T Lauwers

A Glière

S Basrour

Resonant optical transduction for photoacoustic detection

Keywords: Fiber-optic Fabry-Perot, photoacoustic sensor, optical transduction, acoustic sensor, hinged cantilever microphone

A highly sensitive optical transduction system suitable for photoacoustic trace gas detection is presented. The system includes a thin deformable hinged cantilever assembled on an optical fiber to form a Fabry-Perot cavity, whose length varies according to the acoustic pressure disturbance. Consequently, the optical power of the reflected light fluctuates at acoustic frequencies around the working point, which is stabilized to prevent from environmental drift of the interference fringes. The resonant mechanical structure proposed in this study shows a spectral response in good agreement with FEM simulation, good linearity and stability, with a noise equivalent pressure of 12 µPa/√Hz.

INTRODUCTION

Optical transduction methods are useful for remote detection in harsh environments where electronics may be damaged by high temperature or sensitive to electromagnetic noise for example. In the field of acoustics, optical transductions are indeed a very sensitive solution for some applications such as photoacoustic detection ( [START_REF] Wissmeyer | Looking at sound: optoacoustics with all-optical ultrasound detection[END_REF], [START_REF] Kuusela | Photoacoustic Gas Analysis Using Interferometric Cantilever Microphone[END_REF]), acoustic noise measurement and ultrasound detection, in gaseous or liquid environment.

A wide range of optical sensors has been developed for acoustic measurement and can be found in the literature, based on fiber coupling [START_REF] Dass | Micro-tip Cantilever as Low Frequency Microphone[END_REF], fiber Bragg grating [START_REF] Li | D-Shaped Fiber Bragg Grating Ultrasonic Hydrophone With Enhanced Sensitivity and Bandwidth[END_REF] or classical interferometric systems like Mach-Zehnder [START_REF] Gallego | High-sensitivity ultrasound interferometric single-mode polymer optical fiber sensors for biomedical applications[END_REF] or Michelson [START_REF] Murray | Fiber-Wrapped Mandrel Microphone for Low-Noise Acoustic Measurements[END_REF] interferometer. The Fabry-Perot (FP) interferometer is also of great interest, with high sensitivities and reduced dimension, especially in the case of fiber tip FP sensors where the sensing element is placed directly at the end of an optical fiber. Due to the cylindrical symmetry of the system, circular membranes are often preferred for the sensitive element. Several materials have been proposed, like silver [START_REF] Liu | Extrinsic Fabry-Perot fiber acoustic pressure sensor based on large-area silver diaphragm[END_REF], graphene [START_REF] Li | Analyzing the applicability of miniature ultra-high sensitivity Fabry-Perot acoustic sensor using a nanothick graphene diaphragm[END_REF] or parylene [START_REF] Gong | Parylene-C diaphragm-based fiber-optic Fabry-Perot acoustic sensor for trace gas detection[END_REF], with a noise equivalent pressure ranging from 33 µPa/√Hz to 83 µPa/√Hz in the audible frequency range. Chen et al. [START_REF] Chen | Ultra-high sensitive fiber-optic Fabry-Perot cantilever enhanced resonant photoacoustic spectroscopy[END_REF] proposed recently a stainless steel cantilever resonator well adapted to fiber tip FP acoustic sensor, with higher sensitivities due to the free end of the cantilever and reaching a noise equivalent pressure of 8 µPa/√Hz at a frequency of 1 kHz.

In this paper, we present a new geometry, based on a resonant hinged cantilever, suitable for acoustic detection in the kHz range, with high sensitivity and easy to install. The acoustic sensor will shortly be placed into a photoacoustic cell usable for the detection of gas traces.

DESCRIPTION AND DESIGN OF THE SENSITIVE PART

Description of the transducer

The FP cavity is composed of two mirrors (Figure 1a,d): the first one (M1) corresponds to the fiber endface while the end mirror (M2) is a reflective membrane, designed to be sensitive to weak acoustic perturbations. The optical fiber is screwed on a mechanical cylinder that supports the thin membrane and forms the interferometric cavity. A probe laser light is injected in the optical fiber and a photodetector converts the reflected light into a measurable electric signal, proportional to the acoustic perturbation. * thomas.lauwers@cea.fr; phone +33(0)4 38 78 67 05 In order to enhance the displacement caused by the acoustic wave, a cantilever beam is shaped on the membrane, resulting in a coupled mechanical structure, combining the circular plate and the cantilever dynamics (Figure 1b). The free end of the cantilever is located at the center of the membrane, so that a maximum displacement of the structure is probed by the laser, indicated by the red dot on the figure. However, to reach a resonance frequency in the kHz range, either a very thin membrane or a long cantilever is needed. A new geometry, consisting in a hinged cantilever beam, is thus proposed here (Figure 1c). As the hinge considerably decreases the fundamental resonance frequency of the cantilever, this geometry simultaneously allows an easier micromachining of the membrane (40 µm thickness) and a millimetric length cantilever.

The ventilation slit, corresponding to the gap between the cantilever frame and the rest of the membrane, must be chosen as thin as possible in order to maximize its acoustic resistance and thus the pressure differential existing between the two sides of the cantilever.

The FP cavity length 𝐿 cav influences both the optical sensitivity and the acoustic behavior of the sensor. On the one hand, a thin cavity reduces the optical losses, which increases the contrast of the interference pattern and thus enhances the optical sensitivity. However, a too small value of the cavity length causes a large interfringe period, which may be not covered by the laser wavelength tunability range. On the other hand, on the acoustic side, given the ventilation slit, a thick cavity favors an increase of the differential pressure at the working frequency and thus of the mechanical displacement. However if the cavity length is too large, the static pressure or unwanted low frequency pressure variation will not equilibrate on both sides of the membrane, causing an important instability of the optical fringes. Finally, the optical cavity length is chosen as large as possible while keeping a reasonable interference contrast.

In the following sections, a detailed study is presented for the two configurations: the plain clamped-free cantilever (Figure 1b) and the hinged cantilever (Figure 1c).

