the FPGA, thus in follow-up studies, also thanks to the flexibility of our system, we foresee to scale up the number of neurons and synapses and to upgrade the computational algorithms to deal with more complex experimental designs. From a technological point of view, the current state of the art makes possible the use of devices with a large number (thousands) of recording electrodes [START_REF] Berdondini | Active pixel sensor array for high spatio-temporal resolution electrophysiological recordings from single cell to large scale neuronal networks[END_REF][START_REF] Frey | Microelectronic system for highresolution mapping of extracellular electric fields applied to brain slices[END_REF]. Such an improvement would also allow to have more information about functional connectivity of the biological network [START_REF] Pastore | Identification of excitatory-inhibitory links and network topology in large-scale neuronal assemblies from multi-electrode recordings[END_REF]) and thus developing more realistic, in terms of topology, artificial models. In this work, we arbitrarily modeled the network connectivity with a random adjacency matrix since the use of MEAs with 60 electrodes made impossible to correctly identify the topological properties (e.g., hubs, recurring connections, modules, etc.) of the network under investigation.

We are aware that the road is still long to target human applications. Despite this, we think that the extensive work performed represent an important milestone to start from. The next fundamental (and critical) step would be to test the neuromorphic prosthesis in vivo, for example on animal models affected by ischemic or traumatic lesions [START_REF] Guggenmos | Restoration of function after brain damage using a neural prosthesis[END_REF]. Even if the adaptation to the new experimental set-ups will require time, we believe these are necessary steps to further push the translational potential of our system, which will be able to create real innovation in the clinical therapeutics. processing performed by the board: the first step is spike detection followed by network burst (NB) detection monitoring module 1. After NB detection, delivering stimulation to module 2 of the BNN (BB approach) or to the SNN is possible. In the second modality, there is also NB detection of the SNN, which can result in stimulation delivered to the BNN (HBB approach).

Figure titles and legends

Figure 1 .

 1 Figure 1. Interfacing a biological neural network and neuromorphic neuroprosthesis. A,

Figure 2 .

 2 Figure 2. A laser ablation-induced lesion can disconnect two neuronal modules. A1, Schematic of the first experimental protocol. Experiments with no lesion: we recorded four consecutive hours of spontaneous activity (S1-S4). A2, Schematic of the second experimental protocol. Experiments with lesion: we recorded one hour of spontaneous activity (S1) followed by laser ablation and three consecutive hours of spontaneous activity post lesion (SPL1-SPL3). The grey-shaded area indicates 20 minutes of no recording due to the execution of the lesion. B1, A 20 s raster plot of the network bursting activity of one representative experiment during the S1 phase. B2, a 20 s raster plot of the network bursting activity of one representative experiment during SPL3. C1, Cross-correlation (CC) function for one representative experiment during the S1-S4 phases. The CC profiles between the spike trains of each module (light blue) in the four phases of the experiment were high and stable (lines shifted for the sake of clarity). Time axis [-500, +500] ms. C2, CC profile between the spike trains of each module for one representative experiment with lesion. Before the lesion (light blue profile), CC was high; following the lesion (dark grey), CC collapsed to zero (lines shifted for the sake of clarity). Time axis [-500, +500] ms. D1 Percentage of active channels with respect to S1 for

Figure 3 .

 3 Figure 3. Bidirectional bridging is effective in reconnecting functionally and anatomically disconnected neuronal modules. A, Schematic of the experimental protocol. We recorded 20 minutes of spontaneous activity (S1) followed by laser ablation. The grey-shaded area indicates 20 minutes of no recording during ablation. Dots represent two hours of no recording after the lesion to maintain a stable activity in both modules. Then, we recorded 20 minutes of SPL activity (SPL3) followed by 20 minutes of the bidirectional bridging (BB) protocol and another 20 minutes of spontaneous activity (SPL4). B1-4, The 20 s-long raster plots of representative experiments (respectively, from phases S1, SPL1, BB and SPL4). In B3, Blue and red lines represent electrical

Figure 5 .

