Patent Application
20190029650
Focused ultrasound (FUS) is a non-invasive mechanism of thermal therapy that can be guided by magnetic resonance imaging (MM) or ultrasound (US) imaging. Both MRI guided FUS (MRgFUS) and US guided FUS (USgFUS) can accurately measure displacement caused by acoustic radiation force of an ultrasound beam. USgFUS can monitor tissue elastic properties (elastic modulus and shear wave velocity) before, after, and dynamically during treatment. MRgFUS can monitor temperature rise and thermal dose in relation to the clinical standard of tissue death in thermal ablation therapies. However, limitations in these technologies remain: For example, USgFUS cannot measure temperature while MRgFUS cannot efficiently make images of tissue elastic properties.
A technology is described for obtaining elastic tissue displacement measurements at a plurality of focal points in an image volume. The elastic tissue displacement measurements may provide the ability to remotely palpate an ablated tissue volume and monitor the formation of lesions created using FUS pulses. Monitoring lesion formation may increase the efficiency of MRgFUS ablation procedures by improving the accuracy in estimating the tissue volume that has been effectively treated.
In one example, a reference MR-ARFI image of an anatomical region that is to be treated using FUS pulses can be captured. The reference MR-ARFI image can provide a phase reference for focal points that are to be exposed to the FUS pulses. Thereafter, active MR-ARFI images for focal points located in the anatomical region can be captured during exposure of the focal points to the FUS pulses. The active MR-ARFI images can be interleaved with the reference MR-ARFI image to create a combined image of the anatomical region containing the focal points. A tissue displacement measurement can then be calculated for the focal points exposed to the FUS pulses using the combined image of the anatomical region, and the tissue displacement measurement can be used to monitor treatment of the tissue included in the anatomical region.
There has thus been outlined, rather broadly, the more important features of the invention so that the detailed description thereof that follows may be better understood, and so that the present contribution to the art may be better appreciated. Other features of the present invention will become clearer from the following detailed description of the invention, taken with the accompanying drawings and claims, or may be learned by the practice of the invention.
These drawings are provided to illustrate various aspects of the invention and are not intended to be limiting of the scope in terms of dimensions, materials, configurations, arrangements or proportions unless otherwise limited by the claims.
While these exemplary embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, it should be understood that other embodiments may be realized and that various changes to the invention may be made without departing from the spirit and scope of the present invention. Thus, the following more detailed description of the embodiments of the present invention is not intended to limit the scope of the invention, as claimed, but is presented for purposes of illustration only and not limitation to describe the features and characteristics of the present invention, to set forth the best mode of operation of the invention, and to sufficiently enable one skilled in the art to practice the invention. Accordingly, the scope of the present invention is to be defined solely by the appended claims.
Definitions
In describing and claiming the present invention, the following terminology will be used.
The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a particle” includes reference to one or more of such materials and reference to “subjecting” refers to one or more such steps.
As used herein with respect to an identified property or circumstance, “substantially” refers to a degree of deviation that is sufficiently small so as to not measurably detract from the identified property or circumstance. The exact degree of deviation allowable may in some cases depend on the specific context.
As used herein, “adjacent” refers to the proximity of two structures or elements. Particularly, elements that are identified as being “adjacent” may be either abutting or connected. Such elements may also be near or close to each other without necessarily contacting each other. The exact degree of proximity may in some cases depend on the specific context.
As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
As used herein, the term “at least one of” is intended to be synonymous with “one or more of” For example, “at least one of A,B and C” explicitly includes only A, only B, only C, and combinations of each (e.g. A+B, B+C, A+C, and A+B+C).
Concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a numerical range of about 1 to about 4.5 should be interpreted to include not only the explicitly recited limits of 1 to about 4.5, but also to include individual numerals such as 2, 3, 4, and sub-ranges such as 1 to 3, 2 to 4, etc. The same principle applies to ranges reciting only one numerical value, such as “less than about 4.5,” which should be interpreted to include all of the above-recited values and ranges. Further, such an interpretation should apply regardless of the breadth of the range or the characteristic being described.