Mechanical structure and coupling with acoustics

In the configuration showed above, the cantilever is shaped directly on the membrane and no additional element is added to the mechanical structure. Using a single layer of material greatly simplifies the assembly and reduces the fabrication steps but gives rise to another difficulty, that is the mechanical coupling between the plate and cantilever dynamics, which complicates the design of the system. To describe how the coupled system behaves, a first approach consists in considering the two isolated structures and to calculate analytically the fundamental resonance frequency of the simple clamped-free beam using the Euler-Bernouilli theory and the clamped circular plate using the Kirchhoff-Love theory:

𝑓 0,beam = 𝛼 CF 2𝜋 𝑡 𝐿 2 √ 𝐸 12𝜌 and 𝑓 0,plate = α plate 2𝜋 𝑡 𝑅 2 √ 𝐸 12𝜌(1 -𝜈 2 ) (1)
Where 𝑓 0,beam (resp. 𝑓 0,plate ) denotes the resonance frequency of the first mode of a clamped-free beam (resp. clamped circular plate), 𝛼 𝐶𝐹 = 3.52 and α plate = 10.22 are the coefficient corresponding to the fundamental mode of resonance, 𝑡 is the thickness, 𝐿 the length of the beam, 𝑅 the radius of the plate, 𝜌 the mass density of the material used, 𝐸 the Young modulus and 𝜈 the Poisson coefficient. In order to represent analytically the dynamics of the two samples (Figure 1b,c), it is useful to consider the reduced frequency, defined as the ratio between the two resonance frequencies:

𝑓 red = 𝑓 0,beam 𝑓 0,plate = 𝛼 CF 𝛼 plate √1 -𝜈 2 × ( 𝑅 𝐿 ) 2 (2)
If 𝑓 red > 1, the fundamental mode of the plate will be at a lower frequency and will disturb the beam dynamics. Thus, we want to design the sensor in the regime where 𝑓 red < 1 in order to decouple the plate and beam dynamics. To approximate the coupled structure to a cantilever, the condition 𝐿/𝑅 ≫ 1 is needed, which is not achievable with the geometry of Figure 1b. One way to avoid the unwanted plate resonance is to design a hinge on the cantilever on a thicker structure. This shifts the first resonance of the plate to higher frequencies while keeping the resonance of the cantilever at the same frequency.

We show in Figure 2 the resonance frequency and reduced frequency of the two samples introduced in Figure 1b,c To obtain a precise prediction of the hinged cantilever behavior, a FEM simulation has been performed that takes in account the complete membrane geometry and the coupling between mechanic and acoustic phenomena. We can see on Figure 3 a 3D view with two different physical domains modeled: the white volume corresponds to the acoustic domain, while the colored surface corresponds to the mechanical domain, which separates the acoustic domain in two parts linked by the ventilation slit (FP cavity above and external environment below).

The mechanical domain has been modeled by a 2D shell with a perfectly clamped boundary condition on its circular external limit. The high aspect ratio of the membrane (𝑅/𝑡 ~ 100) lies in the domain of validity of the shell theory. The acoustic domain has been modeled by a thermoacoustic model, involving the linearized Navier-Stokes equations system. This model has been chosen because some characteristic lengthscales of the domain (ventilation slit and membrane thickness) are of the same order as the acoustic boundary layers. The ventilation is fixed to the minimum size allowed by laser cutting (50 µm).

Figure 3. On the left, 3D view of the simulated system. The colormap displayed on the membrane corresponds to the mechanical displacement at the cantilever resonance frequency. On the right, mesh of the 2D plate.

To simulate the acoustic response of the transducer, a harmonic pressure condition is applied on the external surface of the hemispheric domain situated below the shell. This boundary condition simulates an incoming plane wave because the domain size is smaller than the typical acoustic wavelength considered in the simulation (𝜆 𝑎𝑐 > 10 cm at 2 kHz). Above the shell the optical cavity is closed with wall boundaries (no slip and isothermal condition). The system is solved for different frequencies and the cantilever maximum displacement is calculated. The transfer function, expressed in nm/Pa, is compared to the experimental result in section 4.2.

Optical readout

The optical intensity reflected from the Fabry-Perot cavity is written 𝐼 𝑟 = 𝐼 𝑖 × 𝑅 FP , where 𝐼 𝑖 is the incident power and 𝑅 FP the reflectivity obtained for a two light-beam interferometer:

𝑅 FP (𝜆, 𝐿 cav ) = 𝑅 1 + 𝑅 2 + 2√𝑅 1 𝑅 2 cos ( 4𝜋𝐿 cav 𝑛 𝜆 ) (3)
𝑅 1,2 are the reflectivities of the fiber endface and the membrane, 𝑛 the index of the medium (in our case 𝑛 = 1). In this model, the reflectivity is a function of the optical cavity length 𝐿 cav and the laser wavelength 𝜆. In the presence of an acoustic perturbation 𝑝, the cavity length oscillates at the acoustic angular frequency 𝜔 𝑎𝑐 with an amplitude 𝛿𝐿(𝑝). This cavity length modulation affects the reflected intensity 𝐼 𝑟 (𝑝) = 𝐼 𝑟 + 𝛿𝐼 𝑟 :

𝛿𝐼 𝑟 (𝑝) = 𝐼 𝑖 𝑑𝑅 FP 𝑑𝐿 𝛿𝐿(𝑝) sin (𝜔 𝑎𝑐 𝑡) (4)
A way to maximize this signal is to have a working point fixed to the maximum of the derivative, called quadrature point Q (see Figure 6). For long measurements, the working point shifts, because de FP cavity is sensitive to environmental factors like temperature or humidity. The solution is to work in a closed-loop system, where the working point Q follows the fringe drift (this closed-loop system is detailed in [START_REF] Mao | Stabilized Fiber-Optic Fabry-Perot Acoustic Sensor Based on Improved Wavelength Tuning Technique[END_REF]).

Sensor sensitivity

From the previous sections, we can define an optical sensitivity in mV/nm. This quantity corresponds to the voltage variation measured by the photodetector for a given displacement 𝛿𝐿:

𝑆 mV/nm = 𝐺 𝑃𝐷 𝐼 𝑖 [ 𝑑𝑅 FP 𝑑𝐿 ] 𝑄 = 𝑉 𝑄 𝑅 𝐹𝑃 (𝑄) [ 𝑑𝑅 FP 𝑑𝐿 ] 𝑄 (5)
Where 𝐺 𝑃𝐷 denotes the photodetector gain in V/W, 𝑉 𝑄 the DC voltage measured at the working point from the reflected light and 𝑅 FP the reflectivity of the Fabry-Perot cavity.

