The scaling behavior, characterized by the diverging dynamical critical exponent (Griffiths singularity), indicates that the quantum fluctuation manifests itself as superconducting puddles, in marked contrast to the thermal fluctuation. We suggest that an evolution from the quantum metallic to the quantum Griffiths state is generic nature in highly crystalline 2D superconductors with weak pinning potentials.Superconductor–insulator transition is one of the remarkable phenomena driven by quantum fluctuation in two-dimensional (2D) systems. Such a quantum phase transition (QPT) was investigated predominantly on highly disordered thin films with amorphous or granular structures using scaling law with constant exponents. Here, we provide a totally different view of QPT in highly crystalline 2D superconductors. According to the magneto-transport measurements in 2D superconducting ZrNCl and MoS Superconductor-insulator transitions predominantly occur in highly disordered thin films. Here, Saito et al. report that a quantum metallic state transforms via the quantum Griffiths state to a weakly localized metal at high magnetic fields in a crystalline two-dimensional superconductor. In this scenario, the ground state is either superconductor or insulator distinguished by a quantum critical point (QCP), which is characterized by the critical sheet resistance and a critical tuning parameter for degree of disorder, magnetic field, or carrier density. However, in recently found highly crystalline 2D superconductors3, such as the gate-induced single crystal surfaces4 and the mechanically exfoliated atomic layers5, the dirty-boson scenario for the magnetic field-induced SIT needs to be modified using a different picture incorporating a wide quantum metallic state/vortex liquid state. Such a metallic state following the fragile zero-resistance state occurs because of the quantum creep motion of vortices originating from the minimal disorder and the extremely weak pinning.Two-dimensional (2D) superconductors have been well-known platforms for the study of a quantum phase transition (QPT). In granular or amorphous superconducting thin films, which were initial 2D superconductors with atomic layer thickness, a direct superconductor–insulator transition (SIT) was a consequence of the QPT occurring at zero temperature. The SIT has been for a long time discussed based on the so called “dirty-boson model”, which is applied to the highly and homogeneously disordered systemsBc2MF) without showing localized behavior. Thus, the crossover or transition from the quantum metallic state to the normal state at low temperatures, including superconducting fluctuation regime, emerges as a new unsolved problem of the QPTs in the highly crystalline 2D superconductors10. Recently, there appeared a couple of clues for this issue. One is the gate-induced superconducting surface of a ZrNCl single crystal, in which the finite-size scaling (FSS) law of transport property does not obey the dirty-boson scheme any more4. Others are molecular-beam-epitaxy grown Ga trilayer11, NbSe2 monolayer12, and LaAlO3/SrTiO3 (110) interface13, in which a different type of the QCP, the quantum Griffiths singularity14, was observed at ultralow temperatures.Although the resistance in the quantum metallic state is nonzero, this state starts far below the mean field upper critical field  with those single crystal flakes (see “Methods” for details), in which almost all the carriers are accumulated in the topmost layer with 1–2 nm at high gate voltages, resulting in truly 2D superconductivity at low temperatures16.ZrNCl and MoSres Fig. , both ofRsheet(T) at VG = 6.0 V (sheet carrier density n2D is 4.8 × 1014 cm−2 at 30 K) for zero and finite magnetic fields B applied perpendicular to the surface of ion-gated ZrNCl. In zero magnetic field, the ZrNCl-EDLT exhibits superconductivity with a critical temperature Tc of 14.6 K. Here, Tc is defined as the temperature where the sheet resistance becomes a half of the normal state value, and is almost equal to the mean field transition temperature Tc0 estimated by thermal fluctuation theories4. By applying B, the resistive transitions are considerably broadened because of the thermal phase fluctuation, and then level off at low temperatures due to the quantum phase fluctuation, indicating the quantum metallic state. This quantum metallic state, which appears once the magnetic field is switched on, possibly originates from weak pinning potentials and large fluctuations reflecting the two-dimensionality4. Such a stable quantum metallic state does not appear in atomically ordered 2D superconductors grown by molecular-beam-epitaxy18, possibly because of the atomic steps of substrate working as strong pinning centers. In the exfoliated 2D superconductors like ZrNCl, MoS2, and NbSe2, such atomic steps are basically absent16.Figure Bc2MF(T) and superconducting onset are crucial. For this purpose, we adopted the Ullah–Dorsey (UD) scaling theory19 (see Supplementary Note Bc2MF(T), where the excess conductance due to the thermal superconducting fluctuation, Gfl ≡ 1/Rsheet(T) – 1/RN(T), in finite B is described with the Hatree approximation as follows:For establishing a global phase diagram of 2D superconductors, the estimation of both mean field upper critical field RN(T) is the sheet resistance in the normal state, s = 1 in the case of a 2D system20 and TcMF(B) the mean field transition temperature in a magnetic field, corresponds to the temperature on the Bc2MF(T) curve. As shown in Fig. Rsheet(T) at B = 9.0 T as RN(T) and TcMF(B) as fitting parameters, Gfl(T) curves in the ZrNCl-EDLT at T > TcMF(B) and B = 0.1–1.8 T collapse onto a single curve with the slope of −1 in log–log plots, obeying the UD scaling law of Eq. (TcMF(B) or Bc2MF(T) as shown in Fig. Tonset and Bc, which are defined later. The TcMF(B) at 0.1 T is close to the temperature for 50% of the normal state resistance. With increasing B, Rsheet(TcMF)/RN increases and goes over 90% around TcMF(B) ∼ Tc0/2. At lower temperatures below Tc0/2, where the UD scaling theory does not holds19, we simply defined TcMF(B) as the temperature for 95% of the normal resistance. TcMF(B) or Bc2MF(T) thus obtained obeys the Wertharmer–Helfand–Hohenberg (WHH) theory21 as shown in the dashed curve in Fig. TcMF(B) or Bc2MF(T) curve of the MoS2-EDLT (VG = 5.0 V and n2D = 1.3 × 1014 cm−2) as shown in Fig. Here, 2. In both cases, the isotherms show multiple crossing points, indicating that each R–B curve cross at different points. The cross points of R–B curves at neighboring temperatures, which are defined as Bc(T), are plotted in Fig. Tonset of resistance drop in a magnetic field, defined by the temperature where dRsheet/dT = 0 . Because both Tonset(B) or Bc(T) curve is above the mean field curve, it is interpreted as the onset temperature (or magnetic field) of superconducting fluctuation. Both Fig. Bc(T) and Bc2MF(T) increases with decreasing T in ZrNCl or almost unchanged in MoS2, respectively. This behavior cannot be explained by the effect of thermal fluctuation, which results in the decrease of the interval, and signifies the occurrence of the quantum fluctuation at low temperature and high magnetic fields.After knowing the mean field curve, we next investigate the superconducting onset. Figure 22 and Ta films23, suggesting that the present system is not classified into the conventional universality class, which exhibits a direct superconductor–insulator transition with a single crossing point. A possible scenario for the quantum fluctuation above Bc2MF(T) is the quantum Griffiths singularity, which was first theoretically proposed to understand the divergence of the dynamical exponent in QPTs in various lattice models with randomness25. The existence of the quantum Griffiths singularity has been experimentally applied first to magnetic metal systems28 and recently to 2D superconductors13  the scaling function with f (0) = 1, z and v the dynamical and static critical exponent, respectively. To examine the evolution of the effective critical exponents zv with the decrease (or increase) in T (or B), five representative crossing points were selected both for ZrNCl and MoS2, respectively, and then the FSS analysis at various temperature regimes were performed. During the scaling, we derived zv by assuming that the functional forms of f(x) both for x > 0 and x < 0 unchanged (see Supplementary Note zv is not constant but varies as a function of magnetic field in both systems: in the low magnetic field (high temperature) regime, zv is around 0.5, while it increases with increasing (decreasing) magnetic field (temperature), exceeding 1 −0.6, which is the evidence of quantum Griffiths singularity at characteristic critical magnetic field Bc*. This diverging behavior of the critical exponent with multiple crossing points is in stark contrast to that in the conventional dirty metallic films, which shows temperature-independent constant critical exponents with a single critical field2. Such a divergent critical exponent consistent with the Griffiths singularity indicates that rare-ordered regions exist even above Bc2MF with a rather long time-scale and finite length scale due to the quantum fluctuation. Such rare regions are interpreted as superconducting puddles in this particular case.We have tested the scenario of the quantum Griffiths singularity by introducing the FSS law for magnetoresistance expressed as,g 1 Fig. . FinallyBc(T) (orange squares) and Tcross(B) (blue triangles), and a mean field curve (black solid curve). The former corresponds to the onset of superconducting fluctuation terminating at the QCP characterized by the quantum Griffiths singularity at B = Bc* and T = 0 K. The latter Tcross(B) represents the crossover boundary between the thermal and quantum vortex creep region derived from the Arrhenius plot analysis of Rsheet(T) data in Fig. Bc(T) is extrapolated to the onset temperature Tonset of the Aslamazov–Larkin-type fluctuation29 at B = 0, the region above TcMF(B) at low magnetic fields is dominated by thermal fluctuation of the order parameter amplitude. This state crossovers to the thermal creep  below TcMF(B) and then to the quantum creep (quantum phase fluctuation) region below Tcross(B) with decreasing temperature. At high magnetic fields, on the other hand, thermal fluctuation region shrinks because of the decrease of TcMF(B). However, with further decreasing temperature, Bc(T) shows an upturn, which is a signature of the emergence of quantum fluctuation. The Tcross(B) curve seems smoothly connected to the upturn of Bc(T) at low temperatures. This feature suggests that the quantum fluctuations in highly crystalline 2D superconductors govern the evolution of the ground state, stemming from the quantum metallic state at a very low magnetic field  with the quantum Griffiths singularity /Cr (5 nm) electrodes were patterned onto an isolated thin flake in a Hall bar configuration, and a side gate electrode was patterned onto the substrate. A droplet of ionic liquid covered both the channel area and the gate electrode. Ionic liquid N,N-diethyl-N-(2-methoxyethyl)-N-methylammonium bis (trifluoromethylsulphonyl) imide (DEME-TFSI) was selected as a gate medium. The sheet carrier densities n2D induced electrostatically for the ZrNCl-EDLT at VG = 6.0 and the MoS2-EDLT at VG = 5.0 V, which were determined by the Hall effect measurements at 30 and 15 K, were 4.8 × 1014 cm−2 and 1.3 × 1014 cm−2, respectively.Bulk ZrNCl and 2−4 Torr).The temperature-dependent resistance under magnetic fields was measured with a standard four-probe geometry in a quantum design physical property measurement system (PPMS) combined with two kinds of AC lock-in amplifiers . The gate voltage was supplied by a Keithley 2400 source meter at 230 K, which is just above the glass transition temperature of DEME-TFSI, under high vacuum (less than 10The data that support the findings of this study are available from the corresponding author on reasonable request.Supplementary Information