Any steps recited in any method or process claims may be executed in any order and are not limited to the order presented in the claims. Means-plus-function or step-plus-function limitations will only be employed where for a specific claim limitation all of the following conditions are present in that limitation: a) “means for” or “step for” is expressly recited; and b) a corresponding function is expressly recited. The structure, material or acts that support the means-plus function are expressly recited in the description herein. Accordingly, the scope of the invention should be determined solely by the appended claims and their legal equivalents, rather than by the descriptions and examples given herein.
Elastographic Imaging
In the case of thermal ablation, treatment efficacy is defined in terms of the desired cell death. The relative effects of thermal therapies are usually estimated in terms of thermal dose, which is a non-linear function of temperature. However, several different acute tissue states can result in eventual cell death and it is difficult to consistently determine when the endpoint is reached. The uncertainty in treatment outcome leads to the possibility of an ineffective under-treatment or an over-treatment that is effective but may damage surrounding normal tissues. More accurate treatment outcome assessment would make it possible to successfully execute the desired treatment while minimizing the damage to normal tissues.
Thermal dose: The thermal dose metric has been developed in an attempt to standardize the effects of thermal treatments with different temperature distributions and time histories. Although, there have been several methods studied to measure temperature with ultrasound, challenges remain that keep ultrasound from being used to monitor temperature in FUS treatments. Mill can measure temperature change in aqueous tissues but not in lipids and requires knowledge of the starting baseline temperature.
Tissue elasticity: Tissue mechanical properties, such as elasticity or stiffness, change with thermal ablation. At high thermal dose, cells can become completely coagulated and water can be removed resulting in greatly increased stiffness. Both ultrasound and MRI elastography methods have shown that tissue elasticity changes with temperature and changes irreversibly at even low levels of thermal dose. Advanced diagnostic ultrasound systems can rapidly image tissue displacement and shear waves produced by the radiation force of short, intense, focused ultrasound pulses and can detect changes in shear wave velocity due to thermal ablation procedures. MR-elastography, using an external source to induce shear waves in the tissue and phase contrast displacement measurement methods, has been used to assess changes in elasticity in conjunction with thermal ablation. In a study using FUS in ex vivo bovine tissue, the elastic shear modulus was found to increase with ablation and the increase was nearly linear in ultrasound energy deposited. Implementing diagnostic ultrasound or MR-elastography tissue vibrators in conjunction with MRgFUS introduces logistical challenges.
Focused ultrasound (FUS) is a non-invasive interventional technique that focuses ultrasound energy deep within the body to quickly heat and cause necrosis in tumors or other diseased tissues while sparing the surrounding normal tissues. FUS has been used to treat benign and malignant solid tumors, as well as a number of neurological pathologies, including movement disorders, epilepsy, chronic pain, and psychiatric disorders. As a new treatment option for breast cancer, FUS yields improved cosmetic outcomes by maintaining breast architecture and avoiding scarring. If treatment outcomes can be more accurately assessed, FUS can offer a non-invasive option for treating localized primary tumors, avoid the discomfort and potential complications associated with general anesthesia and surgery, and be a viable treatment alternative when radiation and chemotherapy limits have been reached.
MRI has the unique capability to obtain high-resolution 3D images of healthy and diseased tissues for diagnosis, treatment planning, guidance and assessment of thermal therapy procedures. MRI can also image temperature change over the treatment volume allowing determination of thermal dose and facilitating real-time control, safety monitoring, and online treatment optimization. Several other MRI parameters change with the state of the tissue. The MRI water diffusion coefficient, MRI relaxation times T1 (longitudinal) and T2 (transverse), and the exchange rate between free and protein bound water depend on the temperature as well as the state of water in the tissue. Thermal therapy can change the amount of water in the tissue, resulting in irreversible changes in these MRI parameters. Finally, exogenous contrast can be used in MRI to interrogate the state of the vascular supply to a tumor, which can be affected by thermal therapy.
To assist FUS application as described herein, MRI can obtain high-resolution 3D images of healthy and diseased tissues for diagnosis, treatment planning and assessment. MRI can also image temperature change over the treatment volume allowing determination of thermal dose (which predicts tissue necrosis) and facilitating real-time control, safety monitoring, and online treatment optimization.
