Method and device for non-invasive absolute (mean) intracranial pressure (A-ICP) measurement and / or monitoring

Abstract

Non-invasive measurement of intracranial pressure (ICP), e.g., mean ICP, is disclosed. A probe adjacent to the head emits energy, such as ultrasound, and receives a reflected signal. A processing unit derives an ICP waveform from the signal. The pressure mechanism applies external pressure to the exterior of the head intermittently, gradually increasing the external pressure. The processing unit is configured to detect a decrease in the amplitude of the ICP waveform (which occurs in some embodiments only after an intermediate period of ICRS compensation), and the processing unit is configured to determine the person's ICP from the sum of the external pressures applied from when the amplitude is at or after an initial value A1 to a final value at which the amplitude remains stable with additional increases in the applied external pressure. In some cases, the final value is earlier, but the processing unit extrapolates the sum to the point at which the amplitude remains stable with additional increases in pressure.

Description

[Technical Field]

[0001] The present invention relates to devices and methods for non-invasively measuring intracranial pressure (ICP), such as mean ICP or absolute ICP or absolute mean intracranial pressure (ICP), in a mammalian subject (e.g., a human). [Background technology]

[0002] Standard methods for measuring intracranial pressure (ICP) involve drilling a hole in the skull and inserting an intraventricular catheter, a subdural screw, or an epidural sensor operably connected to an external pressure sensor or transducer. These invasive methods generally require a neurosurgeon to perform, are expensive to perform, pose a risk of complications to the patient, and are therefore not always available when desired or needed. Furthermore, it is clear as a matter of common sense that having to open a patient's head to obtain an important parameter (intracranial pressure (ICP)) is less desirable than obtaining the parameter without having to open the patient's head. There are limits to how often a patient's head can be opened.

[0003] To overcome the problems of invasive methods and make ICP measurement more readily available, considerable effort has been devoted to devising noninvasive methods and devices for measuring ICP. U.S. Patent Nos. 5,951,477 and 8,926,515 describe ultrasonic Doppler devices that detect the pulsatility index of blood flow within the ophthalmic artery, both for the intracranial and extracranial portions. The eye, whose blood flow is being monitored, is subjected to a small pressure sufficient to equalize the pulsatility index measurements of the internal and external portions of the ophthalmic artery. The pressure at which such equalization occurs is used as a reference for automatic calibration of the device so that continuous absolute intracranial pressure measurements can be made over a specified sampling period.

[0004] This method has many drawbacks and limitations. First, it does not take into account that pressure on the eyeball causes mechanical irritation of the eye. As a result, the autonomic sympathetic nervous system of the eye triggers reflex cerebral vasospasm (CVS), which in turn causes inaccuracies in absolute ICP measurements, resulting in results that do not accurately represent the actual ICP. This is particularly the case in 80% of traumatic brain injury (TBI) patients who suffer from cerebral vasospasm (CVS). Second, iatrogenic cerebral vasospasm (CVS) after occlusion of the eyeball and the superior and inferior ophthalmic veins and the retrobulbar venous vortex causes a decrease in the amount of electroencephalographic output signal from the eyeball to the intracranial cavity (cavernous sinus), resulting in considerable inaccuracies in the use of this method.

[0005] Third, the results of transorbital Doppler imaging of the ophthalmic artery are variable and depend on the operator and the variability of each individual's anatomy. The reproducibility and reliability of Doppler imaging are very low.

[0006] Fourth, 10–25% of patients with traumatic brain injury suffer from bilateral or unilateral periorbital ecchymosis, subcutaneous hemorrhage, subcutaneous facial-orbital emphysema, and orbital fractures, making the above-mentioned method unusable in these patients. For intensive care unit patients with severe brain injury whose ICP is elevated between 20 and 60 mmHg, the accuracy of this method is low, making it impractical for widespread use. Noninvasive ICP measurements, such as those described in U.S. Patent Nos. 5,951,477 and 8,926,515, are likely to be useful only in healthy individuals, if at all.

[0007] To the applicant's knowledge, there are no widely used noninvasive methods or devices for ICP monitoring or measurement. An article in Surgical Neurology International by Marium Naveed et al., "Noninvasive Intracranial Pressure Monitoring - A Review of Available Modalities," published April 5, 2017, reviewed 196 peer-reviewed articles discussing 15 noninvasive modalities and concluded that "no noninvasive ICP monitoring modality yet exists to replace invasive techniques," summarizing the situation as follows (citations omitted): Intracranial pressure (ICP) is defined as the pressure within the skull, and therefore within the brain tissue and cerebrospinal fluid (CSF). Normal ICP is usually considered 5-15 mmHg in healthy supine adults, 3-7 mmHg in children, and 1.5-6 mmHg in infants. An ICP greater than 20 mmHg is considered elevated, and is considered an important cause of secondary injury leading to irreversible brain damage and death. ICP monitoring is used in several conditions, including traumatic brain injury, intracerebral hemorrhage, subarachnoid hemorrhage, hydrocephalus, malignant infarction, cerebral edema, CNS infection, and hepatic encephalopathy. In all of these conditions, in light of other parameters, ICP monitoring can influence management for better outcomes. There are several conditions in which it is important to monitor ICP. Even slight variations can require changes in management. The gold standard for monitoring ICP is an intraventricular catheter connected to an external pressure transducer. The catheter is placed into one of the ventricles through a cranial burr hole. Catheters can also be used for therapeutic CSF drainage and for the administration of medications. Although catheters are an accurate and cost-effective method of ICP monitoring, they are associated with many complications. These include the risks of infection, bleeding, obstruction, difficult placement, and malposition. Other invasive methods for ICP monitoring, which carry the same complications as intraventricular catheterization, include intraparenchymal monitors, subdural devices, and epidural devices, as well as lumbar puncture measurements.Because of the many complications associated with invasive ICP monitoring, researchers and clinicians have sought to develop reliable noninvasive modalities for ICP monitoring. From the use of fontograms in the 1970s to ongoing experiments on the acoustoelastic effect on ICP, no noninvasive alternative to invasive techniques for ICP monitoring exists. Summary of the Invention

[0008] Certain embodiments of the present invention take into account venous and cranial outflow of cerebrospinal fluid (CSF) and measure (intraparenchymal pressure) IPP (intraventricular pressure) IVP, supra- and subtentorial pressures (SUPTP, SUBTP), and regional pressures in the ICRS volume, increasing the accuracy, reliability, and reproducibility of ICP measurements. In contrast, the methods disclosed in U.S. Patent Nos. 5,951,477 and 8,926,515 do not take into account venous and cranial outflow of cerebrospinal fluid (CSF) and do not measure (intraparenchymal pressure) IPP, (intraventricular pressure) IVP, subtentorial pressures (SUPTP, SUBTP), or regional pressures in the ICRS volume.