 5 Figure5. The hybrid bidirectional bridging approach is effective when a neuronal assembly must be replaced. A, Schematic of the experimental protocols. We recorded 20 minutes of spontaneous activity (S1) followed by laser ablation. Grey-shaded area indicates 20 minutes of no recording during ablation. Dots represent two hours of no recording after the lesion to obtain stable activity in both modules and to test different stimulation channels. Then, we recorded 20 minutes of SPL activity (SPL3) followed by 20 minutes of a hybrid bidirectional bridging (HBB) protocol and another 20 minutes of spontaneous activity (SPL4). B1, Top, 20 s-long raster plot depicting the BNN bursting activity involving both modules before lesion. Bottom, activity of SNN uncorrelated with the BNN. The networks are not linked. B2, Top, 20 s-long raster plot after lesion showing uncorrelated bursting activity on BNN modules 1 and 2. Bottom, same as that in B1. B3, 20 s-long raster plot during HBB depicting two hybrid events. The first event on the left was an NB detected on module 1 of the BNN. The detection resulted in a stimulation pulse delivered to 10 excitatory neurons of the SNN (blue line, bottom). An NB on the SNN was detected 18 ms after the stimulation and triggered the delivery of a stimulation pulse to module 1 of the BNN (grey line, top). B4, 20 s-long raster plot depicting the uncorrelated activity of BNN modules (top) and SNN network (bottom). C, MFR during the 4 experimental phases was stable (colour code as in panel a: S1: light blue dot; SPL3, SPL4: dark grey dots; HBB: red dot). No significant difference was found (one-way repeated measures analysis of variance. p<0.001, DF=3, F=3,16; Bonferroni test: all comparisons with p>0.05). D1, CC function during the 4 experimental phases. Colour code the same as that in panel A. Note that during BB, the cross-correlation function (red) recovers even if not completely with respect to the initial profile (light blue). D2, CC area was highly reduced during the post-lesion phases. The CC area partially recovered during the BB protocol and collapsed again when stimulation was switched off (one-way repeated

Acknowledgements

The presented research results has received funding from the European Union's Seventh Framework Programme (ICT-FET FP7/2007-2013, FET Young Explorers scheme) under grant agreement n° 284772 BRAIN BOW (www.brainbowproject.eu).

The authors would like to thank: Dr Daisuke Ito, Dr Marina Nanni, Dr Claudia Chiabrera, and Dr Giacomo Pruzzo for precious technical support in performing the in vitro experiments at IIT. The authors are grateful to Dr Marianna Semprini for useful comments on the final drafts of the manuscript. The authors wish to thank Prof. Sergio Martinoia, Prof. Sylvie Renaud, Prof. Sylvain Saighi and Prof. Ari Barzilai for their mentorship during the BrainBow project and for useful discussions on the final results.

Declaration of Interests

The Authors report no competing interests. stimulation pulses delivered from module 1 to module 2 and vice versa, respectively. C, MFR during the 4 experimental phases was stable (colour code as in panel a: S1: light blue dot; SPL3, SPL4: dark grey dots; BB: red dot). No significant difference was found (one-way RM ANOVA, p=0.469, DF = 3, F = 0.872) D1, CC function during the 4 experimental phases. Small arrows indicate the blanking period of 8 ms following each stimulation. Colour code the same as that in panel a. Note that during BB, the cross-correlation function (red) recovers even if not completely with respect to the initial profile (light blue), while it stays at zero during the spontaneous activity phases post lesion (SPL3 and SPL4, dark grey profiles). D2, CC area was highly reduced during the post-lesion phases. The CC area partially recovered during the BB protocol and collapsed again when stimulation was switched off (one-way repeated measures analysis of variance; degrees of freedom=3; F=101,832. S1 vs SPL3 p=5.67E-13; S1 vs SPL4 p=7.54E-13; S1 vs BB p=1.60E-07; BB vs SPL3 p=1.77E-06; BB vs SPL4 p=2.81E-06; SPL4 vs SPL3 p=1). E1, NBR remained stable during the experiments. No significant difference was found (one-way repeated measures analysis of variance: p=0.501, DF=3; F=0.810).

