Method and device for non-invasive determination and / or monitoring of intracranial compliance

Abstract

The present invention relates to a method for non-invasive determination and / or monitoring of intracranial compliance of a biological material (02), having the following steps: a) performing a sonospectroscopy of the biological material (02), which is the human or animal skull; b) comparing the transmitted acoustic signal with the corresponding received acoustic signal, wherein an n-dimensional function and a propagation time value characterizing the biological material (02) are determined; c) determining an increase in the biological material (02), measuring an increase in the length and / or volume of the biological material (02); and d) determining the intracranial compliance of the biological material (02) based on the comparison performed in step b) and the measurement performed in step c). The present invention also relates to a device for non-invasive determination and / or monitoring of intracranial compliance of a biological material (02).

Description

[0001] The present invention relates to a method and a device for non-invasive determination and / or monitoring of intracranial compliance for biomaterials according to the preamble of the independent claim.

[0002] The development of intracranial pressure (ICP) changes in the human or animal skull significantly complicates many brain diseases and significantly affects activity, mortality, and further prognosis. For example, it has been found that 18% of patients with severe brain damage (such as after traumatic brain injury and / or stroke) have permanent functional damage, which requires long-term vocational and / or social rehabilitation. The extent of these damages depends not only on the initial severity of each trauma but is also significantly affected by secondary brain damage. Therefore, intracranial pressure changes that are not recognized in time and adequately treated can have significant parthenogenetic importance. Thus, the measurement of intracranial pressure is an important indicator for treatment decisions when treating patients with severe brain damage. Therefore, it is not surprising that the prior art proposes the preferably continuous measurement of intracranial pressure, which is not only treatment-related but also prognosis-related.

[0003] Various methods and devices for measuring intracranial pressure are known in the prior art. However, to date, the measurement of intracranial pressure has only been carried out by neurosurgical intracranial implanted pressure probes, the measurement being carried out by ventricular or epidural pressure probes and allowing continuous monitoring of intracranial pressure, even over longer periods. However, disadvantageously, the methods and devices known in the prior art are invasive and they require neurosurgery, including the associated risk of infection.

[0004] Therefore, the prior art has continuously tried to develop non-invasive methods and devices for monitoring intracranial pressure. In this regard, reference is made to transcranial Doppler ultrasound (TCD), which allows a direct, non-invasive analysis of the cerebral hemodynamics of the main basal cerebral arteries. However, the disadvantage of this method is that it can only make an approximate assertion about the intracranial pressure in the human or animal skull. The disadvantage also lies in the fact that transcranial Doppler ultrasound examinations are difficult to perform and must therefore be carried out by specially trained medical staff.

[0005] In addition, other direct, non-invasive methods and / or devices for monitoring intracranial pressure are known in the prior art. In this regard, the references include but are not limited to the following: "The pulsating brain: A review of experimental and clinical studies of intracranial pulsatility", "Pulsed Phase Lock Loop Device for Monitoring Intracranial Pressure During Space Flight", "Noninvasive assessment of intracranial pressure waveforms by using pulsed phase lock loop technology: Technical note", "Detection of skull expansion with increased intracranial pressure", "Investigation of intracranial media ultrasonic monitoring model", "Intracranial Pressure Dynamics Assessed by Noninvasive Ultrasound During 30 Days of Bed Rest", "Intracranial Pressure Monitoring: Invasive versus Non-Invasive Methods—A Review" and "Noninvasive Intracranial Volume and Pressure Measurements Using Ultrasound (Head and Spinal)". However, the disadvantages of these methods and / or devices known from the prior art are that it is impossible to accurately determine and / or monitor intracranial pressure and the associated brain damage.

[0006] In addition, arterial Doppler ultrasound, as a recognized diagnostic technique for monitoring extracranial neck vessels, particularly the carotid and vertebral arteries, is known in the prior art. Thus, arterial Doppler ultrasound can provide valuable information regarding calcification and associated blood turbulence and / or anemia / ischemia. However, the problem is that the thickness of the skull and the associated sound absorption impede similar detailed imaging procedures for examining intracranial vessels. Thus, on the one hand, imaging ultrasound technology is an important and proven instrument in the medical field for diagnosis and treatment, where unfortunately, these systems only provide information about the internal structure of an object but not the composition of the object in 2D or 3D images.

[0007] Therefore, there is a great need for methods and devices for non-invasive determination and / or monitoring of intracranial compliance of biological materials, which ensure a simple, rapid, reliable, and sufficiently precise determination and / or monitoring of the state of biological materials in order to timely identify changes in intracranial pressure and / or adequately treat it. In addition, the methods and devices should be suitable for inexpensive production, should work reliably, and should be suitable for short-term or long-term determination and / or monitoring of biological materials. Another aspect is that the determination and / or monitoring of intracranial compliance should be performed in such a way that it is not error-prone, error-free, low-maintenance, low-noise, has no side effects, and does not harm the individual patient. Thus, the object of the present invention is to provide methods and devices for non-invasive determination and / or monitoring of intracranial compliance of biological materials to overcome the above difficulties, particularly to timely identify changes in intracranial pressure and / or secondary brain damage.

[0008] This object is achieved in an unexpectedly simple but effective manner by a method and a corresponding device for non-invasive determination and / or monitoring of intracranial compliance of biological materials according to the teachings of the independent main claims.

[0009] According to the present invention, a method for non-invasive determination and / or monitoring of intracranial compliance of biological materials is proposed, which comprises the following steps:

[0010] a) Performing spectroscopy of the biological material by emitting a plurality of acoustic transmission signals of different frequencies and / or amplitudes into the biological material and receiving the corresponding reflected and / or transmitted acoustic reception signals of different frequencies and / or amplitudes after having passed through the biological material, and the biological material being a human or animal skull; and

[0011] b) Comparing the acoustic transmission signals with the corresponding acoustic reception signals to determine an n-dimensional function and a flight time value characteristic of the biological material; and

[0012] c) Determining the expansion of the biological material by measuring the linear expansion and / or volume expansion of the biological material, and

[0013] d) Determining the intracranial compliance of the biological material based on the comparison performed in step b) and the measurement performed in step c).