Some FUS systems use diagnostic ultrasound for guidance, combining the therapeutic and diagnostic transducers into one unit. Although ultrasound cannot monitor temperature accurately or generate 3D images comparable to MM, it can provide a real-time view of the FUS focus. Advanced diagnostic ultrasound systems can rapidly image the tissue displacement and shear waves produced by the radiation force of short, intense, focused ultrasound pulses. The acoustic radiation force density, Γa, is given by
where I is the acoustic intensity, a is the pressure absorption coefficient, and c is the speed of sound. Assuming linear tissue response, the resulting displacement (w) is expected to be linear with the applied force: w∝Γa/μ where μ, the local Lamé shear constant, is a measure of tissue stiffness. MRI methods using motion encoding gradients synchronized with a short FUS pulse can make 2D or 3D images of the tissue displacement caused by the radiation force.
Although Magnetic Resonance Acoustic Radiation Force Impulse (MR-ARFI) may be unable to measure spatial distribution of tissue elastic properties, MR-ARFI imaging can produce 2D and 3D images of acoustic radiation force applied at a single point. This MR-ARFI map showing the position and quality of the focal spot can be complementary to MR thermometry and can be useful during all aspects of MRgFUS therapy. MR-ARFI sequences have been used for both beam localization and adaptive focusing. The technology includes 3D MR-ARFI methods that image the 3D single-point tissue displacement fields and includes analytic models of this field (see de Bever J, Todd N, Odeen H, Parker D L. Evaluation of a 3D MR Acoustic Radiation Force Imaging Pulse Sequence Using a Novel Unbalanced Bipolar Motion Encoding Gradient. Magn Reson Med 2015, which is incorporated herein by reference). 3D acquisition allows band-limited interpolation to accurately locate the ultrasound focus and the resulting displacement distribution in 3D. Despite the ability of MRI to make 2D and 3D images of single point displacement fields, efficient methods to image tissue elastic properties at more than a single point are lacking.
Despite the great potential of focused ultrasound in non-invasive therapy, treatment endpoint assessment has been a challenge. Subject motion causes temperature measurement artifacts that add inaccuracy to thermal dose as an endpoint measure. MRI images such as T2w (weighted images) or late Gadolinium enhanced (LGE) images made acutely after treatment may not be specific to tissue that will become necrotic. Diagnostic ultrasound, which can measure tissue elastic properties, can require removing the patient from an MRI scanner and using a hand-held probe, both leading to registration problems. The ability to make efficient, multipoint measurements of tissue elastic properties with MRI may be a highly important adjuvant assessment of the state of tissue before and after treatment.
The methods described herein can expand the current capabilities of MR-ARFI by enabling MRI to evaluate changes in tissue elastic properties over a large area instead of at a single point. MRgFUS is a single modality that can both generate a therapeutic effect and assess tissue damage with both thermal and mechanical mechanisms. Simultaneous displacement and temperature change measured by the developed mpMR-ARFI protocol can be used to estimate an effective tissue elasticity and to track the changing tissue properties with temperature and thermal dose over time demonstrating the potential clinical utility of the technique. The effective elasticity parameter can also be correlated to the independently measured Lame shear constant in ex vivo tissues. The effective elasticity can be proportional to the ratio of displacement to temperature increase.
Furthermore, this approach allows elastic displacement measurements at a plurality of points in the image volume to be obtained, thereby effectively acquiring a low resolution image of tissue elasticity in the same time that conventional MR-ARFI measures displacement at a single point. Volumetric tissue elasticity measurements made before and between sonications can provide the ability to perform what may be called remote palpation of the evolving thermal lesion formed by the MRgFUS treatment at multiple positions and times during the procedure. This can increase the amount of information available to determine a successful outcome.
The FUS pulses can be either or both simultaneous and temporally interleaved with each TR and between TR's. Each TR is a repetition time (usually about 30 to 50 msec), and a 3D image generally uses many of these TR's (maybe 128×32). Each 3D volume is acquired with multiple sets of measurements (multiple TR's) and for each instance of the 3D volume, one or more FUS pulses are interleaved by:
Pushing multiple points in the same TR (and therefore in the same instance of the 3D volume) by:
1) applying a single pulse with 2 or more focal points (this may be simultaneous, but 2 to 4 points in the same pulse can be used);
2) by switching rapidly (about 5 msec) between 2 or more focal positions; or
3) both 1) and 2);
Pushing different sets of points in the subsequent interleaved instances of the 3D volume.
