Method for imaging brain vascular activity

Abstract

Traumatic brain injury and aneurysm-related bleeding are important causes of death and severe disability in human and animal subjects. More specifically, brain injury is significantly caused by secondary ischemic injury in coma subjects. The present disclosure proposes a reliable method for monitoring vascular activity in at least one region of the brain of a human or animal, the method comprising obtaining a time series of 3D Doppler scans of the brain in the region with an ultrasound probe (4) that has been implanted through a borehole (BH) in the human or animal, and calculating a temporal evolution (21, 22, 23) of at least one vascular parameter of the region based on the 3D Doppler scans of the time series.

Description

Technical Field

[0001] The present disclosure is directed to methods and apparatus for imaging cerebral vascular activity in humans or animals. Background Art

[0002] Traumatic brain injury and aneurysm-related hemorrhage are important causes of death and severe disability in human and animal subjects. More specifically, brain damage is apparently caused by secondary ischemic injury in comatose subjects. Maintaining cerebral blood supply in comatose subjects is a cornerstone of neurocritical care. Therefore, reliable methods for monitoring cerebral vascular activity, and in particular for imaging early secondary ischemia, are crucial for appropriate neurocritical care.

[0003] Unfortunately, existing imaging modalities are not capable of accomplishing this task. For example, the transcranial Doppler imaging mode is limited by the spatial coverage. Therefore, the transcranial Doppler imaging mode does not allow observation of brain vascular activity outside the spatial coverage, hindering the imaging of early secondary ischemia outside the limited spatial coverage. In addition, the transcranial Doppler imaging mode is not suitable for monitoring brain vascular activity. Similarly, neither the computed tomography (CT) perfusion imaging mode nor the magnetic resonance (MR) perfusion imaging mode is suitable for monitoring brain vascular activity. On the other hand, the intracranial pressure monitoring mode allows monitoring of brain vascular activity. However, the intracranial pressure monitoring mode does not allow imaging of early secondary ischemia.

[0004] Therefore, there is a need to reliably monitor brain vascular activity in humans or animals. Summary of the invention

[0005] To this end, the present disclosure proposes a method for imaging vascular activity in at least one region of the brain of a human or animal, the method comprising:

[0006] (a) obtaining a time sequence of three-dimensional 3D Doppler scans of the brain in the region based on ultrasound measurements of the region performed using an ultrasound probe having an array of at least one ultrasound transducer, the ultrasound probe having been implanted in the human or animal body through a burr hole;

[0007] (b) calculating the time evolution of at least one vascular parameter of the zone based on the 3D Doppler scan of the time series.

[0008] Depending on the embodiment, the proposed method advantageously allows monitoring of cerebral vascular activity.Due to the calculated and even in some embodiments continuous temporal evolution of at least one vascular parameter of said zone, ischemia occurring in said zone, in particular early secondary ischemia, can be detected.

[0009] It is worth noting that in some embodiments, the inventors of this case have achieved imaging of vascular activity in an area covering 80% of the pig brain. In other words, ischemia occurring anywhere in the four regions of the pig brain, especially early secondary ischemia, can be detected by the method disclosed herein.

[0010] Additionally, in some embodiments, an ultrasound probe may have been implanted through the burr hole for a duration between one hour and several days, allowing for monitoring of brain activity over that duration.

[0011] The following features may optionally be implemented alone or in combination with other features:

[0012] In one or more embodiments, the method further comprises:

[0013] (a1) obtaining an additional time series of additional images of the brain in the region based on additional ultrasound measurements performed on the region using the ultrasound probe,

[0014] (b1) calculating an additional time evolution of at least one additional vascular parameter of the region based on said additional images of said additional time series,

[0015] Wherein the additional image is selected from the group consisting of: B-mode ultrasound images, elastography images, and any combination thereof.

[0016] In some embodiments, an additional time series may be acquired in parallel with the time series of the 3D Doppler scan. That is, for some of the time points of the time series of the 3D Doppler scan, and even for each time point in some embodiments, an additional image of the brain in the region may be obtained. The additional image may be a 2D or 3D image. Acquiring a B-mode ultrasound image may allow enriching information about the region by calculating an additional time evolution of at least one additional vascular parameter of the region. The additional vascular parameter may be the ventricular size of the ventricle in the region. Acquiring an elastic imaging image may allow enriching information about the region by calculating an additional time evolution of at least one additional vascular parameter of the region. The additional vascular parameter may be the intracranial pressure in the region.

[0017] In one or more embodiments, the method further comprises:

[0018] (c) triggering a warning based on a change in the time evolution of the at least one vascular parameter exceeding a threshold value.

[0019] Thus, in some embodiments, changes in abnormal cerebral blood supply may be automatically detected. For example, detection of a decrease in the value of a vascular parameter may allow detection of ischemia. Alternatively or in combination, detection of a spike in the temporal evolution of at least one vascular parameter may allow detection of migration of a blood clot prior to vascular occlusion and the resulting ischemia.

[0020] In one or more embodiments, triggering of the warning is based on the duration of a change in the time evolution of at least one vascular parameter exceeding a threshold value.

[0021] For example, a warning may be triggered when a change in the time evolution of at least one vascular parameter exceeds a threshold for a duration between 1 s and 10 h. An example of a usable duration is 1 minute. Thus, artificial changes may not trigger a warning, enhancing the reliability of the method.

[0022] In one or more embodiments, the method further comprises obtaining a baseline of the at least one vascular parameter, and the change in the time evolution of the at least one vascular parameter depends on the baseline.