We mimic unique honeycomb structure as well as its functions of storing honey and pollen to assemble Au nanoparticle pattern on honeycomb-like Al nanobowl array by utilizing solid state dewetting process. Patterned Au nanoarrays of ‘one particle per bowl’ with tunable plasmonic bands ranging from the visible to the near-infrared region are fabricated by finely selecting the initial thickness of Au film, the geometry of Al nanobowl array and the thermal treatment parameters. This work presents a powerful approach to assemble Au nanoparticles into high density nanoarrays with superior spatial resolution, offering highly concentrated electromagnetic fields for plasmonic sensor applications. In nanometer world, we mimic honeycomb structures and its versatile functions to precisely assemble patterned Au nanoarrays on honeycomb-like substrates by means of a facile solid state dewetting (SSD) process6. SSD describes the formation of island particles when solid state matters  are heated to sufficiently high temperatures (below melting temperature). This process can be used to manipulate metallic nanostructures with preset parameters by utilizing nanotemplates and optimizing the total surface energy of metallic thin film, substrate and their interfaces15.In nature, honeycomb typically shows a closely packed hexagonal wax cells where honey and pollen are stored. This most efficient, least wasteful and strongest building system continues inspiring human to engineer honeycomb-like structures20. Therefore, it is vital to seek for suitable nanotemplates with high spatial resolution, uniform unit size as well as tunable surface morphology to modulate the SSD process and subsequent nanopatterning.When a metallic thin film is dewetted on a nanotemplate, the formation of nanoisland array depends on the template structures. Hence, the pattern of template determines the spatial resolutions of dewetted metallic nanoarray. The spatial resolution controls the plasmonic characteristics of the metallic nanoarrays, which are critical for plasmonic sensor applications, such as surface-enhanced Raman scattering and surface-enhanced fluorescence22, focused ion beam lithography24, optical interference lithography9 and colloidal lithography12, can allow one to design the template morphologies. However, electron beam lithography and focused ion beam lithography are too expensive in practical applications, and optical interference and colloidal lithography are typically limited by the low spatial resolutions owing to the wavelength of optical sources and the size of colloidal spheres, respectively. Alternatively, titania nanotube27 and anodic aluminum oxide (AAO)30 produced by electrochemical self-assembly approaches were typically employed as templates to rationally engineer metallic nanostructures with high spatial resolutions and density. However, the dewetted metallic nanostructures on titania nanotube or AAO may probably generate core-satellite nanostructures28 leading to exhibiting additional hybrid plasmonic modes among the visible to the near-infrared (NIR) region, which are not satisfying in high sensitive sensor applications31.Currently, common methods for nanotemplate fabrication, such as electron beam lithography32. Herein, a series of Au nanoparticles can be well assembled into nanopatterns on ordered Al nanobowl array with ‘one particle per bowl’. The patterned Au nanoarrays exhibit high spatial resolutions and tunable plasmonic bands over a broad range from the visible to the NIR region.In this work, we induce initial instabilities in as-deposited Au film by using Al nanobowl array template to assemble patterned Au nanoarrays by SSD process. Compared with other templates discussed above, the bowl structures of template offers a much higher spatial resolution for the dewetted metallic nanoarray with uniform unit size. Besides, the Al nanobowl array presents a high structural flexibility regarding achievable bowl size ranging from ~50 to ~400 nmThe assembly of Au nanoparticles into honeycomb-like Al nanobowl array by SSD process is schematically shown in Fig. VAAO = 40 V) are illustrated in Fig. D value of each nanobowl is ~100 nm. Moreover, the average D value can be tailored from 60 nm to 150 nm by adjusting the VAAO value from 20 V to 60 V, and the functional relationship between D and VAAO is approximately linear35.The SEM image and the high-resolution 2D AFM image of Al nanobowl array (VAAO = 40 V) with different thicknesses as shown in Fig. 37 and the character of thermal evaporation method, which both facilitate the subsequent SSD process dramatically. However, it is worth to note that the Au film (tAu = 2.5 nm) is quite different from the other two ones, exhibiting discontinuous cracking morphology. According to previous study6, SSD process is typically initiated at the edge of thin film or defect sites. Hence, the discontinuous and continuous Au film are supposed to display different results after SSD process12.Then, thin layers of Au are thermally evaporated onto the Al nanobowl arrays 39.When the Au-coated Al nanobowl arrays undergo thermal treatment, the Au films start to interact with the topography of underlying Al nanobowl arrays as shown in Fig. 3 and cracks in the Au film, resulting in subsequent SSD process mainly takes place at each bowl position independently. It should be noted that the dent position between adjacent protrusions also hold small amount of Au, which also endures a SSD process during the thermal treatment, leading to the formation of the small patches surrounding the nanobowl  with different thermal treatment temperatures: 300 °C, 350 °C and 400 °C, respectively. At lower thermal treatment temperature (300 °C and 350 °C), there are relatively more small Au nanoparticles existing at the dent position compared with 400 °C. The average diameter of Au nanoparticles also rises with increasing of thermal treatment temperature, indicating the small Au nanoparticles at dent position diffuse to the bowl position  of 20 V . In order to obtain highly ordered Al nanobowl arrays, a two-step electrochemical anodizing process was adopted45. The Al foils were first anodized for 2 h followed by immersion into a mixture of chromic acid (1.8 wt%) and phosphoric acid (6 wt%) at 75 °C (1:1 in volume) for 2 h. The AAO layer which grew during the first step was removed and the surface of the Al foil became bright again. The second anodizing step and AAO removal process were carried out the same as the first step. Finally, Al nanobowl array templates with different unit sizes (denoted as D) can be obtained.High purity Al foils  were firstly degreased by acetone and deionized water, and then electro-polished by using a mixture of ethanol and perchloric acid with volume ratio of 4:1 under a constant direct-current voltage of 15 V for 3 min to further remove the surface impurities. After rinsing in deionized water and drying, the Al foils were anodized separately in a 0.3 M oxalic acid solution at 4 °C at a constant direct-current voltage (denoted as tAu) was monitored by Film Thickness Monitor (Taiyao FTM-V). Au films with different tAu values were thermally evaporated onto the Al nanobowl array templates and the evaporation rates were all maintained at ~0.01 nm s−1 with initial chamber pressure below 2 × 10−4 Pa. Next, thermal treatments were conducted at 400 °C (300 °C or 350 °C) for sufficient times under a pressure of ~0.1 Pa in a CVD furnace, and followed by rapid cooling in air.The Au film evaporation procedure was conducted in a Thermal Evaporation System (ZHD-400), and the film thickness (denoted as Atomic Force Microscopy (AFM) (BRUKER Dimension Icon) was used to investigate the surface morphology of Al nanobowl array template. Field Emission Scanning Electron Microscopy (FE-SEM) (FEI Inspect F50) was employed to observe the morphological evolutions of the surface nanostructures under different synthesis parameters. The UV-Vis spectra were acquired from a SHIMADZU UV-2600 Spectrophotometer. Image-Pro Plus Version 6.0 was used to calculate the Au nanoparticle diameter distributions.Supplementary Info


Solution-based precipitation on polymer microballoons produces very stable and luminescent, ceramic materials of extremely low density. As a result of the – compared to established template-directed syntheses – reduced mass of polymer that is lost upon calcination, micron-sized particles are obtained with mesoporous walls, low defect concentrations, and nanoscale wall thicknesses. They can be produced with larger diameters (~25 µm) compared to known hollow spheres and exhibit an optimized flow behavior. Their temperature sensing properties and excellent fluidic follow-up behavior are shown by determining emission intensity ratios in a specially designed heating chamber. Emission spectroscopy and imaging, electron microscopy and X-ray diffraction results are presented for aerosolizable Y2O3 with an optimized dopant concentration (8%). Challenges in the field of thermofluids can be addressed by combined application of thermometry and particle image velocimetry with such hollow microparticles.Recently developed laser-based measurement techniques are used to image the temperatures and velocities in gas flows. They require new phosphor materials with an unprecedented combination of properties. A novel synthesis procedure is described here; it results in hierarchically structured, hollow microspheres of Eu Reports on nanosized materials are frequent4, but microstructures may be even more promising for certain applications like gas phase thermometry or the microencapsulation of drugs, cosmetics, inks, pigments, and chemical reagents5. Recent successes on closing the size-scale gap relied on photolithography or additive manufacturing as well as on the pyrolysis of polymeric microlattices, to create three-dimensional microarchitectures of TiN ceramics6 or Ni-P metamaterials7, just to name two examples. Bioinspired materials with hierarchical structures have been obtained also by freeze casting8. Hollow structures promise extraordinary functionalities, carbon for example is discussed for the superior lightweight mechanics of its nanolattices9 and the excellent catalytic activity of bimetal nanoparticles in its hollow nanospheres10. It is important to emphasize that while there is a significant lack in the synthesis methodology for hollow particles on the microscale, very interesting nanoparticles of phosphor materials have been described, e.g. SrAl2O4:Eu2+,11 or MOF@Fe3O4/SiO212. Even hollow nanophosphors were synthesized, examples being Gd2O2SO413 or SrZrO3:Eu3+ for thermometry applications14.New hollow and multiscale structures of materials for sustainable energy consumption and other applications are very much sought after15. Now, a new type of tracer particles of phosphor materials with an excellent thermal and fluidic follow-up behavior was developed for this purpose and is presented here, both in terms a) of synthesis and characterization and b) of applicability in thermometry (proof-of-concept). One of the major challenges in thermofluids poses the ideal heat-transfer, for example in film cooling of gas turbines16. Thermographic phosphors are used for contact-free temperature sensing17. Combustion