Using the analytical formula for the reflectivity we can easily calculate the derivative and find:

𝑆 mV/nm = 𝑉 𝑄 𝑅 1 + 𝑅 2 ( 8𝜋𝑛 𝜆 ) √𝑅 1 𝑅 2 (6)
The mechanical sensitivity has been calculated numerically with FEM simulation, and corresponds to the displacement at the center of the membrane given an incident acoustic pressure 𝑝:

𝑆 nm/Pa = 𝑑𝐿 𝑑𝑝 (𝜔 𝑎𝑐 ) (7)
Where 𝜔 𝑎𝑐 is the acoustic angular frequency. The final sensor sensitivity can be written 𝑆 mV/Pa = 𝑆 mV/nm × 𝑆 nm/Pa , leading to the linear sensor relation:

𝑉(𝑝) = 𝑆 mV/Pa × 𝑝 (8)

FABRICATION

The membrane is processed by laser cutting on a thin stainless steel film. The two main difficulties of the micro fabrication of the cantilever beam are the thermal dissipation during the process and the minimal spot size achievable by the laser:

-Thermal dissipation has been reduced with the use of a heat sink and an optimized laser cut path. The use of thicker films also increases the thermal inertia and reduces the risk of residual strain on the final structure.

-

The minimal size achievable is limited by the wavelength of the laser. For the Nd:YAG laser used (Cielle, Tau Tech), the spot size has a diameter of 35 µm, leading to a minimal cutting size ranging from 50 µm to 100 µm. This limitation causes a decrease of the mechanical sensitivity of the structure. The ventilation size chosen for the sample shown on Figure 4 left is of 50 µm, which is close to the spot laser size and thus generates an irregular laser cut.

The membrane support is realized in aluminum, with a controlled optical cavity length and a SMA fiber thread for direct mechanical alignment (see Figure 4). The membrane is glued to the support with a UV glue, which has the advantage of curing quickly when exposed to UV light.

EXPERIMENTAL RESULTS

Description of the experiment

To test the hinged cantilever frequency response and sensitivity, an acoustic experimental bench was installed (Figure 5). The light from a laser diode (Toptica, model DL pro) propagates through an optical fiber towards the sensor, and the reflected light is retrieved from the third port of an optical circulator. A photodetector (Femto, model OE-200) measures the light intensity variation with a large bandwidth (500 kHz). A lock-in amplifier (Zurich Instrument, model HF2LI) is used for both the acoustic excitation on a calibrated speaker at the resonance frequency 𝑓 res and the demodulation of the optical signal at the same frequency (AC channel). The DC channel is employed to control that the working point stays at the quadrature point, where the maximum slope of the interference fringe is obtained.

Sensor characterization

The first step of the sensor characterization consists in the measurement of the optical sensitivity. For this purpose, a wavelength scan is carried out to obtain the experimental Fabry-Perot reflectivity. As shown on equation 3, the cavity length 𝐿 cav fixes the interfringe period while the two reflectivities 𝑅 1,2 fix the offset and the contrast of the reflected optical fringes. Figure 6 shows the experimental optical response and the fitted analytical model.

For this sample, we calculate a cavity length of 343 µm, 𝑅 1 = 2.45 % and 𝑅 2 = 1.15 %. 𝑅 1 is identified to be the reflectivity of the fiber endface and 𝑅 2 the effective reflectivity of the membrane mirror. By knowing the refractive index of the fiber core we obtain a theoretical reflectivity of 3.3 % at 1.55 µm, which is slightly higher than the experimental reflectivity. This difference can be easily explained by the fact that the fiber end used has not been cleaved. The second mirror experimental effective reflectivity is very low with respect to the expected theoretical reflectivity. This is due to the optical loss of the optical cavity which can be explained by several factors, namely the loss of the optical cavity originating from the fiber divergence, the imperfect shape of the second mirror and the lack of precise alignment. The Figure 7 (right) compares the measured and calculated frequency response of the hinged cantilever, with a 4 % error on the predicted resonance frequency but an experimental displacement of 65 nm/Pa which is half that of the simulated displacement.

The measured amplitude loss and resonance shift can come from the assembly of the membrane on the support (stiffness of the glue and uneven distribution of the glue on the edges of the membrane). Most importantly, the quality of the laser cutting can cause geometrical variations of the cantilever. The ventilation slit size has been chosen as small as possible i.e. with the same order of magnitude as the marking laser spot size, which led to defects on the cut path, especially in the region close to the hinge (Figure 4 left). These defects, as well as the imperfect clamping due the glue characteristics and dispense, are not taken into account in the numerical model and could explain the differences between the simulation and the experiment.

The measured noise standard deviation at resonance frequency is equal to 𝜎 = 1.44 μV/√Hz. Using the calibrated sensitivity of 117 mV/Pa, we find a Noise Equivalent Pressure (NEP) of 12 µPa/√Hz at 2040 Hz. Due to the imperfection of the insulation box, it is difficult to dissociate the white noise coming from the laboratory environment from the sensor's own noise. This, as well as the inaccuracies of the membrane cut-out, leads to a NEP slightly higher than expected but still close to that of the state of the art fiber tip FP acoustic sensors [START_REF] Chen | Ultra-high sensitive fiber-optic Fabry-Perot cantilever enhanced resonant photoacoustic spectroscopy[END_REF]. Nevertheless, the new geometry proposed here offers many advantages in terms of simplicity of fabrication and assembly.

CONCLUSION AND PERSPECTIVES

We have proposed in this paper a new membrane geometry for fiber tip Fabry-Perot acoustic sensor, based on a hinged cantilever beam fabricated by laser micromachining technique. The cantilever has the dimension of 3 mm x 1 mm, cut on a stainless steel circular membrane with a diameter of 9 mm and a thickness of 40 µm. The hinge is an extension of the beam and measures 100 µm x 200 µm. We showed that, with this geometry, it is possible to obtain a high sensitivity and to uncouple the beam and the plate dynamics. Moreover, the significant thickness of the plate allows an easy handling and gluing of the membrane on the support, as well as a reduction of the thermal strain during the cutting process.

