Patent Grant
11656310
This application is a U.S. national phase application of International Application No. PCT/EP2019/081863 filed on Nov. 20, 2019, which claims the benefit of EP Application Serial No. 18209210.6 filed on Nov. 29, 2018 and is incorporated herein by reference.
The invention relates to magnetic resonance imaging, in particular to real-time fMRI.
Magnetic resonance imaging (MRI) scanners rely on a large static magnetic field (B0) to align the nuclear spins of atoms as part of the procedure for producing images within the body of a patient. These images can reflect various quantities or properties of the subject. For example, the hemodynamic response of brain activation causes magnetic and electric changes in the activated brain area. MRI allows visualizing magnetic changes, e.g. based on the cerebral blood flow or blood-oxygen-level dependent (BOLD) effect. The latter is usually referred to as functional MRI (fMRI).
A major problem in fMRI is that the BOLD signal changes are small and that there are also non-BOLD related effects that cause signal changes. The most common sources for non-BOLD signal changes are, head motion, cardiac and respiratory effects, also, scanner related artefacts cause signal changes.
Olafsson V. T. et Al: proceedings of ISMRM, vol 11, page 132 discloses a method for estimating ΔR2* in an fMRI experiment directly from a single echo, estimate of a baseline image and a baseline R2*.
Olafsson V. T. et Al: proceedings of ISMRM, vol 12, page 45 discloses a method for dynamic update of R2* and field map in fMRI.
The invention provides for a medical imaging system, a computer program product, and a method in the independent claims. Embodiments are given in the dependent claims.
Embodiments may enable detecting small fMRI signal changes. These changes are caused by a physiological response to the increased neuronal activity: the BOLD contrast. However, signal changes can also be caused by other effects, e.g. motion, cardiac and respiratory effects, scanner instabilities. It is essential to distinguish these signal changes from the changes caused by the true BOLD response. The present disclosure may enable a better BOLD contrast for real-time fMRI applications, including neurofeedback.
In one aspect the invention provides for a method of medical imaging. The method comprises: receiving, for a current active time window and during a brain activity analysis session, fMRI data of a region of interest of a subject in an active state. The method further comprises generating from the fMRI data a transverse relaxation, T2*, map using a predefined model of fMRI data variations. The generated T2* map may be compared with a reference T2* map. A BOLD response of the region of interest during the current active time window may be estimated using the results of the comparison.
The region of interest may, for example, be the brain of the subject. The time window may also be referred to as a dynamic.
The method may, for example, be executed while the subject is in an active state period, wherein the current active time window is a time interval of that active state period. This may enable to identify small fMRI signal changes in real time.
The BOLD response may be used to observe different areas of the brain of the subject, which are found to be active at any given time while the subject is being under brain analysis tests.
A T2* map may, for example, be obtained from a R2* map or vice versa, where R2*=1/T2*. The present method may be configured to be executed on R2* maps as described herein with T2* map. In case of R2* maps, the logic of interpreting the BOLD response versus brain activities may be inverted in order to obtain the interpretation logic for T2* maps.
The present disclosure may enable to determine the BOLD changes for each time point individually. The BOLD changes can then be used as a feedback signal. This neurofeedback may enable that the subject can be trained to correct aberrant brain activity.
The present disclosure may, for example, enable a successful neurofeedback training as the feedback is given on true BOLD effects, e.g. the subject is not training to respond to the respiratory cycle. The T2* information is used to measure the true BOLD response and thus, giving the feedback on the real BOLD signal changes. The present disclosure may provide more insights in the functioning of the brain e.g. without giving neurofeedback, by just performing a task, variations in the activation patterns may be identified.
According to one embodiment, the method further comprises repeating the method steps during the session for each subsequent active time window. This embodiment may be advantageous as it may enable a continuous and real time analysis of the variation of the fMRI signal over longer time interval. This may enable a better modeling of the fMRI signal changes.
According to one embodiment, the method further comprises splitting the brain activity analysis session into interleaved resting state periods and active state periods of the subject, wherein the active time window occurs in an active state period of the subject that follows a resting state period. Interleaving different state periods may enable to detect both small fMRI changes between single time windows of a same state of the subject as well as global fMRI changes between periods of different states.