[0009] 1. A non-invasive method for measuring mean intracranial pressure (ICP) in a human, comprising: using at least one probe positioned adjacent to an external tissue layer of the person's head, emitting energy into pulsating one or more of brain tissue, cerebral blood vessels, and ventricles of the head and receiving reflected signals; deriving, using a processing unit, from the signal or from an image associated with the signal, an ICP waveform having identifiable amplitudes whose fluctuations correspond to pulsations of one or more of brain tissue, cerebral blood vessels, and ventricles; applying intermittent external pressure to an exterior surface of the head using a pressure mechanism in communication with the processing unit; the mechanism includes a pressure applicator that is used to apply an initial external pressure and then a pressure mechanism that applies incrementally increasing external pressure to the exterior surface; after the ICP waveform begins to decrease in amplitude from an initial amplitude value A1 (in some embodiments, a processing unit instructs the pressure mechanism to stop applying external pressure when the amplitude reaches a final amplitude value A2), determining the person's ICP from the sum or extrapolated sum of applied external pressures beginning at or after the initial amplitude value A1 and ending by the time of the final amplitude value A2; One of the following is true: (i) the final value is the value at which the amplitude remains constant with additional increases in the applied external pressure, and the processing unit is configured to determine the ICP from the sum of the applied external pressures; or (ii) the final value A2 is a value at which the amplitude decreases from the initial value A1 towards but not to the point at which the amplitude remains constant with further increases in the applied external pressure, and the processing unit is configured to determine the ICP or estimated ICP by extrapolating the sum to the point at which the amplitude remains constant with further increases in the applied external pressure.

[0010] In some embodiments, the energy is applied using a steerable one-dimensional ultrasound probe positioned on the person's forehead and focused on the region in the brain where the pulsation occurs. In some embodiments, the one-dimensional ultrasound probe is operated at a frequency of 0.5 to 1.5 MHz. In some embodiments, the region in the brain is at least one of the third ventricle, the lateral ventricle, the thalamic-striatal vein and the central cerebral vein of the third ventricle cavity, the edges of the third ventricle and lateral ventricle, the fourth ventricle, the choroid plexus veins of the ventricles, and the cortical pulsation.

[0011] In some embodiments, the signals are ultrasound signals recorded on a sagittal plane at 20 to 50 degrees relative to the horizontal (axial) plane.

[0012] In some embodiments, the energy is applied using a steerable two-dimensional (2D) ultrasound probe attached to the temporal region of the head or mounted to obtain at least one of (i) axial slices, (ii) coronal slices, and (iii) oblique slices, where the 2D probe is focused on a region within the brain where pulsation occurs in one or more of brain tissue, cerebral blood vessels, and ventricles. In some embodiments, the 2D US probe is operated at a frequency of 1.5 to 2.5 MHz. In some embodiments, the region within the brain is one of the following: the rim of the third ventricle, the central cerebral vein, and the thalamo-striatal vein.

[0013] In some embodiments, the external pressure is applied in uniform, stepwise increments.

[0014] In some embodiments, the external pressure is applied to both sides of the person's head in a bitemporal direction.

[0015] In some embodiments, the processing unit is configured to extrapolate the sum using the ratio of A1 to the difference between A1 and A2, taking into account how many times external pressure was applied from time A1 to time A2.

[0016] In some embodiments, deriving the ICP waveform from the ultrasound signals is achieved by a Fast Fourier Transform performed on the signals derived from the pulsations of the one or more of the brain tissue, cerebral blood vessels, and ventricles in the region of the brain where the brain tissue pulsates to obtain the distribution of the resonant frequencies in a spectrum, and performing an Inverse Fourier Transform to reconstruct the ICP waveform from the pulsations.

[0017] Another aspect of the invention is an apparatus for the non-invasive measurement of mean intracranial pressure (ICP) in a human, the apparatus comprising: at least one probe positioned adjacent to an external tissue layer of the person's head, the probe configured to emit energy into pulsating one or more of brain tissue, cerebral blood vessels, and ventricles of the person's head and receive reflected signals; a processing unit configured to derive from the signal or from an image associated with the signal an ICP waveform corresponding to one or more brain tissues, cerebral blood vessels, and ventricles through which the fluctuations pulsate; a pressure mechanism in communication with the processing unit and configured to apply external pressure to an exterior surface of the head by applying an initial external pressure and then gradually increasing the applied external pressure; the processing unit is configured to detect a decrease in amplitude of the ICP waveform, the decrease starting from an initial value A1 of the amplitude and detecting a final value A2 of the amplitude; the processing unit is configured to determine the person's ICP from a sum of applied external pressures beginning at and after an initial value A1 time and ending by a final value A2 time; One of the following is true: (i) the final value is a value at which the amplitude remains constant with additional increases in the applied external pressure, and the processing unit is configured to determine the ICP from the sum of the applied external pressures; (ii) the final value A2 is a value at which the amplitude has decreased from the initial value A1 towards the initial value A1 but has not yet reached a value at which the amplitude remains constant with further increases in the applied external pressure, and the processing unit is configured to determine the ICP or estimated ICP by extrapolating the sum to the point at which the amplitude remains constant with further increases in the applied external pressure.

[0018] In some embodiments, the at least one probe comprises an ultrasound probe configured to emit ultrasound energy and receive reflected signals.

[0019] In some embodiments, the processing unit is configured to execute an image processing algorithm to measure at least three of the following: baseline, amplitude, phase shift, and change in resonant frequency of an ICP waveform.

[0020] In some embodiments, the at least one probe is a steerable one-dimensional ultrasound probe positioned on the person's forehead and configured to focus on an area within the brain where the brain tissue pulsates. In some embodiments, the one-dimensional ultrasound probe is configured to operate at a frequency of 0.5 to 1.5 MHz. In some embodiments, the area within the brain is at least one of the third ventricle, the lateral ventricle, the thalamic-striatal vein and the central cerebral vein of the third ventricle cavity, the edges of the third ventricle and lateral ventricle, the fourth ventricle, the choroid plexus veins of the ventricles, and the cortical pulsation.

[0021] In some embodiments, the at least one probe is a steerable two-dimensional USB ultrasound probe attached to the temporal region of the head or configured to obtain at least one of (i) axial slices, (ii) coronal slices, and (iii) oblique slices, and the two-dimensional probe focuses on an area in the brain where pulsation occurs in one or more of brain tissue, cerebral blood vessels, and ventricles. In some embodiments, the two-dimensional ultrasound probe is configured to operate at a frequency of 1.5 to 2.5 MHz. In some embodiments, the area in the brain is one of the rim of the third ventricle, the central cerebral vein, and the thalamo-striatal vein.

[0022] In some embodiments, the signals are aligned in a sagittal plane at 20 to 50 degrees relative to the horizontal (axial) plane.

[0023] In some embodiments, the external pressure is applied in uniform, stepwise increments.

[0024] In some embodiments, the external pressure is applied to both sides of the person's head, in a bitemporal direction, or in a coronal, axial, or oblique direction.

[0025] In some embodiments, the pressure mechanism comprises one of: (a) a pressure applicator including an inflatable sleeve that is applied to the person's head, or (b) a helmet configured to apply pressure to specific locations on the person's skull.

[0026] In some embodiments, the processing unit is configured to extrapolate the sum using the ratio of A1 to the difference between A1 and A2, taking into account how many times external pressure was applied between time A1 and time A2.

[0027] In some embodiments, the processing unit is configured to derive the ICP waveform from the ultrasound signal by a Fast Fourier Transform performed on the brain pulsation in a region of the brain where the brain tissue pulsation occurs to obtain a distribution of resonant frequencies in the spectrum, and an Inverse Fourier Transform is performed to generate a non-invasive ICP waveform of the brain pulsation.