E2, Probability of the single-module NB (Prob smNB) was close to one after the lesion. During the BB protocol, the probability was similar to the pre-lesion condition. (Friedman's repeated measures analysis of variance; p<0.001, DF=3, Chi-square=24.3. SPL4 vs S1 and SPL3 vs S1: p<0.001). p=2.72E-09; S1 vs HBB: p=9.16E-04; HBB vs SPL3 p=1.16E-07; HBB vs SPL4 p=1.02E-06; SPL4 vs SPL3 p=0.73643). E1, NBR did not change during HBB with respect to the S1 phase (one-way repeated measures analysis of variance. p=0.005, DF=3; F=6,069; S1 vs SPL3 p=0.02482; S1 vs SPL4 p=1; S1 vs HBB p=1; HBB vs SPL3 p=0.01022; HBB vs SPL4 p=1; SPL4 vs SPL3 p=0.00674). E2, Probability of a single-module NB (Prob smNB) was close to one after the lesion.

During the HBB protocol, the probability was similar to that in the pre-lesion condition (one-way repeated measures analysis of variance. p<0.001, DF=3; F=453,439; S1 vs SPL3 p=4.96E-13; S1 vs SPL4 p=1. 03E-12;S1 vs HBB p=0.22606;HBB vs SPL3 p=1.94E-12;HBB vs SPL4 p=4.30E-12;SPL4 vs SPL3 p=1).

Supplemental video

Performing the lesion, related to Figure 2. Video recorded during a laser ablation of the connections between two modules (visible on the left and right side) of a bimodular cell culture. Video recorded on November 16th 2016. Duration 18s. Link: https://data.mendeley.com/datasets/bnjckk2kht/draft?a=bb802c21-d45c-4c17-be78-


Professor Jean Bousquet
email: jean.bousquet@orange.fr

Marc Meissonnier

Veronique Michalet

Anne Toupnot

Delphine Paccard

Michel Noguès

Josep M Antó

Jean Pierre Riso

Maud Collomb

Véronique Michalet

Josep M Anto

Thierry D'abboville

Laurent Duranton

A novel approach to integrated care using mobile technology within home services. The ADMR pilot study

Keywords: Social workers, mobile technology, home services, care model, elderly

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

Introduction

The demographic changes and the rapid increase of the old age population represent major challenges in the economy, the society and medical care. A major goal for old age care is to enable older persons to live in their homes under good circumstances (1). The care model for supporting the old age people in living independently at home relies on the informal and formal assistance of caregivers and social workers. There is a growing global recognition of the role of informal carers of older people (2).

However, the role of social workers is less well approached. Information and Communication Technology (ICT) offers new approaches for informal care services in old age people [START_REF] Bergstrom | An integrative review of information and communication technology based support interventions for carers of home dwelling older people[END_REF]. Informal carers and social workers of non-medical home services are gaining importance and may be able to participate in care pathways by detecting health deterioration and sounding an alert.

The ADMR (Aide à domicile en milieu rural, https://www.admr.org) is France's leading personal care non-profit network. Dedicated ADMR volunteers (over 100,000 people) and staff (93,700 workers) work together to deliver high-quality local services and enable families and vulnerable people, particularly seniors, to live well in their own home, meeting their wants and needs whilst maintaining their independence.

As a proof-of-concept, a longitudinal observational pilot study was carried out in the ADMR section of one of the French states (Gard). Employees of the ADMR home services followed 130 old age people living at home and who were no more than moderately impaired. A single visual analogue scale (VAS) was used on a smartphone of the home service employee to assess the global health status of the seniors every time they were visited. An alert system was devised to inform the old age person and/or a responsible person of any deterioration in health status. All medical and social events were recorded throughout the study. The study was funded by the CARSAT (Caisse d'Assurance Retraite et Santé au Travail, Regional retirement and occupational health insurance agency), a member of the French national Social Security organization [START_REF] Nogues | Integrated platform for home services using new products and services for senior citizens Call CNAV-CARSAT 2015[END_REF].

Materials and methods

Setting: ADMR of the Gard state.