According to one embodiment, the resting state period immediately precedes the active state period of the current active time window.
According to one embodiment, the method further comprises receiving fMRI data obtained in a resting state period of the subject, subdividing the resting time period to a set of successive non-overlapping reference time windows, wherein a reference time window has the same length as the active time window; generating a T2* map for each determined reference time window and combining the generated T2* maps of the determined reference time windows resulting in the reference T2* map. Taking the resting state period of the present session as reference may increase the accuracy of the estimated BOLD responses e.g. compared to a case where a reference map is a theoretical one or of a map obtained from another different session.
According to one embodiment, the method further comprises excluding from the set of reference time windows a predefined subset of time windows occurring at the beginning of the resting state period, for the generating of the T2* maps. By excluding the first subset of dynamics of the resting state period, the BOLD response delay from a previous active state period may not interfere with the BOLD responses used for the generation of the reference T2* map. This may further increase the accuracy of the estimated BOLD responses. The subset of time windows may, for example, comprise 3 time windows of 2 second each.
According to one embodiment, the method further comprises performing the method steps for each voxel in the fMRI data, wherein the comparison is performed between T2* value of each voxel of the generated T2* map and the T2* value of the same voxel in the T2* reference map. This may enable to identify specific small areas of the brain that are active.
According to one embodiment, the fMRI data comprises multiple echo image data obtained at respective echo times, TE, wherein generating the T2* map comprises fitting the T2* values variations over the echo time using the following model:
where TE is the echo time and S0 is the signal at TE=0. This may enable an accurate estimate of the T2* values. This model may be advantageous because it separates between changes in S0 which are non-BOLD variations of the signal intensity from the real BOLD variations that are encoded in T2* variations. Changes in S0 can be caused by motion, cardiac and respiratory effects. Also scanner instabilities contribute to variations in S0.
According to one embodiment, the BOLD response is indicative of an active state of a portion of the region of interest whose associated voxel has a T2* value of the T2* map higher than the reference T2* value of that voxel, and the BOLD response being indicative of a resting state of a portion of the region of interest whose associated voxel has a T2* value of the T2* map smaller than the reference T2* value of that voxel.
According to one embodiment, the fMRI data comprises a plurality of MRI images at a plurality of different echo times following an application of an excitation RF pulse.
In another aspect the invention further provides for a computer program product comprising machine executable instructions for execution by a processor, wherein execution of the machine executable instructions causes the processor to perform the methods of any of the preceding embodiments.
In another aspect, the invention further provides for a medical imaging system comprising: a memory for storing machine executable instructions; and a processor for controlling the medical imaging system, wherein execution of the machine executable instructions causes the processor to: receive, for a current active time window and during a brain activity analysis session, fMRI data of a region of interest of a subject in an active state; generate from the fMRI data a transverse relaxation, T2*, map using a predefined model of fMRI data variations; compare the generated T2* map with a reference T2* map; estimate a blood-oxygen-level dependent (BOLD) response of the region of interest during the current active time window using the results of the comparison.
It is understood that one or more of the aforementioned embodiments of the invention may be combined as long as the combined embodiments are not mutually exclusive.
As will be appreciated by one skilled in the art, aspects of the present invention may be embodied as an apparatus, method or computer program product. Accordingly, aspects of the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, micro-code, etc.) or an embodiment combining software and hardware aspects that may all generally be referred to herein as a ‘circuit,’ ‘module’ or ‘system’. Furthermore, aspects of the present invention may take the form of a computer program product embodied in one or more computer readable medium(s) having computer executable code embodied thereon.