chambers can be optimized based on surface temperature measurements18, and earlier we showed optimized, custom-made powders of a variety of phosphor materials to be useful for further thermometry method development20. Now, to measure flow and temperature simultaneously and thus optimize gas-processes for maximum energy efficiency, aerosolized particles were probed for combined thermometry and particle image velocimetry to measure and visualize the properties of gas streams. Single-shot laser-induced spectroscopy requires phosphor particles with sufficient sensitivity and excellent fluidic follow-up properties, meeting the challenge to yield a very good signal-to-noise ratio and sufficient temperature resolution on a microsecond timescale. For this purpose, particles were specially designed concerning their fluidic following behavior, temperature adaption, and emission intensity. We predicted low-density microscale powders to be optimal for particle image velocimetry and developed a new synthesis route to hollow microspheres of crystalline phosphor materials with good stability and efficiency at high temperatures. We were aiming at diameters of several micrometers to obtain good following behavior, a considerably smaller wall-thickness for fast temperature adaption, and high crystallinity to yield high emission intensity. Y2O3:Eu is an excellent model system since it is a well-established red emitting phosphor22 with high brightness and good thermal as well as mechanical stability. It has been prepared by many different methods , but never as microscale and hollow particles in scalable amounts. Here we demonstrate an elegant route to hierarchically structured particles with high crystallinity. Furthermore, we provide a proof-of-concept of aerosolized particles enabling high-temperature thermometry.It is of high practical relevance to meet the challenge of measuring at the same time gas-phase temperature and velocity flows to investigate turbulent mixing phenomena, as discussed in a very recent and extensive review on thermographic phosphor particles2O3:Eu is formed. The unconventional template plays a crucial role in the process. Compared to full templates, the hollow, micrometer-sized polymer balloons with a very low-density (24 kg.m−3) cause low carbon contents of the precursor materials and low CO2 losses during thermolysis. This results in very small, nanoscale pores (mesopores according to IUPAC28) in the ceramic walls that enhance the stability and crystallinity of the thermographic microspheres, which is both very important for the envisioned use in particle image velocimetry. High-resolution transmission (HRTEM) and high-resolution scanning electron microscopy (HRSEM) images exhibit hollow microspheres  J/(g·K) at 423 K) and compacted (cp = 0.44(0) J/(g·K) at 423 K), had specific heat capacities comparable to those of bulk material as reported in literature (cp = 0.45 J/(g·K) for undoped Y2O329, see Supplementary information for further discussion). Surface determination resulted in a value of ~11 m²·g-1. Furthermore, all samples were subjected to energy-dispersive spectroscopy to verify the composition. A miscibility up to 12% Eu was observed, and the doping concentration of Eu optimal for thermometry was determined by luminescence measurements at room temperature under static conditions. A doping concentration of about 8% (a = 1062.0(2) pm, compared to a = 1062.2(1) pm for bulk Y2O3:8%Eu in literature30 exhibited the highest emission intensity. Thus, samples of hollow microspheres of Y2O3 with 8% Eu were then used to demonstrate one of the diverse possible applications of hollow microspheres: gas phase thermometry. This presumes that the microspheres rapidly adapt to the surrounding gas phase temperature. We predicted microspheres to be advantageous compared to solid particles due to their much lower thermal inertia. Because of the lower slip between velocities of the gas phase and the microspheres during rapid acceleration typical for turbulent motions, their minute mass inertia should be additionally favorable for particle image velocimetry31. For thermometry, the temperature-dependent spectral properties of Y2O3:Eu were exploited. Two transitions in Eu3+, 5D0 → 7F0,1 and 5D0 → 7F2, were used for temperature reading. The relative intensities of the spectral bands in the range of 580 to 650 nm change upon UV excitation (266 nm), as indicated in Fig. 3+ in Y2O333 and can be calibrated against thermocouples.By differential scanning calorimetry it was shown  particles require several hundred grams of phosphor material. Due to the restricted amounts of product available from the novel synthesis procedure at this early stage of investigations, a new and sophisticated measurement concept was developed to allow for a proof-of-concept for hollow microspheres thermometry. To demonstrate that the newly designed particles are especially suitable for this method of temperature measurement, a test rig was designed based on momentum transfer to aerosolize the microspheres into the gas phase. The working principle is outlined in Fig. 2O3:Eu hollow microspheres were placed onto a metal membrane. This membrane was set into oscillation transferring momentum to the microspheres such that they float the entire volume of the chamber. Due to the low mass inertia and the low flow velocity within the chamber, the microspheres remained unsupported in air for the full period of measurement. Luminescent centers of the microspheres were excited electronically using a vertically oriented two-dimensional UV laser light sheet that intersects the chamber centrally. The luminescence emission was recorded by two CCD cameras. Each of the cameras was equipped with interference filters covering a specific spectral range  were chosen as templates. All other chemicals were purchased from Acros Organics and used without further purification.Hollow particles of Y3)3·6H2O , Eu(NO3)3·6H2O  and urea (99.5%) were dissolved in 25 ml demineralised water and were added slowly to the suspension via a dropping funnel, while the reaction temperature was increased up to 363 K. The ratio of Y and Eu was chosen according to the targeted doping concentration; the total amount added up to 1 mmol. The amount of urea was 3 g (50 mmol). The reaction mixture was stirred for 3 h and then cooled to room temperature. The suspension was transferred into a separating funnel. The precursor-coated templates were separated from small amounts of undesired bulk precipitate, then filtered in a suction filter and washed with demineralised water, ethanol, and diethyl ether, and dried. Slightly yellow precursor particles were transferred into an alumina crucible and heat-treated in air . Afterwards the samples were characterized through X-ray diffraction, scanning electron microscopy and energy-dispersive X-ray spectroscopy.In a typical synthesis, microballoons (2.5 g) were transferred into a 250 ml three-neck round bottom flask with addition of 125 ml of demineralised water. The suspension obtained was stirred and heated to 342 K. Meanwhile Y. For Rietveld refinement, the published structure of Y2O339 was chosen as a starting model and the TOPAS suite of programmes40 was used.X-ray powder diffraction data were collected at room temperature by a powder diffractometer  with Cu radiation  equipped with an energy-dispersive X-ray spectrometer  and a transmission electron microscope .Differential scanning calorimetry measurements were executed using a Netzsch instrument (DSC 404 F1 Pegasus) and platinum crucibles in an atmosphere of dried Ar.Surface determination was performed by nitrogen adsorption-desorption at 77 K . Data evaluation was carried out with the software QuadraWin (version 6.0).2O3:Eu hollow microspheres. The box-shaped chamber has dimensions of 200 × 165 × 165 mm. The metallic frame is equipped with eight cartridge heaters  to vary the temperature of the chamber between 294 and 469 K. Side and top walls are either made of copper (6 mm) or quartz plates (3 mm). The high thermal conductivity of the copper plates ensures a rapid homogenization of the chamber temperature. Two opposite copper side walls are equipped with narrow quartz windows providing access for the laser radiation. Perpendicular to the axis of laser propagation a larger quartz window enables imaging of luminescence emitted from single microspheres  of YPhosphor thermometry is used for measuring gas phase temperatures. This presumes a low thermal inertia of the phosphor particles. For an adequate signal-to-noise ratio, the dimensions of individual particles have to be at the micrometer scale. These two requirements motivated the use of hollow microspheres.2O3:Eu changes with temperature. For planar temperature measurements two spectral bands were monitored separately using two CCD cameras. These spectral bands were selected by appropriate bandpass filters and are denoted as “blue” (Sphblue) and “red” (Sphred) channels. For a thermographic phosphor such as Y2O3:Eu, the intensity ratio (r) of the “blue” and “red” filter band is a function (equation (41:Following a pulsed UV laser excitation 266 nm), the emission spectrum of the phosphor Y66 nm, th41. For this purpose, the emission spectra of Y2O3:Eu hollow microspheres were recorded upon UV excitation in an electrical tube furnace using a Czerny-Turner type spectrometer in combination with a CMOS camera. As a result of these preparatory measurements, Fig. The temperature-dependent term is usually calibrated against thermocouple measurements. Spectral bands must be properly selected to combine as best as possible a high temperature sensitivity with high luminescence intensitiesHollow microspheres were excited by the fourth harmonic (266 nm) of a pulsed Nd:YAG laser  operated at 5 Hz. A combination of half-wave plate and polarizer was used to adjust the laser pulse energy to 35 mJ which was constantly monitored. Using a set of spherical and cylindrical lenses the laser beam was formed into a 40 mm high and 200 µm thick light sheet intersecting the optically accessible chamber centrally. Upon single-pulse excitation, the luminescence signal was collected perpendicularly to the laser light sheet and parallelized by an achromatic lens . Using a dichroic beam splitter  the luminescence signal was split into its “blue” and “red” channels. Additional interference filters in front of each CCD camera monitoring both channels were centered at 580 nm and 610 nm, respectively . The CCD cameras  were equipped with a Nikkor and a Carl Zeiss Objective , respectively. The field-of-view was 52 × 40 mm and a 2 × 2 pixel hardware binning was applied to reduce read-out noise. Finally, a spatial resolution of 230 µm was achieved. The camera’s exposure times were set to 2 ms, starting 10.5 µs prior to the laser excitation.Very large hollow spheres or agglomerates cause high luminescence intensities exceeding the dynamic range of the CCD cameras. Accordingly, saturated pixels were identified by their count-level and were excluded from any further analysis.The background is specific to the “blue” and “red” channel and was subtracted from each image. Mean background images were recorded separately with the UV-laser in operation but without any aerosolized seeding particles.41. For identifying individual microspheres in a first step, an intensity threshold of 50 counts was applied to the images of the “red” and 20 counts to the “blue” channel to remove remaining background noise. Subsequently microspheres were identified as local maxima within sub-regions extending 3 by 3 pixels. If for an ensemble average of 100 individual images the number of microspheres identified in the field of view ranged between 4 × 1010 and 7 × 1010 particles/m3, the image sequence was accepted for further processing.The densities of aerosolized hollow microspheres varied over time. Images with too low/too high densities were excluded from further processing. Too high densities of aerosolized microspheres are prohibitive due to multiple scattering that causes systematic errorsThe images of the “blue” and “red” channels were mapped onto each other in physical space using a calibration target  and registered by a custom-made Matlab algorithm.A 7 × 7 pixel moving average filter was applied to reduce noise and to prepare for the ratio operation.According to eqn.  the inteA 4 × 4 binning was applied to increase the signal to noise ratio.Using spatially homogeneous conditions at room temperature a flat field correction was conducted to correct for vignetting and inhomogeneous CCD sensitivities.A 7 × 7 pixel moving average filter was applied to smooth the ratio.2O3:Eu hollow microspheres can replace solid phosphor particles but with much reduced thermal inertia and mass inertia.The resulting intensity ratio of a 1.5 mm × 1.5 mm sub-region at the center of the chamber was spatially averaged and correlated to the reading of a thermocouple . The thermocouple was placed prior to each measurement of the mean intensity ratio at the central position of this sub-region. A calibration curve resulted that allows to trace back the optical measurement to a well-accepted temperature standard used in engineering. Figure Converting digital images of the “blue” and “red” channel into temperatures requires a sequence of post-processing steps.Supplementary Information