[0014] The basic concept of the method according to the invention is based on the fact that for a sufficiently accurate detection of a changing intracranial pressure and a corresponding adequate treatment, it is sufficient to determine and / or monitor the intracranial compliance of the skull of a human or an animal. In this process, it has been detected that, based on the acoustics of the human or animal skull, the flight time of an acoustic signal is measured and simultaneously the changes in the cross-section and the speed of sound are measured. Based on this data, the intracranial compliance can be reliably determined within a sufficient measurement range and conclusions can thus be drawn regarding the intracranial pressure, the cerebral blood flow and / or the pathological condition, in particular by separating the measured values. This is based on the fact that within the scope of the invention, it has been detected that the concept according to the invention (i.e. different possible methods for acoustic applications, acoustic cerebral imaging (ACG)) can be applied to biological materials. It has thus been detected that the use of multiple frequencies reveals the dispersion characteristics of brain tissue and allows a specific interpretation of the signal changes. Dispersion is the effect in which the non-linear, frequency-dependent compression modulus of a medium results in different propagation speeds for different acoustic frequencies. In non-linear materials, such as biological tissues, especially human or animal brain tissue, the effect of acoustic wave dispersion can be clearly observed and measured. This is the effect in which the compression modulus of a non-linear frequency-dependent medium results in different propagation speeds for different acoustic frequencies. Since the characteristics of the compression modulus depend on the specific characteristics of the medium, such as composition, mixing concentration, dispersion and / or in some cases also on the chemical composition, the pattern of the frequency-dependent propagation speed can be used to identify the medium. In other words, it can be seen from the following equations (Equation 1) and (Equation 2) that the propagation speed c(f) is a function of the frequency and / or the wavelength. It depends on the compression modulus or the elastic modulus K of the liquid medium v It also depends on the compression modulus K of the solid medium B .

[0015]

[0016]

[0017] It can be seen from equations (Equation 1) and (Equation 2) that the compression modulus K can be decomposed into the volume V, the volume change dV and the corresponding pressure change dp. By analogy, a given density ρ can be decomposed into the mass m and the volume V.

[0018] In addition, within the scope of the present invention, it has been detected that if the structure of the corresponding biological material is considered, the above equations (Equation 1) and (Equation 2) can only be applied to the human or animal skull. As a result, it has been detected that performing sonography on the biological material alone is not sufficient to determine the intracranial compliance of the biological material in a sufficient manner. Instead, it is also necessary to consider the expansion of the human or animal skull caused by intracranial pressure during systole. This depends to a large extent on different factors such as age, intracranial pressure, and / or the presence of at least one pathological condition, and as demonstrated by volunteers during bed rest, it can be as high as 20 μm. Within the scope of the present invention, it has been detected that the expansion and contraction of the skull are caused by changes in intracranial pressure and are counteracted by the hardness of the surrounding skull. Measuring the expansion of the human or animal skull during systole can provide valuable information about the changing intracranial pressure, cerebral blood flow, and / or at least one pathological condition.

[0019] The term "method and device for non-invasive determination and / or monitoring" relates to a method for detecting the intracranial compliance of a biological material, by which the intracranial compliance can be determined accurately and reliably within a sufficient measurement range. It is conceivable that the method is based on the detection of intracranial compliance and its changes, which can be an improvement or a deterioration. Preferably, such changes are detected over time. More preferably, the detection is repeated once or at regular or irregular intervals and is carried out temporarily or permanently in order to be able to detect changes in intracranial compliance. This is particularly important because the biological material to be examined is not a static system. In addition, it is possible to monitor under what conditions and / or influences the change in intracranial compliance progresses or decelerates. Furthermore, the origin and / or cause of such changes can be displayed. The method according to the present invention may also include additional steps carried out after or between the explicitly named basic steps a) to d). The method is preferably automatable.

[0020] The term "biological material" relates to the human or animal skull, which is known to those skilled in the art. In addition, the anatomical and / or physiological environment of the skull and / or brain and the general and specific characteristics of the vascular system of the brain are known to those skilled in the art.

[0021] The term "determination of intracranial compliance" relates to the detection of the current value of intracranial compliance. Preferably, the determination is carried out in a semi-quantitative, quantitative, direct, and / or indirect manner. Thus, by detecting intracranial compliance, further information about the material to be examined can be received indirectly.

[0022] The term "monitoring of intracranial compliance" relates to the tracking and / or prediction of the measured values of intracranial compliance. For example, but not exclusively, the monitoring can be displayed numerically and / or graphically. To improve the accuracy of the monitoring, it is preferably carried out at regular or irregular intervals or permanently. The advantage of monitoring over a longer period of time is that predictions, prognoses, and / or evaluations of changes in intracranial compliance can be made.

[0023] As is known to those skilled in the art, determination and / or monitoring are generally not 100% accurate. Therefore, this term relates to a statistically significant probability regarding the accuracy of detection or tracking and / or prediction. Whether such determination and / or monitoring is statistically significant can be determined by those skilled in the art without creativity by methods known in the professional field. Statistical evaluation tools are an example, such as the evaluation of confidence intervals, p-values, student t-tests, Mann-Whitney U-tests, etc. The corresponding intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99% correct. The p-value is preferably 0.1, 0.05, 0.01, 0.005 or 0.0001. The determination and / or monitoring of intracranial compliance within the scope of the present invention is preferably at least 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.95%, 99.99% or 100% correct.

[0024] The term "intracranial compliance" is used as an interchangeable synonym for the term "cranial volume-pressure relationship", both of which are known to those skilled in the art and describe the connection between the cranial volume and the intracranial pressure in the human or animal skull. When the cranial volume (ICV) increases, the increase in intracranial pressure is usually buffered by removing venous blood and cerebrospinal fluid from the skull. As is known to those skilled in the art, intracranial compliance depends on various factors, such as pressure changes within the skull, elastance (the opposite of compliance), hydraulic compliance (the relationship between the instantaneous change in cranial volume and / or the corresponding change in intracranial pressure), and / or the movement of the cranial bones at the sutures. In addition, it is known that intracranial pressure increases non-linearly with the increase in cranial volume, as described by the pressure-volume index. In addition, standard values are known to those skilled in the art.