The ADMR is a national non-profit network that has been active throughout France for over seventy years. The organization helps families and vulnerable people to live well in their own home, throughout their life, by providing bespoke, reliable and professional day-to-day home services. They include housekeeping, shopping, meal preparation or delivery, nursing care, remote assistance, minor DIY/gardening and even childcare, nurseries and micro-nurseries. There are 2,700 organizations with 100,000 volunteers and 93,720 employees working nationwide to meet the daily needs of 716,000 clients. Within the Gard state (France), 18 local organizations with 106 volunteers and 611 employees serve 4,737 clients. Dedicated ADMR volunteers and staff work together to deliver high-quality local services and enable families and vulnerable people, particularly seniors, to live well in their own home, meeting their wants and needs whilst maintaining their independence. Volunteers contribute to developing the services and running the organization. Administrative staff manage the launch of the care plans and visit schedules. The staff includes home helpers and carers (501 in Gard), social services technicians and personal assistants. Each service has its own team with specific qualifications combining people skills and professional expertise. In serving their clients, ADMR organizations create jobs in the areas where they operate. More broadly, the ADMR is seen by its clients and public leaders as essential to the community and local development.

Old age persons:

Retired people of over 65 years of age and served by Gard-ADMR were classified by the French National multidimensional scale, known as the AGGIR autonomy evaluation scale, for "Autonomie, Gérontologie, Groupes IsoRessources" (5). This scale classifies people's autonomy from 1 (worst impairment) to 6 (normal). The participants included in the study were GIR 5 to 6.

Home services employees: 65 ADMR employees participating in the study used a smartphone for their work. Most were cleaning the household. All participants volunteered to be included in the study without any financial incentive. After finishing their work, they always noted their time spent with them.

The 1 hour training consisted of showing how the VAS should be used (10 min) and of discussing the study. In particular, the full study was presented to the employees to allow them to be able to answer any questions that might be asked by the old age subjects.

We highlighted several points:

• The difference between their feelings regarding the state of health of the senior and a medical diagnosis;

• Who to contact should they find themselves in a situation they considered problematic.

• Their role after triggering an alert;

• A reminder of the ethical rules such as the obligation to respect privacy, the privacy of the person and discretion. It was also pointed out that the employee should not attempt to make a medical diagnosis or replace the health care professional.

 Unless in an absolute emergency, the employee should not him/herself contact the doctor or nurse The use of the VAS scale was systematically explained to the substitute employees.

Each session ended with an open discussion between supervisors and employees. The conclusions were used to improve the following training sessions.

Alert system: At the end of each working session, employees quoted the time spent and a single VAS (0 to 100 arbitrary units) with "evaluation of health state" and two smilies automatically appeared on the Smartphone (Figure 1). The reproducibility of the VAS was extensively tested in rhinitis (6)[START_REF] Caimmi | Validation of the MASK-rhinitis visual analogue scale on smartphone screens to assess allergic rhinitis control[END_REF](8)[START_REF] Bousquet | Treatment of allergic rhinitis using mobile technology with real-world data: The MASK observational pilot study[END_REF][START_REF] Bedard | Mobile technology offers novel insights on control and treatment of allergic rhinitis. The MASK study[END_REF](11). The employees used their finger on the VAS to report on the health status. Visits took place regularly but varied from daily to weekly.

An alert system was devised and used for all people. It complies with the EU General Data Protection Regulation (GDPR) for privacy. The European data protection law applies to personal data, i.e. "any information relating to an identified or identifiable natural person (Art. 4 para. 1 no. 1 GDPR) [START_REF]Definitions[END_REF]. As of May 2018, the GDPR applies: Directive 2002/58/EC (13) as amended by Directive 2009/136/EC (14). The information retrieved as well as the VAS levels were all included in a single database in an authorized system hosting personal data with automated anonymization.

After a baseline of one day, a drop of two consecutive days in VAS of ≥20% automatically initiated an alert. Moreover, an alert was systematically sent when VAS was 0/100, whatever the previous levels.