[0028] In yet another aspect of the present invention, there is provided an apparatus for non-invasively measuring mean intracranial pressure (ICP) in a person, the apparatus comprising: at least one probe positioned adjacent to the person's head and configured to emit energy into pulsating tissue or cavities within the brain (or head) and receive reflected signals; a processing unit configured to derive an ICP waveform from the signal or from an image associated with the signal; a pressure mechanism in communication with the processing unit, the pressure mechanism configured to apply external pressure to the person's skull when a surface of the mechanism contacts the person's skull; The processing unit is configured to detect a decrease in amplitude of an ICP waveform beginning from an initial amplitude value A1, and determine the person's ICP from a sum of applied external pressures, or an extrapolated sum of applied external pressures, beginning at or after the time of the initial value A1 and ending by a time of a final value A2. In some embodiments, the processing unit is configured to detect an intracranial reserve space (ICRS) interim period and detect such a decrease in amplitude of the ICP waveform occurring after the ICRS interim period is completed. In some embodiments, the processing unit is also configured to communicate to a pressure mechanism to stop the external pressure when the amplitude reaches a final value.

[0029] In certain embodiments of the present invention, mean ICP (sometimes referred to as "M-ICP") can be obtained noninvasively and reliably with accuracy comparable to the "gold" standard of ICP measurement, i.e., invasive measurement. In some embodiments of the present invention, a person's noninvasive ICP can be measured repeatedly, instead of having to wait a certain number of days between invasive ICP measurements, as neurosurgeons must. The present invention also avoids any surgery to the patient's head. In certain embodiments, the present invention also broadens the applicability of ICP measurement compared to invasive ICP measurement, since it can be used in individuals whose Glasgow Coma Scale (GCS) scores are too low (i.e., less than about 8) to undergo invasive ICP measurement according to current medical protocols.

[0030] Furthermore, in certain embodiments, the average ICP measurement measured by the present invention is more accurate than other methods and devices because, in certain embodiments, the processing unit takes into account the patient's intracranial reserve space (ICRS) in the sense that it determines the noninvasive ICP measurement by summing the amount of external pressure applied during a period after the drop in ICP wave amplitude, which occurs only after any effects caused by the subject's intracranial reserve space (ICRS). As shown in Figure 7, the effect of having spare ICRS capacity means that after the critical point when some resistance is overcome and some tissue deformation begins to occur, in many or most patients, there is an intermediate period in which the ICP waveform amplitude is relatively flat compared to before and after the intermediate period, and the ICP value initially increases, then decreases, after which the ICP value increases more significantly. The reason the ICP waveform amplitude is relatively flat during this intermediate period (sometimes referred to herein as the "ICRS intermediate period" or "ICRS-occupied intermediate period") is due to the effect of the spare ICRS capacity that a person has in their skull. What happens during this ICRS interim period is that the body's own compensatory mechanisms move the person's cerebrospinal fluid (CSF) from the intracranial space into the spinal cord space or spinal channel space, thereby reducing the person's intracranial pressure. According to certain embodiments, the present invention configures processing unit 30 to calculate only the sum (or extrapolated sum) of applied external pressures during the period after the potential impact of ICRS volume (i.e., after the ICRS interim period), i.e., after the body's compensatory mechanisms have acted (if they could have acted initially assuming intracranial reserve space). The fact that spare ICRS volume (intracranial reserve space) is taken into account makes the ICP measurement of the present invention more accurate. Many attempts to measure ICP, whether invasive or non-invasive, are inaccurate because they do not take ICRS volume into account.

[0031] Certain embodiments of the methods and devices of the present invention can provide reliable non-invasive ICP measurements for a wide range of patients requiring ICP measurement or monitoring, including, but not limited to, patients with subskin bleeding, patients with basilar skull fractures, and patients with CSF leaks.

[0032] As used herein (including in FIG. 7), "simulated ICP" or "simulated ICP" refers to an estimated expected ICP value after applying respective magnitudes of external pressure to a person's head in accordance with certain embodiments of the present invention.

[0033] These and other features, aspects, and advantages of the present invention will become better understood with reference to the following drawings, description, and claims. [Brief explanation of the drawings]

[0034] Various embodiments are herein described, by way of example only, with reference to the accompanying drawings. [Figure 1] FIG. 1 is a top view diagrammatically illustrating an apparatus including an ultrasound probe, a mechanism for applying external pressure to the skull for non-invasive measurement of A-ICP, and a digital ICP waveform, according to one embodiment of the present invention. [Figure 2A] FIG. 2A is a top view diagram that schematically illustrates a mechanism for applying external pressure to a person's skull for non-invasive measurement of A-ICP according to one embodiment of the present invention. [Figure 2B] FIG. 2B is a front view that schematically illustrates a mechanism for applying external pressure using different contact points than those shown in FIG. 2A, according to one embodiment of the present invention. [Figure 3] FIG. 3 shows an ultrasound image resulting from the use of a 2D ultrasound probe and an ICP waveform derived from this image using a processing unit, according to an embodiment of the present invention. [Figure 4] FIG. 4 is a top view that schematically illustrates a mechanism for applying external pressure connected to a motor and a processing unit, according to one embodiment of the present invention. [Figure 5] FIG. 5 shows schematic top views of various configurations of contact points for a pressure application mechanism, according to embodiments of the present invention. [Figure 6] FIG. 6 is a schematic diagram of an alternative pressure application mechanism, according to an embodiment of the present invention. [Figure 7] 7 shows two graphs: the lower graph shows ICP waveform amplitude changing over time, and the upper graph shows a simulation of ICP changing as a result of applied external pressure superimposed on a non-invasively derived ICP waveform, according to one embodiment of the present invention. [Figure 8] FIG. 8 is a graph illustrating the reduction in amplitude of an ICP waveform in accordance with an embodiment of the present invention. [Figure 9] FIG. 9 is a graph of the decrease in amplitude of the ICP waveform due to the application of external pressure. [Figure 10] FIG. 10 is a flowchart illustrating a method according to one embodiment of the present invention. [Figure 11] FIG. 11 is a schematic diagram of an apparatus according to one embodiment of the present invention. [Figure 12] FIG. 12 is a flowchart illustrating a method according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0035] The following detailed description is the best presently contemplated mode for carrying out the invention. The description is not to be taken in a limiting sense, but is made merely for the purpose of illustrating the general principles of the invention, the scope of which is best defined by the appended claims.

[0036] The present invention generally provides devices and methods for non-invasively measuring and / or monitoring a person's absolute intracranial pressure (ICP, sometimes referred to as "(A)ICP"). Although ICP values ​​are theoretically dependent on atmospheric pressure, the present invention ignores atmospheric pressure variations because such changes in atmospheric pressure are typically negligible. In certain embodiments, normal atmospheric pressure (around 760 mmHg) is treated as if it were zero, and ICP measurements are independent of atmospheric pressure.