[0025] The method according to the present invention includes step a) for performing the sonics of a biomaterial, in which a plurality of acoustic transmission signals of different frequencies and / or amplitudes are sent into the biomaterial, and the corresponding reflected and / or transmitted acoustic reception signals of different frequencies and / or amplitudes are received after passing through the biomaterial. In a further step, the acoustic transmission signals are compared with the corresponding acoustic reception signals, in which an n-dimensional function characteristic of the biomaterial and the flight time value and / or phase shift are determined as equivalents. It is conceivable that, in addition to the flight time value, the frequency shift of the assigned acoustic signal is determined by each pair of transmission and reception signals. In other words, this means that for each pair of transmission and reception signals of a corresponding or specific frequency, the method according to the present invention finally determines a data pair based on the corresponding flight time and (if applicable) frequency shift.

[0026] From each pair of transmitted and received signals at a corresponding or specific frequency, the method according to the invention finally determines a data pair from the corresponding time-of-flight value and (if applicable) frequency shift, and stores it, if necessary, in a device with a corresponding configuration at the corresponding frequency. Performing this method accumulates a very large result data record, since for each frequency and assigned pair of transmitted and received signals, one result data record with the corresponding time-of-flight and (if applicable) frequency shift is determined, stored, and / or graphically displayed. Therefore, it is preferably aimed to perform data reduction; for example, a reduced data record is derived from the detected result data record in a data reduction device, where the reduced result data record characteristically represents the detected result data record and has a smaller data volume. How to perform data reduction is generally arbitrary and depends on the expertise of those skilled in the art.

[0027] The term "acousto-spectroscopy" relates to the acoustic examination of a medium by drawing conclusions from changes in sound waves and / or vibrations in the audio frequency range (20 kHz to 1 GHz), in particular in the range of ultrasonic and / or longitudinal waves, where the changes are based on the interaction of the structures contained in the biological material with the sound waves and / or vibrations. In this way, a biological material can be examined non-invasively by acousto-spectroscopy in order to determine changes in the structure of the medium in this way. Acousto-spectroscopy is preferably carried out with the aid of a suitable device which is partly or completely arranged on the biological material and is suitable for emitting, transmitting, enhancing, and / or receiving vibrations in the material, such as an acoustic transmission element and / or a receiving element.

[0028] It is also aimed according to the invention that, based on a comparison of the corresponding pairs of transmitted and received signals, preferably based on the corresponding result data records received, an n-dimensional function characteristic of the biological material and the time-of-flight value and / or phase shift as equivalents can be determined. The terms "n-dimensional function" and "function in n dimensions" are known to those skilled in the art as interchangeable synonyms. In addition, suitable methods and devices for detecting the time-of-flight value, such as but not limited to, transit time measurement, are known to those skilled in the art. The terms "transit time measurement" and "time-of-flight" are used as interchangeable synonyms for a method of indirectly measuring distance and / or speed by measuring the time it takes for a signal to pass through a measurement section. Preferably, only the time difference is determined substantially, such that the transit time measurement constitutes a relative time system with an undefined zero point.

[0029] Within the scope of the present invention, it has been detected that the speed of wave propagation depends directly on the characteristics of the biological material and thus indirectly reflects its characteristics. Therefore, it is conceivable that the density of the biological material changes due to the removal of venous blood from the skull of a human or animal. In addition, it is conceivable that the speed of wave propagation changes due to cerebral blood flow (diastole / systole) and / or cerebral tissue perfusion.

[0030] Subsequently, in step c), the expansion of the biological material is determined, where the linear expansion and / or the volume expansion of the biological material is measured. This step is particularly important because it has been detected within the scope of the present invention that due to the expansion of the skull, phase changes and / or time dilation or time contraction must occur during the performance of sonospectroscopy as equivalents of the transmitted signal. The expansion range of the skull to be examined is up to 20 μm and depends on different factors such as age, intracranial pressure, and / or pre-existing physical conditions. Preferably, the expansion is determined during systole. The determination of the expansion is preferably carried out in a semi-quantitative, quantitative, direct, and / or indirect manner. In addition, it is conceivable to use a device suitable for determining the expansion of the biological material, by means of which the linear expansion and / or the volume expansion of the biological material can be adequately measured in an accurate manner. It is conceivable that the suitable device measures the expansion directly or indirectly using devices and / or methods known in the prior art.

[0031] The functional relationship can be displayed as a trend in a two-dimensional function, for example but not exclusively having a value progression over time, such as linear, logarithmic, exponential, logistic, polygenic functions, and / or combinations of the above.

[0032] The term "comparison" relates to the comparison of the corresponding values with each other, in particular the comparison of the sound transmission signal with the corresponding sound reception signal. It should be understood that the comparison carried out in this case involves the comparison of the corresponding parameters and / or values.

[0033] Within the scope of the present invention, the comparison, determination, and / or detection are preferably carried out in a computer-aided manner. In order to perform these steps in a computer-aided manner, for example steps b), c), and / or d), a person skilled in the art can use all the tools they know, such as computers and / or computer programs. In addition, the computer program can evaluate the corresponding results, for example, it can automatically deliver the evaluation of the values. In addition, it is conceivable that steps b) and / or d) are assisted by, for example, an analysis unit, an evaluation unit, and / or an assessment unit. Preferably, the continuous sound transmission signals and / or sound reception signals can also be considered in the comparison, so that based on this comparison, a prediction can be made about how the conditions change over time.

[0034] Within the scope of the present invention, it should be understood that the result of the method (i.e., the determination of intracranial compliance) directly or indirectly depends on the biological material to be examined. Therefore, it is conceivable that a slight and insignificant change, a large and significant change, and / or no change in the intracranial compliance of the biological material are indicators of the change in intracranial compliance over time. The change in intracranial compliance can preferably be an improvement and / or deterioration of the compliance. In this case, it is conceivable that the result of the method can be displayed as a time specification by absolute values and / or relative values.

[0035] In a last step, the intracranial compliance of the biological material is determined based on the comparison made in step b) and the measurements made in step c). Those skilled in the art understand that this determination can be achieved by calculation, back-calculation, derivation, and / or conclusion, in particular based on one or more assumptions. In addition, it is conceivable to evaluate the result of the determination.