Any combination of one or more computer readable medium(s) may be utilized. The computer readable medium may be a computer readable signal medium or a computer readable storage medium. A ‘computer-readable storage medium’ as used herein encompasses any tangible storage medium which may store instructions which are executable by a processor of a computing device. The computer-readable storage medium may be referred to as a computer-readable non-transitory storage medium. The computer-readable storage medium may also be referred to as a tangible computer readable medium. In some embodiments, a computer-readable storage medium may also be able to store data which is able to be accessed by the processor of the computing device. Examples of computer-readable storage media include, but are not limited to: a floppy disk, a magnetic hard disk drive, a solid state hard disk, flash memory, a USB thumb drive, random access memory (RAM), read only memory (ROM), an optical disk, a magneto-optical disk, and the register file of the processor. Examples of optical disks include compact disks (CD) and digital versatile disks (DVD), for example CD-ROM, CD-RW, CD-R, DVD-ROM, DVD-RW, or DVD-R disks. The term computer readable-storage medium also refers to various types of recording media capable of being accessed by the computer device via a network or communication link. For example a data may be retrieved over a modem, over the internet, or over a local area network. Computer executable code embodied on a computer readable medium may be transmitted using any appropriate medium, including but not limited to wireless, wire line, optical fiber cable, RF, etc., or any suitable combination of the foregoing.
A computer readable signal medium may include a propagated data signal with computer executable code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electro-magnetic, optical, or any suitable combination thereof. A computer readable signal medium may be any computer readable medium that is not a computer readable storage medium and that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.
‘Computer memory’ or ‘memory’ is an example of a computer-readable storage medium. Computer memory is any memory which is directly accessible to a processor. ‘Computer storage’ or ‘storage’ is a further example of a computer-readable storage medium. Computer storage is any non-volatile computer-readable storage medium. In some embodiments computer storage may also be computer memory or vice versa.
A ‘processor’ as used herein encompasses an electronic component which is able to execute a program or machine executable instruction or computer executable code. References to the computing device comprising a ‘processor’ should be interpreted as possibly containing more than one processor or processing core. The processor may for instance be a multi-core processor. A processor may also refer to a collection of processors within a single computer system or distributed amongst multiple computer systems. The term computing device should also be interpreted to possibly refer to a collection or network of computing devices each comprising a processor or processors. The computer executable code may be executed by multiple processors that may be within the same computing device or which may even be distributed across multiple computing devices.
Computer executable code may comprise machine executable instructions or a program which causes a processor to perform an aspect of the present invention. Computer executable code for carrying out operations for aspects of the present invention may be written in any combination of one or more programming languages, including an object-oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as C or similar programming languages and compiled into machine executable instructions. In some instances, the computer executable code may be in the form of a high level language or in a pre-compiled form and be used in conjunction with an interpreter which generates the machine executable instructions on the fly.
The computer executable code may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the internet using an internet service provider).
Aspects of the present invention are described with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems) and computer program products according to embodiments of the invention. It is understood that each block or a portion of the blocks of the flowchart, illustrations, and/or block diagrams, can be implemented by computer program instructions in form of computer executable code when applicable. It is further understood that, when not mutually exclusive, combinations of blocks in different flowcharts, illustrations, and/or block diagrams may be combined. These computer program instructions may be provided to a processor of a general-purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.
These computer program instructions may also be stored in a computer readable medium that can direct a computer, other programmable data processing apparatus, or other devices to function in a particular manner, such that the instructions stored in the computer readable medium produce an article of manufacture including instructions which implement the function/act specified in the flowchart and/or block diagram block or blocks.
The computer program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.
A ‘user interface’ as used herein is an interface which allows a user or operator to interact with a computer or computer system. A ‘user interface’ may also be referred to as a ‘human interface device.’ A user interface may provide information or data to the operator and/or receive information or data from the operator. A user interface may enable input from an operator to be received by the computer and may provide output to the user from the computer. In other words, the user interface may allow an operator to control or manipulate a computer and the interface may allow the computer indicate the effects of the operator's control or manipulation. The display of data or information on a display or a graphical user interface is an example of providing information to an operator. The receiving of data through a keyboard, mouse, trackball, touchpad, pointing stick, graphics tablet, joystick, gamepad, webcam, headset, pedals, wired glove, remote control, and accelerometer are all examples of user interface components which enable the receiving of information or data from an operator.
A ‘hardware interface’ as used herein encompasses an interface which enables the processor of a computer system to interact with and/or control an external computing device and/or apparatus. A hardware interface may allow a processor to send control signals or instructions to an external computing device and/or apparatus. A hardware interface may also enable a processor to exchange data with an external computing device and/or apparatus. Examples of a hardware interface include, but are not limited to: a universal serial bus, IEEE 1394 port, parallel port, IEEE 1284 port, serial port, RS-232 port, IEEE 488 port, Bluetooth connection, wireless local area network connection, TCP/IP connection, Ethernet connection, control voltage interface, MIDI interface, analog input interface, and digital input interface.