[0037] In some embodiments, the present invention provides devices and methods for noninvasively measuring and / or monitoring a person's mean intracranial pressure (ICP) over time (although in certain embodiments, for a short period of time). Thus, the mean ICP can be a person's ICP obtained from measurements taken over a short period of time, such as a few seconds, up to several hours or longer. In some cases, several such noninvasive ICP measurements (each with a gap between them) are taken and averaged together to obtain a single average ICP over the entire period. However, for continuous (gap-free) mean ICP measurements, the time range is from about a few seconds to about 1-2 minutes, and this single measurement represents the average ICP. For ICP measurements that include one or more gaps, such an average ICP measurement can extend over several hours by averaging several measurements taken during this period, each of which may last 2-3 seconds or more (up to about 2 minutes). Generally, monitoring a person's ICP can be performed using certain embodiments of the methods and devices of the present invention over any desired period of time. ICP measurements of the same person can be repeated at intervals shorter than one day, or even shorter than one hour. Thus, in certain embodiments, the present invention provides for non-invasive, accurate, and reliable repeated or recurring monitoring of ICP, in which ICP (or mean ICP) is non-invasively monitored or measured every hour, every 30 minutes, every quarter hour, every 10 minutes, or every 5 minutes for a day, week, or month.

[0038] The present invention in certain embodiments is a method for non-invasive measurement of absolute intracranial pressure (ICP) in patients with severe brain injury due to, for example, traumatic brain injury (TBI), brain swelling, or other intracranial space-occupying lesions (SOLs), such as ischemic and hemorrhagic stroke, brain tumors, unconscious patients of unknown cause, and healthy or conscious patients. The present invention differs from prior knowledge in the art by demonstrating that moderate external pressures applied to the skull without causing pain to the patient can induce micron-sized local deformations of the skull, affecting amplitude changes in non-invasive intracranial pressure (ICP) waves. The present invention is based on an unexpected observation by one of the authors, J.D., et al., that, in certain embodiments, involves imaging techniques, such as ultrasound imaging techniques, for observing the motion (pulsation), e.g., multi-axis spatial motion, of brain tissue and ventricles, and in some embodiments, imaging of cerebral arteries and veins caused by ultrasound energy gradients between transmission and reception by an ultrasound transducer in contact with the outer soft tissue layers or skull of a patient's head. In certain embodiments, the present invention allows for real-time imaging of the vertical pulsation of brain tissue, the edges of brain ventricles, and brain tissue and cerebral blood vessels (arteries and veins) inside the ventricular cavities.

[0039] The present invention, in some embodiments, derives waveforms from signals or signal-related images received as a result of at least one probe, e.g., ultrasound images generated from emitting and receiving signals on a person's skull using a one-dimensional or two-dimensional probe (or both, e.g., simultaneously). In some embodiments, waveforms (referred to herein as ICP waveforms) are acquired (and displayed) by a processing unit at the same time that at least one probe is being used to emit energy-received reflected signals and images while external pressure (e.g., intermittent external pressure) is being applied to the person's skull, e.g., in step increments.

[0040] The waveform amplitude and its decrease are used in some embodiments by the processing unit (or by the observer) to determine which applied pressure to use when using the total applied pressure to derive the person's intracranial pressure (and to determine when to terminate the application of external pressure to the person's skull), i.e., to determine the start and end points of the applied pressure used in calculating the ICP value. Additionally, other characteristics of the ICP waveform, such as a baseline shift (e.g., an increase in the baseline) or a shift in the phase of the amplitude relative to the baseline (i.e., going below the baseline rather than above it), are used by the processing unit in some embodiments to determine or confirm the start point of the applied pressure used to calculate the ICP value.

[0041] For example, a decrease in amplitude to zero or a negligible or nearly negligible amount results in cessation of application of external pressure in some embodiments. In another example, a decrease in amplitude by a significant amount, such as more than 75%, more than 90%, more than 95%, or more than 95-99%, results in cessation of application of external pressure in some embodiments. In some embodiments, a decrease in amplitude sufficient to allow for further decrease in amplitude to be estimated, such that the total decrease in amplitude is by a significant amount, or to zero or a negligible or nearly negligible amount, results in cessation of application of external pressure.

[0042] In certain embodiments of the present invention, a decrease in amplitude is used to trigger a command to stop applying external pressure only when this decrease occurs, after a specific physiological phenomenon occurs, namely deformation of intracranial tissue and typically a baseline change in the ICP waveform.

[0043] Pulsations of tissues and / or ventricles within the brain are sometimes said to arise from intracranial pressure and a person's heart rhythm. The amplitude of these brain tissue pulsations may be recorded on a graph as a waveform, hereinafter referred to as an ICP waveform or ICP waveform. For comparison purposes, it should be noted that when invasive ICP measurements are performed by drilling a hole through the skull and inserting an intraventricular catheter, subdural screw, or epidural sensor, such measurements yield both an ICP wave indicating ICP variability as well as a scalar magnitude or value representing a person's intracranial pressure (over time). In contrast, ICP waveforms obtained from ultrasound images herein indicate ICP variability but lack an associated scalar (or other) magnitude or value representing a person's intracranial pressure (over time or even at a given point in time). Therefore, the term "ICP waveform" as used herein does not refer to, and does not refer to, a person's actual intracranial pressure values, for example, measured invasively (or otherwise) over time or instantaneously. However, the present invention, in certain embodiments described herein, is a processing unit that combines this ICP waveform with pressure applied externally to the skull to creatively derive an intracranial pressure value (e.g., a scalar value representing the magnitude of a person's intracranial pressure) that, in certain embodiments, is as accurate as an invasively measured ICP value.

[0044] In certain embodiments, the present invention noninvasively measures a person's intracranial pressure, e.g., mean ICP, in a manner that is independent of the angle of ultrasound insonation. In certain embodiments, energy from the probe of the present invention can noninvasively penetrate the skull of 99% of patients. In certain embodiments, the present invention noninvasively measures a person's intracranial pressure, e.g., mean ICP, in a manner that is independent of the skill or precision of a technician or operator of the device 10 or method 100 of the present invention. These factors, in certain embodiments, increase the reliability and reproducibility of the method 100 and device 10 of the present invention. In contrast, the use of Doppler imaging and ultrasound with frequency gradients depends on the skill of the operator and the angle of insonation and, therefore, would produce less reproducible and reliable ICP measurements.

[0045] The principles and operation of a method and apparatus for non-invasive absolute (mean) measurement and / or recurrence monitoring of intracranial pressure (A-ICP) may be better understood with reference to the drawings and accompanying description.

[0046] 1-9, 11-12, in one embodiment, the present invention is an apparatus 10 for non-invasive measurement (and / or recurrence monitoring) of mean intracranial pressure (ICP) in a person. In embodiments where the processing unit 30 or other parts of the apparatus are separate from other elements of the apparatus 10, the apparatus may also be referred to as a system 10.

[0047] 1, device 10 includes at least one probe 20 arranged or configured to be positioned adjacent to an outer tissue layer, typically a soft outer tissue layer, of a person's or subject's head. The probe may be an ultrasound probe, or in other embodiments, a probe that generates other forms of energy, e.g., microwaves, radio waves, near-infrared radiation, or terahertz waves, that are directed toward pulsating at least one of brain tissue, cerebral blood vessels, and ventricles of the person's head. The at least one probe is configured to receive reflected signals and / or images associated with the reflected signals.