[0036] Thus, by the method according to the invention, the intracranial compliance of the human or animal skull can be determined and / or monitored in a simple, rapid, reliable, and sufficiently precise manner, so as to detect the intracranial compliance, for example, temporarily or permanently. The determination and / or monitoring can also be performed in real time. The simplicity of the method according to the invention not only allows trained medical personnel to use the invention, but also everyone can use the invention - whether for self-control in a private household or by emergency medical technicians, nurses, and / or assistant staff. Advantageously, within the scope of the present invention, it has been detected that the method has a measurement range of several microseconds and a resolution of a single picosecond, so it constitutes a suitable tool for non-invasive determination and / or monitoring of the intracranial compliance of the human or animal skull, which also significantly contributes to supporting medical diagnosis in cases of intracranial pressure, cerebral blood flow, and / or at least one pathological condition. In this way, changes in intracranial pressure can be identified in a timely manner and treated adequately, which particularly has a positive impact on the patient's mobility, mortality, and / or prognosis.

[0037] Advantageous embodiments of the invention are indicated in the dependent claims, which can be implemented individually or in combination.

[0038] In an embodiment of the invention, it is conceivable that the method further comprises:

[0039] e) Detecting the intracranial pressure, cerebral blood flow, and / or pathological condition of the biological material based on the intracranial compliance detected in step d).

[0040] By this embodiment, additional important factors can be obtained from the detected intracranial compliance by calculation, back-calculation, derivation, and / or conclusion (with assumptions).

[0041] The term "intracranial pressure (ICP)" relates to the pressure inside the skull and thus in the brain tissue and cerebrospinal fluid. As is known to those skilled in the art, intracranial pressure is generally crucial for brain tissue perfusion and thus for brain function, as it counteracts the pressure to pump blood into the brain. In addition, those skilled in the art know the reciprocal relationship between the cerebrospinal fluid volume and the blood volume, such as the Monro-Kellie doctrine, according to which the volumes of the brain, blood, and cerebrospinal fluid are constant for a complete skull. Therefore, an increase in one component will lead to a decrease in one or both of the other components. In addition, standard values are known to those skilled in the art. Preferably, the intracranial pressure can be derived from the above equations (Equation 1) and (Equation 2) and depends on the linear expansion and / or volume expansion of the skull.

[0042] The terms "cerebrospinal fluid (CSF)", "cerebrospinal fluid", and "fluid" are known to those skilled in the art and are used interchangeably within the scope of the present invention as synonyms for the body fluid surrounding the brain and spinal cord, commonly known as brain fluid, cerebral fluid, or spinal fluid. In addition, standard values are known to those skilled in the art.

[0043] The term "cerebral blood flow (CBF)" is known to those skilled in the art and relates to a measure of the blood supply to the brain over a given period of time. In addition, standard values are known to those skilled in the art. It is known from the prior art that the cerebral blood flow is approximately 15% of the cardiac output, with a volume of approximately 750 ml per minute. In addition, within the scope of the present invention, the total cerebral blood flow is distinguished from the actual cerebral blood flow. Preferably, the cerebral blood flow is calculated from the above equations (Equation 1) and (Equation 2).

[0044] The term "pathological condition" relates to any damage to the human or animal skull and is thus of particular importance. Pathological conditions are, for example, traumatic brain injury, brain damage, stroke, congestion, cerebral edema, insufficient blood flow, cerebral ischemia, cerebral hemorrhage, especially intracranial, intraparenchymal, and / or extraparenchymal cerebral hemorrhage, subarachnoid hemorrhage, thrombosis, irritation, and / or vascular changes, reduced cerebral tissue perfusion, and / or tissue perfusion. Preferably, the pathological condition can be derived from the above equations (Equation 1) and (Equation 2). More preferably, the location of the pathological condition can be localized in the human or animal skull.

[0045] Therefore, through this additional step, additional key values for the timely detection and adequate treatment of patients can be obtained from the previously determined intracranial compliance.

[0046] In another embodiment of the present invention, it is conceivable that the method further comprises:

[0047] f) displaying the detections performed in step d) and / or step e).

[0048] With this embodiment, the measured values can be displayed numerically and / or graphically to simplify the understanding of the measurements carried out in step d) and / or step e). A person skilled in the art knows suitable ways for the output of the displayed values. Step f) can also be supported by an output unit.

[0049] In another embodiment of the invention, it is conceivable to emit an acoustic transmission signal at a first location of the biological material and to receive an acoustic reception signal at a second location of the biological material, and the first location and the second location are identical or are arranged opposite to each other. With this embodiment, the device required to carry out the method can be arranged in a space-saving manner and comfortably for the patient to be examined, and thus the above values can be detected simultaneously in a reliable manner.

[0050] Furthermore, it is conceivable that the determination of the acoustics and / or dilation of the biological material is carried out essentially in the regions of the left and right brains and the longitudinal cerebral fissure. It has been detected within the scope of the present invention that if the structure of the human or animal skull is taken into account, the above equations (Equation 1) and (Equation 2) allow for the best possible detection of the aforementioned values. It has been detected that the influence of the skin, muscle, skull bone, and / or cerebrospinal fluid on the acoustic signal can be ignored, and thus they can be regarded as constants. However, the regions of the left and right brains and the longitudinal cerebral fissure, including part of the cerebrospinal fluid, largely depend on the cardiac cycle and the perfusion of the brain tissue. Therefore, these regions of the biological material are suitable for carrying out the method according to the present invention.

[0051] The term "essentially" means that the value or region involved only has minor, in particular insignificant, variations, offsets, and / or deviations. It is conceivable, for example, that the determination of the acoustics and / or dilation of the biological material is carried out at a location slightly deviating from the preferred regions of the left and right brains and the longitudinal cerebral fissure, which means that it has no effect or an insignificant effect on the detection to be carried out.

[0052] Furthermore, it is conceivable that the determination of the acoustics and / or dilation of the biological material is carried out essentially in the direction of the frontal plane (coronal plane) of the skull slightly above the external auditory canal. Therefore, it has been detected within the scope of the present invention that the region most suitable for carrying out the measurement method is the surface located in the direction of the frontal plane of the skull and slightly above the external auditory canal. With this embodiment, the intensity and / or the intensity of the sound wave can be maximized because this region of the skull system is characterized by the lowest degree of suppression of the sound wave. Therefore, it is very likely to receive a complete echo from the opposite skull bone, so that based on the above analysis, a simplified, layered structure of the skull system can be adopted.

[0053] Unless otherwise specified, it is assumed that the definitions and / or interpretations of the above terms apply to all the following aspects described in this specification.