The measured frequency response is in good agreement with the FEM simulation and the transducer shows a good linearity and a high sensitivity, with a NEP of 12 µPa/√Hz at resonance. A more compact system is being developed, with improved fabrication process, higher sensitivity and the use of a currentcontrolled DFB laser for a finer closed-loop control. This system will then be integrated in a photoacoustic sensor for trace gas detection.

Figure 1 .

 1 Figure 1. Schematic of the fiber tip FP sensor (a), the designed membranes (b, c) and 3D view of the fiber system (d). Red dots indicate the location of the probe laser spot. M1 depicts the first fiber/air interface, M2 the stainless-steel mirror and Lcav the FP cavity length.

  . The first sample (S1) is a cantilever beam of 2 mm x 1 mm shaped on a 10 µm thick circular plate with a diameter of 9 mm. The second one (S2) is a 3 mm x 1 mm hinged cantilever beam cut on a 40 µm thick plate with the same diameter. The hinge consists of an extension of the beam of 100 µm x 200 µm. The hinged cantilever resonance is calculated with a Finite Element Method (FEM) model on a 2D shell structure (COMSOL Multiphysics, COMSOL AB, Sweden). An eigenmode resolution is performed. As can be seen on the resonance frequency plot (Figure2left), the fundamental resonance of the cantilevers are close, around 2 kHz for S1 and 2.5 kHz for S2. On the right, we can see that the geometry leads to coupled resonance for the 10 µm case (𝑓 red = 1.7), while the 40 µm plate resonates at higher frequencies without any perturbation on the beam dynamics (𝑓 red = 0.5).

Figure 2 .

 2 Figure 2. On the left, evolution of the resonance frequency with the length of the beam. On the right, reduced frequency versus L/R is plotted. The analytical frequency of the 10 µm thick cantilever (S1) is plotted in blue and the numerical frequency of the 40 µm thick hinged cantilever (S2) is plotted in red.

Figure 4 .

 4 Figure 4. On the left, microscope view of the 3 mm x 1 mm cantilever beam with the 100 µm x 200 µm hinge (bottom). On the right, membrane assembled on the SMA optical fiber.

Figure 5 .

 5 Figure 5. Diagram of the acoustic calibration setup. Optical fibers are drawn in green, electric connections in black.

Figure 6 .

 6 Figure 6. FP interference fringes for the hinged cantilever beam with a 343 µm long cavity. Reflected power is referenced with respect to incident light in port 2.The second step is to stabilize the Q-point at the maximum slope of the fringes (DC reflected signal at Q-point 𝑉 𝑄 = 160 mV) and to make the acoustic measurement. A frequency sweep is performed to locate the resonant frequency which is found to be 2040 Hz. An acoustic calibration is then made at 2040 Hz (Figure7on the left), giving an acoustic sensitivity of 𝑆 mV/Pa = 117 mV/Pa. The comparison of the simulation sensitivity in nm/Pa and the experimental sensitivity in mV/Pa is made with the normalization using the optical sensitivity given in equation 6.

Figure 7 .

 7 Figure 7. On the left, calibration measurement of the acoustic sensor (measured data is plotted in red and linear fit in continuous blue line). On the right, transverse beam displacement in nm/Pa evaluated at the laser spot location for different acoustic frequencies with an integration time of 1s. The blue curve corresponds to the simulation result and the red curve corresponds to the experimental measurement normalized by the fitted optical sensitivity 𝑆 mV/nm .


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A mes amis, A Hugo, mon meilleur ami, Merci pour ton soutien indéfectible, ton réconfort, Ton amitié m'est précieuse.

A Anne--Laure, En souvenir de nos années lycée, de nos week--ends normands avec ta famille The delayed HMR is the most common semi--quantitative parameter used to evaluate the cardiac MIBG uptake in neurological indications. A HMR of less than 1.48 is associated with PD or DLB. A HMR of more than 1.48 is considered as a normal value and associated with MSA, PSP or CBD [START_REF] Lamotte | Accuracy and cutoff values of delayed heart to mediastinum ratio with (123)I--metaiodobenzylguanidine cardiac scintigraphy for Lewy body disease diagnoses[END_REF]. A HMR cut--off at 1.20 could help to differentiate PD from DLB as shown in a precedent study [START_REF] Lamotte | Accuracy and cutoff values of delayed heart to mediastinum ratio with (123)I--metaiodobenzylguanidine cardiac scintigraphy for Lewy body disease diagnoses[END_REF]. At present, HMR calculation is well standardized and reproducible using a conventional Anger camera [START_REF] Flotats | Proposal for standardization of 123I--metaiodobenzylguanidine (MIBG) cardiac sympathetic imaging by the EANM Cardiovascular Committee and the European Council of Nuclear Cardiology[END_REF]. However, a new dedicated cardiac single photon emission computed tomography (SPECT) camera using cadmium--zinc--telluride (CZT) detectors had improved the routine of myocardial perfusion imaging: better count detection sensitivity, decreased acquisition time, decreased injected radiopharmaceutical doses, improved energy resolution leading to better photon energy discrimination for dual--isotope imaging [START_REF] Takahashi | Performance of a semiconductor SPECT system: comparison with a conventional Anger--type SPECT instrument[END_REF]. To date, only a few studies have evaluated myocardial sympathetic innervation imaging and HMR using CZT cameras and the framework of Parkinson syndromes has never been treated (8) (9) [START_REF] Blaire | Determination of the Heart--to--Mediastinum Ratio of 123I--MIBG Uptake Using Dual--Isotope (123I--MIBG/99mTc--Tetrofosmin) Multipinhole Cadmium--Zinc--Telluride SPECT in Patients with Heart Failure[END_REF]. Therefore, the aim of the study was to evaluate the potential diagnostic value and the reproducibility of cardiac dual isotope ( 123 I--MIBG and 99m Tc-tetrofosmin) CZT imaging in parkinsonian syndromes.