Phosphate–phosphate oligomerization is shown to drive its recognition properties as revealed in co-assemblies with stackable macrocyclic hosts. 2PO4···H2PO4···H2PO4]3–. The solution behaviour, studied as a function of solvent quality, highlights how dimers and trimers of phosphate drive formation of higher order stacks of cyanostar into dimer, trimer and tetramer co-assemblies. Solution behaviors differ significantly from simpler complexes of bisulfate hydroxyanion dimers. Phosphate oligomerization is: (1) preferred over ion pairing with tetrabutylammonium cations, (2) inhibits disassembly of the complexes upon dilution, and (3) resists interference from competitive anion solvation. The phosphate oligomers also appear critical for stability; complexation of just one phosphate with cyanostars is unfavored. The cyanostar's ability to self-assemble is found to create a tubular, highly electropositive cavity that complements the size and shape of the phosphate oligomers as well as their higher charge. When given the opportunity, phosphate will cooperate with the receptor to form co-assembled architectures.The importance of phosphate in biology and chemistry has long motivated investigation of its recognition. Despite this interest, phosphate's facile oligomerization is only now being examined following the discovery of complexes of anion–anion dimers of hydroxyanions. Here we address how oligomerization dictates phosphate's recognition properties when engaged with planar cyanostar macrocycles that can also oligomerize by stacking. The crystal structure of cyanostar with phosphate shows an unprecedented tetrameric stack of cyanostar macrocycles threaded by a phosphate trimer, [H Presumably, the propensity of phosphate to oligomerize as well as the characteristics of the receptors will help determine the types of complexes it forms. We test these ideas here using stackable cyanostar macrocycles that can let the phosphates oligomerize into linear assemblies upon complexation.Phosphate is important to structural biology,rocycles . While brization . PhosphaComplexation of multiple phosphates has only a few examples in solution. Most examples seen in the solid stateK = 225 M–1 in dichloromethane, 600 M–1 in acetonitrile)e.g., 4 : 4 stoichiometry,4–.The self-recognition properties of cyanostar macrocycles present a unique environment in which to interrogate the stabilization of hydroxyanion oligomers of phosphate. The anion-binding cavity of cyanostar and its propensity to self-associate by stacking (+) cations for charge balance. In solution, the 4 : 3 cyanostar–phosphate assembly, as well as 3 : 2, 3 : 3 and 2 : 2 co-assemblies, are identified from equivalence points paired with unique 1H NMR signals associated with the different stacking modes, i.e., cyanostar tetramer, trimer, and dimer. We see a distribution of species (low fidelity) in all solvent systems examined. This feature emphasizes phosphate's almost pathological tendency to oligomerize and cyanostar's ability to let it happen. Phosphate's unrestricted co-assembly with cyanostar also marks just one of the many specific differences relative to bisulfate's truncation as anion–anion dimers. Unlike bisulfate, co-assemblies of cyanostar stacks and phosphate oligomers are resistant towards ion pairing in chloroform, resist falling apart upon dilution in dichloromethane–acetonitrile, and resist competitive solvation by addition of methanol to dichloromethane. We also demonstrate co-assembly in the solid state with a 1D chain that is composed of a rare repeat of six phosphates and one phosphoric acid (H3PO4). Ultimately, it is the phosphate and its propensity to oligomerize that marshals cyanostar stacking to enable the linear organization of the co-assemblies. Nevertheless, the receptor's stabilizing electropositive pockets with their shapes and sizes dictate both the extent and geometry of the phosphate oligomers.Our findings show that phosphate oligomerization, in contrast to bisulfate dimerization,+) phosphate  is indicative of borderline strong hydrogen bonds.4···HSO4]2–.1H NMR signals of the cyanostar and cation signals acquired from the crystals dissolved in solution  between cation and anion is significantly longer than the sum of van der Waals distances of constituent atoms (H···O) ∼2.7 Å as well as being longer than the corresponding contact in the bisulfate structure  with an additional one equivalent of TBA+ as the salicylate salt. To validate the generality of the molecular chain in the solid state, crystals were also grown using the equally weak BArF anion; the same crystal structure was obtained. Interestingly, neither the salicylate nor BArF anions are incorporated into the crystal, and thus, we assume that they remain in the mother liquor.Unexpectedly, the addition of extra TBA+ counter cations; 4(CS) : 6(H2PO4–) : 1(H3PO4) : 6(TBA+). The acid likely emerges on account of its modest acidity, pKa1 = 2.1 (water). Consistently, the acid form is not seen with cyanostar complexes of bisulfate, which is attributed to sulfuric acid's strength, pKa1 = –3 (water).The stoichiometry in the unit cell is consistent with a ratio of four cyanostars, six phosphates, one phosphoric acid, and six charge-balancing TBACS) : 6(H2PO4–) : 1(H3PO4) : 6(TBA+) crystal structure observed with the extra cations  from the six phosphates (H2PO4–).The 4( cations  is signi cations . This st3) of these crystals  might drive formation of a 2 : 2 : 2 species as a consequence of enhanced ion pairing. While the NMR titration with phosphate in chloroform . Examination of the cation's NMR signals during the titration as well as from a measurement of its diffusion coefficient at 1 eq.  with a few other minor peaks. It is only with the addition of 2 eq. , 2 : 2(2–), 3 : 3 : 1(2–) and 2 : 2 : 1(1–). Furthermore, the signature for the tetrameric and trimeric stacks are seen in 1H NMR titrations conducted at 10 mM . We believe that molecules of methanol partially solvate the bisulfate anion inside the cyanostar complex. With phosphate, however, use of methanol as a co-solvent does not truncate the anion's oligomerization. Rather, the titration data  but the non-traditional electrostatic interactions (anion–anion) does not; the microenvironment of the stacked cyanostars presumably playing a critical role.The sequence of species follows the expectations of mass balance but it differs from pure dichloromethane in an interesting way. In dichloromethane, the triple stack can support a trimer of phosphates when ion paired with TBAThe resistance of phosphate's oligomerization to competitive solvation is another clear departure from bisulfate. A comparison of the ESI-MS is consistent with the differences between the two anions  only moves 0.11 ppm, while with perchlorate in the tight 2 : 1 complex it was 0.45 ppm.Another unexpected feature emerges in the recognition of phosphate, specifically, it appears there is poor affinity between cyanostars and just one phosphate, te 1 mM, , 298 K tTo further investigate the weak stability of the 2 : 1 phosphate complex, we conducted variable concentration studies. We selected 1 eq. of anion and a 40/60 v/v% methanol : dichloromethane solvent mixture in order to compare our findings to the variable concentration data recorded with bisulfate.31Taken together, these observations suggest that complexation of phosphate by cyanostar is much greater when the more highly charged dimer dianion and trimer trianion can be formed during the addition of more equivalents of the anion. The behavior observed with phosphate indicates an all or nothing binding: that is, we believe the complexes of the dimers and trimers of phosphate have populations (and stabilities) significantly greater than a single phosphate. Thus, phosphate appears dormant as a guest until it can start to oligomerize. This type of behaviour has been reported elsewhere.17Based on the study with bisulfate,The phosphate-based species are also more robust upon dilution when compared to bisulfate complexes in an acetonitrile–dichloromethane mixture. With 1 eq. of bisulfate, the 3 : 2 complex gave way to the 2 : 1 sandwich complex at relatively high concentrations (500 μM). When using phosphate, however, we see the 3 : 2 and 4 : 3 species are retained down to 50 μM . This fiεeff = 4.8, y, and 2 : 2 : x. In the methanol and acetonitrile mixtures (Overall, we see phosphate oligomerization gets expressed across all solution conditions. In chloroform (mixtures , howevermixtures . This femixtures . Even th2PO4···H2PO4···H2PO4]3– inside cyanostar tetramers and trimers as well as phosphate dimers [H2PO4···H2PO4]2– inside cyanostar trimers or dimers are observed. Low-fidelity mixtures are seen across various solutions on account of the dominance of oligomerization. The co-assemblies are extremely robust and display behaviors differing significantly from bisulfate in the solid state and in solution. Oligomerization of phosphate is seen to decrease the importance of ion pairing interactions in offsetting the long-range coulombic repulsions emerging when multiple anions are hydrogen bonded to one another. The oligomerization even impacts affinity in a positive manner with a single phosphate appearing to sit dormant until it can oligomerize. We also see that the recognition of anion–anion species is more complex with phosphate than bisulfate on account of its facile protonation and access to phosphoric acid. Ultimately, phosphate's oligomerization is key to understanding its recognition by larger receptors where the shape and size of the receptor appears to control the extent and geometry of the oligomers formed.Phosphate oligomerization drives the formation of higher order co-assemblies in cooperation with cyanostar. Phosphate trimers [HThere are no conflicts of interest to declare.Supplementary informationClick here for additional data file.Crystal structure dataClick here for additional data file.