[0054] Furthermore, the present invention provides a device for non-invasive determination and / or monitoring of intracranial compliance of a biological material according to any one of the foregoing method claims. The device according to the present invention comprises a first means for performing acoustics spectroscopy of the biological material, wherein the first means comprises an acoustic transmission element for transmitting a plurality of acoustic transmission signals of different frequencies and / or amplitudes into the biological material and an acoustic reception element for receiving corresponding reflected and / or transmitted acoustic reception signals of different frequencies and / or amplitudes after having passed through the biological material, and wherein the biological material is a human or animal skull. Furthermore, the device comprises an evaluation unit for comparing the acoustic transmission signals with the corresponding acoustic reception signals, wherein an n-dimensional function characteristic of the biological material and a time-of-flight value and a phase shift as equivalents can be determined. Furthermore, the device comprises a second means for determining the dilation of the biological material, wherein the second means comprises measuring devices such as, but not limited to, strain gauges, pressure sensors, capacitance sensors, etc. for measuring the linear dilation and / or volume dilation of the biological material. Finally, the device further comprises an analysis unit for determining the intracranial compliance of the biological material based on the comparison performed and the measurement performed.

[0055] The device according to the present invention is preferably self-learning and / or self-calibrating in order to obtain the best possible determination and / or monitoring of intracranial compliance. Also preferably, the device is used for acoustic cerebral imaging (ACG). More preferably, the device is suitable for temporarily or permanently determining and / or monitoring the biological material.

[0056] The term "first means" relates to any means known to the person skilled in the art from the prior art, which is suitable for emitting, transmitting, enhancing and / or receiving vibrations in a biological material in the audio frequency range, in particular in the range of ultrasonic waves and longitudinal waves. The means is preferably partly or entirely arranged on the biological material.

[0057] Preferably, the first means is an acoustic transmission element for transmitting a plurality of acoustic transmission signals of different frequencies and / or amplitudes into the biological material and / or an acoustic reception element for receiving corresponding reflected and / or transmitted acoustic reception signals of different frequencies and / or amplitudes after having passed through the biological material.

[0058] The term "second means" relates to any means known to the person skilled in the art from the prior art, which is suitable for measuring the dilation of a biological material, in particular the linear dilation or / and volume dilation of the biological material. The measurement can be performed directly or indirectly using means and / or methods known from the prior art.

[0059] The term "evaluation unit" relates to a unit suitable for comparing the acoustic transmission signals with the corresponding acoustic reception signals. Suitable evaluation units are known to the person skilled in the art, such as computers and / or computer programs. Furthermore, the computer can evaluate the result of the comparison.

[0060] The term "analysis unit" relates to a unit for evaluating or detecting the intracranial compliance of a biological material. The analysis unit is, for example, a computer or a computer program.

[0061] The device according to the invention is advantageous because it has a sufficiently precise sensitivity for simply, rapidly, reliably and sufficiently accurately determining and / or monitoring the intracranial compliance of a biological material, which can be carried out temporarily or permanently. This determination and / or monitoring can also be carried out in real time. Furthermore, the device advantageously has a measurement range of a few microseconds with a resolution of a single picosecond, and thus constitutes a suitable instrument for the non-invasive determination and / or monitoring of the intracranial compliance of a biological material, which significantly contributes to supporting medical diagnosis in the case of intracranial pressure, cerebral blood flow and / or pathological conditions. According to everyday use, the device is also sufficiently robust for long-term use.

[0062] Advantageous embodiments of the invention are indicated in the dependent claims, which can be implemented individually or in combination.

[0063] In an embodiment of the invention, it is conceivable that the analysis unit is configured to detect the intracranial pressure, cerebral blood flow and / or pathological conditions of a biological material (as described in more detail above) based on the detected intracranial compliance.

[0064] Furthermore, it is conceivable to include an output unit for illustrating the detection performed by the analysis unit. The term "output unit" relates to a unit suitable for illustrating the detected values. By means of this embodiment, the intracranial compliance and the values associated therewith, namely the intracranial pressure, cerebral blood flow and / or pathological conditions, can be illustrated numerically and / or graphically in order to simplify the understanding of the detection. Suitable output units for illustration are known to the person skilled in the art.

[0065] Furthermore, it is conceivable that, as described in more detail previously, an acoustic transmission element is arranged at a first position of the biological material, an acoustic receiving element is arranged at a second position of the biological material, and the first position and the second position are identical or arranged opposite each other.

[0066] Furthermore, it is conceivable that, as described in more detail previously, the determination of the acoustics and / or dilation of the biological material is carried out essentially in the regions of the left and right brains and the longitudinal cerebral fissure.

[0067] In another embodiment, it is conceivable that the first device, the second device, the evaluation unit, the analysis unit and / or the output unit are disposable in one component. Preferably, the component is an acoustic mixing sensor, a headband, a head strap and / or headphones. The advantage of this embodiment is that the device is compact, easy to operate and easy to transport.

[0068] In another embodiment, it is conceivable that the device is implemented as rotatable and / or movable to change its position and enable improved detection of intracranial compliance and the resulting values (i.e., intracranial pressure, cerebral blood flow, and pathological conditions), in particular to localize pathological conditions.

[0069] From the following description of preferred embodiments related to the dependent claims, further details, features, and advantages of the invention are apparent. The individual features can be implemented alone or in combination with each other. The invention is not limited to the exemplary embodiments. The exemplary embodiments are schematically shown in the figures. The same reference numerals in the various figures refer to the same or functionally identical elements or elements that correspond to each other in their functions.

[0070] In the figures:

[0071] Figure 1 a schematic view of a device according to the invention is shown; and

[0072] FIG. 2 shows a schematic view of the structure of the human skull ( Figure 2A ) and a corresponding layered model of the human skull from Figure 2A ; and Figure 2B );and

[0073] FIG. 3 shows first ( Figure 3A ) and second ( Figure 3B ) schematic views of the most suitable regions of the human skull for performing the method according to the invention or for arranging the device according to the invention; and

[0074] Figure 4 an overview of the signal attenuation along the measurement path in the human skull is shown; and

[0075] Figure 5 a graphical view of data collected from a 72-year-old patient is shown; and

[0076] Figure 6 a graphical view of the propagation of the cardiac pulse pressure signal, in particular intracranial pressure measurements recorded by an intracranial pressure probe, is shown.