[0023] A baseline may be selected as a reference for at least one vascular parameter in a zone. In some embodiments, a change in the time evolution of at least one vascular parameter may be calculated as a relative change in the value of the vascular parameter relative to the baseline. In some embodiments, a threshold for the change in the time evolution of at least one vascular parameter in a zone may be defined based on the baseline. For example, the threshold may be a percentage of the relative change relative to the baseline. The percentage may be between -100% and +500%, preferably -50%. That is, different thresholds may be set for vascular parameters and / or zones. Furthermore, different thresholds may therefore be set for different subjects. Therefore, in some embodiments, different thresholds may be configured for each subject, vascular parameter and brain zone, allowing for increased sensitivity in detecting changes in vascular activity.

[0024] In one or more embodiments, the method further comprises:

[0025] (d) obtaining at least a first ultrasound localization microscopic image of the brain in the region based on a first additional ultrasound measurement performed of the region with the ultrasound probe.

[0026] In one or more embodiments, a 3D Doppler scan may be calculated based on the ultrafast ultrasound image. Acquiring at least one additional ultrasound localization microscopic image may allow obtaining at least an image of the region with a higher resolution, enriching the information about the region. In addition, the at least one additional image may be acquired using the same ultrasound probe as the 3D Doppler scan acquisition. Thus, the same probe may allow monitoring of vascular activity in the region by 3D Doppler scanning, detecting abnormal changes, and obtaining better insight into activity in the region by higher resolution imaging.

[0027] In one or more embodiments, the method further comprises, based on the triggered alert:

[0028] (e) obtaining at least a second ultrasound localization microscopic image of the brain in the region based on a second additional ultrasound measurement of the region performed with the ultrasound probe,

[0029] (f) comparing the at least second ultrasound localization microscopy image with the at least first ultrasound localization microscopy image.

[0030] Advantageously, the additional baseline may be based on an additional first ULM image, allowing for precision in assessing changes in vascular parameters. For example, the first ULM image may be acquired before acquiring the time series of 3D Doppler scans. That is, an additional baseline with a higher resolution may be acquired before acquiring the time series of 3D Doppler scans. Subsequently, a second ULM image may be acquired based on the triggered alert, in particular when the alert is triggered. The second ULM image may be compared with the first ULM image. In particular, the value of at least one vascular parameter of the area in the second ULM image may be compared with the value of at least one vascular parameter of the area in the first ULM image. Thus, the comparison between the ULM images before and after the triggered alert may allow for quantifying changes in vascular activity due to the triggered alert with a resolution of up to micrometers.

[0031] In one or more embodiments, the at least one vascular parameter is selected from the group consisting of: blood flow, blood velocity, blood volume, arterial resistance index, and any combination thereof.

[0032] Calculating parameters among blood flow, blood velocity, blood volume, arterial resistance index and any combination thereof may allow to derive the behavior of at least one region of the vascular network. Thus, the vascular activity of at least one region may be quantified without requiring a large amount of information from different types.

[0033] In one or more embodiments, at least one 3D Doppler scan of the time series is registered to at least one of a brain atlas, a computed tomography scan of the brain, a magnetic resonance imaging scan of the brain, and any combination thereof.

[0034] Registering at least one Doppler scan to a brain atlas, a CT scan of the brain, an MRI scan of the scan, and any combination thereof may allow for combining complementary information of the subject, such as anatomical information and physiological information. Specifically, the brain atlas may be a structural brain atlas, a vascular brain atlas, or a functional brain atlas. Registering at least one 3D Doppler scan to a brain atlas may further allow for comparison of vascular activity between different subjects whose burr holes do not always have the same location.

[0035] In one or more embodiments, the time series of 3D Doppler scans of the brain in the region is divided into regions of interest, and the method further comprises, for each region of interest:

[0036] (b1) calculating a time evolution of at least one vascular parameter of the region of interest based on the 3D Doppler scan of the time series.

[0037] Dividing the region into regions of interest may allow increasing the granularity of the computed temporal evolution. Thus, different behaviors in the regions of interest of the region may be observed. That is, additional local information in the regions of interest may be utilized to obtain a global view of the imaged region of the brain, increasing the sensitivity of the observation.

[0038] In one or more embodiments, the ultrasound is coupled to an accelerometer configured to detect movement of the person or animal, and the warning is triggered based on the detection of the movement.

[0039] Detecting movement of the person or animal, in particular movement of the head of the person or animal, may allow distinguishing false positive warnings. More precisely, the subject may move or be manipulated, which may temporarily modify the vascular activity in the imaging area. In this case, the modification of the vascular activity may not be pathological and a warning may not be triggered.

[0040] In one or more embodiments, the ultrasound probe is rotated between measurements to obtain at least a 3D Doppler scan of said time series.

[0041] Rotating the ultrasound probe between measurements allows a 3D Doppler scan to be obtained using an ultrasound probe suitable for 2D imaging. In addition, the same pattern of interrogating ultrasound beams can be used to obtain 2D Doppler images acquired at different rotation angles, providing uniformity in the acquisition of 3D Doppler scans. Alternatively, a matrix array probe can be used to acquire a 3D Doppler scan.

[0042] In one or more embodiments, a pause is observed between two consecutive rotations of the ultrasound probe.