A ‘display’ or ‘display device’ as used herein encompasses an output device or a user interface adapted for displaying images or data. A display may output visual, audio, and or tactile data. Examples of a display include, but are not limited to: a computer monitor, a television screen, a touch screen, a tactile electronic display, a Braille screen, a cathode ray tube (CRT), a storage tube, a bi-stable display, an electronic paper, a vector display, a flat panel display, a vacuum fluorescent display (VF), light-emitting diode (LED) displays, an electroluminescent display (ELD), plasma display panels (PDP), a liquid crystal display (LCD), organic light-emitting diode displays (OLED), a projector, and a head-mounted display.
Magnetic Resonance imaging data is defined herein as being the recorded measurements of radio frequency signals emitted by atomic spins using the antenna of a magnetic resonance apparatus during an MRI scan. Magnetic resonance image data is defined herein as being the reconstructed two-dimensional or three-dimensional visualization of anatomic data that is reconstructed from the magnetic resonance k-space data. Visualization of the magnetic resonance image data can be performed using a computer.
In the following preferred embodiments of the invention will be described, by way of example only, and with reference to the drawings in which:
Like numbered elements in these figures are either equivalent elements or perform the same function. Elements which have been discussed previously will not necessarily be discussed in later figures if the function is equivalent.
The memory 110 is shown as containing machine-executable instructions 120. The machine-executable instructions 120 enable the processor 104 to perform various data processing tasks and also in some examples to control other components of the medical imaging system 100. The machine-executable instructions 120 enable the processor 104 to perform at least part of the present method.
The methods described herein may be in the form of a source program, executable program (object code), script, or any other entity comprising a set of instructions to be performed. When a source program, then the program needs to be translated via a compiler, assembler, interpreter, or the like, which may or may not be included within the memory 110, so as to operate properly in connection with an OS. Furthermore, the methods can be written as an object oriented programming language, which has classes of data and methods, or a procedure programming language, which has routines, subroutines, and/or functions.
Each of the resting state periods 201A-N is subdivided into resting time windows 202A-202N of equal duration. Each of the active state periods 203A-N is subdivided into active time windows 204A-204N of equal duration. The active time windows 204A-N have the same duration as the resting time windows 202A-N. Only time windows of one resting state period and one active state period are shown for clarity purpose.
For example, the subject may have to perform a silent word generation task during active state periods. The brain activity analysis session 200 may, for example, consist of 32 s resting state periods interleaved with 32 s active state periods. The total scan duration of the brain activity analysis session 200 may, for example, be 416 second, resulting in 7 resting state periods, interleaved with 6 active state periods of 16 time windows each.
The brain activity analysis session 200, as defined in
The time granularity of the resting state periods, active state periods and brain activity analysis session are provided for exemplification purpose. The skilled person in the art would understand that other configurations of brain activity analysis sessions such as different time window durations etc. may be used with the present method.
In step 213, a transverse relaxation, T2*, map may be generated from the fMRI data using a predefined model of fMRI data variations. The model may describe the variation of the acquired signals as function of TE. One example model may describe a signal decay for each multi echo acquisition as follows:
where TE is the echo time and S0 is the signal at TE=0.
In step 215, the generated T2* map may be compared with a reference T2* map. The reference T2* map may, for example, be obtained as follows.
Reference fMRI data may be obtained during a resting state period e.g. 201A of the subject. A T2* map may be generated for each resting time window 202A-N of the resting state period. The generated T2* maps may be combined resulting in the reference T2* map. The fMRI data are considered as reference data because they are acquired during a resting state period of the subject. An example of determining the reference map is described in
In step 217, a BOLD response of the region of interest during the current active time window may be estimated using the results of the comparison. The changes in T2* values are related to the BOLD variations. A T2* value increases regionally as a result of the BOLD response in activated areas. The changes in S0 contain non-BOLD variations of the signal intensity which can be caused by motion, cardiac and respiratory effects. Also scanner instabilities (e.g. of the imaging system 300) contribute to variations in S0.