[0077] Figure 1 The device 01 according to the invention arranged on the biomaterial 02 human skull is schematically shown. It can be clearly seen in Figure 1 that the device 01 has a first device 10, and the first device 10 includes an acoustic transmission element 11 arranged at a first position X1 and an acoustic reception element 12 arranged at a second position X2. It can be clearly seen that the first position and the second position X1, X2 are arranged opposite to each other, and acoustics is performed slightly above the external auditory canal in the frontal plane (coronal plane) of the skull 02.

[0078] In addition, the device 01 has a second device 30, which has a measuring device 31, such as a strain gauge, a pressure sensor, a capacitance sensor, etc. The evaluation unit 20 and the analysis unit 40 are also integrated in Figure 1 it. It is also conceivable that they are intended as non-integrated components. The values recorded by the device 01 can also be transmitted to an output unit (not shown).

[0079] The following embodiments are only for illustrating the present invention. They are not intended to limit the subject matter of the claims in any way.

[0080] Example 1: Acoustic cerebral imaging (ACG) based on the concept of the present invention

[0081] As described in detail above, within the scope of the present invention, it has been detected that the concept according to the present invention (i.e., acoustic cerebral imaging (ACG)) can be applied to biological materials. Thus, it has been detected that the use of multiple frequencies shows the dispersion characteristics of brain tissue and provides some explanations for signal changes. Dispersion is such an effect in which the non-linear, frequency-dependent compression modulus of the medium results in different propagation speeds for different acoustic frequencies. In non-linear materials, such as biological tissues, especially human and animal brain tissues, the effect of longitudinal wave dispersion can be clearly observed and measured. This is such an effect in which the compression modulus of the non-linear frequency-dependent medium results in different propagation speeds for different acoustic frequencies. As described above, the characteristics of the compression modulus depend on the specific characteristics of the medium, such as composition, mixing concentration, distribution, and / or in some cases chemical composition, so the pattern of frequency-dependent propagation speed can be used to identify the medium.

[0082] In order to apply the above equations (Equation 1) and (Equation 2) to the human or animal skull, the structure of the corresponding biological material must be considered. In Figure 2A it, the structure of the human skull is roughly shown, and in Figure 2B it, the corresponding layered model of the human skull in Figure 2A is roughly shown.

[0083] Figure 2A and 2B The tissue structures of the human skulls 1a, 1b, 2, 3 (with ventricles), 4, and 5 shown in are explained in Table 1 below

[0084] Table 1: Overview of the influence of the tissue structures from Figure 2A and 2B on the change in the acoustic wave flight time

[0085]

[0086]

[0087] Table 1 clearly shows that Figure 3A and 3BThe skin (1a), muscle (1b), cranial bones (2), and cerebrospinal fluid structures of the human skull shown in the figure have no effect on the spectroacoustics performed and can thus be considered constants. However, the left and right brains (4), the longitudinal cerebral fissure (5), including parts of the cerebrospinal fluid (3), have an impact on the spectroacoustics performed, and this impact depends to a large extent on the cardiac cycle and blood circulation in the brain tissue. These regions are the "points of interest" for further examination.

[0088] The data should be obtained using the time-of-flight method according to the following equation (Equation 3). If we have a set of tissue layers T, then the total propagation time is obtained by summing the propagation times of each tissue in the group.

[0089]

[0090] The concept according to the present invention and the model based on said concept can be easily upgraded or modified, for example by adding additional tissue layers. If accurate and detailed dispersion data can be obtained, the dispersion of a specific tissue can be modeled as a non-linear function of frequency. For a given tissue i, the propagation time t i (f) can be calculated according to the following equation (Equation 4).

[0091]

[0092] In the above equation (Equation 4), d i is the depth that the sound wave travels through the tissue, c 0i is the base velocity defined at the base frequency f 0i , and Δ i is the dispersion trend of the tissue, which characterizes the dependence of frequency on the propagation velocity. The signal is transmitted by an ultrasonic probe and recorded by another sound wave (transmission) or the same sound wave (reflection). As described above, the velocity of the transmitted signal depends on the medium. Based on the anatomical analysis of the human cranial system, it can be demonstrated that according to the region, the propagation conditions of the sound wave are very different. This leads to considerations regarding optimizing the direction of tissue examination. Therefore, it is detected that the direction of the frontal plane (coronal plane) shown in Figure 3A should be selected for transmission or reflection measurement.

[0093] The limitation related to minimizing the ultrasonic intensity prompts the search for regions in the cranial system characterized by minimal sound wave suppression. The analysis shows that the region most suitable for implementing this measurement method is the surface slightly above the external auditory canal, as shown in Figure 3b. Selecting such a measurement direction is likely to result in a complete echo from the opposite cranial bone. Based on the above Figure 2A and Figure 2B and the analysis in Table 1, a simplified, layered structure of the cranial system can be adopted.

[0094] By using a layered model of the human skull (as above Figure 2A and Figure 2B and as shown in Table 1) as input, together with the physical values of the different skull tissues shown in Table 2 below, the propagation time of the acoustic signal and the signal attenuation along the measurement path through these structures can be determined.

[0095] Table 2: Basic parameter assumptions of the human skull brain model

[0096]

[0097] In Figure 4 for the structures shown in Figure 2A and 2B i.e., skin (1a), muscle (1b), skull bone (2), cerebrospinal fluid (3), left brain (4a), right brain (4b) and cerebral longitudinal fissure (5), the signal attenuation along the measurement path in the human skull is shown. In addition, the ultrasonic signal attenuation of the human head model and the expected flight time along the measurement path are shown in Table 3 below.

[0098] Table 3: Ultrasonic signal attenuation of the human head model and the expected flight time along the measurement path.

[0099]

[0100] Considering the transmission mode, the measurement process includes "introducing" acoustic waves into the central brain system at a selected location X1 (as Figure 3A and 3B shown), and then receiving at a relative location X2 depending on the propagation direction of the acoustic beam. Therefore, this method preferably requires two ultrasonic probes - one for transmitting the acoustic signal and one for receiving the acoustic signal.

[0101] The cerebrovascular system is very complex, and thus, the blood supply state of the brain greatly affects its physical and chemical parameters. Intracranial pressure depends on the intracranial fluid volume, tissue volume, and pulsatile volume caused by the pulsation of the intracranial arterial blood vessels. Through the known normal cerebral blood circulation or cerebral blood flow (CBF), such as 50 mL / 100 g / min, for an average brain weight of 1375 g, the average CBF value has been detected to be approximately 690 ml per minute. This results in a blood value of approximately 11.6 ml per second (estimated as the volume per heartbeat). Based on this, the flight time measurement value and the speed of sound change and / or acoustic wave change can be calculated based on the standard cranial tissue perfusion CBF. During the period when the volunteers were at rest in bed, the detected bone movement was up to 20 μm, and it can be calculated by the following equation (Equation 5).