[0043] For deep imaging of brain regions, high power transmission may be required. In addition, the ultrasound probe may have a small aperture, especially because the ultrasound probe is configured to fit in a borehole. Therefore, if a pause is not observed between two consecutive rotations of the ultrasound probe, the heating safety limit of the probe may be exceeded. Therefore, implementing a pause between two consecutive rotations of the ultrasound probe may allow staying under the heating safety limit of the probe.

[0044] The present disclosure also provides a device for imaging vascular activity in at least one region of a brain of a human or animal, the device comprising:

[0045] (a) an ultrasound measurement device adapted to perform ultrasound measurement of the zone using an ultrasound probe having an array of at least one ultrasound transducer, the ultrasound probe being implantable through the drill hole;

[0046] (b) a computing module adapted to:

[0047] - calculating a time sequence of three-dimensional 3D Doppler scans of said zone from said ultrasound measurements;

[0048] - calculating the time evolution of at least one vascular parameter of said zone based on said 3D Doppler scans of said time series.

[0049] In an embodiment of the device the calculation module is adapted to detect an epileptic seizure and / or delayed ischemia, vasospasm, hemorrhage, hypoperfusion, hyperperfusion or edema based on the temporal evolution of at least one vascular parameter of said zone.

[0050] In another aspect, a computer software is proposed, which comprises instructions for implementing at least a part of the method defined herein when the software is executed by a processor. In another aspect, a computer-readable non-transitory recording medium is proposed, on which software is registered to implement the method defined herein when the software is executed by a processor.

[0051] In another aspect, a method for imaging vascular activity in at least one region of a brain of a human or animal is presented, the method comprising:

[0052] - performing a burr hole in the skull of said human or animal;

[0053] - implanting an implantable ultrasound probe having an array of at least one ultrasound transducer through said burr hole;

[0054] - obtaining a time sequence of three-dimensional 3D Doppler scans of the brain in said region based on ultrasound measurements performed on said region with said implantable ultrasound probe;

[0055] - calculating the time evolution of at least one vascular parameter of said zone based on said 3D Doppler scans of said time series. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Additional features, details and advantages will be shown in the following detailed description and in the accompanying drawings, in which:

[0057] Figure 1

[0058] Figure 1is a block diagram illustrating an embodiment of a device according to the present disclosure.

[0059] Figure 2

[0060] Figure 2 Show the use Figure 1 A possible method for obtaining a series of 3D Doppler scans using a device.

[0061] Figure 3

[0062] Figure 3 A portion of an apparatus used in one particular embodiment is shown.

[0063] Figure 4

[0064] Figure 4 A portion of an apparatus used in one particular embodiment is shown.

[0065] Figure 5

[0066] Figure 5 (a) shows a 2D Doppler image of a region of the brain obtained using the method of the present disclosure.

[0067] Figure 5 (b) Display and Figure 5 ULM image of the same brain region in (a), obtained using the method of the present disclosure.

[0068] Figure 5 (c) Display Figure 5 (b) Enlarged view of the ULM image.

[0069] Figure 6

[0070] Figure 6 (a) shows examples of 3D Doppler scans before and after a stroke, obtained using the method of the present disclosure.

[0071] Figure 6 (b) shows examples of perfusion CT images before and after a stroke.

[0072] Figure 7

[0073] Figure 7 (a) shows an example of a 2D Doppler image during stroke establishment, which is obtained using the method of the present disclosure.

[0074] Figure 7(b) shows an example of a metric of the evolution of at least one vascular parameter during stroke establishment, said metric being obtained using the method of the present disclosure. DETAILED DESCRIPTION

[0075] In the drawings, the same reference numerals refer to the same or similar elements.

[0076] The present disclosure proposes a method and apparatus for imaging vascular activity in at least one region of the brain of a human or animal by obtaining a time sequence of three-dimensional 3D Doppler scans in said region. The 3D Doppler scans are obtained using an ultrasound probe that has been implanted through a burr hole. The time sequence of 3D Doppler scans enables the value of at least one vascular parameter in at least one region of interest of said region to be obtained. Based on the value of at least one vascular parameter from the time sequence of 3D Doppler scans, a measure of the time evolution of the at least one vascular parameter is calculated.

[0077] Regions of the brain may cover 25% to 100% of the brain.

[0078] exist Figure 1 An example of an apparatus 1 for imaging vascular activity (VA APP) which can be used to perform the method according to the present disclosure is shown above.

[0079] The apparatus 1 may comprise a processor 2 (PROC), for example a dedicated signal processing device controlled by a computer or a group of computers (possibly a group of computers including a server).

[0080] The processor 2 may include a computing module 3 (COMP), the operation of which will be explained later.

[0081] The processor 2 may control the probe 4 (PRB).

[0082] In the example considered here, the probe 4 may be, for example, an ultrasound probe.

[0083] The probe 4 may include an array 6 (ARR) of ultrasound transducers. The array may be a linear array suitable for producing a 2D image of a slice of the area to be imaged, or a 2D array suitable for producing a 3D image of the area. When the array is a 2D array, the array may be a sparse matrix of transducers, as known in the art.

[0084] A typical array of transducers may contain hundreds to thousands of transducers. In some instances, the array may also be limited to a single transducer adapted to image only one line of the zone in the direction of the depth from the transducer, or to a few transducers adapted to image multiple lines of the zone, respectively, in the direction of the depth from the transducer.