High-sugar/high-fat foods are related to binge-eating behaviour and especially people with low inhibitory control may encounter elevated difficulties to resist their intake. Incentive sensitization to food-related cues might lead to increased motivated attention towards these stimuli and to cue-induced craving. To investigate the combined influence of olfactory and visual stimuli on craving, inhibitory control and motivated attention, 20 healthy controls and 19 individuals with binge-eating viewed chocolate and neutral pictures, primed by chocolate or neutral odours. Subjective craving and electroencephalogram activity were recorded during the task. N2 and Late Positive Potential (LPP) amplitudes were analysed. Patients reported higher craving than controls. Subjective craving, N2 and LPP amplitudes were higher for chocolate versus neutral pictures. Patients showed a higher relative increase in N2 amplitudes to chocolate versus neutral pictures than controls. Chocolate images induced significant increases in craving, motivated attention and measures of cognitive control. Chocolate odour might potentiate the craving response to visual stimuli, especially in patients with binge-eating. In our modern society, food is omnipresent; it can be easily purchased and rapidly consumed, without the need of further processing steps. The ubiquity of food in the environment may be highly problematic for some individuals, leading to obesity or even eating disorders. Binge eating disorder (BED) and bulimia nervosa (BN) are both marked by recurrent binges and high experienced cravingChocolate is one of the most heavily craved foods and perceived as highly problematic with regard to the controllability of its intakeWith regard to olfactory cue-induced craving, research has shown that the smell of food leads to both intensified craving and increased food intake in restrained as well as in normal eaters89As to the effect of food odours on brain activity, basic studies in humans have reported a reduction of low frequency electroencephalogram (EEG) activity in response to different odours13et al., 2015b).With regard to visual stimuli, incentive salience of food cues, which corresponds to the craving or “wanting” for these stimuli21Low inhibitory control is another important aspect of overeating, loss of control over food intake and addictive behaviours252730The main aim of this study was to compare BEP to HC with regard to their craving and neurophysiologic response towards visual chocolate stimuli. Thereby it was hypothesized that chocolate pictures would evoke higher craving (self-report) and LPP and N2 amplitudes than neutral pictures (hypothesis 1a) and that there would be a positive relation between self-reported craving and LPP and N2 amplitudes (hypothesis 1b). With regard to group differences, it was hypothesized that BEP compared to HC would have more craving (self-report), more motivated attention (LPP) and less cognitive control (N2) resources (hypothesis 2). Moreover, we expected an increase of state chocolate craving throughout the experiment (hypothesis 3). A second aim was to explore the influence of chocolate odour on the processing of visual chocolate stimuli; we hypothesized that olfactory and visual stimuli would have an additive effect, leading to a potentiated response (hypothesis 4). The third aim was to test if there are differences between BEP and HC in the response to chocolate odour alone. We expected a higher subjective craving reaction towards odour stimuli in BEP than in HC (hypothesis 5); regarding theta frequency, due to the explorative nature of this aim, no directional hypothesis was put forward.n = 20, age 20–56 years, see means (M) and standard deviations (SD)) was recruited from students of the University of Barcelona and through a snowball system from hospital staff. The BEP group  was recruited from consecutive referrals to the ED unit of Bellvitge University Hospital and diagnosed by means of semi-structured face-to-face interviews to either BN (n = 12) or BED (n = 7) according to the criteria of the fifth edition of the Diagnostic and Statistical Manual . See The HC group  or being obese (Body Mass Index [BMI] ≥ 30) or underweight (BMI < 18.5).Exclusion criteria for all participants were: being male, younger than 18 years, current or life-time history of chronic illness (which could influence electrophysiology) or neurological condition , having used in the last 24 hours psychoactive medication or drugs that may interfere with smell-taste capacity or cortical activity, current substance dependence, lifetime diagnosis of psychotic disorder, functional anosmia , and pregnancy. Additionally, in the HC group, an exclusion criteria was a lifetime diagnosis of ED, assessed by means of Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) (First The study was conducted in compliance with the Declaration of Helsinki (1975) and the Spanish legislation and norms, after revision and approval by the local ethics committee (CEIC Ciutat Sanitària i Universitària de Bellvitge). All participants signed informed consent. The study participation consisted of two parts of approximately one hour each, which were realized either in one or in two separate sessions (50% of HC and 63% of BEP did two sessions). The first part was to check inclusion criteria, participants were weighed and measured (height and head circumference), and were tested regarding their olfactory capacity. In the second part participants filled in a laboratory questionnaire , food eaten this day, menstrual cycle, and intake of coffee, alcohol and drugs in the last 24 hours), then the EEG electrodes were placed on the participant’s scalp and she did the experimental task with a duration of 26 minutes. Participants were instructed to have a normal meal two hours before doing the second session and then to refrain from eating until completion of the experiment.Hypotheses were tested in a controlled mixed study design. The intra-factors “odour type” and “picture type” were presented at random and counter-balanced order, with 4 combinations of chocolate versus neutral valence in the two sensory modalities . Each condition was done twice, in two consecutive sections with 8 blocks of 56 trials each, leading to a total of 224 neutral and 224 chocolate picture trials see .et al.Visual stimuli were 56 pictures each of chocolate products and neutral office items, used and kindly placed at our disposal by Frankort and colleagues (2014). Pictures were presented in random order on a grey computer screen using the stimulus delivery software Presentation ; one block consisted of 56 trials, each starting with a fixation cross (500 ms), followed by the picture (1200 ms). Each visual block was preceded by a 1 min olfactory exposure to either chocolate or neutral odour, presented by a laboratory assistant; the participant had her eyes closed during this exposure. During the olfactory stimulation, participants were exposed to the smell of either a piece of chocolate or a pencil (as in Frankort Food Chocolate-Craving Questionnaire (FCCQ) – State and Trait Version32visual analogue scale (VAS) scaling from 0 (very little) to 100 (very strong) asking “At this moment, how much desire to eat do you have?” at 17 time points throughout the experiment, once at baseline and then after each of the odour and visual presentations in the eight blocks.Subjective chocolate craving was assessed on three different levels: trait craving was assessed during the baseline assessment session and state craving was assessed before and after the experimental manipulation through the Additional psychometric questionnaires were used in order to assess difficulties in emotion regulation . 60 active Ag/AgCI electrodes were inserted into an EEG recording cap (EASYCAP GmbH), distributed after the 10–20 system, the Cz electrode was used as online reference. Four electrodes were placed next to the eyes in order to control for eye movements. Impedances were reduced to be smaller than 20 KOhm using the SuperVisc high-viscosity electrolyte gel for active electrodes. A sampling rate of 500 Hz and an online filter between 0.1 and 100 Hz were used.The N2 was measured at electrodes AFz , AF3, F1, F3 (left N2) and AF4, F2, F4 (right N2) as the amplitude and latency of the maximum negative peak in the time window 180–350 ms after visual stimulus onset. The time window for the LPP was set to 300–1000 ms after visual stimulus onset and measured as the maximum positive peak at centro-parietal electrode sites: Pz , CP1, CP3, P1, P3, P5 (left LPP) and CP2, CP4, P2, P4, P6 (right LPP). See Statistical analyses were conducted with SPSS20 for Windows. For a description of the sample, socio-demographic and clinical variables were compared between the two groups using analysis of variance (ANOVA).In order to test hypotheses 1a, 2 and 4, for momentary craving in response to picture stimuli, the mean VAS value of the two blocks for each condition was used in an analysis of covariance (ANCOVA) adjusted for baseline momentary craving, with the repeated factors “odour prime”  and “picture type”  and the between subjects factor “group” (HC/BEP). For each of the ERPs (N2 and LPP) the additional factor “localization” was added, wherefore a 2 × 2 × 3 × 2(“group” BEP/HC) ANOVA was calculated for main effects of picture type (hypothesis 1a) and group (hypothesis 2). For hypothesis 4, interaction effects were analysed. Pairwise comparisons were used to follow up main and interaction effects.r > 0.24 (corresponds to d > 0.5) and large for r > 0.3 (corresponds to d > 0.8)39Partial correlations including the covariates age and baseline-mood were calculated for each group to look at the relation between dependent measures, i.e. between subjective craving ratings and electrophysiological brain response (hypothesis 1b). Correlations were considered as moderate for For hypothesis 3, state chocolate craving (FCCQ-S) before and after the experimental task was compared using repeated measures (“time” pre/post) ANOVA with the between subjects factor “group” (BEP/HC).For hypothesis 5 regarding momentary craving in response to odour stimuli, an ANCOVA adjusted for baseline momentary craving, with the repeated factor “odour type”  and the between subjects factor “group” (HC/BEP) was calculated using the mean of the four VAS ratings assessed after odour presentation. For the QEEG data, theta frequency was compared by use of a 2 × 2(“group” BEP/HC) ANOVA to test for main and interaction effects.p < 0.05 after Bonferroni-Finner correction to avoid Type-I errors. Mauchley’s Test was used to test for sphericity and if the assumption was not met (p < 0.05), Greenhouse-Geisser corrected values were used. Effect sizes were calculated as partial Eta squared (ηp2) for ANOVA or Cohen’s d for mean differences (MD), while ηp2 > 0.01 or d > 0.2 are considered as small, ηp2 > 0.06 or d > 0.5 as moderate and ηp2 > 