[0102]

[0103] Let us adopt a very simplified model, as shown in the following equation (Equation 6). A standard CBF of 50 mL / 100 g / min means that for each heart rate, for example 60 beats per minute (bpm), between diastole and systole, approximately 8% to 10% of the mass will be exchanged.

[0104]

[0105] Furthermore, one can attempt to estimate the change in sound wave velocity according to the above equation (Equation 5). Assuming that according to normal perfusion values, approximately 10% of the CSF is exchanged with blood periodically, one can attempt to calculate the change in the flight time of the sound wave. The corresponding K values for CSF and blood can be calculated from c and ρ according to the following equations (Equation 7) to (Equation 10).

[0106]

[0107]

[0108]

[0109]

[0110] Assuming that the total CSF region (meaning the region where the brain tissue expands due to pulsation) is 1 cm, the diastolic travel time can be calculated using the following equation (Equation 11):

[0111]

[0112] Combined with the result of Equation (Equation 10) and based on the assumption of a maximum cranial expansion of 20 μm, the following equation (Equation 12) allows the calculation of the expected systolic flight time (in a faster medium, because 10% of the CSF is exchanged with blood).

[0113]

[0114] The equations (Equation 11) and (Equation 12) listed above result in a c of the sound flight time in diastole CFS = 1498 m / s. In systole (x = 10% = 0.1), the calculated c of the sound flight time sys = 1506.76 ms. Despite the fact that the sound wave is 1506.76 - 1498 = 8.76 m / s faster in systole, an increased flight time waveform between diastole and systole can be observed. This is because intracranial pressurization during systole causes cranial expansion.

[0115] This indicates that even if the increase in the speed of sound due to the exchange of CSF and blood exceeds 8.75 m / s for a specific region of interest, the overall acoustic propagation time of the packets increases due to the longer distance or longer path. When subtracting t dia from t sys , we obtain a maximum difference of 94 ns, as shown in the following equation (Equation 13). The time-of-flight measurement has sufficient resolution, which is more than ten times better than the expected range of approximately 94 n (better than 90 ps).

[0116] t dia -t sys =|6,67556 μs - 6,76953 μs| = 0,09396 μs = 93,96 ns (Equation 13)

[0117] The maximum difference of 94 ns shown in the equation (Equation 13) is a benchmark achieved using the method and device according to the present invention. Therefore, it is a suitable tool for supporting medical diagnosis in the case of intracranial pressure and other pathologies in medical diagnostics. The time of about ±45 ns should be measured with sufficient resolution, which means better than 100 times (about 400 ps step) and faster than 30 measurements per second. At the same time, it must be noted that the time-of-flight difference (increase / decrease) can decrease when the skull expansion decreases, or even turn negative when the skull stops expanding due to increased intracranial pressure. This can be very useful information for emergency medical care.

[0118] Example 2: Diffusion ultrasound as a non-invasive diagnostic system

[0119] Acoustic cerebral imaging (ACG) uses ultrasonic quasi-constant wave packets of different frequencies to query the medium in order to provide the propagation time for each transmission frequency. This method provides an estimate of the dispersion pattern c(f) of a specific contained medium. The observed changes in the propagation speed are usually very small, and very precise measurements of the propagation speed are required. Instead of measuring the speed of sound in the medium, it is easier to accurately measure the propagation time of the ultrasonic signal.

[0120] By assuming that the constant dimension d is known, the propagation speed c(f) can be very precisely estimated according to the propagation time t(f) by the above equation (Equation 4).

[0121] The received signal requires a very high sampling frequency in order to accurately measure the propagation time t(f). To achieve the necessary accuracy, a sampling frequency in the GHz range is required (exactly 2.5 GHz at 400 ps resolution). Therefore, for a signal transmitted from a transmitter to a receiver, the time resolution must be in the sub-nanosecond range. Such a system would be very expensive and have unacceptable power requirements for portable devices. Instead, it is known that ultrasonic signals can be described not only by their frequency but also by phase information, as shown in the following equation (Equation 14).

[0122]

[0123] Therefore, the phase information of the ultrasonic wave and its amplitude must be used to overcome the requirement for a high sampling frequency in order to provide an accurate estimate of the propagation time. It is well known that the phase information only covers the range from -π to +π. Therefore, it can only be used to obtain additional information about one period of the signal. In addition, this information itself remains repetitive. In this case, a phenomenon in wave theory, namely the beat-note, is used. In acoustics, a beat is an interference pattern between two sounds with slightly different frequencies, perceived as a periodic variation in volume, the rate of which is the difference between the two frequencies. A beat-note is the result of the combination of two continuous wave signals with pitches that are close but not identical. The difference in frequencies produces a beat. The frequency of the beat-note is given by the following equation (Equation 15).

[0124] f 拍 = f1 - f2 (Equation 15)

[0125] The closer f1 and f2 are, the lower the resulting frequency difference beat f 拍 and the longer the resulting beat phase period T 拍 = 1 / f 拍 becomes. Using this beat-note method, specific points in the signal can be clearly identified. Once this unique point is found, the phase information of each frequency can be used to accurately calculate the propagation time in a specific situation. In addition to the observed changes in the propagation speed, different attenuation curves can also be observed. The interdependence between the wave speed and attenuation conforms to the Kramers–Kronig relation, which shows the relationship shown in the following equation (Equation 16), and so on.

[0126]

[0127] In Equation (Equation 16), c1, c2 are the propagation speeds (sound speeds) of waves with circular frequencies ω1 or ω2, and α(ω) is the attenuation of a wave with circular frequency ω. After introducing ω = 2πf, ω1 = 2π*f1, and ω2 = 2π*f2, the following equation (Equation 17) applies:

[0128]

[0129] This frequency-dependent attenuation pattern and the corresponding propagation speed can be used to identify the state of the medium or to track in real time possible changes in the brain tissue. To obtain the time resolution required for useful medical diagnostic images (as Figure 5 shown), some basic requirements for phase determination must be met. In Figure 5 , the time-of-flight waveform heart rate curve of a 72-year-old patient is shown; it was recorded by an ACG system as part of an authorized clinical study. The X-axis shows the time [t] in seconds (s), and the Y-axis shows the time of flight in microseconds (μs).