[0085] The following detailed description is made for the case of a linear or 2D array, such that the device produces a Doppler image (more generally: ultrasound measurement) having pixels (more generally: Doppler samples). In the case where the array will contain only one transducer or a few transducers, the device will produce an image limited to one line (ultrasound measurement) or a few lines in the depth direction, the lines having pixels (Doppler samples), and the process will be similar, except for producing ultrasound measurements, which will not require tilted plane waves at different tilt angles and will not require translated diverging waves from different virtual sources.

[0086] The transducer may be adapted to transmit and receive ultrasound waves having a center frequency, for example, between 0.5 MHz and 100 MHz, such as between 1 MHz and 20 MHz. An example of a useful center frequency is 5 MHz.

[0087] In certain embodiments, the probe 4 may further include a motorized device 5 (MOT) adapted to position the array 6 .

[0088] Now about Figure 2 An example of a method for 3D Doppler scanning acquisition is explained.

[0089] The array 6 of transducers can be controlled by the processor 2 to transmit divergent ultrasound waves in the area to be imaged and receive the resulting backscattered ultrasound waves at a rate of, for example, 6 kHz (pulse repetition frequency PRF), i.e., about every 0.2 ms. More generally, the pulse repetition frequency PRF can exceed 500 Hz. The received signals are registered as a raw data set for each transmitted divergent ultrasound wave. The continuously transmitted divergent waves are transmitted by N virtual sources (VS) that are spaced relative to the width (α) in the area to be imaged. 成像 ) direction, i.e., the lateral direction relative to the array 6 For example, the position of the kth virtual source (1≤k≤N) can be defined by the following coordinates:

[0090]

[0091] Where L is the transverse aperture of the probe, for example L = 9.1 mm;

[0092] α ,in is the minimum angle between the virtual source and the end of the probe, such as α min =10°;

[0093] α 成像 is the imaging width, for example α 成像 =90°.

[0094] For each image of a zone, a number N of divergent ultrasound waves are transmitted successively by N virtual sources (VS), and N raw data sets are processed to synthesize the image of the zone, which is an in-phase quadrature (IQ) image reconstructed on a polar coordinate grid. The polar coordinate grid may be (elevation angle, radius) = (0.5°, 0.15 mm).

[0095] Thus, in the illustrated case of N=12 and PRF=6kHz, the rate (frame rate) of the composite image of the region is approximately 500 Hz. N may be different from 12, in which case the frame rate of the composite image is different. For example, N=5 may be used.

[0096] Alternatively, the array 6 of transducers may be controlled by the processor 2 to transmit planar ultrasound in the area to be imaged and receive the resulting backscattered ultrasound at a rate of, for example, 5.5 kHz (pulse repetition frequency PRF), i.e., approximately every 18 ms. More generally, the pulse repetition frequency PRF may exceed 500 Hz. The received signal is registered as a raw data set for each transmitted planar ultrasound. The continuously transmitted plane waves have a propagation direction that is tilted at different continuous angles relative to the depth direction in the area to be imaged, i.e., relative to the direction perpendicular to the array 6. For each image of the area, a number N of planar ultrasounds are continuously transmitted at different angles, and the N raw data sets are coherently added to synthesize the image of the area, which is therefore a composite image. For example, N may be 11, where the angle varies between -10 degrees and +10 degrees in steps of 2 degrees. Therefore, in the case of N=11 and PRF=5.5 kHz, the rate (frame rate) of the composite image of the area is 500 Hz. N may be different from 11, in which case the frame rate of the composite image is different. For example, N=5 may be used.

[0097] Subsequently, in both cases, a Doppler image of the zone is calculated by the calculation module 3 based on the synthetic image of the zone. For example, for each Doppler image, 500 consecutive synthetic images are used. Therefore, in this case, the rate of Doppler images is 1 Hz. For each Doppler image, a different number of consecutive composite images can be used, in which case the rate of Doppler images is different. For example, in the example considered here, for each Doppler image, 50 consecutive synthetic images can be used, in which case the rate of Doppler images will be 10 Hz. In general, the rate of Doppler images is at least 2 Hz.

[0098] Vascular parameters can be calculated from the successive composite images, for example using spatial filtering based on single value decomposition (SVD). The successive composite images can be squared and averaged into a final ultra-sensitive Doppler image. Due to the high acquisition frame rate of the image, the sensitivity of the ultrasound signal can be increased without transmitting high-energy ultrasound waves in the brain region.

[0099] More generally, the Doppler image can be calculated by any Doppler technique, including ultra-sensitive Doppler, power Doppler, micro-Doppler, spectral Doppler. The Doppler signals constituting the Doppler image can be, for example, power Doppler, color Doppler, spectral Doppler, vascular resistance index, or any combination thereof. The Doppler signals can be filtered at different Doppler frequency bandwidths to assess the sensitivity of the Doppler signal to blood flow velocity.

[0100] exist Figure 2 In the example of , the processor 2 rotates the array 6 to obtain a three-dimensional 3D Doppler scan of the area by acquiring Doppler images at different rotation angles. For example, the array 6 rotates at a rotation step size (θ_motor) of 2° within a range of 180°. That is, for each 3D Doppler scan, 89 Doppler images are used. For each Doppler scan, a different rotation step size (θ_motor) may be used, in which case the spatial resolution is different. Specifically, in some embodiments, the rotation step size (θ_motor) may depend on the elevation angle (el) of the Doppler image. 切片 For example, the elevation angle (el 切片 ), the larger the rotation step (θ_motor) is.