The threshold of 20/100 was derived from our experience in over 15,000 users with rhinitis (MASKair ® Good Practice of DG Santé [START_REF] Bousquet | MASK 2017: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma multimorbidity using real-world-evidence[END_REF][START_REF] Bousquet | Guidance to 2018 good practice: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma[END_REF]). If an alert occurred, a mail was sent within 24 hours to ADMR Gard notifying it through the private ADMR network. This mail was then sent to the local association that informs (i) the employee who noted the VAS to ensure that it was not a false alert and (ii) the person who was involved in the alert or a nominated referent person (reference person according to the French law 2015-1776: Adaptation de la Société au Vieillissement, December 28, 2015 or designed person).

The alert system was discussed in depth in order to avoid any medical information or intervention (diagnosis or management) carried out by the ADMR employee. Only the global health status assessed by VAS was used.

Each ADMR employee received one hour of training before starting the study. However, when the employee was replaced (holidays or other reasons), the new employee used the system without training.

Ethics: An ethical committee was not required since this was an observational study without any direct medical intervention. However, all persons participating in the study signed a written informed consent with the designation of the reference person.

Size of the study:

As this was an exploratory pilot study, we could not determine the number of subjects to be tested. We estimated that we needed to enroll 150 subjects in order to evaluate 100 assuming that if 10% of old age people typically experience a severe situation in the study time period at population level, 100 subjects might be needed to observe multiple severe situations.

Analysis of the study

After each alert, medical and/or social events were carefully analyzed in a structured manner and an anonymized questionnaire was sent to the beneficiary or the reference person.

Descriptive analyses used parametric tests. Due to the low number of severe medical alerts, a statistical evaluation was not carried out.

Results

Demographic characteristics

130 people were screened ranging in age from 69 to 97 years of age. Eight did not accept the study and 106 were evaluated (Figure 2). Only 2/122 decided to stop the study. There were 8,402 evaluations. Alerts 37 alerts were observed. 21 were confirmed and 16 were false positive. Only the untrained employees reported false positive alerts.

Severe medical alerts

Six severe medical alerts were observed (Table 1) including one cancer undetected by the physician, one diabetes which was worsening and which led to hospitalization, one hospitalization which led to death 6 months later and one hospitalization which resulted in follow-up care. Medical alerts occurred between 3 and 84 visits, but one medical alert occurred on the first day of the study. Three alerts had a VAS score of 0 (50%).

Other alerts

Eight other medical alerts were observed. They included adjustment of treatment (2) and more regular medical visits (6). Moreover, the social plan was adjusted [START_REF] Oubaya | Screening for frailty in elderly subjects living at home: validation of the Modified Short Emergency Geriatric Assessment (SEGAm) instrument[END_REF]. One case led to a closer relationship with the family. Nine social alerts were observed including 5 adjustments of the social plan and 4 closer relationships with the family.

The age of the persons ranged from 67 to 97 years and the mean age was around 80 years. There were more females than males for both severe and other alerts. Baseline VAS was similar in both groups, but the mean value was lower in severe medical alerts due to a person with a zero score. There were fewer visits in the severe medical alert group than in the other one. In the "other alert group" only 4 had a VAS score of zero (23.5%)

Impact on the employees and on the old age people

None of the volunteering employees decided to stop the study. Every 6 months, during a meeting, they all reported their satisfaction in being part of the health system with their restricted capabilities. They were rewarded by the number of alerts reported. Many indicated that when they informed the persons or their referent, their alerts were not taken seriously. On the other hand, ICT alerts were considered.

Discussion

We attempted to determine whether social workers could participate in the health system with all deontological criteria of medicine. To our knowledge, this is the first ICT-based alert system that has shown that employees of home services can provide alerts that are subsequently found of medical interest by health care professionals.

This study surprisingly showed that social workers can detect severe medical alerts that have not been identified by health care professionals. Social workers spend more time than HCPs at the home of the old age people and, more importantly, they have a different viewpoint with regards to these people. Moreover, they regularly visit the people and are able to assess any changes in health status, attitude, mobility, cognitive function or behaviour. Redesigning the delivery of care in old age populations needs to include an integrated in-home programme of care, particularly for the low-income frail old age people [START_REF] Levitt | New strategies and innovations to engage seniors in eldercare[END_REF]. This study shows that social workers can participate in this approach. This study also proposes to better support people living at home and serves as a guide towards better ways of supporting ageing populations to live at home [START_REF] Lyn | Just for Us: in-home care for frail elderly and disabled individuals with low incomes[END_REF][START_REF] Mortenson | No Place Like Home? Surveillance and What Home Means in Old Age[END_REF].