MATERIALS AND METHODS

Patient population

This study was a monocentric observational study, performed at the Department of Nuclear

Dual--isotope ( 123 I--MIBG/ 99m Tc--tetrofosmin) CZT acquisition protocol

The imaging protocol was performed according to the recommendations of the European Association of Nuclear Medicine (EANM) Cardiovascular Committee and the European Council of Nuclear Cardiology [START_REF] Flotats | Proposal for standardization of 123I--metaiodobenzylguanidine (MIBG) cardiac sympathetic imaging by the EANM Cardiovascular Committee and the European Council of Nuclear Cardiology[END_REF]. Cardiac dual isotope acquisition with 123 I--MIBG and 99m Tc-tetrofosmin was performed with a CZT camera (D--SPECT® Cardio system, Spectrum Dynamics Medical). All patients received oral administration of Lugol's solution, the day before the exam, the day of the exam --30mn before the administration of 123 I--MIBG --and 48h after the exam, in order to block the thyroid and to protect it. Intravenous 123 I--MIBG and 99m Tc-tetrofosmin were performed 4h and 1h before dual acquisition, respectively. Of note, the injected dose of 123 I--MIBG (150 MBq) was fixed and did not depend on patient weight as per Anger cameras (5.2 MBq/kg). The 99m Tc--tetrofosmin injection led to mandatory perfusion images to draw the heart region of interest (ROI). After resting for 15mn, a 10--s prescan with the 99m Tc--tetrofosmin window was performed in order to help positioned the detectors on the cardiac area. Using a dedicated cardiac CZT SPECT camera, a 10--min list--mode simultaneous dual--radionuclide ( 99m Tc--tetrofosmin and 123 I--MIBG) gated scan was performed.

Images Analysis

As previously described (6), the ROIs were drawn on reoriented images of perfusion.

According to the EANM, ROIs were positioned over the entire heart and the upper mediastinum using transaxial reconstructed SPECT images. Then they were automatically copied from the 99m Tc--tetrofosmin images to the 123 I--MIBG images using the software provided by the manufacturer (Spectrum Dynamics Medical).

Two different investigators, one junior and one senior nuclear medicine physicians, reviewed all SPECT data images and calculated the HMR for each patient. Injected dose of 123 I--MIBG and 99m Tc--tetrofosmin, time between injection and acquisition and time of acquisition were also recorded. Moreover, in dual--isotope condition for CZT SPECT camera, the use of 123 I--MIBG does not have any impact on Left Ventricular Ejection Fraction (LVEF) assessment, as demonstrated before [START_REF] Blaire | Left ventricular function assessment using 123I/99mTc dual--isotope acquisition with two semi-conductor cadmium--zinc--telluride (CZT) cameras: a gated cardiac phantom study[END_REF]. In consequences, the LVEF was evaluated using Quantitative Gated SPECT software (Cedars--Sinai Medical Center) and a cardiologist screened eventually unknown ischemic pathology by systematically reviewed perfusion images.

Statistical analysis

Continuous quantitative variables are reported as mean ± standard deviation. When determining the diagnostic value of cardiac 123 I--MIBG scintigraphy using only senior HMR, continuous variables were compared between groups using non--parametric Mann--Whitney respectively. The mean acquisition duration was equal to 14 ± 1 min. The mean LVEF was 65 ± 0.9 %. Seven patients out of 41 (17%) presented with perfusion abnormalities and were addressed to a cardiologist in order to evaluate the necessity to have a coronarography.

RESULTS

Patient and scintigraphic examination characteristics

Diagnostic value of cardiac 123 I--MIBG scintigraphy based on senior HMR values and using clinical follow--up as reference

The mean HMR value for the entire population was equal to 1.38 ± 0.34. Table 1 displays senior HMR values of LBD+ and LBD--patients. The mean HMR in LBD+ patients was significantly lower than the mean HMR in LBD-patients (1.14 ± 0.21 vs 1.58 ± 0.32, p = 0.0002). A representative example of these two groups of patients can be seen on Figure 1.

Moreover, the mean HMR in PD patients was significantly lower than that in OP patients (1.13 ± 0.19 vs 1.59 ± 0.35, respectively, p = 0.003). Finally, mean HMR were not significantly different between OD patients and DLB patients (p = 0.096) nor between PD and DLB patients (p = 0.536). According to the ROC curve analysis, the optimal HMR cut--off value to discriminate LBD+ (n = 18) from LBD-(n = 18) was 1.24 with an area under the curve equal to 0.86 ± 0.06. This cut-off value led to sensitivity, specificity, positive predictive value and negative predictive values equal to of 72.2%, 94.4%, 92.9% and 77.3 %, respectively. (Figure 2).

Cardiac dual isotope ( 123 I--MIBG/ 99m Tc--tetrofosmin) junior and senior HMR values

According to the junior reader, mean HMR value for the entire population was equal to 1.381 ± 0.338 as compared to 1.380 ± 0.343 for the senior reader. HMR values were not significantly different between the senior and the junior readers (p = 0.966). There was an almost perfect correlation between senior and junior values with a spearman coefficient equal to 0.99 (p<0.0001). Moreover Bland Altman analysis showed a mean difference between senior and junior values equal to --0.000976 (95%CI = --0.0853 -0.0833) (Figure 3). Finally, agreement between readers in discriminating between LBD+ and LBD--patients using the 1.24 HMR cut--off value was almost perfect with a Cohen coefficient kappa value equal to 0.942. One discordance occurred between readers: one patient classified LBD--by the senior, LBD+ by the junior and finally diagnosed LBD+.