[0101] 3D Doppler scans can be reconstructed from Doppler images at different rotation angles by interpolating Doppler images on a Cartesian grid. Doppler images can be corrected using depth attenuation compensation. The 3D Doppler scans can be reconstructed from Doppler images at different rotation angles by interpolating Doppler images on a Cartesian grid ... 3 Rotation (azimuth, elevation, radius) = (θ 电机 ,α 成像 ,R 成像 ) = (2°, 0.5°, 0.15 mm) to interpolate the (corrected) Doppler image in a polar grid. Delaunay triangulation can be used to interpolate the (corrected) Doppler image.

[0102] Figure 3 Schematically shows how the device 1 can be used to image vascular activity in a region of the brain. An ultrasound probe 4 has been implanted through a burr hole (BH). A burr hole BH is a hole drilled in the skin 10 and the bone 11. The burr hole BH opens access to the brain 15 covered by the meninges. The meninges comprise, among other things, three layers (dura mater 12, subarachnoid space 13, pia mater 14). The diameter of the burr hole BH may be between 10 mm and 20 mm, preferably about 15 mm.

[0103] In one embodiment, a method for implanting in a region of a patient's brain and imaging vascular activity comprises the following steps:

[0104] - performing a burr hole in the skull of said human or animal;

[0105] - Insertion of implantable ultrasound probe through the drill hole;

[0106] - obtaining a time sequence of three-dimensional 3D Doppler scans of the brain in said region based on ultrasound measurements performed on said region with said implantable ultrasound probe;

[0107] - calculating the time evolution of at least one vascular parameter of said zone based on said 3D Doppler scans of said time series.

[0108] The surgery is performed under general anesthesia.

[0109] The location of the probe may be determined by the clinician based on the area of ​​the brain to be monitored prior to drilling, such as by a brain navigation system.

[0110] After skin disinfection, a 4 cm linear skin incision can be made on the skull to expose the skull. A burr hole is made using a mechanical drill. The probe is positioned in the burr hole outside of the dura mater, which must be preserved.

[0111] The implantable ultrasound probe is positioned through the bore hole and secured to the bone by any suitable securing member such that the implantable probe is secured relative to the bone in the bore hole.

[0112] In one embodiment, the implantable ultrasound probe is connected to an analysis system outside the skull. For example, the connecting cable is inserted approximately 5 cm under the skin to emerge from the first incision.

[0113] Subsequently, the skin incision was sutured in 2 layers. During the monitoring period, sterile dressings were made daily.

[0114] At the end of the monitoring period, after disinfection of the skin, the previously made incision is reopened. The means for fixing the probe to the bone are removed, allowing the probe and its cable to be removed. The incision is closed in 2 layers.

[0115] The ultrasonic probe 4 is configured to fit into the borehole BH. Figure 3 In the example of, the ultrasound probe 4 has a circular active surface, the diameter of which is smaller than the diameter of the borehole BH. For example, depending on the diameter of the borehole BH, the diameter of the ultrasound probe 4 may be between 6 mm and 16 mm, preferably 11 mm.

[0116] In some embodiments, the burr hole BH may have been pre-drilled to help relieve pressure on the brain when brain tissue is compressed by, for example, overflowing fluid and / or to monitor intracranial pressure (ICP). Alternatively, the burr hole BH may be drilled to insert the ultrasound probe 4.

[0117] The motorized device 5 rotates the array 6 within the borehole BH to obtain Doppler images for a 3D Doppler scan. The processor 2 is adapted to control the motorized device 5.

[0118] In some embodiments, the processor 2 may be configured to obtain an additional time series of additional images of the brain in the region based on additional ultrasound measurements performed on the region using the ultrasound probe 4. Additional images may be acquired by the ultrasound probe 4 after each acquisition of a Doppler image. The additional images may be B-mode ultrasound images and / or elastography images.

[0119] The processor 2 may be configured to control the motorized device 5 to observe a pause between two consecutive rotations of the array 6. For example, the pause duration may be higher than 8 s, preferably about 10 s. An example of a usable pause duration is 11 s. Thus, in a pause duration of 11 s and Figure 2 In the exemplary case of acquiring 89 Doppler images at a rate of 1 Hz as described in the example of FIG. , the total duration for acquiring a 3D Doppler scan is approximately 18 min.

[0120] In a variant, the ultrasound probe 4 may be further coupled to a temperature sensor (not shown). Depending on the temperature measurement, the calculation module 3 may be adapted to select a pause duration between two consecutive rotations. The pause duration may be calculated after each acquisition of a Doppler image so that the increase in temperature within the implanted ultrasound probe 4 does not exceed a threshold value. The threshold value may be set to 2°C according to the safe heating limit of the implantable device.

[0121] In order to achieve monitoring of the zone, the processor 2 may be configured to control the probe 4 to continuously acquire 3D Doppler scans. That is, for two consecutive 3D Doppler scans of a time series, the acquisition of the last Doppler image of the previous 3D Doppler scan may be separated from the acquisition of the first Doppler image of the subsequent 3D Doppler scan by the pause duration observed between two consecutive rotations of the ultrasound probe 4 (i.e., the pause duration observed between the acquisition of two consecutive Doppler images). Alternatively, the processor 2 may be configured to control the probe 4 to observe a pause between two consecutive 3D Doppler scans of a time series, the duration of which is, for example, between 0 min and 60 min, for example, between 1 min and 20 min. An example of an available pause is 10 min. Such values ​​allow both a high temporal resolution of a time series of 3D scans and an acceptable increase in temperature within the implanted ultrasound probe 4 to be achieved.