Multiple focused ultrasound (FUS) pulses can also be temporally interleaved during a single MM acquisition, decreasing total acquisition time and reducing tissue heating compared to acquiring the same points sequentially with single-point MR-ARFI (spMR-ARFI). Acquisition time can be further reduced by focusing at two or more points in each motion encoding interval.
The multi-point MR-ARFI can provide a method to assess MRgFUS treatment endpoint that is complementary to thermal dose and LGE images. By measuring tissue displacement as a function of ultrasound intensity and changes in displacement during the procedure, it can provide the ability to remotely palpate the ablated volume to monitor the formation of lesions created with MRgFUS. This independent monitoring of lesion formation can increase the efficiency of MRgFUS ablation procedures by improving the accuracy in estimating the tissue volume that has been effectively treated.
The technology can involve modifications to a focused ultrasound controller, a MR-ARFI pulse sequence, and new reconstruction methods. MR-ARFI works by applying gradients during a short FUS pulse such that the image phase becomes a function of the tissue displacement. In spin echo (SE) MR-ARFI phase does not depend on temperature, but the refocusing RF pulse used may include long delays between RF pulses (long TR) to avoid reduced image signal and compromised ARFI measurement accuracy. Gradient echo (GRE) MR-ARFI allows short TR (˜50ms), but the image phase may be a function of both temperature and displacement. By acquiring measurements at multiple echo times (TE), phase contributions due to temperature, which may be a function of TE, can be separated from measurements resulting from tissue displacement. Because overly rapid FUS pulsing at a single point may cause unwanted tissue heating, interleaving of the acquisition of points (e.g., 12 to 24) spaced several mm apart can be performed. Interleaving and data sharing may decrease acquisition time and reduce tissue heating compared to single point MR-ARFI.
In one example, the treatment apparatus 104 can include an ultrasound transducer configured to emit FUS pulses at tissue represented by focal points within the anatomical region 116. In another example, the ultrasound transducer can be configured to emit a pressure pattern that simultaneously focuses on two or more focal points within the anatomical region 116. A focal point can be a predetermined volume within the anatomical region 116 that has been selected to receive treatment via one or more FUS pulses.
The computing device 106 can be configured to create a combined image of the anatomical region 116 that includes the focal points. The combined image can be created by interleaving a reference image of the anatomical region 116 and active images that include the focal points in the anatomical region 116. Displacement measurements for the focal points exposed to the FUS pulses can be calculated using the combined image. The computing device 106 can include modules used to create the combined image and calculate displacement measurements. The modules may include a treatment map module 108, an image interleave module 110, a tissue displacement module 112, a temperature monitor module 114, and other modules and/or services.
The treatment map module 108 can be configured to generate a map of an anatomical region 116 (i.e., a treatment map) that includes focal points within the anatomical region 116 to be exposed to simultaneous and/or rapidly interleaved FUS pulses. In one example, an anatomical region MR-ARFI image of an anatomical region 116 can be acquired using the MRI apparatus 102. Focal points that are to be exposed to FUS pulses can be overlaid on the anatomical region MR-ARFI image. As an illustration, a user can add focal points to the anatomical region MR-ARFI image displayed in a graphical user interface (not shown) by selecting a region that is to be treated and adding a graphical representation to the image that represents the focal point. The focal points mark tissue that is to be ablated using FUS pulses. In one example, the treatment map module 108 may be configured to generate a three-dimensional (3D) map of an anatomical region 116 that includes focal points to be exposed to FUS pulses.
The image interleave module 110 can be configured to interleave a reference MR-ARFI image (e.g., a treatment map generated using the treatment map module 108) and active MR-ARFI images to create a combined image of an anatomical region 116 that includes focal points. The reference MR-ARFI image can provide a phase reference for the focal points to be exposed to FUS pulses. An active MR-ARFI image for each of the focal points in the anatomical region 116 can then be acquired during exposure of the focal points to the FUS pulses. That is, the active MR-ARFI image can be acquired using the imaging apparatus 102 during treatment of the anatomical region 116. The reference MR-ARFI image and active MR-ARFI images can then be interleaved to create a combined image of the anatomical region 116 that includes imaging data for the focal points being treated using FUS pulses.