0.14 or d > 0.8 as largeComparisons were considered significant with The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.MD = −1.46, p < 0.01) and more hunger  than HC at baseline before doing the experimental task. However, the time since they had had their last meal did not differ between the two groups (p = 0.13) and correlations between baseline-hunger and dependent variables  were low (rs ≤ 0.3). Age and baseline-mood were both found to have an influence on the correlations between dependent variables, but since the estimated means were very similar (variation of <10%) when adjusting the models by age and baseline-mood into ANCOVAS, in order to simplify the models and to maintain statistical power, it was decided to calculate ANOVAS without adjustments referring to the principle of parsimoniaGroups did not differ in their olfactory capacity and all of the participants had values within the normal range . Chocolate pictures induced higher momentary craving than neutral pictures, which supported hypothesis 1a. A significant main effect of “odour prime”  showed that a preceding chocolate odour led to higher momentary craving than a preceding neutral odour. Pairwise comparisons showed that chocolate compared to neutral odour did not have a significant effect on the rating towards neutral pictures  but it did affect the rating towards chocolate pictures , which gave support for hypothesis 4. There was no main effect for “group”, or significant interaction , wherefore hypothesis 2 was not supported with regard to higher subjective craving in BEP as compared to HC. See M and SD of momentary craving ratings towards picture stimuli.For momentary craving towards visual stimuli, results showed a significant main effect for “picture type”  showed more craving in response to chocolate odour than neutral odour, but no main effect of “group” nor an interaction between “group” and “odour type” (F = 2.18 and p = 0.15) was found, wherefore hypothesis 5 suggesting higher subjective craving in BEP than HC in response to chocolate odour was not supported.Similar to the results for visual stimuli, for the reaction towards odour stimuli a significant main effect of “odour type” . No further main or interaction effects were found .For N2 peak amplitudes, there was a significant main effect for “picture type” (hypothesis 1a) and “localization” and a significant interaction effect between “odour prime”, “picture type” and “group” (hypothesis 4); an interaction between “picture type” and “group” was marginally significant , characterized by a higher difference score, i.e. higher relative N2 amplitudes in BEP  than in HC . See The marginally significant interaction between “picture type” and “group” was explained through lower amplitudes towards neutral stimuli in BEP than in HC. This led to the conclusion, that BEP have a higher increase in activation when comparing chocolate to neutral stimuli than HC. Therefore, a post-hoc analysis was conducted to calculate a difference score by subtracting for each individual the N2 peak amplitude related to neutral stimuli from the N2 peak amplitude related to chocolate stimuli. An ANOVA of this difference score including “group” as between subjects factor showed a significant effect of “group” (F < 2.5 and p > 0.09), explained through shorter latencies for the central N2 compared to the left and right lateralized N2 . There were no further main or interaction effects . As expected by hypothesis 1a, chocolate pictures led to significantly higher amplitudes than neutral pictures; however, contrary to hypothesis 2, there were no differences between HC and BEP in LPP amplitudes. Highest LPP amplitudes were found at right parietal electrode sites compared to left and central sites, activation at central sites was higher than at left parietal sites  .For LPP peak values, there was a significant main effect of “picture type” (hypothesis 1a) and “localization” and a significant interaction between “picture type” and “localization” (see F < 2.1 and p > 0.16). The LPP peaks for chocolate pictures were earlier in latency than those for neutral pictures. An earlier latency was found for the right LPP compared to central and left LPPs. Latencies did not differ between left and central localization .Contrary to expectations, there were no significant effects for “group” or “odour type” in theta frequency  and higher LPP amplitudes (rs = 0.12 to 0.48). Surprisingly, for BEP this pattern was different: higher momentary craving (VAS) and higher state craving (FCCQ-S) predicted smaller N2 (rs −0.02 to −0.41) and LPP amplitudes (rs = 0.06 to −0.41) .With regard to hypothesis 1b of a positive relation between subjective and electrophysiological dependent variables, results differed between groups. For HC, momentary craving was positively correlated with N2 and LPP amplitudes, high correlations were found for chocolate pictures primed by chocolate odour. Higher state chocolate craving at baseline went along with higher N2 (F = 42.87 and p < 0.001) and of “group” (F = 5.57 and p < 0.05). There were higher P1 amplitudes for chocolate  than for neutral  pictures and HC  had higher amplitudes than BEP . Because of these group differences, the analyses for N2 and LPP amplitudes were repeated, including the P1 amplitudes of each condition as covariates. Although F- and p-values changed slightly by controlling for this factor, in the whole the evidence did not change. The only comparison which lost statistical significance after controlling for P1 amplitudes was the main effect of “localization” for LPP amplitudes. Apart from this, the results found before were supported after taking into account the group differences in P1 amplitudes.Since from visual inspection it appeared that there are big differences between the two groups in P1 amplitudes, a post-hoc analysis with regard to P1 peaks was conducted. Peak amplitudes for the P1 were extracted for each individual at occipital electrodes (Oz and POz) as the maximum positive peak in the time interval 60–150 ms after stimulus onset. An ANOVA including the factors “odour prime” (2), “picture type” (2) and “group” (2) showed a significant main effect of “picture type”  in response to chocolate than HC. However, study results did not show significant differences between groups with regard to LPP amplitudes, wherefore the hypothesis of more motivated attention in BEP compared to HC in response to chocolate stimuli was not supported. Hypothesis 4 of an additive effect of olfactory and visual stimuli was supported only for BEP in that chocolate pictures preceded by chocolate odour led to higher N2 amplitudes than chocolate pictures preceded by neutral odour. The influence of chocolate odour compared to neutral odour stimulation was not visible in theta frequency changes for either of the groups (hypothesis 5).The current study aimed to compare the subjective craving and event-related brain response of individuals with BE and healthy individuals towards visual and olfactory chocolate stimuli. Additionally, the study aimed to explore the additive effect of olfactory and visual stimuli on craving induction.The first set of analyses referred to subjective data, showing that both groups had an increase in craving through the experimental manipulation, BEP reported more craving at baseline and after the experiment than HC. When controlling for baseline craving, chocolate pictures evoked a higher momentary craving response than neutral pictures in participants as a whole, but there were no differences between the two groups. These results were mirrored by ERP amplitudes, with higher amplitudes for chocolate than for neutral pictures in both groups.As expected, there was a significantly higher central N2 for chocolate than for neutral stimuli. There were no group differences in the absolute N2 amplitudes towards chocolate pictures, but the difference in activation between chocolate minus neutral stimuli was higher for BEP than for HC, i.e. the relative increase in response to chocolate pictures after accounting for activation during neutral pictures was higher for patients with binge-eating than for HC. The N2 has been related to response conflict and cognitive inhibitory control in basic research during Go/No-Go tasks25Regarding motivated attention, a late, right lateralized, posterior component consistent with the LPP was higher in amplitude for chocolate than for neutral pictures. The hypothesis of BEP having more motivated attention towards chocolate stimuli than HC was however not supported by our data. In contrast to earlier findingsThe second aim referred to a potential “supralinearity” or additive effect of olfactory and visual stimuli on craving induction. Results of subjective data partly support this hypothesis, by showing an increased craving response towards chocolate pictures primed by chocolate odour, while chocolate versus neutral odour did not modulate the self-reported craving towards neutral stimuli. The influence of a preceding odour stimulus was not visible in the amplitudes of the visually evoked ERPs (N2 and LPP) in the whole sample. There was however a higher N2 amplitude for BEP towards chocolate pictures preceded by chocolate odour than chocolate pictures preceded by neutral odour, which was not found in HC. This might indicate a higher susceptibility of BEP to the odour of food stimuli. A recent study has shown that after appetitive conditioning, formerly neutral images lead to increased amplitudes of the N2-P3 componentThe third study aim was to look at the effect of olfactory stimulation on electrophysiological activity. Similar to the results for visual stimuli, participants reported more craving after smelling chocolate than neutral odour. Contrary to our hypotheses, no differences between groups were found. Furthermore, theta power density was analysed during neutral and chocolate odour presentation, but results did not show any differences between odour types or groups regarding this measure.Although this study has many strengths, such as a sample of individuals with BE psychopathology, an experimental design and the comparison of subjective and electrophysiological measures, there are some limitations which have to be considered. First of all, the total sample was too small to have enough power to discover complex interactions with small effect sizes, wherefore some group differences may not have been detected. Second, the patient sample was a mixed sample of BN and BED patients; although both patient groups struggle with BE and there is a high cross-over between these diagnostic categoriesThis is an important issue for future research. An olfactometer could be used for a simultaneous and precise, event-related presentation of odour stimuli, which may allow a better understanding of the interaction between olfaction and vision in stimulus induced craving. To better understand the meaning of enhanced ERPs in food