[0122] In a first embodiment, the angular position (θ) of the last Doppler image of the previous 3D Doppler scan 最后 / 先前 ) can correspond to θ 最后 / 先前 =θ 第一 / 先前 +180°-θ 电机 , where θ第一 / 先前 The angular position (θ) of the first Doppler image corresponding to the previous 3D Doppler scan 第一 / 先前 ). The angular position (θ) of the first Doppler image of the subsequent 3D Doppler scan 第一 / 后续 ) can correspond to θ 第一 / 后续 =θ 最后 / 先前 +θ 电机 =θ 第一 / 先前 mod(180°), where mod(180°) is the modulus. In this first embodiment, the array 6 may be rotated by incrementing the angular position by a rotation step (θ_motor). Alternatively, in a second embodiment, the angular position (θ_motor) of the first Doppler image of a subsequent 3D Doppler scan is 第一 / 后续 ) can correspond to θ 第一 / 后续 =θ 最后 / 先前 -θ 电机 In this second embodiment, the array 6 may be rotated by decrementing the angular position by a rotation step (θ_motor). In some embodiments, the first and second embodiments may be alternated in order to save one rotation of the array 6 between two consecutive 3D Doppler scans.

[0123] Figure 4 The registration of a 3D Doppler scan on a known brain atlas is shown, which is a pre-existing brain atlas. Such maps can be used for human brains and some animal brains, such as pigs. In some variations, the 3D Doppler scan can be registered to a CT scan of the subject's brain and / or an MR scan of the subject's brain, alternatively or in combination.

[0124] The calculation module 3 is adapted to select a region of interest for the 3D Doppler scan. The region of interest may be equal to the imaging zone. Alternatively, the region of interest may be smaller than the imaging zone. The region of interest may be selected based on a vascular region. For example, the region of interest may be selected based on a vascular brain atlas. Alternatively or in combination, the region of interest may be selected based on a CT scan of the subject's brain and / or an MR scan of the subject's brain. Depending on the embodiment, the region of interest may or may not cover the entire imaging zone.

[0125] Once the region of interest is determined, the calculation module 3 can average the Doppler signals on the region of interest through 3D Doppler scanning, thereby obtaining the time evolution of the vascular parameters in the region of interest. In addition, when acquiring additional time series, the B-mode ultrasound signal and / or the elastic imaging signal can be averaged on the region of interest through additional images, thereby obtaining the time evolution of additional vascular parameters in the region of interest. The content explained below for vascular parameters based on 3D Doppler scanning also applies to additional vascular parameters, except for the features specific to the Doppler mode.

[0126] exist Figure 4In the example of , three areas of interest (AOI1, AOI2, AOI3) and associated time evolution curves (21, 22, 23) are represented, where the abscissa is time (T) and the ordinate is the value of the vascular parameter (VP).

[0127] The indicated areas of interest AOI1, AOI2, AOI3 correspond to the internal cerebral vein (ICV), the transverse sinus (TS) and the thalamostriate system vein (TsS), respectively.

[0128] The temporal evolution of a vascular parameter in a region of interest can be used as a reliable biomarker for certain health disorders associated with cerebral vascular activity, such as delayed ischemia, vasospasm, hemorrhage, hypoperfusion, hyperperfusion, or edema. For example, a decrease in the value of a vascular parameter in a region of interest can correspond to ischemia in the region of interest.

[0129] For this purpose, the calculation module 3 may be adapted to calculate at least one vascular parameter from the time series of 3D Doppler scans, the at least one parameter being selected from the group consisting of: blood flow, blood flow velocity, in particular systolic velocity and / or diastolic velocity, blood volume and arterial resistance index.

[0130] In some embodiments, a relative 3D Doppler scan is calculated.Thus, at least one vascular parameter may be the difference between the values ​​observed in the two 3D Doppler scans.

[0131] In order to determine whether the temporal evolution of a vascular parameter is normal, the calculation module 3 may compare said evolution with a threshold value. The threshold value may be set by a professional, for example a medical practitioner.

[0132] In a variant, a baseline of the vascular parameter is obtained and the threshold is based on the baseline. For example, the threshold may be a percentage of the baseline. The percentage may be between -100% and +500%, preferably -50%. For example, when the vascular parameter is blood volume, a percentage between -100% and -10%, preferably -50%, may be selected. Thus, the threshold may allow detection of a decrease in blood volume that may be due to ischemia. In another example, when the vascular parameter is blood flow, a percentage between +10% and +500%, preferably +50%, may be selected. Thus, the threshold may allow detection of an increase in blood flow that may be due to incipient vasospasm.

[0133] In a variant, the baseline is derived from a first 3D Doppler scan of the time series of 3D Doppler scans.For example, the baseline is a value of a vessel parameter in a 3D Doppler scan of the time series of 3D Doppler scans.

[0134] Alternatively or in combination, in a variant, an additional baseline is derived from a first ultrasound localization microscopy (ULM) image of the brain in the region. For example, the additional baseline is a value of a vascular parameter in the first ULM image. The first ULM image may be a 2D or 3D image of the brain in the region, preferably a 3D image of the brain in the region. The first ULM image for the additional baseline may be obtained before acquiring the time series of 3D Doppler scans. The first ULM image for the additional baseline and the 3D Doppler scan may be obtained using the same probe 4. The first ULM image for the additional baseline may be obtained using the same parameters as the 3D Doppler scan. In particular, the same rotation step size θ_motor may be used.