The tissue displacement module 112 can be configured to calculate a tissue displacement measurement for focal points exposed to FUS pulses using a combined image of an anatomical region 116 created using the image interleave module 110 as described above. The tissue displacement measurement may be a function of FUS pulse intensity and changes in tissue displacement during exposure of tissue to a FUS pulse. For example, a thermal dose delivered by FUS pulses to tissue located at the focal points can be measured in tandem with measuring tissue displacement of tissue being exposed to the FUS pulses, and the measurements can be used to determine the tissue displacement measurement.
In one example, the temperature monitor module 114 can be configured to monitor the temperature in the anatomical region 116 being exposed to the FUS pulses and provide the temperature to the tissue displacement module 112 which uses the temperature to calculate a tissue displacement measurement. In one example, the temperature may be calculated by performing baseline subtraction between a sequence of MR-ARFI reference images.
The tissue displacement module 112 can be configured to assess tissue damage occurring at focal points according to a tissue displacement measurement and determine whether a treatment endpoint has been realized based in part on the tissue displacement measurement. For example, the tissue displacement module 112 may monitor tissue damage by detecting and monitoring the formation of lesions during treatment as explained in greater detail later.
The computing device 106 can comprise a processor-based system. The various processes and/or other functionality may be executed on one or more processors that are in communication with one or more memory modules. In one example, a number of computing devices 106 may be arranged in one or more server banks or computer banks or other arrangements. The computing device 106 may be connected to a network. The network may include any useful computing network, including an intranet, the Internet, a local area network, a wide area network, a wireless data network, or any other such network or combination thereof. Components utilized for such a system may depend at least in part upon the type of network and/or environment selected. Communication over the network may be enabled by wired or wireless connections and combinations thereof.
FUS control software can be modified to allow a trajectory of short FUS pulses. To increase the number of points excited, the phases of the multiple-element phased array FUS transducer can be adjusted to focus (and perform ARFI displacement) simultaneously at two or more well separated points. Because phased-array ultrasound transducers can rapidly steer between different focal points, multiple points can be interrogated during a single acquisition interval. The power of phased-array transducers can be used to create volumetric ablation points through creating simultaneous focal spots or through rapid electronic scanning of a single focal point. A 3D Gradient echo MR-ARFI/temperature sequence can be used that interleaves multipoint acquisition with data sharing. As an illustration, if Nfz focal positions can be acquired in a multipoint ARFI map (e.g. Nfz=24), then the same 3D volume can be acquired Nfz times with FUS pulses (ON images) and once without FUS pulses (OFF images) (e.g. Nfz+1=25). The OFF image serves as the phase reference image for all of the ON images. Because the displacement pattern may be broad in the ultrasound propagation (slice encoding) direction, acquisition time can be reduced or Nfz increased by only acquiring a few central slice encoding measurements (|kz<kcent) for the Nfz ON images. The outer slice encodings (kcent<|kz|<Nz/2) for all ON images can be obtained from the OFF image. OFF image acquisition can be interleaved with the ON image acquisitions to further reduce tissue heating.
In one specific example,
The technology includes 3D MR-ARFI in both spin echo and gradient echo implementations (
The FUS controller and the 3D MR-ARFI sequence were modified to perform interleaved acquisition of multiple points.
Image reconstruction can be performed by combining the outer slice encoding OFF image measurements with the data of each of the Nf, ON images to form high-resolution images for each FUS point. Because the same volume may be imaged many times (e.g., as many as 25 times), and because only the image phase may be expected to change between acquisitions, magnitude averaging can be incorporated for increased image SNR (Signal-to-Noise Ratio). The phase for temperature and displacement for each FUS point may be determined from each ON image separately. Also, displacement modeling can be used to obtain elasticity distributions around each point.
In one example, to shorten acquisition time: 1) TR can be reduced by at least a factor of two because tissue heating is spread by interleaving; 2) Because the displacement pattern is broad in the propagation direction, only central lines in kz can be acquired and the outer lines can be obtained from the single OFF image; 3) Fractional phase and slice encoding can be applied; and 4) Because the same volume is being acquired multiple times with only differences in the phase distribution, undersampling with constrained reconstruction can be used to improve efficiency. Taken together the efficiencies listed can achieve an acceleration factor of 24 (2×2×3/2×2). The same efficiencies applied to spMR-ARFI can achieve an approximate acceleration factor of 4 (2×4/3×3/2×1), giving mpMR-ARFI a 6-fold gain in efficiency over spMR-ARFI.