processing, future studies should also look at neural generators of these potentials. This could also be helpful to inform about possible targets to reduce craving through neuromodulation, as proposed in recent research4546The main conclusions of the current study are that chocolate pictures are related to higher amplitudes in electrophysiological measures of cognitive control (N2) and motivated attention (LPP) than neutral pictures; while BEP might have lower baseline N2 activity, they showed a higher relative increase in response to chocolate cues than HC. When considering self-report, although BEP reported more craving than HC at baseline and after the experiment, when controlling for that variable, there were no differences between the two groups in the craving reaction towards chocolate stimuli . Furthermore, an additive effect of olfactory and visual stimuli on cue-induced craving was partially supported. Chocolate odour to some extent increased the incentive value and craving reaction towards visual chocolate images in both healthy and BEP, but BEP seem to be more susceptible to this effect.How to cite this article: Wolz, I. et al. Subjective craving and event-related brain response to olfactory and visual chocolate cues in binge-eating and healthy individuals. Sci. Rep.7, 41736; doi: 10.1038/srep41736 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Color patterns of 3-dimensional (3D) shear wave elastography (SWE) is a promising method in differentiating tumoral nodules recently. This study was to evaluate the diagnostic accuracy of color patterns of 3D SWE in breast lesions, with special emphasis on coronal planes.A total of 198 consecutive women with 198 breast lesions  were included, who underwent conventional ultrasound (US), 3D B-mode, and 3D SWE before surgical excision. SWE color patterns of Views A (transverse), T , and C  were determined. Sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC) were calculated.P = 0.001). In malignant lesions, “Stiff Rim” was significantly more frequent in View C  than in View A  and View T . AUC for combination of “Crater Sign” and conventional US was significantly higher than View A  and View T , and specificity significantly increased  without significant change in sensitivity  as compared with conventional US.Distribution of SWE color patterns was significantly different between malignant and benign lesions (In conclusion, combination of conventional US with 3D SWE color patterns significantly increased diagnostic accuracy, with “Crater Sign” in coronal plane of the highest value. Shear wave elastography (SWE), as a brand new method of elastography, induces shear waves that transversely propagate in the tissue, using an acoustic radiation force created by a focused US beam. SWE could provide both qualitative and quantitative elastic information in real time, which was proved to be of highly intra- and interobserver reproducibility in breast lesions.Breast ultrasonic elastography has become a routine tool in addition to conventional B-mode ultrasound (US) during the last few years. Although strain elastography with freehand compression was demonstrated useful for differential diagnosis of breast lesions, with sensitivity of 79% to 98% and specificity of 72% to 88%, The important conclusion was that adding SWE features to conventional B-mode analysis improved specificity of breast mass assessment  without loss of sensitivity. Other studies showed similar results of improved diagnostic performance with increased specificity,–8 could increase positive predictive values for nonmass lesions in breast, and thus could reduce unnecessary biopsies of low-suspicion Breast Imaging Reporting and Data System (BI-RADS) category 4A masses. Besides, several studies have indicated the correlation between SWE quantitative features and histologic prognostic factors—breast cancers with higher mean stiffness values at SWE had poorer prognostic features.,11Previous studies have demonstrated the diagnostic performance of SWE in breast lesions, among which the prospective multicenter, multinational study—BE1—was of the largest sample.,13 However, both the 2 studies focused on comparison of quantitative features of SWE, without emphasis on qualitative features, especially comparison of color patterns among transverse, sagittal, and coronal planes. As 1 important qualitative feature, color patterns of SWE first proposed by Tozaki and Fukuma was proved to be useful in differential diagnosis of breast lesions, and diagnostic value of “Stiff Rim” sign, as 1 type of the color patterns of SWE indicating malignancy, was emphasized by Zhou et al. Therefore, the purpose of our study was to determine whether 3 views reconstructed by 3D SWE could provide more information about color patterns and thus improve diagnostic performance, with emphasis on that of coronal planes.The diagnostic values of SWE features mentioned above were for 2-dimensional (2D) SWE, while there were only 2 published studies in 3-dimensional (3D) SWE of breast lesions so far, which demonstrated that diagnostic accuracy of 3D SWE was no better than 2D SWE.22.1This retrospective study was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center, and verbal informed consent was provided by all participating women at times of examinations. From May 2014 to August 2014, 210 consecutive women with 210 breast masses detected by palpation and/or imaging were enrolled, who underwent examinations of conventional 2D US, 3D B-mode, and 3D SWE before surgical excision. Five patients with history of ipsilateral breast surgery and 1 patient with breast implants were excluded, and so were 6 patients with large masses (over 4 cm) which could not be covered by the maximum range of SWE color overlay and thus may impair judgment of SWE color patterns of breast lesions. Finally, 198 women  with 198 breast masses constituted the study cohort.2.2Conventional US and SWE examinations were performed using the Aixplorer US system  by 1 of 3 radiologists with 5 to 20 years of experience in breast imaging. All participating investigators were experienced in performing and/or interpreting over 4000 breast US examinations in the prior 2 years and have practiced SWE on a minimum of 200 cases over the last 6 months. Conventional 2D US and color Doppler was performed with a SL15–4 multifrequency linear-array transducer. We first used the default preset of breast, with center frequency at “GEN” mode, median frequency rate, dynamic range at 70 dB, acoustic power 0.0 dB, and tissue tuner 1480 m/s. When scanning lesions with deep location, we downgraded the center frequency to “PEN” mode, while upgraded to “RES” with superficial location. The color scale was preset at 4 cm/s. For each breast mass, at least 2 orthogonal B-mode images, 1 color Doppler flow image, and 1 pulsed wave Doppler image when necessary were acquired and saved for analysis.,13 3D SWE was carried out with the scale setting at default value—180 kPa.3D B-mode and SWE were performed with a SLV16–5 transducer, which was very lightly applied to avoid compression and kept still during 3D B-mode and SWE data acquisition. The volume scan was automatically performed by using a slow-tilt movement of the sectorial mechanical transducer. Immediately after data acquisition, volume data were reconstructed and displayed in 3 orthogonal planes—transverse (View A), sagittal (View T), and coronal (View C), and then converted to multislice display mode  to have a full view of each slice in 3 planes.2.3,17 When the 2 principle investigators did not reach agreement on the classification, another experienced radiologist was invited to discuss and finally reach a consensus.Before 3D B-mode and SWE imaging, independent and blinded review of conventional US images of all lesions was performed by 2 principle investigators with 20 years of experience in breast US and classified into appropriate categories according to the American College of Radiology (ACR) BI-RADS to indicate probability of malignancy: BI-RADS Category 3 indicated probably benign; Category 4A, low suspicion for malignancy; Category 4B, moderate suspicion for malignancy; Category 4C, high suspicion for malignancy; and Category 5, highly suggestive of malignancy.2.4 To analyze hypothetical effect of 3D B-mode imaging on diagnostic performance of BI-RADS Category assessment, BI-RADS Categories adjacent to cutoff value of diagnosing benign and malignant lesions were regulated according to presence of “Converging Pattern” (upgraded if presence and downgraded if not).The reconstructed coronal planes were observed carefully slice by slice to identify the presence of the “Converging Pattern” in the surrounding tissue and the margin of the lesion, which was highly suggestive of malignancy and defined as hyperechoic bands of fibrous tissue converging toward the hypoechoic central core of the mass Fig. .[21] To 2.5 There were other SWE color patterns defined by BE1 investigators: Pattern 5 (horseshoe), a localized colored area at the margin of the lesion which created an open circle; and Pattern 6 (spots above/below), colored areas visible above and/or below the lesion. Yet another pattern described by BE1 was “Void Area Inside the Lesion”, defined as a lack of SWE signal inside the lesion while the rest of the SWE Box filled correctly, which in our study was included into Pattern 3 if closed circle appeared at the margin or into Pattern 5 if colored area created an open circle. In each plane, the slice showing the maximal diameter of the lesion was selected to determine the SWE color patterns of Views A, T, and C, respectively. Independent and blinded review of 3D SWE images of all lesions was performed by 2 principle investigators with 20 years of experience in breast US to determine the SWE color patterns. Another experienced radiologist was invited to discuss and finally reach a consensus when the 2 principle investigators did not reach agreement.Each lesion was observed successively in transverse (View A), sagittal (View T), and coronal (View C) planes in multislice mode to determine the SWE color pattern, including mainly 4 patterns proposed by Tozaki and Fukuma as follows: Pattern 1 (no findings), the lesion and surrounding tissue both displaying as homogeneously blue without visual difference in between; Pattern 2 , light blue or green stripes extending beyond the lesion and continuing vertically in cords on the cutaneous side or the thoracic wall side; Pattern 3 (stiff rim), a localized colored area appeared at the margin of the lesion and created a continuous closed circle; and Pattern 4 (colored lesion), heterogeneously colored areas present in the interior of the lesion. Patterns 1 and 2 were assumed to be benign, and Patterns 3 and 4 were assumed to be malignant. BI-RADS Categories adjacent to cutoff value were adjusted according to SWE color pattern . BI-RADS Categories did not change with other