[0135] In another variation, the threshold value depends on the diameter of the blood vessels in the region of interest. For example, the threshold value may be measured as a percentage of the blood vessel diameter. In another variation, the threshold value depends on the elasticity of the blood vessels in the region of interest. For example, the threshold value may be measured as a percentage of the blood vessel elasticity. These variations may be implemented alone or in combination with other variations.

[0136] exist Figure 4 In the example of , different thresholds (τ1, τ2, τ3) are set for different areas of interest. Warning A2 is triggered based on the blood vessel parameter in the area of ​​interest AOI2 exceeding the threshold τ2 at time tA2.

[0137] The processor 2 may further be configured to trigger a warning based on the duration of the change in the time evolution of the at least one vascular parameter exceeding a threshold. For example, a warning may be triggered when the change in the time evolution of the at least one vascular parameter exceeds the threshold for a duration between 1 s and 10 h, preferably 1 min. Thus, an isolated instantaneous change in the time evolution exceeding the threshold may not be interpreted as an abnormal change in the vascular parameter.

[0138] The apparatus 1 as described above may also include an accelerometer 7 coupled to the ultrasound probe 4. The accelerometer may detect movement of the person or animal whose brain is being imaged. A warning may be triggered based on said detection of said movement. For example, when the accelerometer detects movement of the person or animal due to external reasons such as movement / manipulation of the body, a warning may not be triggered even if the vascular parameter exceeds a threshold value. Specifically, in this case, a warning may be triggered only when the vascular parameter exceeds the threshold value for a predetermined duration, as explained above.

[0139] The device 1 may further be configured to obtain an additional second ultrasound localization microscopic image of the brain in the region of interest where the warning has been triggered. The additional second image may be a 2D image or a 3D image.

[0140] exist Figure 5In the example of (a), reference has been made to Figure 2 The described method obtains 2D Doppler images of regions of the brain. Figure 5 The additional second image of (b) is an ultrasound localization microscopy (ULM) image of the same area of ​​the brain. Figure 5 (c) Yes Figure 5 (b) Enlarged view of the dashed sub-area. Figure 5 The second ULM images of (b) and 5(c) achieve sub-wavelength resolution. Figure 5 The second ULM images of (b) and 5(c) can be used to accurately quantify vascular parameters. Specifically, the blood flow velocity and direction can be accurately quantified.

[0141] In a variation, when an additional baseline is derived from a first ULM image of the brain in the region, a second ULM image of the brain in the region may be compared to the first ULM image and / or the additional baseline.

[0142] Specifically, in a variant, in a first step, an additional baseline is derived from a first ULM image of the brain in the region. In a second step, a time series of 3D Doppler scans is obtained and the time evolution of at least one vascular parameter is calculated using the method of the present disclosure. As described above, a warning can be triggered based on a change in the time evolution of at least one vascular parameter exceeding a threshold. The warning can depend on the baseline of at least one vascular parameter. The baseline can be obtained based on a 3D Doppler scan, such as a first 3D Doppler scan of the time series. Based on the warning, at least a second ULM image of the brain in the region can be obtained using the same probe 4 as the first ULM image and the 3D Doppler scan of the time series. The second ULM image can be compared with the first ULM image and / or the additional baseline derived from the first ULM image. That is, the time series of 3D Doppler scans and the resulting time evolution of at least one vascular parameter can allow monitoring of the brain in the region to detect abnormal activity and trigger a warning. Due to the first ULM image acquired before the time series of 3D Doppler scans and the second ULM image acquired when the warning is triggered, it is possible to quantify changes in the vascular activity of the region with microscopic resolution. Therefore, the method of the present disclosure can be used to continuously monitor vascular activity through 3D Doppler scanning, and accurately quantify changes in vascular activity through ULM images when a warning is detected.

[0143] like Figure 6 (a) shows that the method disclosed herein can be used to detect stroke after ischemia. Figure 6 In the example of (a), the approximate ischemic core (in Figure 6 (b) on the left) compared to the approximate ischemic core in a 3D Doppler scan after a stroke (in Figure 6Fewer vessels were observed in (a, right side). In addition, a 25% reduction in Doppler signal in the ischemic core was observed between the 3D Doppler scans before and after the stroke (0.161 to 0.105 normalized Doppler signal).

[0144] Figure 6 (b) Computed tomography (CT) imaging experiments are shown confirming the formation of an ischemic core after stroke. Figure 6 (b) Perfusion computed tomography scan showing blood volume in sagittal view. Figure 6 (b) left) and a CT scan obtained after the stroke ( Figure 6 A decrease in perfusion of approximately 60% (14.0 to 4.9 arbitrary units of CT blood volume) was observed in the dashed area of ​​the ischemic core between (right side of (b)).

[0145] Figure 7 (a) Demonstrate the establishment of Figure 6 2D Doppler images of the same region of the brain acquired during the stroke assessed in (a) and 6(b). The 2D Doppler images are acquired using the method of the present disclosure. For example, based on a time series of 3D Doppler scans in which an ischemic core is observed, 2D Doppler images of a region corresponding to the ischemic core at different times (a 3D Doppler scan is constructed based on the 2D Doppler images) can be retrieved.