Because the same volume is imaged many times (e.g., 25 times for
In some aspects, small phase variation may occur between the multiple interleaved ON images. One option is to interleave one or more additional OFF images to increase the background phase similarity between ON and OFF images. If a single interleaved OFF image does not adequately match the phase of all ON images, then one can either interleave more OFF images, or eliminate the cause of the unwanted phase difference. Stimulated echoes may also result in spurious phase contributions from sequential FUS pulses and can be determined by testing for eddy currents, rewinder gradients errors, and incomplete spoiling. Such echoes can be reduced or eliminated by reducing MRI flip angle or increasing TR. If TR is increased, at least 2 points per MEG can be maintained.
Simultaneous volumetric temperature and displacement measurements can depend differently on the tissue elasticity and thermal properties: w∝2αI/μc and ΔT∝αI. Because there may be issues of relative timing of measurement, as well as blurring by the ARFI Green's function and by thermal diffusion, one cannot solve for μ directly. However, the independence does allow qualitative discrimination between changes in absorption and elasticity. Accordingly, an effective elasticity parameter μeff∝2ΔT/cw can be used as a metric to correlate with clinical ablation.
The described volumetric mpMR-ARFI can confirm thermal dose endpoints to remotely palpate a volumetric ablation procedure at multiple time points during the ablation procedure. From these mpMR-ARFI displacement and temperature measurements before and after application of MRgFUS ablation, with 3D dynamic temperature distribution monitored by 3D MRTI, the distribution of changes in tissue displacement, temperature, and μeff can be correlated with the corresponding distribution of thermal dose. The manual palpability of the lesions in the ex vivo tissues can be correlated to changes in tissue stiffness as assessed with mpMR-ARFI and bench measurements. MRgFUS ablation-induced elasticity changes can also be correlated to the accumulated thermal dose as obtained by MRTI.
In one example, a change in elasticity may be obtained by combining a change in temperature (i.e., an increase in temperature) and a change in tissue displacement prior to exposing focal points to FUS pulses and after exposing the focal points to the FUS pulses. If tissue properties remain substantially static, and if the FUS pulse has the same intensity, then the temperature change with the FUS pulse (temperature rise) and the tissue displacement due to the FUS pulse may be the same before the treatment and after the treatment. However, the treatment likely changes the elasticity of the tissue and may also change an absorption coefficient (e.g., absorb more strongly after the treatment). If the tissue absorbs more strongly and is stiffer, the effects may compensate for the displacement and the effects may show the same displacement, even though the tissue has changed. However, any difference in the temperature increase can be used to tell whether more or less energy is being absorbed before or after the treatment. If the temperature increase is greater after the treatment, then the absorption coefficient increased. Thus, the ratio of displacement to temperature increase gives an estimate of effective elasticity. If the ratio changes, this indicates that the elasticity has changed. Namely, the temperature increase may be primarily related to the FUS energy absorbed by the tissue and the measured tissue displacement may be due to both the FUS energy absorbed and the tissue elastic property. By taking the ratio of the temperature increase and the displacement, the energy absorption can be eliminated as a factor in the elasticity change estimate.
The memory device 820 may contain modules 824 that are executable by the processor(s) 812 and data for the modules 824. For example, the memory device 820 may contain a treatment map module, an image interleave module, a tissue displacement module, a temperature monitor module, and other modules. The modules 824 may execute functions that perform the methods described earlier. A data store 822 may also be located in the memory device 820 for storing data related to the modules 824 and other applications along with an operating system that is executable by the processor(s) 812.
Other applications may also be stored in the memory device 820 and may be executable by the processor(s) 812. Components or modules discussed in this description that may be implemented in the form of software using high programming level languages that are compiled, interpreted or executed using a hybrid of the methods.
The computing device may also have access to I/O (input/output) devices 814 that are usable by the computing devices. An example of an I/O device is a display screen 830 that is available to display output from the computing devices. Other known I/O devices may be used with the computing device as desired. Networking devices 816 and similar communication devices may be included in the computing device. The networking devices 816 may be wired or wireless networking devices that connect to the internet, a LAN, WAN, or other computing network.