[0048] While the following discussion discusses non-limiting implementations of the present invention using ultrasound probes 20, it should be understood that the following discussion is also applicable to probes that emit and enumerate reflected signals of other forms of energy. In certain embodiments, the at least one probe 20 is an ultrasound probe 20 configured to emit ultrasound energy into pulsating at least one of brain tissue, cerebral blood vessels, and ventricles within the head, in some embodiments. In certain embodiments, the at least one ultrasound probe 20 is configured to generate an ultrasound energy gradient, for example, between the energy of the emitted ultrasound signal and the energy of the reflected ultrasound signal. In some embodiments, the at least one probe 20 is configured to perform digital (in some cases, "real-time") tracking of these brain tissues, blood vessels, and / or ventricles to generate a non-invasive ICP waveform. In certain embodiments, the invasively generated ICP guided waves are similar to or equivalent in variability to the invasively induced ICP guided waves. The at least one probe 20 may further be configured to receive ultrasound signals that bounce off the tissue and / or ventricles and are received by the at least one probe 20. In some embodiments, the at least one probe is configured to track pulsations at different locations, in different brain tissue volumes, and / or in different directions (i.e., multi-axis pulsations or brain volume pulsations). In certain embodiments, the at least one probe 20 is in communication with a processing unit 30 including a display monitor 39 for displaying ultrasound images.

[0049] The at least one probe 20, which in some embodiments is a one-dimensional ultrasound probe 20 and may be steerable or adjustable, is configured to be placed on a person's head, in one non-limiting example, on the person's forehead (and in other embodiments adjacent to other parts of the head), and can focus on areas within the brain where pulsations occur in at least one of the brain tissue, cerebral blood vessels, and ventricles of the head. In some embodiments, the areas within the brain where ultrasound or other energy is focused are at least one of the third ventricle, lateral ventricles, thalamic-striatal veins and central cerebral veins of the third ventricle, the edges of the third ventricle and lateral ventricles, the fourth ventricle, choroid plexus veins of the ventricles, cavernous sinuses and convex sinuses, and cortical pulsations. In some embodiments, the areas in the brain on which the ultrasound or other energy is focused are at least two, at least three, at least four, or all of the following: the third ventricle, the lateral ventricles, the thalamic-striatal vein and the central cerebral vein of the third ventricle, the edges of the third and lateral ventricles, the fourth ventricle, the choroid plexus veins of the ventricles, the cavernous and convex sinuses, and the cortical pulsation. For example, in some embodiments, the one-dimensional ultrasound probe is configured to operate at a frequency of 0.5 to 1.5 MHz. The advantage of a one-dimensional ultrasound probe is that it penetrates the skull better. In some versions, the ultrasound signal is aligned on a sagittal plane at 20 to 50 degrees relative to the horizontal (axial) plane. In certain embodiments, the one-dimensional probe 20 is attached to a region of the person's head to obtain at least one (i) axial, (ii) coronal, or (iii) oblique slice, or to be focused in a bitemporal direction.

[0050] In other embodiments of the at least one probe 20, the at least one probe is steerable or adjustable, and in one non-limiting example, is a two-dimensional ultrasound probe (e.g., a USB probe) configured to be attached to a person's head in the temporal region of the head and capable of focusing on an area within the brain where pulsation occurs in at least one of the brain tissue, cerebral blood vessels, and ventricles. In some embodiments, the area within the brain where ultrasound or other energy is focused is one of the edge of the third ventricle, the central cerebral vein, and the thalamostriatal vein. An advantage of a two-dimensional probe is that it receives better images. This is important because in some embodiments, it allows the technician to identify the target space and more precisely aim the ultrasound beam. The two-dimensional ultrasound probe 20 can be configured to operate at a frequency of 1.5 to 2.5 MHz. In certain embodiments, the two-dimensional probe 20 is attached to a region of the person's head to obtain at least one of the following slices: (i) axial, (ii) coronal, (iii) oblique, or bitemporal.

[0051] In some embodiments, a one-dimensional probe is used at one contact point and a two-dimensional probe is used at another contact point simultaneously. While specific regions of the brain for one-dimensional probes and two-dimensional probes are proposed, these are non-limiting examples, and any region of the head that allows access to brain tissue and / or ventricle pulsation may be utilized. Note that, because the forehead is particularly thick, in some embodiments, it is useful to use a one-dimensional probe when the probe is located on the forehead.

[0052] Accordingly, the device 10 may also include a processing unit 30, including a hardware processor, software, and memory, configured to derive an ICP waveform from the ultrasound signal. The ICP waveform, for example, has a distinct amplitude, the fluctuations of which correspond to the pulsation of at least one of the brain tissue, cerebral blood vessels, and ventricles in the head. In some embodiments, the derivation of the ICP waveform is achieved by a fast Fourier transform performed on the brain pulsation within a selected region to obtain a distribution of resonant frequencies within a spectrum. An inverse Fourier transform is then performed to reconstruct the noninvasive ICP waveform of the brain pulsation, e.g., to reconstruct, render, or derive a multi-axis volumetric curve of the brain pulsation, e.g., in real time. In some embodiments, a two-dimensional pulsation is generated. In some embodiments, this two-dimensional pulsation is further converted into a three-dimensional or multi-dimensional pulsation by including signals from both horizontal and vertical positions held by the at least one probe 20. As used herein, the term real-time refers to the real time perceived by the user, which in some embodiments means less than 50 milliseconds.

[0053] In any version of the device 10 herein, the device 10 and its components (probes 20, processing unit 30, and pressure mechanism 40) are configured such that, in certain embodiments, application of external pressure (or any portion thereof) is performed while at least one probe 20 is being used to generate ultrasound signals and / or while the processing unit 30 is being used to derive an ICP waveform from those signals.

[0054] Processing unit 30 is configured to detect a decrease in the amplitude of the ICP waveform. As can be seen in FIG. 8, this, in some embodiments, is used to determine which external pressure value to use in summing such pressure values ​​to derive the person's ICP. In FIG. 8, in one embodiment, the sum of P5 through P10 or the sum of P6 through P10 can be used to derive the person's ICP value. In some embodiments, as can be seen in FIG. 7, for example, in the lower graph, processing unit 30 is also configured to detect a baseline increase and / or phase shift in the ICP waveform or its amplitude. This identifies the starting point of the external pressure value, which in some embodiments is when there is a decrease in the amplitude of the waveform following a baseline and / or phase shift. In the lower graph of FIG. 7, the decrease in amplitude following a baseline and / or phase shift occurs after an intermediate period designated in the graph as "ICRS Volume."

[0055] Accordingly, in some embodiments of apparatus 10 (and method 100), processing unit 30 is also configured to detect ICRS intermediate periods and, upon completion of such intermediate periods, identify a decrease in the amplitude of the ICP waveform that specifically occurs after the completion of the ICRS intermediate period. As discussed above, this improves the accuracy of measurements of a person's ICP or mean ICP.