[0146] Figure 7 (b) Display with inclusion Figure 7 (a) Acquisition of a 2D Doppler image of FIG. 1 , an example of a measure of the evolution of the Doppler signal in the ischemic core. Figure 7 A large number of Doppler peaks are detected in (a)(2), which are later than Figure 7 (a)(1) The baseline obtained and preceded Figure 7 (a)(3) to Figure 7 (a) The significant decrease observed in (5) (blood flow decreased by approximately 38%). The large Doppler spike and subsequent significant decrease may be due to clot migration prior to vessel occlusion. Therefore, the measure of the evolution of the Doppler signal can be used as a reliable biomarker for ischemic core formation.

[0147] When the subject has two or more boreholes, the above explanation can be repeated. In this case, the computing module 3 can control two or more ultrasound probes 4 that have been respectively inserted into the two or more boreholes in parallel to implement at least a portion of the previously described method. Therefore, a larger brain area can be imaged. In addition, the information obtained by the two or more ultrasound probes 4 can be collected to achieve a higher spatial resolution.

[0148] It is worth noting that the device 1 as described above can also be used to monitor brain perfusion during surgery. In particular, the device 1 can be used to provide a reliable measure of cerebral blood flow throughout the brain during long surgeries that may last several hours, such as cardiac surgery. Thus, early detection of vascular accidents during surgery can be achieved.

Claims

1. A method for imaging vascular activity in at least one region of the brain of a human or animal, the method comprising: (a) obtaining a time sequence of three-dimensional 3D Doppler scans of the brain in the region based on ultrasound measurements of the region performed using an ultrasound probe (4) having an array of at least one ultrasound transducer (6), the ultrasound probe (4) having been implanted in the human or animal body through a burr hole (BH); (b) calculating the time evolution (21, 22, 23) of at least one vascular parameter of the zone based on the 3D Doppler scan of the time series.

2. The method according to claim 1, further comprising: (a1) obtaining an additional time series of additional images of the brain in the region based on additional ultrasound measurements performed on the region using the ultrasound probe (4), (b1) calculating an additional time evolution (21, 22, 23) of at least one vascular parameter of said zone based on said additional images of said additional time series, in, The additional images are selected from the group consisting of: B-mode ultrasound images, elastography images, and any combination thereof.

3. The method according to claim 1 or 2, further comprising: (c) triggering a warning (A2) based on a change in the time evolution of the at least one vascular parameter exceeding a threshold value (τ1, τ2, τ3).

4. The method of claim 3, further comprising obtaining a baseline of the at least one vascular parameter, and wherein: The calculation of the change in the time evolution of the at least one vascular parameter depends on the baseline.

5. The method according to any one of claims 1 to 4, further comprising: (d) obtaining at least a first ultrasound localization microscopic image of the brain in the region based on a first additional ultrasound measurement performed on the region using the ultrasound probe (4).

6. The method according to claim 5 in combination with any one of claims 3 and 4, characterized in that: Based on the triggered warning (A2), the method further comprises: (e) obtaining at least a second ultrasound localization microscopic image of the brain in the region based on a second additional ultrasound measurement performed on the region with the ultrasound probe (4), (f) comparing the at least second ultrasound localization microscopy image with the at least first ultrasound localization microscopy image.

7. The method according to any one of the preceding claims, characterized in that The at least one vascular parameter is selected from the group consisting of: blood flow, blood velocity, blood volume, arterial resistance index, and any combination thereof.

8. The method according to any one of the preceding claims, characterized in that At least one 3D Doppler scan of the time series is registered to at least one of a brain atlas, a computed tomography scan of the brain, a magnetic resonance imaging scan of the brain, and any combination thereof.

9. The method according to any one of the preceding claims, characterized in that The time series of 3D Doppler scans of the brain in the region is divided into areas of interest (AOI1, AOI2, AOI3), and wherein the method further comprises, for each area of ​​interest (AOI1, AOI2, AOI3): (b1) calculating the time evolution of at least one vascular parameter of the region of interest based on the 3D Doppler scan of the time series (21, 22, 23).

10. The method according to any of the preceding claims in combination with claim 2, characterized in that The ultrasound probe (4) is coupled to an accelerometer (7) configured to detect movement of the person or animal, and wherein the warning (A2) is triggered based on the detection of the movement.

11. The method according to any one of the preceding claims, characterized in that The ultrasound probe (4) is rotated between measurements to obtain at least a 3D Doppler scan of the time series.

12. The method according to claim 11, characterized in that A pause is observed between two consecutive rotations of the ultrasound probe (4).

13. A device (1) for imaging vascular activity in at least one region of the brain of a human or animal, the device (1) comprising: (a) an ultrasound measurement device adapted to perform ultrasound measurements of the zone using an ultrasound probe (4) having an array (6) of at least one ultrasound transducer, the ultrasound probe (4) being implantable in the human or animal body through a bore hole (BH); (b) a computing module (3) adapted to: - calculating a time sequence of three-dimensional 3D Doppler scans of said zone from said ultrasound measurements; - calculating the time evolution (21, 22, 23) of at least one vascular parameter of said zone based on said 3D Doppler scan of said time series.

14. The device according to claim 13, characterized in that The calculation module (3) is adapted to detect epileptic seizures and / or delayed ischemia, vasospasm, hemorrhage, hypoperfusion, hyperperfusion or edema based on the temporal evolution (21, 22, 23) of the at least one vascular parameter of the zone.

15. Computer software comprising instructions for implementing at least part of the method according to any one of claims 1 to 12 when the software is executed by a processor.

16. A computer-readable non-transitory recording medium having software registered thereon for implementing the method according to any one of claims 1 to 12 when the software is executed by a processor.

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