The components or modules that are shown as being stored in the memory device 820 may be executed by the processor(s) 812. The term “executable” may mean a program file that is in a form that may be executed by a processor 812. For example, a program in a higher level language may be compiled into machine code in a format that may be loaded into a random access portion of the memory device 820 and executed by the processor 812, or source code may be loaded by another executable program and interpreted to generate instructions in a random access portion of the memory to be executed by a processor. The executable program may be stored in any portion or component of the memory device 820. For example, the memory device 820 may be random access memory (RAM), read only memory (ROM), flash memory, a solid state drive, memory card, a hard drive, optical disk, floppy disk, magnetic tape, or any other memory components.
The processor 812 may represent multiple processors and the memory device 820 may represent multiple memory units that operate in parallel to the processing circuits. This may provide parallel processing channels for the processes and data in the system. The local interface 818 may be used as a network to facilitate communication between any of the multiple processors and multiple memories. The local interface 818 may use additional systems designed for coordinating communication such as load balancing, bulk data transfer and similar systems.
While the flowcharts presented for this technology may imply a specific order of execution, the order of execution may differ from what is illustrated. For example, the order of two more blocks may be rearranged relative to the order shown. Further, two or more blocks shown in succession may be executed in parallel or with partial parallelization. In some configurations, one or more blocks shown in the flow chart may be omitted or skipped. Any number of counters, state variables, warning semaphores, or messages might be added to the logical flow for purposes of enhanced utility, accounting, performance, measurement, troubleshooting or for similar reasons.
Some of the functional units described in this specification have been labeled as modules, in order to more particularly emphasize their implementation independence. For example, a module may be implemented as a hardware circuit comprising custom VLSI circuits or gate arrays, off-the-shelf semiconductors such as logic chips, transistors, or other discrete components. A module may also be implemented in programmable hardware devices such as field programmable gate arrays, programmable array logic, programmable logic devices or the like.
Modules may also be implemented in software for execution by various types of processors. An identified module of executable code may, for instance, comprise one or more blocks of computer instructions, which may be organized as an object, procedure, or function. Nevertheless, the executables of an identified module need not be physically located together, but may comprise disparate instructions stored in different locations which comprise the module and achieve the stated purpose for the module when joined logically together.
Indeed, a module of executable code may be a single instruction, or many instructions and may even be distributed over several different code segments, among different programs and across several memory devices. Similarly, operational data may be identified and illustrated herein within modules and may be embodied in any suitable form and organized within any suitable type of data structure. The operational data may be collected as a single data set, or may be distributed over different locations including over different storage devices. The modules may be passive or active, including agents operable to perform desired functions.
The technology described here may also be stored on a computer readable storage medium that includes volatile and non-volatile, removable and non-removable media implemented with any technology for the storage of information such as computer readable instructions, data structures, program modules, or other data. Computer readable storage media include, but is not limited to, non-transitory media such as RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical storage, magnetic cassettes, magnetic tapes, magnetic disk storage or other magnetic storage devices, or any other computer storage medium which may be used to store the desired information and described technology.
The devices described herein may also contain communication connections or networking apparatus and networking connections that allow the devices to communicate with other devices. Communication connections are an example of communication media. Communication media typically embodies computer readable instructions, data structures, program modules and other data in a modulated data signal such as a carrier wave or other transport mechanism and includes any information delivery media. A “modulated data signal” means a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal. By way of example and not limitation, communication media includes wired media such as a wired network or direct-wired connection and wireless media such as acoustic, radio frequency, infrared and other wireless media. The term computer readable media as used herein includes communication media.
Although the subject matter has been described in language specific to structural features and/or operations, it is to be understood that the subject matter defined in the appended claims is not necessarily limited to the specific features and operations described above. Rather, the specific features and acts described above are disclosed as example forms of implementing the claims. Numerous modifications and alternative arrangements may be devised without departing from the spirit and scope of the described technology. The foregoing detailed description describes the invention with reference to specific exemplary embodiments. However, it will be appreciated that various modifications and changes can be made without departing from the scope of the present invention as set forth in the appended claims. The detailed description and accompanying drawings are to be regarded as merely illustrative, rather than as restrictive, and all such modifications or changes, if any, are intended to fall within the scope of the present invention as described and set forth herein.
This application claims priority to U.S. Provisional Application No. 62/278,879, filed Jan. 14, 2016 which is incorporated herein by reference.
This invention was made with government support under Grant Nos. CA172787 and EB013433 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2017/012827 | 1/10/2017 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62278879 | Jan 2016 | US |