[0056] The decrease in amplitude that processing unit 30 is configured to detect is defined to begin at an initial amplitude value A1 and can be the result of an increase in external pressure. Processing unit 30, in some embodiments, is also configured to detect a final value A2. In some embodiments, when the amplitude reaches the final value, processing unit 30 is configured to transmit a command to pressure mechanism 40 to stop applying the external pressure (or in certain embodiments, someone or something other than processing unit 30, such as an operator of device 10 or pressure mechanism 40, can stop the external pressure when the decrease in amplitude is deemed to reach the final value). Processing unit 30 is configured to determine the person's ICP from the sum of the external pressures applied from at or after the initial value A1 to the final value A2. One of the following is true: (i) the final value is the value at which the amplitude remains stable with additional increases in the applied external pressure, and the processing unit is configured to determine the ICP from the sum of the applied external pressures; (ii) The final value A2 is the value to which the amplitude is reduced from the initial value A1, and the amplitude at the final value approaches but does not reach the amplitude at which it remains stable with additional increases in the applied external pressure. The processing unit is configured to determine the ICP or estimated ICP by extrapolating the sum to the point at which the amplitude remains stable with additional increases in the applied external pressure. An example of version "(i)" can be seen in FIG. 8, where the initial value may be P6 and the final value is P10 in some embodiments. Deformation began between P5 and P6. An example of version "(ii)" of FIG. 8 is where the initial value may be P6 and the final value may be, for example, P7, and the processing unit 30 estimates what P8 to P10 will be or how to estimate it using known mathematics, for example, based on the rate or rate at which the amplitude decreases between each pressure application.

[0057] Typically, the final value (or extrapolation of the sum of the external pressure amounts (or extrapolation of the external pressure amounts) up to the point where the amplitude of the waveform drops to the final value) is very small compared to the initial value, and at the final value, the amplitude remains stable with further increases in the applied external pressure after the amplitude drops significantly. For example, in some embodiments, the amplitude is found to remain stable with further increases in the applied external pressure after the amplitude drops to zero or a negligible amount, or to 1% to 5% of the initial value of the amplitude, or in other embodiments, to 5% to 10% (or 10% to 15%) or 15% to 20% of the initial value of the amplitude.

[0058] In some embodiments where processing unit 30 is configured to extrapolate the total applied external pressure, processing unit 30 uses the ratio of A1 to the difference between A1 and A2, possibly taking into account how many times external pressure was applied from time A1 to time A2.

[0059] There are several mathematically robust ways to perform the extrapolation. In one non-limiting embodiment shown in Figure 9, if P1 is the first application of external pressure that occurs after the amplitude of the ICP waveform decreases, and P2 is the second application of external pressure that is incrementally higher than P1, and if the amplitude of the ICP waveform decreases by 25% from X1 (corresponding to A1) to X2 as the externally applied pressure increases from P1 to P2, processing unit 30 is configured in some embodiments to extrapolate the total applied external pressure by assuming that the sum of P3+P4+P5 is P1+P2+P3+P4+P5 (P5=0), even though this sum did not actually occur. This is because the number of times external pressure must be applied before the amplitude of the ICP waveform remains stable at A2 (i.e., zero or negligible) increases by at most three times in the applied external pressure, and the total applied external pressure is extrapolated accordingly.

[0060] In some embodiments, the processing unit 30 is configured to execute image processing algorithms that measure at least three of the following: a baseline change, an amplitude value, a phase shift, and a change in resonant frequency of the ICP waveform.

[0061] In certain embodiments, the person's ICP is determined by processing unit 30 from the sum of applied external pressures (or possibly an extrapolated sum of applied external pressures). This is a non-invasive determination that represents the person's ICP, or absolute ICP, or average ICP (or average absolute ICP) during a time period from an initial value to a final value. In some embodiments, this time period includes at least one systolic cardiac cycle and at least one diastolic cardiac cycle of the person. In certain non-limiting implementations, this time period includes at least two, or at least three, or at least five, or at least 10, or between 2 and 10, or between 2 and 20 systolic cardiac cycles and at least two, or at least three, or at least five, or at least 10, or between 2 and 10, or between 2 and 20 diastolic cardiac cycles.

[0062] In certain embodiments, a person's average ICP is obtained by noninvasively taking several measurements of ICP over a period of time (in any of the embodiments described herein) with gaps in between, and then averaging these noninvasive ICP measurements together to obtain the person's "average ICP" over the entire period (from the first to the last noninvasive measurement, including gaps in between). In one non-limiting example, a non-invasive ICP measurement is taken anywhere from 2 seconds to 2 minutes, and then some time may pass (whether 15 minutes, 30 minutes, or 1 hour, in this non-limiting example), after which a further non-invasive ICP measurement is repeated (preferably using the same method as used in the first non-invasive measurement). This can be repeated for any desired period of time, such as 30 minutes, 1 hour, 2 hours, or any other period required to obtain an average ICP. All of these non-invasive ICP measurements are then averaged together.

[0063] In some embodiments, (A) to derive and / or display the ICP waveform used to measure ICP, software magnification is used to increase the zoom of a selected image region, e.g., a 2-4 mm image of brain tissue at a depth of 2-17 cm from the surface of the head from the pulsating region, and observe the pulsation of brain tissue in that region synchronized with the cardiac rhythm, caused by the ultrasound energy gradient. In some embodiments, a fast Fourier transform is performed on the ultrasound signals from at least one of the brain tissue, cerebral blood vessels, and ventricle pulsations in the selected region to obtain the distribution of resonant frequencies in the spectrum. An inverse Fourier transform is then performed to generate a curve of cerebral pulsation, which can then be used to reconstruct, render, or derive a multi-axis volumetric curve of cerebral pulsation, e.g., in real time, with the ICP waveform.

[0064] In some embodiments, artificial intelligence is used to further process the ultrasound signals or to further process the transformed data resulting from application of a Fourier transform and / or a fast Fourier transform to such signals. In some embodiments, artificial intelligence may be used to derive a three-dimensional ICP waveform from signals generated from the two-dimensional ultrasound probe 20.

[0065] Once the ICP waveform is displayed on a device, such as a digital device, which may be a computer screen or the screen of a mobile communication device such as a smartphone, a pressure application device 40 (described below with reference to FIGS. 1-2B ) is activated, applying an initial pressure followed by a greater pressure to the external surface of the head, for example, in uniform stepwise increments. At some stage, the amplitude of the ICP waveform decreases. This may be the result of an increase in external pressure. The incremental increase in pressure is stopped when the signal amplitude remains stable with additional increases in applied pressure or when the amplitude decreases by a predefined percentage from the initial signal amplitude. In some embodiments, the amount of amplitude decrease induced by external pressure (and therefore the amount of external pressure required to reach that decreased amount) is proportional to ICP and dependent on the patient's skull resistance, and is therefore unique to each patient.

[0066] In some embodiments, the present invention is implemented using an apparatus comprising an US probe, a pressure application device, and a processor or computer comprising memory, a display device, and software, which may be, for example, a personal computer, a laptop or tablet computer, a smartphone, or a dedicated device configured to perform the method.

[0067] In some embodiments, device 10 includes a pressure mechanism 40 in communication with processing unit 30. The pressure mechanism may include a pressure applicator 42 configured to apply external pressure to the external surface of the head intermittently, for example, by applying an initial external pressure and then gradually increasing the external pressure applied to the external surface. In some embodiments, device 10 includes a pressure gauge 44, which may be any device or mechanism for measuring the externally applied pressure.