The complementarity between social and health care workers may be used in different settings such as (i) the assessment of more handicapped people living at home or in nursing homes, (ii) patients using hospital care at home or (iii) the transition from hospital to home. The population studied is not representative of the general population since people benefiting from home services in the study have specific characteristics defined by financial help from the French state or local public institutes. They usually have a low income and may be more prone to remoteness. These characteristics may also explain the high rate of alerts. The employees who were trained for one hour to explain the study aims did not provide any false alerts. On the other hand, those who replaced the usual employees were not trained and elicited some false alerts.

The potential consequences of false alerts were not considered in this pilot study.

Conclusions

A new vision for ageing at home may be considered since social workers have been shown to be able to identify overall health care status and to send an alert of medical relevance. This study is now deployed to other ADMR federations in France in order to confirm it and to refine the alert system.

The benefits of this pilot study are for the old age people, the employees and the medical system.

Figure 1 :Figure 2

 12 Figure 1: The alert system

Table 1 : Severe medical alerts

 1

	Age Sex VAS	VAS	Number of	Medical problem	Social	Medical	Outcome
			first visit	alert	evaluations		action	action
				(%	Before
				drop)	alert
	1 97	F	10	0	84	Worsening of health		Hospitalization Death (6
						status			months
									later)
	2 83	M	0	-	First visit	Recent vision	yes	Hospitalization Nursing
						problems in a diabetic			home
						patient
	3 71	M	10	0	42	Worsening of health	yes	Hospitalization Follow
						status			up care
	4 87	F	10	5 (50%) 88	Fall with fracture		Hospitalization
	5 68	F	10	5 (50%) 3	The emergency squad		Change in
						was called twice in the		medical care
						past week without		by the
						medical follow up		physician
	6 77	F	10	4 (60%) 23	Patient treated for		Diagnosis of a
						breast cancer with		pancreatic
						chemotherapy		cancer

Table 2 : Characteristics of severe medical and other alerts

 2

		Severe medical alert	Other alert
	N	6	17
	Mean age (yr)	79.7 ± 10.0	81.4 ± 8.8
	Sex (M/F ratio)	2/6	5/24
	Baseline VAS (/10)	7.7 ± 4.1	8.8 ± 2.6
	Alert VAS (/10)	3.75 ± 2.5	2.0 ± 2.3
	Number of visits before alert	28.8 ± 32.7	44.5 ± 34.8

Funding

Funding for this study was received from Caisse d'Assurance Retraite et Santé au travail, Languedoc-Roussillon (CARSAT-LR) and Aide à domicile en milieu rural (ADMR).

Ethical approval

This is an observational study for which approval from an ethical committee was not necessary. However, written informed consent was obtained for each participant.

Provenance and peer review

This article has undergone peer review.

Research data (data sharing and collaboration)

There are no linked research data sets for this paper. Data will be made available on request.

Contributors

Jean Bousquet conceptualized the paper, drafted the manuscript.

Marc Meissonnier conceptualized the paper

Véronique Michalet was responsible for the administration of the ADMR Gard project and the investigation.

Anne Toupnot was responsible for the administration of the ADMR Gard project and the investigation.

Delphine Paccard reviewed the project as the funding source.

Michel Noguès reviewed the project as the funding source.

Josep M Anto proposed the methodology.

Jean Pierre Riso is the director of ADMR Gard.

Maud Collomb was responsible for the administration of the project by ADMR France and the funding of part of the project. Thierry d'Abboville was responsible for the administration of the project by ADMR France and the funding of part of the project.

Laurent Duranton was responsible of the IT.

All authors reviewed the paper and approved the final version.

Conflict of interest

The authors declare that they have no conflict of interest.