DISCUSSION (Anglais)

In the present study, we performed simultaneous dual--isotope acquisitions with 99m Tc-tetrofosmin and 123 I--MIBG. This dual--isotope acquisition allowed the simultaneous assessment of cardiac innervation and function. Therefore, this dual isotope scintigraphy allows diagnosing pathological perfusion that is to say myocardial infarctions for example, in particular in old or diabetic patients, where these pathologies could be silent. To our knowledge, this is the first dual--isotope study combining 123 I--MIBG and 99m Tc--Tetrofosmin with a multipinhole CZT camera to assess cardiac neuronal function in parkinsonian syndromes. CZT--SPECT has many advantages compared to conventional SPECT: it is faster, without motion artifacts and has a better spatial resolution and sensitivity [START_REF] Takahashi | Performance of a semiconductor SPECT system: comparison with a conventional Anger--type SPECT instrument[END_REF]. A precise and early diagnosis in parkinsonian syndromes is the key to correct management and prognostication especially if neuroprotective strategies are developed in the near future [START_REF] Takatsu | Cardiac sympathetic denervation from the early stage of Parkinson's disease: clinical and experimental studies with radiolabeled MIBG[END_REF] This is what allow the myocardial innervation CZT imaging which has high specificity (94.4%) and positive predictive value (92.9%), according to our study. All 41 consecutive patients were seen in a university hospital setting and all files reviewed by two neurologists experts and a nuclear cardiologist involved in cardiac MIBG imaging. Besides, final diagnosis were made in agreement with international diagnosis criteria. We have done an appropriate selection of patients in order to get rid of false--positive results (exclusion criteria). Indeed, decreased myocardial MIBG uptake is not specific of LBD: we can find it in various heart diseases or in diabetes by damaging the postganglionnic sympathetic neurons. Besides, some drugs (ie: tricyclic, tetracyclic antidepressants, reserpine) (11) (12) can influence MIBG uptake as possible sources of false--positive results. In our study, we demonstrated that the cardiac dual isotope CZT imaging was very useful to differentiate PD and DLB from other types of parkinsonism with a HMR significantly lower in PD and DLB than in the other group.

This result was consistent with a previous study realized on a dual--head camera system (2).

We found an optimal HMR cut--off value to discriminate LBD+ from LBD-of 1.24 which is lower than in the precedent study using a dual--head camera system (HMR of 1.48). We can explain it because of our population, composed of many geriatric patients (mean age = 72 ± 11 years). Indeed, there is an age--related degeneration: the myocardial 123 I--MIBG uptake has been reported to decrease significantly with age [START_REF] Estorch | Myocardial iodine--labeled metaiodobenzylguanidine 123 uptake relates to age[END_REF]. Our study showed an excellent reproducibility when using this specific cut--off set 1.24. The main limitations of our study were the small number of subjects included because it was carried out in a single university hospital and the short clinical follow--up (around a year and a half). Besides, the clinical diagnosis was used as the gold standard in this study because of the impossibility to have a histopathological confirmation: therefore, there might have some incorrect clinical diagnosis in some cases. It could be interesting in future studies to have a larger number of subjects and a longer clinical follow--up.

DISCUSSION (Français)

Dans notre étude, nous avons réalisé des acquisitions simultanées en double isotope en utilisant le 99m Tc--tétrofosmine et le

ABREVIATIONSCBD : Figure 1 : 12 Figure 2 : 13 Figure 3 :

 :1122133 FIGURES INDEX

INTRODUCTION

  Parkinson syndromes are defined by all the symptoms which result from a dysfunction of the nigro--striatal system: bradykinesia, extrapyramidal rigidity and tremor. It includes idiopathic Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD) and other non-degenerative syndromes (iatrogenic, vascular, metabolic). The diagnosis of the parkinsonian syndromes is entirely clinical. However, in some atypical cases, nuclear imaging can be useful. Indeed, an early diagnosis of those disorders is essential for a suitable management of the patient and an appropriate assessment of the prognosis, especially with the development of neuroprotective treatments. A recent study (1) suggested that the combination of cerebral 123 I--N--fluoropropyl--2b--carbomethoxy--3b--(4--iodophenyl) nortropane ( 123 I--FP--CIT) and cardiac 123 Iodine--metaiodobenzylguanidine ( 123 I--MIBG) scintigraphy may improve the diagnosis accuracy in differentiating PD from non--PD. 123 I--FP--CIT or cerebral 18 F--Fluoro--L--3,4--dihydroxyphenylalanine ( 18 F--FDOPA) positron emission tomography (PET) aim at evaluating dopaminergic denervation in order to discriminate between degenerative parkinson syndromes that display scintigraphic alterations and non--degenerative parkinson or non--parkinson syndromes displaying normal examinations: essential tremor, iatrogenic tremor, Alzheimer Disease, vascular or psychogenic disorder (normal values). Cardiac 123 I--MIBG innervation scintigraphy with heart--to--mediastinum ratio (HMR) can be used to differentiate PD and DLB from other parkinsonian syndromes (2)(3). Metaiodobenzylguanidine (MIBG) is a norepinephrine analogue that is taken up in the postsynaptic adrenergic neurons. Cardiac 123 I--MIBG scintigraphy allows evaluating myocardial sympathetic innervation and especially noradrenergic postsynaptic cardiac denervation which is a common feature in PD and DLB (4).

  Medicine of the University Hospital of Caen (France). From November 2016 to July 2018, we prospectively included all patient referred to our unit by our department of Neurology for a cardiac dual isotope ( 123 I--MIBG/ 99m Tc--tetrofosmin) CZT scintigraphy to characterize a clinical parkinsonian syndrome, as part of our clinical routine. Patients with history of heart failure, diabetes or ongoing neuroleptic treatment were excluded because that could possibly interfere with the cardiac 123 I--MIBG uptake[START_REF] Solanki | A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta-iodobenzylguanidine (MIBG)[END_REF] [START_REF] Lee | Cardiac 123I--MIBG scintigraphy in patients with drug induced parkinsonism[END_REF]. Informed consent was obtained from all individual participants included in the study. A specific identification number was then assigned to each patient. All procedures in studies involving human participants were performed in accordance with the ethical standards of the institutional research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.Clinical evaluationTwo neurologists experts evaluated all patients one year after the cardiac 123 I--MIBG scintigraphy in order to obtain a final diagnosis based on clinical parameters. International clinical diagnostic criteria were used to determine final clinical diagnosis (Diagnosis and management of dementia with Lewy bodies for DLB (13), Clinical Diagnosis of Progressive Supranuclear Palsy: The Movement Disorder Society Criteria for PSP (14), MDS Clinical Diagnostic Criteria for Parkinson's Disease for PD (15), Criteria for the diagnosis of corticobasal degeneration for CBD (16) and Second consensus statement on the diagnosis of multiple system atrophy for MSA (17)) . These two neurologists classified the patients into two different groups: patients with a Lewy body Disease (LBD+) and patients without Lewy Body Disease (LBD--). LBD+ included DLB and PD. LBD-- included other types of dementia OD and other types of parkinsonism OP (including Undetermined Parkinsonism UP, PSP, MSA and CBD). We also recorded age, gender, the mean follow--up time after the onset of the symptoms to the dual isotope exam and if the patient had a 123 I--FP--CIT before the cardiac 123 I--MIBG scintigraphy.