[0068] The external pressure can be applied in uniform, stepwise increments. In some embodiments, as shown in FIGS. 1, 2a, 2b, 4, and 5, the external pressure is applied bitemporally or in a coronal, axial, or oblique direction to each side of the person's head. In some embodiments of the device 10 (or method 100), "intermittently" means every second, or every three-quarters of a second, or every two seconds, or every one and a half seconds. In some versions, the time interval between the application of pressure is set to correspond to a known or expected time interval between pulsations of at least one of the brain tissue, cerebral blood vessels, and ventricles in the person's head whose ICP is being measured. Thus, in some embodiments, the intermittent application of external pressure is set to correspond to the time interval between two consecutive heartbeats of the person, or, for example, between corresponding portions of the person's heartbeat or cardiac rhythm (such as between diastolic or systolic portions). The person may have structures adjacent to the head for comfort and to facilitate maintaining the head in a stationary position—such structures are represented as rectangles in FIGS. 1 and 2a.

[0069] In one embodiment, as shown in Figure 4, a first group of pressure sensors 425, such as tensor sensors, are positioned to contact the person's skull at one point, and a second group of pressure sensors 425, such as tensor sensors, are positioned to contact the person's skull at a second point, with the first and second points being substantially 180 degrees apart. In some embodiments, for example, when there are three sensor groups, articulation 42A is used to ensure contact of the sensors with the subject's skull. The sensors may be held by or attached to plate 420.

[0070] Figure 4 shows an example where the first and second points are on two different sides of the skull and a plate 420 is used to hold a pressure sensor 425. Although air pressure is referred to as "ATM P(AP)" in Figure 4, air pressure is not used in determining mean ICP for reasons previously mentioned (air pressure is treated as zero). The present invention in certain embodiments is independent of variations in atmospheric pressure.

[0071] Figure 5 shows another example, with two distinct points at the front and back of the skull. Figure 5 shows various non-limiting examples of multiple contact points for plates 420 holding or attached to pressure sensors 425, including those configured diagonally. Each example in Figure 5 shows a single pair of plates 420, although in some embodiments there are multiple pairs of plates 420, for example, two, three, or more of the configurations shown in Figure 5 or Figure 4.

[0072] In another non-limiting embodiment shown in FIG. 6, a helmet 41A is worn by a patient, and between the outer wall 41B and the inner surface / wall 41C of the helmet 41A are balls 41D containing air or fluid. The balls 41D represent contact points against the patient's skull. In one embodiment, extending from each of the balls 41D on the helmet 41A is a tube connecting to a compressor 49. The compressor 49 is configured to fill the balls 41D to create pressure. In the non-limiting version shown in FIG. 6, multiple tubes may converge into a single tube before entering the compressor 49, and a pressure gauge 44 may be located there. The compressor 49 may include a processor 49A, or the compressor 49 may be in communication with the processing unit 30 so that the compressor 49 is instructed when to apply pressure and fill a pair of balls to apply external pressure.

[0073] In some embodiments, pressure mechanism 40 comprises one of: (a) a pressure applicator including an inflatable sleeve that is applied to the person's head, or (b) a helmet configured to apply pressure to specific locations on the person's skull.

[0074] In one embodiment shown in Figures 1, 2a, and 2b, a pressure application device 41 (see Figure 2A) includes two pressure application components 42, a mechanism 46 for incrementally increasing pressure, and a pressure gauge 44 attached to the patient's head with the pressure application components 42 on both sides of the patient's head, enabling bitemporal pressure application to the skull. The top graph in Figure 1 is an A-mode (one-dimensional) echo-EEG diagram. The bottom graph shows non-invasive (NI) ICP waves. The left side of the graph shows the NI ICP wave before external pressure is applied to the head, and the right side of the graph shows the NI ICP wave after pressure is applied. The downward arrow indicates where pressure is applied, causing a baseline elevation, phase shift, and amplitude decrease of the NI ICP wave. In a second embodiment of the present invention, shown in the top view of Figure 2A, the front view of Figure 2B, and a schematic diagram in Figure 3, measurements are performed using a steerable two-dimensional (2D) USB ultrasound probe 20 for 2D sector imaging of the brain (Figure 3). Scanning is performed at a low frequency of 1.5 to 2.5 MHz, providing good penetration of the ultrasound beam into the cranial cavity. In this embodiment, the ultrasound probe 20 is attached to the temporal region, and the same pressure application device 41 is attached to the head as in the first embodiment. Figure 3 shows a 2D ultrasound image 38 captured by the probe 20 described above and an ICP waveform 37 generated by the device from pulsations from region B. Referring to the ICP waveform in Figure 3, A1 is the initial amplitude signal when the pressure application device 41 begins to apply external pressure to the skull at point P. The pressure is gradually increased until it reaches a value P1, at which point the baseline rises, the waveform phase reverses, and the amplitude of the ICP waveform signal decreases. A2 is the signal amplitude when external pressure is no longer applied, and P2 is the pressure that causes the ICP waveform signal amplitude to change from A1 to A2. (A) ICP is calculated from the measured pressures (P1, P2) as follows: (A) ICP = (P2 - P1) mmHg

[0075] The mechanism for incrementally increasing pressure 46 can be provided in several different embodiments known in the art. For example, mechanism 46 can include a compressor 49 or a stepper motor and pistons that move air or another fluid through conduits to apply pressure to the head components 42 on either side. In some embodiments, there are multiple pistons, as is known in the art for controlled fluid dispensers such as syringes.

[0076] Certain embodiments of the pressure application device 41 include a compressor or motor, at least one piston movable within a housing, a fluid source, either liquid or gas, e.g., air, and an applicator 48 configured to engage the subject's head and hold the two pressure-application components 42 in place. The pressure-application device 41 may also include a manometer 44 (i.e., any device or mechanism for measuring externally applied pressure), which may be analog or digital. In certain embodiments, a digital manometer is used so that instantaneous pressure values ​​can be communicated to a processor or computer containing software algorithms configured to use output signals from the at least one ultrasound probe 43 and manometer 44 to interact with the compressor motor 47 (FIG. 4), determine when and how much fluid, e.g., air, should be delivered, and when to stop increasing the pressure. The applicator 48, which holds the two pressure-application components 42 in place on the subject's head, can take many forms, such as an elastic band, a Velcro strip, a headphone-like configuration, or a plastic or metal frame. With the exception of pressure application component 42, some or all of the other elements of pressure application device 41 may be attached to applicator 48 or may be located remotely to reduce the weight of applicator 48 and thereby increase patient comfort.

[0077] In some embodiments, the detection of ICP waveform compression (amplitude reduction) for a predetermined amplitude reduction is accomplished by (i) visual detection of the waveform by a user or (ii) automatic detection by a computer device. The computer or processor 30 includes a software algorithm configured to process data received from the US probe to generate an ICP waveform and an image processing algorithm configured to measure the amplitude of the waveform. The software within the device's computer or processor is configured to automatically stop increasing the pressure based on observing that increasing the pressure does not further reduce the amplitude of the ICP waveform, or when the amplitude has decreased by a predetermined percentage of the amplitude before external pressure was applied by the pressure application device 1.