[0130] Assuming that the acoustic measurement band of interest for the ACG is between 0.7 MHz and 2.7 MHz, this will set the following expectations for the signal phase resolution. We require that the phase resolution be better than 400 ps at a frequency of 0.7 MHz - the higher the frequency, the higher the time resolution, and the shorter the wavelength - which means that the time resolution will be higher. Assuming that the average speed of the acoustic quasi-constant wave packet in the skull is 1540 m / s, we can obtain an explanation based on the equations listed above and the following equation (Equation 18).

[0131]

[0132] As can be seen from Equation (Equation 18), this 2.2 mm is exactly the length of one cycle (360° or 2π phase), with a duration of 1.4285714 μs. Therefore, the required phase resolution must be in the range of 0.1° or better.

[0133] Example 3: Evaluation of time-of-flight measurement of patients

[0134] When using ICP monitoring in clinical practice, it is very important to determine the validity of the obtained pressure values. Therefore, accessing a high-resolution view of the intracranial pressure waveform can enable a more accurate analysis of the obtained intracranial pressure. Therefore, when performing the method according to the present invention, it is important to verify whether the obtained ICP signal truly represents the intracranial pressure. In this way, those skilled in the art should ensure that there is actually an oscillating pressure curve, where there are gradually decreasing P1, P2, and P3 notches, which indicate the propagation of the cardiac pulse pressure signal. Such an oscillating pressure curve is shown in an exemplary manner in Figure 6 , which shows the propagation of the cardiac pulse pressure signal, particularly the intracranial pressure measurement recorded by an intracranial pressure probe. The X-axis shows the time [t] in milliseconds (ms), and the Y-axis shows the intracranial pressure (ICP).

[0135] It should be understood that, compared with Figure 6The deviation of the pressure curve shown as an example in [text] can indicate altered intracranial compliance, altered intracranial pressure, disrupted cerebral blood flow, and / or a pathological condition. For example, reversed P1 and P2 notches indicate a state where autoregulation is disturbed.

[0136] Careful observation Figure 5 of the waveform in [text] can support the conclusion of Use Case 1 above, as it shows a difference in the time-of-flight measurements of approximately 50 ns between diastole and systole. It also indicates that the patient's autoregulation is disturbed, as the P1 and P2 notches are reversed, which can be seen at seconds 6, 7, 8, 9, 14, 15, and 16.

Claims

1. A method for non-invasive determination and / or monitoring of intracranial compliance of a biological material (02), comprising the following steps: a) Performing spectroscopy of the biological material (02), emitting a plurality of acoustic transmission signals of different frequencies and / or amplitudes into the biological material (02) and receiving corresponding reflected and / or transmitted acoustic reception signals of different frequencies and / or amplitudes after having passed through the biological material (02), and the biological material (02) being a human or animal skull, and wherein the determination of the spectroscopy and / or expansion of the biological material (02) is carried out substantially in the direction of the frontal plane of the skull, above the external auditory canal, in the region of the left and right brains and the longitudinal cerebral fissure; and b) Comparing the acoustic transmission signals with the corresponding acoustic reception signals, determining an n-dimensional function and a flight time value characteristic of the biological material (02); and c) Determining the expansion of the biological material (02), measuring the linear expansion and / or volume expansion of the biological material (02), and d) Determining the intracranial compliance of the biological material (02) based on the comparison made in step b) and the measurement made in step c).

2. The method according to claim 1, wherein the method further comprises the following steps: e) Determining the intracranial pressure, cerebral blood flow and / or pathological condition of the biological material (02) based on the intracranial compliance determined in step d).

3. The method according to claim 2, wherein the method further comprises the following steps: f) Displaying the determination made in step d) and / or in step e).

4. The method according to any one of claims 1 to 3, wherein the acoustic transmission signal is emitted at a first position (X1) of the biological material (02) and wherein the acoustic reception signal is received at a second position (X2) of the biological material (02), and wherein the first position and the second position (X1, X2) are the same or are arranged opposite to each other.

5. A device (01) for non-invasive determination and / or monitoring of intracranial compliance of a biological material (02) according to any one of the preceding method claims, having a first device (10) for performing spectroscopy of the biological material (02), wherein the first device (10) comprises an acoustic transmission element (11) for transmitting a plurality of acoustic transmission signals of different frequencies and / or amplitudes into the biological material (02) and an acoustic reception element (12) for receiving corresponding reflected and / or transmitted acoustic reception signals of different frequencies and / or amplitudes after having passed through the biological material (02), and the biological material (02) being a human or animal skull, and wherein the determination of the spectroscopy and / or expansion of the biological material (02) is carried out substantially in the direction of the frontal plane of the skull, above the external auditory canal, in the region of the left and right brains and the longitudinal cerebral fissure; having an evaluation unit (20) for comparing the acoustic transmission signals with the corresponding acoustic reception signals, wherein an n-dimensional function and a flight time value characteristic of the biological material (02) can be determined; A second device (30) for determining the swelling of the biomaterial (02), wherein the second device (30) includes measuring equipment (31) for measuring the linear swelling and / or volume swelling of the biomaterial (02); and An analysis unit (40) for determining the intracranial compliance of the biomaterial (02) based on the comparison made and the measurement performed.

6. The device (01) according to claim 5, wherein the analysis unit (40) is configured to determine the intracranial pressure, cerebral blood flow and / or pathological condition of the biomaterial (02) based on the determined intracranial compliance.

7. The device (01) according to claim 6, which includes an output unit for displaying the determination made by the analysis unit (40).

8. The device (01) according to any one of claims 5 to 7, wherein the acoustic transmission element (11) is arranged at a first position (X1) of the biomaterial (02) and wherein the acoustic reception element (12) is arranged at a second position (X2) of the biomaterial (02), and wherein the first position and the second position (X1, X2) are the same or arranged opposite to each other.

9. The device (01) according to any one of claims 5 to 7, wherein the first device (10), the second device (30), the evaluation unit (20), the analysis unit (40) and / or the output unit (50) are arranged in one component.

10. The device (01) according to any one of claims 5 to 7, wherein the device (01) is implemented to be rotatable and / or movable.

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