In one example, steps 213-217 may be executed voxel-wise. That is, for each voxel of the fMRI data, the T2* value may be generated by, for example, fitting the model to the voxel values as function of the echo time TE (e.g. if 10 echo times are used, 10 voxel values may be fitted). This results in T2* values (T2* map) for voxels of the fMRI data. For each voxel of the fMRI data, a comparison is performed between the T2* value of the voxel and the reference T2* value of the same voxel and the BOLD response may be estimated for the voxel by based on that comparison result.
The method as described herein may, for example, be performed on fMRI data in the native space. The received fMRI data may be acquired in the subject's native space.
The magnetic resonance imaging system 302 comprises a magnet 304. The magnet 304 is a superconducting cylindrical type magnet with a bore 306 through it. The use of different types of magnets is also possible; for instance it is also possible to use both a split cylindrical magnet and a so called open magnet. A split cylindrical magnet is similar to a standard cylindrical magnet, except that the cryostat has been split into two sections to allow access to the iso-plane of the magnet, such magnets may for instance be used in conjunction with charged particle beam therapy. An open magnet has two magnet sections, one above the other with a space in-between that is large enough to receive a subject: the arrangement of the two sections area similar to that of a Helmholtz coil. Open magnets are popular, because the subject is less confined. Inside the cryostat of the cylindrical magnet there is a collection of superconducting coils. Within the bore 306 of the cylindrical magnet 304 there is an imaging zone 308 where the magnetic field is strong and uniform enough to perform magnetic resonance imaging. A region of interest 309 is shown within the imaging zone 308. The magnetic resonance data that is acquired typically acquired for the region of interest. A subject 318 is shown as being supported by a subject support 320 such that at least a portion of the subject 318 is within the imaging zone 308 and the region of interest 309.
Within the bore 306 of the magnet there is also a set of magnetic field gradient coils 310 which is used for acquisition of preliminary magnetic resonance data to spatially encode magnetic spins within the imaging zone 308 of the magnet 304. The magnetic field gradient coils 310 are connected to a magnetic field gradient coil power supply 312. The magnetic field gradient coils 310 are intended to be representative. Typically magnetic field gradient coils 310 contain three separate sets of coils for spatially encoding in three orthogonal spatial directions. A magnetic field gradient power supply supplies current to the magnetic field gradient coils. The current supplied to the magnetic field gradient coils 310 is controlled as a function of time and may be ramped or pulsed.
Adjacent to the imaging zone 308 is a radio-frequency coil 314 for manipulating the orientations of magnetic spins within the imaging zone 308 and for receiving radio transmissions from spins also within the imaging zone 308. In this example the radio-frequency coil 314 is a head coil and the region of interest 309 images the brain of the subject 318.
The radio frequency antenna may contain multiple coil elements. The radio frequency antenna may also be referred to as a channel or antenna. The radio-frequency coil 314 is connected to a radio frequency transceiver 316. The radio-frequency coil 314 and radio frequency transceiver 316 may be replaced by separate transmit and receive coils and a separate transmitter and receiver. It is understood that the radio-frequency coil 314 and the radio frequency transceiver 316 are representative. The radio-frequency coil 314 is intended to also represent a dedicated transmit antenna and a dedicated receive antenna. Likewise the transceiver 316 may also represent a separate transmitter and receiver. The radio-frequency coil 314 may also have multiple receive/transmit elements and the radio frequency transceiver 316 may have multiple receive/transmit channels. For example if a parallel imaging technique such as SENSE is performed, the radio-frequency could 314 will have multiple coil elements.
Within the bore 306 of the magnet 304 there is a subject indicator 322. The subject indicator may, for example, provide an audio and/or visual stimulus to the subject 318. The subject indicator 322 is able to provide a stimulus in one of two different distinct states; an active state and a resting state. When the subject indicator 322 shows an active state the subject 318 either thinks particular thoughts or performs particular physical activity such as moving a limb or performing another action. The subject indicator 322 could, for example, have a light which is visible to the subject 318, be a display, or provide an audio signal. The transceiver 316, the gradient controller 312, and the subject indicator 322 are shown as being connected to the hardware interface 106 of the computer system 102.