patterns.As proposed by Tozaki and Fukuma,2.6The diagnostic performance of “Stiff Rim” Pattern alone was specially analyzed. BI-RADS Categories adjacent to cutoff value were regulated according to the presence of “Stiff Rim” (upgraded if presence and downgraded if not).As mentioned above, malignant breast lesions frequently showed as “Converging Pattern” in coronal plane, thus making lesions of “Stiff Rim” Pattern in coronal plane (View C) present as a mass surrounded by a colored rim with radiating hyperechoic bands and appear like craters. So in our study, “Stiff Rim” in coronal plane (View C) was renamed as “Crater Sign”.2.7When we combined SWE with B-mode of coronal plane , BI-RADS Categories were upgraded with the presence of 1 of “Converging Pattern” and “Crater Sign” or both the 2, while downgraded without the presence of “Converging Pattern” nor “Crater Sign”. The diagnostic performance of adjusted BI-RADS Categories was analyzed.2.8All the lesions enrolled underwent surgical excision, and histopathologic outcome was used as the Golden Standard. Final diagnosis for each lesion was made by a pathologist with 20 years of experience in breast pathology who was blinded to the US results.2.9 The Fisher exact test was used to compare independent groups for categorical variables. Nonparametric tests for trend were used for analysis across ordered groups. The McNemar test was used for paired comparison of proportions (sensitivity and specificity). A P < 0.05 was considered to indicate a statistically significant difference.Statistical analyses were performed by using SPSS, version 19.0 . To evaluate diagnostic performance, receiver operating characteristic (ROC) curves was analyzed by using MedCalc for Windows, version 13.1.2.0 . Sensitivity, specificity, and area under the ROC curve (AUC) were calculated. The optimal cutoff values were determined by using the Youden index. Comparison of AUC was performed using the method proposed by DeLong et al.33.1P = 0.372).Of the 198 lesions, 125 (63.1%) were malignant, and 73 (36.9%) were benign .The distribution of SWE color patterns of breast lesions, as divided into benign and malignant groups, was shown in Table P = 0.013) and View T  (P = 0.035). In Views A, T, and C, the proportion of lesions showing “Stiff Rim” was significantly higher in IDC than in DCIS , while in IDC lesions alone, this proportion was significantly higher in View C than in View A (P = 0.003) and View T (P = 0.012).In malignant groups, “Stiff Rim” Pattern was significantly more frequently shown in View C  than in View A  , while sensitivities of SWE color patterns significantly increased in Views A, T, and C , without significant difference in between , without significant difference in between. As compared with conventional US, sensitivities of combination of conventional US with 3D SWE color patterns in Views A and C significantly increased , while that of View T did not show significant difference ; specificities increased without statistical significance   and View T  (P = 0.009). Comparing with conventional US, specificity for combination of conventional US with “Stiff Rim” in View C (“Crater Sign”) significantly increased , without significant change in sensitivity , which was higher than sensitivities of View A  and View T    than View A  (3.7P = 0.001). Adjusting conventional BI-RADS US Categories 4A and 4B by “Converging Pattern”, specificity significantly increased .In reconstructed coronal plane of 3D B-mode US, 73.6% (92/125) of malignant lesions presented as “Converging Pattern”, significantly higher than benign lesions . “Crater Sign” significantly increased specificity of diagnosing malignant and benign lesions  without significant loss in sensitivity .“Crater Sign”, defined as “Stiff Rim” in View C , was shown in 60.8% (76/125) of malignant lesions and significantly more frequent in IDC than DCIS , and both higher than “Converging Pattern” adjusted Category  and “Crater Sign” adjusted Category , yielding significantly higher sensitivity than the latter 2 methods alone . The specificity did not show significant difference with that of either single method alone, but significantly increased compared with that of conventional US   comparing with conventional BI-RADS Category   than in transverse (51.2%) and sagittal planes (54.1%) (P < 0.05), which aroused our notice of the probably higher value of coronal plane. The presence of “Stiff Rim” indicated high stiffness of the surrounding tissue in malignant lesions, which might be caused by the desmoplastic reaction or the infiltration of cancer cells into the peritumoral tissue.,20 As indicated by Zhou et al, the “Stiff Rim” sign at less than 180 kPa significantly increased sensitivity without significant loss of specificity while providing similar AUC compared with conventional US. Similarly in our study, the sensitivity of 3D SWE color patterns in each view of the 3 orthogonal planes significantly increased, with similar specificity and AUC comparing with conventional US. What is new and worth mentioning is that BI-RADS Category adjusted by “Stiff Rim” in coronal plane yielded the highest AUC (0.929) and sensitivity (85.6%) among the 3 orthogonal planes (P < 0.05) and significantly higher specificity (90.4%) than conventional US (78.1%). This result probably indicated higher value of “Stiff Rim” in coronal plane, which was renamed as “Crater Sign” in our study since malignant breast lesions more frequently showed as “Converging Pattern” in coronal plane of 3D B-mode images.Diagnostic performance of SWE color patterns have been demonstrated useful in breast lesions.–23 As commonly recognized as a manifestation of aggressive cancer, “Converging Pattern” might be caused by traction of Cooper ligaments into a neoplasm and desmoplastic reaction induced by the invasion of cancer cells and thus presented as hyperechoic bands of fibrous tissue converging toward the hypoechoic mass. In our study, a majority of malignant lesions presented as “Converging Pattern” in coronal planes, consistent with previous studies. Combination of conventional US with “Converging Pattern” significantly increased specificity (P < 0.05). Based on “Converging Pattern”, the colored “Stiff Rim” surrounding the lesions in coronal plane looked like the crater and thus was renamed as “Crater Sign” in our study, which was first proposed so far. Parallel test of “Converging Pattern” and “Crater Sign” yielded significantly higher sensitivity than either of the 2, and significantly higher specificity than conventional US.In practice, architectural distortion and spiculation of breast lesions are important features that highly indicate malignancy, which could be clearly observed in coronal plane of 3D B-mode images and characterized by a similar “Converging Pattern”.Better performance of “Stiff Rim” in coronal plane (Crater Sign) than transverse and sagittal planes may be attributed to the significantly higher frequency of “Stiff Rim” Pattern, part of which presented as “Horseshoe” in transverse and sagittal planes, without the elasticity information of part of the tumor edge , which was probably due to significant acoustic attenuation in the posterior part of the lesion on B-mode images. Since SWE features was determined according to the slice showing maximal diameter, the reconstructed coronal plane is consequently less affected by acoustic attenuation and seems to provide more information about SWE of the whole lesion, including SWE color pattern mentioned above and even other qualitative features such as shape of lesion, heterogeneity of elasticity, and quantitative parameters such as maximum, minimum, and mean value of elasticity. The discovery of “Crater Sign” might draw attention to the diagnostic value of SWE information of coronal plane, which might be lost in transverse and sagittal planes in some lesions.In malignant groups, there were a part of lesions presented as “Colored Lesions”, coronal plane did not show greater advantages over transverse and sagittal planes among this group of lesions. However, the pattern of “Stiff Rim” constituted of the majority of malignant group, so diagnostic performance of SWE color pattern of “Crater Sign” in coronal plane was worth highlighting.,26 Jiang et al found that breast tumors with “Coverging Pattern” were more likely to be small, while Lamb et al demonstrated no significant correlation between the two. If correlation exists, the exclusion of lesions of large size may cause selection bias to study cohort, but it would not change the result of higher frequency of “Stiff Rim” in coronal plane than transverse and sagittal planes of 3D SWE. Third, 3D technique probably produces more artifacts owing to the compression factor of heavier 3D transducer and movement during image acquisition. So the radiologists were instructed to very lightly apply the transducer to avoid compression and kept still during 3D B-mode and SWE data acquisition, and generous amount of coupling agent was applied. When assessing color pattern of 3D SWE, the slice showing the maximal diameter was selected in all the 3 orthogonal planes, thus we consider that color pattern of coronal plane, from which the slice selected was not so near to skin, may be less influenced by artifacts than transverse and sagittal planes.This study also had some limitations. First, selection bias may exist because of retrospective study, and patients enrolled were scheduled for surgical excision, which could explain the higher malignant rate of BI-RADS 4A Categories of conventional US than that of ACR BIRADS-US. By reviewing those malignant lesions assessed as BI-RADS 4A Categories by conventional US, we found that most lesions lacked of malignant features, such as irregular shapes, blurred edges, posterior acoustic attenuation, calcifications, and hypervascularity. However, after combining with 3D SWE, quite a part of these lesions showed as “Stiff Rim” or “Colored Lesion” and BI-RADS Categories were upregulated. Second, large masses which could not be covered by the maximal range of SWE color overlay were excluded in our study, while there were controversy about relationship between the size of lesions and the presence of “Coverging Pattern” in the coronal plane.In conclusion, combination of conventional US with 3D SWE color patterns significantly increased diagnostic accuracy of differentiating benign from malignant lesions in all the 3 orthogonal planes. Sensitivities and AUC of combining conventional US with 3D SWE color patterns significantly increased. Owing to significantly higher frequency of “Stiff Rim” in coronal plane, which was renamed as “Crater Sign” in this study, coronal plane yielded the highest AUC and sensitivity of diagnosing malignant lesions among the 3 orthogonal planes and significantly higher specificity than conventional US. Further perspective studies of large sample would be needed for validation of our results.