Forty--one

  patients were included (20 females and 21 males; mean age: 72 ± 11 years). In patients for whom the onset of symptoms was recorded (n=24, 58%), the mean time between the onset of the symptoms and the dual isotope exam was 4.8 ± 3.4 years. The mean clinical follow--up time after the dual isotope examination was 1.6 ± 0.5 years. Of the 41 patients, 18 (44%) were finally diagnosed LBD+ (DLB, n = 9, 22%; PD, n = 9, 22%) and 18 (44%) were diagnosed LBD-(OD, n = 3, 7%; OP, n = 15, 37%). No diagnosis could be definitely stated for 5 patients (12%): 2 patients (5%) with no available follow up and 3 (7%) "inclassable" patients.Cardiac 123 I--MIBG scintigraphy was mostly performed either to differentiate DLB from OD (n=12) or to differentiate PD from OP (n=24). Sixteen patients had a 123 I--FP--CIT before the cardiac 123 I--MIBG scintigraphy and only two were negative (no denervation). 123 I--MIBG injection was administrated 235 ± 36 min and 99m Tc--tetrofosmin injection 61 ± 26 min before dual acquisition with mean injected doses equal to 152 ± 8 MBq and 383 ± 99 MBq,

Figure 1 :

 1 Figure 1: Representative images of one LBD--patient (a) and one LBD+ patient (b) a. Example of normal cardiac dual isotope scintigraphy: LBD--. A: perfusion planar reconstruction, B: innervation

Figure 2 :

 2 Figure 2: ROC curve for the differential diagnosis between LBD+ and LBD--using planar imaging with the HMR (AUC: area under the curve)

Figure 3 :

 3 Figure 3: Spearman correlation (a) and Bland--Altman analysis (b) between senior and junior HMR values

  diabète, par altération des neurones sympathiques post--ganglionnaires. De plus, certains médicaments (ex : antidépresseurs tricycliques/tétracycliques, réserpine)[START_REF] Solanki | A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta-iodobenzylguanidine (MIBG)[END_REF] [START_REF] Lee | Cardiac 123I--MIBG scintigraphy in patients with drug induced parkinsonism[END_REF] peuvent influencer la fixation du MIBG et ainsi donner des résultats faux--positifs. Dans notre étude, nous avons montré que la scintigraphie cardiaque double isotope sur caméra CZT était très utile pour distinguer Maladie de Parkinson et Démence à Corps de Lewy d'autres types de syndromes parkinsoniens avec un HMR inférieur dans le premier groupe par rapport au second. Ce résultat était concordant avec une précédente étude réalisée avec une gamma-caméra à double tête (2). Nous avons determiné un cut--off optimal pour la valeur du HMR de 1,24 afin de différencier MCL+ et MCL--, qui est inférieur à celui de l'étude précédente avec la gamma--caméra double tête (HMR = 1,48). Nous pouvons expliquer cette difference avec notre population, composée principalement de patients de gériatrie (âge moyen = 72 ± 11 ans). En effet, il existe une dégénerescence liée à l'âge : il a été démontré que la fixation cardiaque du 123 I--MIBG diminue de façon significative avec l'âge (21). Notre étude a démontré une excellente reproductibilité en utilisant ce cut--off de 1,24. Les principales limites de notre étude étaient le nombre faible de patients inclus, car celle--ci était réalisée dans un unique CHU, et la courte période de suivi (environ un an et demi). De plus, le diagnostic clinique étant utilisé comme gold standard dans notre etude, car il est impossible d'avoir une confirmation anathomopathologique, il doit exister quelques erreurs de diagnostics cliniques. Il serait intéressant dans de futures études d'avoir un plus large échantillon de patients et un suivi clinique plus long. VU, le Président de Thèse VU, le Doyen de la Faculté VU et permis d'imprimer en référence à la délibération du Conseil d'Université en date du 14 Décembre 1973 Pour le Président de l'Université de CAEN et P.O

ISOTOPE ( 123 I--MIBG/ 99M TC--TETROFOSMIN) CZT ACQUISITION PROTOCOL 7 IMAGES ANALYSIS 8 STATISTICAL ANALYSIS 8 RESULTS 10 PATIENT AND SCINTIGRAPHIC EXAMINATION CHARACTERISTICS 10 DIAGNOSTIC VALUE OF CARDIAC 123 I--MIBG SCINTIGRAPHY BASED ON SENIOR HMR VALUES AND USING CLINICAL FOLLOW--UP AS REFERENCE 11 CARDIAC DUAL ISOTOPE ( 123 I--MIBG/ 99M TC--TETROFOSMIN) JUNIOR AND SENIOR HMR VALUES 14 DISCUSSION (ANGLAIS) 16 DISCUSSION (FRANÇAIS) 18 CONCLUSIONS 20

  ......................................................................................................................... 15