The memory 110 is further shown as containing the pulse sequence commands 330. The pulse sequence commands are either commands or data which can be converted into such commands which enable the processor 104 to control the magnetic resonance imaging system 302. The memory 110 is further shown as containing magnetic resonance imaging data 332 that was acquired by controlling the magnetic resonance imaging system 302 with the pulse sequence commands 330. The pulse sequence commands 330 may also contain instructions which cause the subject indicator 322 to change between indicating the active and resting state during individual acquisitions of the magnetic resonance imaging data 332. Data which can be used to determine later which state the magnetic resonance imaging data 332 is in the meta data 334. The meta data 334 is shown as being stored in the memory 110.
In step 501, fMRI data is acquired (e.g. by imaging system 300) with a multi-echo EPI sequence. Using multi-echo EPI sequences may enable a more detailed analysis of the brain activity. An example of multi echo data may be acquired with echo times of 12, 35 and 58 ms, respectively, for each time window of resting state periods and active state periods of the brain activity analysis session 500. The repetition time TR is, for example, 2000 ms. During each TR a full brain volume is recorded, for example 27 slices, wherein each slice has a resolution of 64×64. This may be used for generating fMRI data while the subject is performing a task, for example, silent word generation. This may enable to evaluate Brain activation during silent word generation using the fMRI data. Other resolutions are possible.
The signal decay for each multi echo acquisition is described by model equation
where TE is the echo time and S0 is the signal at TE=0. The changes in T2* are related to the BOLD variations. The T2* increases regionally as a result of the BOLD response in activated areas. The changes in S0 are non-BOLD variations of the signal intensity which can be caused by motion, cardiac and respiratory effects. Also scanner instabilities contribute to variations in S0.
The model equation is fitted in step 503 to the measured signals per voxel of the acquired fMRI data and S0 and T2* maps are generated. The fitting may, for example, be done in Matlab, using the Matlab function ‘fit’. A single exponential (‘Exp1’) was fitted with additional fitting options: ‘TolFun’, 0.1, ‘TolX’, 0.1, ‘MaxFunEvals’, 100, ‘MaxIter’, 10. A R2* map may, for example, be generated from T2* map because R2* is the inverse of the T2*: R2*=1/T2*. This means that BOLD related signals will have shorter R2*. An example of a multi-echo acquisition and the derived S0 and R2* maps is show in
Before performing the fitting step 503, the fMRI data may be pre-processed using known pre-processing methods such as realignment. For example, the individual echo data are realigned and smoothed e.g. using spatial smoothing (SPM), such that the fit of step 503 is performed on the realigned and smoothed echo data to get the S0 and the T2*.
In step 507, the R2*series is analyzed with the aim to determine the task activation per time window. For each resting state period 530, the average R2* is determined over a series of time windows 532 as indicated in
For each voxel of the fMRI data, the mean of the R2* values of the voxel dynamic (j) in the time windows 532 are averaged according to average equation
where i is the first time window of the resting state period 530 and n is the number of time windows 532 and j is a time window of the time windows 532.
As indicated in
where
According to the PSC equation, each activation per active state time window, is defined as the PSCt with respect to the previous resting state period. Two effects may be distinguished, namely a BOLD positive effect and BOLD negative effect. According to the BOLD positive effect, the R2* value of a given voxel in the current active state time window decreases (e.g. task(t)<
Regarding the positive BOLD effect (activation), the R2* change of the active state time window 89 of the active state time period 537 is calculated according to average and PSC equations, i.e. the
| Number | Date | Country | Kind |
|---|---|---|---|
| 18209210 | Nov 2018 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/081863 | 11/20/2019 | WO |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2020/109095 | 6/4/2020 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 9116219 | Posse | Aug 2015 | B1 |
| 20120143041 | Hirsch | Jun 2012 | A1 |
| 20120268121 | Hernando et al. | Oct 2012 | A1 |
| Number | Date | Country |
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| 8131414 | May 1996 | JP |
| 2008264014 | Nov 2008 | JP |
| 2014076137 | May 2015 | JP |
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| Number | Date | Country | |
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| 20220034984 A1 | Feb 2022 | US |