	PREAMBULE participé activement à la coordination du projet en collaboration avec le Dr Pierre BRANGER,
	neurologue spécialiste dans les troubles de la mémoire et attaché à notre service de
	Une première étude concernant les performances diagnostiques de la scintigraphie
	Médecine Nucléaire, et le Dr Claire THIRIEZ, neurologue spécialiste en mouvements
	cardiaque double isotope ( 123 Iode--métaiodobenzylguanidine/ 99m Téchnétium--tétrofosmine)
	anormaux. Mes rôles ont ainsi été transversaux :
	INTRODUCTION dans les syndromes parkinsoniens avait déjà été réalisée dans notre service de Médecine 4
	MATERIALS AND METHODS Nucléaire du CHU de Caen, sur la gamma--caméra que nous possédions à l'époque : une 6 • Récolter les données cliniques de l'ensemble des patients
	PATIENT POPULATION caméra double--tête conventionnelle (Symbia T2 True Point, Siemens Medical Solutions, 6 • Informer et recueillir leur consentement éclairé
	CLINICAL EVALUATION • Anonymiser l'ensemble des données des patients Erlangen, Germany). Nous avons acquis depuis une caméra plus récente et plus 6 sophistiquée, utilisant des semi--conducteurs au cadmium, zinc et telluride, autrement de ce même examen en utilisant notre nouvelle caméra, dans le cadre des syndromes parkinsoniens, puisque ce sujet n'avait encore jamais été abordé. En effet, bien que le diagnostic des syndromes parkinsoniens reste clinique, il est parfois délicat et nécessite un ou plusieurs examens d'imageries nucléaires supplémentaires. Le 123 I--Ioflupane DaTSCAN permet de distinguer les syndromes parkinsoniens dégénératifs des autres syndromes parkinsoniens ou des syndromes non parkinsoniens. La scintigraphie cardiaque double isotope ( 123 Iode--métaiodobenzylguanidine/ 99m Téchnétium--tétrofosmine) permet, quant à elle, de différencier Maladie de Parkinson et Démence à Corps de Lewy des autres syndromes parkinsoniens. Ainsi, notre projet a pour but d'évaluer les performances diagnostiques ainsi que la reproductibilité de la scintigraphie cardiaque double isotope ( 123 Iode--métaiodobenzylguanidine/ 99m Téchnétium--tétrofosmine) sur caméra CZT dans les syndromes parkinsoniens. Cette étude a été réalisée par l'équipe caennaise de Médecine Nucléaire du CHU dont le chef de service, le Professeur Denis AGOSTINI, est le référent de cet examen d'imagerie. J'ai • Puis, analyser les examens scintigraphiques selon les matériels et méthodes décrites DUAL--1 appelée caméra CZT. Il nous est ainsi paru évident d'évaluer les performances diagnostiques ci--après.

• Participer à l'analyse statistique, avec l'aide du Docteur Charline LASNON

• Enfin, écrire le manuscrit et élaborer les tableaux et figures.

Table 1 : Senior HMR values in LBD+ and LBD--

 1

	Final clinical diagnosis	HMR
	(n = 41)	Mean ± SD
	LBD+
	All patients n= 18 (44%)	1.14 ± 0.21
	DLB n = 9 (22%)	1.16 ± 0.24
	PD n = 9 (22%)	1.13 ± 0.19
	LBD--
	All patients n = 18 (44%)	1.58 ± 0.32
	OD n = 3 (7%)	1.52 ±0.16
	OP n = 15 (37%)	1.59 ± 0.35
	PSP n = 7 (17%)	1.52 ± 0.28
	MSA n = 6 (15%)	1.53 ± 0.37
	UP n = 1 (2.5%)	2.28
	CBD n = 1 (2.5%)	1.76
	No diagnosis n = 5 (12%)	1.51 ± 0.30

  123 I--MIBG. Cette acquisition double isotope permet l'évaluation simultanée de la fonction et de l'innervation cardiaques. Ainsi, cette scintigraphie double isotope permet de diagnostiquer des pathologies liées à la perfusion comme les infarctus du myocarde, notamment chez les patients âgés ou diabétiques, où ces pathologies peuvent être silencieuses. A notre connaissance, il s'agit de la première étude en double--isotope ( 99m Tc--tétrofosmine / 123 I--MIBG) utilisant une camera CZT afin d'évaluer

	camera CZT le permet ainsi grâce à ses grande spécificité (94,4%) et valeur prédictive
	positive (92,9%). L'ensemble des 41 patients ont été inclus au sein de notre CHU et les
	données ont été évaluées par deux neurologues experts et un médecin nucléaire référent
	dans la scintigraphie cardiaque double isotope. De plus, les diagnostics finaux ont été rendus
	en accord avec des critères diagnostiques internationaux. Nous avons effectué un
	recrutement approprié des patients afin d'éviter les risques de faux positifs (critères

l'innervation du coeur dans les syndromes parkinsoniens. La CZT--SPECT présente de nombreux avantages en comparaison avec la SPECT conventionnelle : plus rapide, moins d'artéfacts, meilleure résolution spatiale et meilleure sensibilité

[START_REF] Takahashi | Performance of a semiconductor SPECT system: comparison with a conventional Anger--type SPECT instrument[END_REF]

. Il est primordial d'avoir un diagnostic précis et précoce dans les syndromes parkinsoniens pour une prise en charge optimale, notamment avec l'avènement potentiel de nouvelles stratégies thérapeutiques neuroprotectrices dans un futur proche

[START_REF] Takatsu | Cardiac sympathetic denervation from the early stage of Parkinson's disease: clinical and experimental studies with radiolabeled MIBG[END_REF]

. La scintigraphie cardiaque double isotope sur d'exclusion). En effet, une diminution de la fixation myocardique du MIBG n'est pas spécifique des DCL : on les retrouve dans différentes maladies cardiaques ou encore le

sentiments respectueux.

TABLE INDEX Table 1: Senior HMR values in LBD+ and LBD--........................................................................ 11

Cardiac dual isotope ( 123 I--MIBG/ 99m Tc--tetrofosmin) CZT imaging in parkinsonian syndromes: diagnostic value and reproducibility

tests. Bonferroni correction was applied. Receiver--operating characteristic (ROC) curve analysis was performed to determine the optimal HMR cut--off value to differentiate LBD + from LBD--using Youden's J statistic. When comparing senior and junior HMR values, a Wilcoxon matched--paired test was used. The correlation between senior and junior values was assessed by mean of a spearman correlation and a Bland Altman analysis [START_REF] Bland | Statistical methods for assessing agreement between two methods of clinical measurement[END_REF]. A p--value < 0.05 was considered as significant. Finally, diagnostic agreement between reviewers was assessed by means of Cohen kappa coefficient. Graphs and analyses were carried out using

CONCLUSIONS

The present study demonstrated that dual isotope ( 123 I--MIBG/ 99m Tc--tetrofosmin) CZT cardiac imaging can diagnose LBD in patients with parkinsonian syndromes with excellent specificity and positive predictive value and almost perfect reproducibility when applying a specific HMR cut--off value set 1.24. Besides, 99m Tc--tetrofosmin imaging could help screening perfusion abnormalities.