[0078] In embodiments of the present invention, high pressure can be applied initially, resulting in a low-amplitude ICP waveform, and then gradually reduced until the baseline drops, the phase changes, and the amplitude increases. External pressure in the manner described above is applied bitemporally. However, the present invention is not limited to the pressure application method described above. Pressure can also be applied in one direction. Pressure application can also be performed by other mechanisms, such as (but not limited to) an inflatable sleeve attached to the patient's head, a helmet 41A with a pressure application option (FIG. 6), or a non-contact method of applying pressure via a high-velocity airflow, or any other method of controlled pressure application that meets the requirements of the present invention.

[0079] In one embodiment, shown in FIG. 10 , the present invention is a non-invasive method 100 for measuring (and / or recurrence monitoring for) mean intracranial pressure (ICP) in a person. Method 100 can include using at least one probe (e.g., probe 20) positioned adjacent to an outer tissue layer (e.g., a soft outer tissue layer) of the person's head to emit energy, e.g., ultrasound energy, radio waves, near-infrared energy, terahertz frequency energy, at pulsating brain tissue, cerebral blood vessels, and / or ventricles of the head, and receiving 110 reflected signals and / or images associated with the signals. In some embodiments, an ultrasound probe is used to emit ultrasound energy and generate an ultrasound energy gradient (e.g., cerebral ergography—CEG) between the emitted and reflected ultrasound signals to track these pulsations and / or generate images reflecting the pulsations and / or signals.

[0080] Another step 120 of method 100 may be to derive an ICP waveform from the signal (or from an image associated with the signal) using, for example, a processing unit including a hardware processor, software, and memory, the ICP waveform having a discernible amplitude, the fluctuations of which correspond to pulsations of at least one of the brain tissue, cerebral blood vessels, and ventricles of the head.

[0081] Method 100 may also include step 130 of intermittently applying external pressure to the external surface of the head using a pressure mechanism 40 in communication with processing unit 30. Mechanism 40 may include, for example, a pressure applicator and, in some versions, a pressure measurement component (commonly referred to as a manometer). In certain embodiments, pressure mechanism 40 is designed to apply an initial external pressure and then incrementally increase the external pressure on the external surface using the applicator. In certain embodiments of method 100, the application of external pressure in step 130 (or any portion thereof) is performed while step 110 is being performed, i.e., while at least one probe 20 is being used to generate signals, and / or in some versions, while step 120 is being performed, i.e., while processing unit 30 is being used to derive an ICP waveform from those signals (or images).

[0082] In some embodiments, method 100 may further include the step of processing unit 30 instructing pressure mechanism 40 to stop applying external pressure when, after a decrease in the amplitude of the ICP waveform, the amplitude reaches a final value A2 after a decrease (which may be the result of an increase in external pressure) beginning at an initial value A1. In certain embodiments, someone or something other than processing unit 30 stops or sends the command to stop applying external pressure to the person's head.

[0083] A further step 140 of method 100, in some embodiments, is determining, by a processing unit, the person's ICP from a sum or extrapolated sum of external pressures that begin to be applied at or after an initial value A1 and end by a final value A2, where one of the following is true: (i) the final value is a value whose amplitude remains stable with additional increases in the applied external pressure, and the processing unit is configured to determine the ICP from the sum of applied external pressures, or (ii) the final value A2 is a value to which the amplitude decreases from the initial value A1, the amplitude at which is toward but not at an amplitude that remains stable with additional increases in the applied external pressure, and the processing unit is configured to determine the ICP or estimated ICP by extrapolating the sum to the point where the amplitude remains stable with additional increases in the applied external pressure. In certain embodiments of method 100, processing unit 30 is also configured to detect an ICRS interim period and to detect any decrease in the amplitude of the ICP waveform that occurs after the ICRS interim period is completed.

[0084] One version of method 100 uses at least one probe adjacent to the head to emit signals at pulsating brain tissue, blood vessels, and / or ventricles (sometimes called brain tissue and / or brain cavities because blood vessels are also a type of tissue) in step 110, receives reflected signals, derives an ICP waveform from the signals in step 120, whose fluctuations correspond to the pulsating tissue, applies external pressure to the head in step 130, and determines the ICP from the sum or extrapolated sum of the external pressures during times when the amplitude of the ICP waveform decreases in step 140.

[0085] The method 100 of the present invention can be performed using any version of the device 10 described above. In some embodiments, the method 100 involves applying ultrasound energy using a steerable one-dimensional ultrasound probe (e.g., an A-mode one-dimensional echo-electroencephalography probe) placed on a person's forehead. The probe is aimed at an area in the brain where pulsation occurs. Such areas in the brain are at least one of the following: the third ventricle, the lateral ventricles, the thalamic striatal veins, and the central cerebral vein of the third ventricle, the edges of the third and lateral ventricles, the fourth ventricle, the choroid plexus veins of the ventricles, and cortical pulsation. In some embodiments, the one-dimensional ultrasound probe operates at a frequency of 0.5 to 1.5 MHz. In some versions, the ultrasound signal is aligned on a sagittal plane at 20 to 50 degrees relative to the horizontal (axial) plane. Measurements may alternatively (or simultaneously) be performed using a steerable two-dimensional (2D) ultrasound probe attached to the temporal region of the head and focused on an area in the brain where brain tissue pulsation occurs. The two-dimensional US probe can be operated at frequencies between 1.5 and 2.5 MHz.

[0086] The areas within the brain are either: the edge of the third ventricle, the central cerebral vein, and the thalamostriatal vein (or the third ventricle, lateral ventricle, thalamostriatal vein and central cerebral vein of the third ventricle, the edge of the third ventricle and lateral ventricle, the fourth ventricle, the choroid plexus veins of the ventricle, and the cortical pulsation).

[0087] In certain embodiments of the method 100, the external pressure is applied in uniform, stepwise increments. The external pressure may be applied to each side of the person's head in a bitemporal direction.

[0088] In some versions of method 100, the processing unit may be configured to extrapolate the sum using the ratio of A1 to the difference between A1 and A2, taking into account how many times external pressure was applied from time A1 to time A2.

[0089] In some versions of method 100, deriving the ICP waveform from the ultrasound signal is achieved by a fast Fourier transform performed on the brain pulsation in the region of the brain where the brain tissue pulsates to obtain the distribution of resonant frequencies in the spectrum, and an inverse Fourier transform is performed to reconstruct the curve of the brain pulsation, e.g., a multi-axis volume curve of the brain pulsation, e.g., to reconstruct, render, or derive a digital real-time pattern of the brain pulsation.

[0090] In one non-limiting embodiment of method 100, probe 20 is a steerable one-dimensional (1D) probe. FIG. 1 is a schematic diagram of a patient's head viewed from above. In this method, a 1D US probe 3 with a frequency of 0.5-1.5 MHz is applied to the patient's forehead and focused on the brain region to be analyzed, i.e., the region where brain tissue pulsation is observed, as shown in FIG. 1, such as the third ventricle 7, the central cerebral vein, or the thalamo-striatal vein. The signal is aligned on a sagittal plane at an angle of 20-50 degrees to the horizontal (axial) plane.

[0091] In some embodiments, the derivation of the ICP waveform is achieved by a fast Fourier transform performed on the brain pulsation in a selected region to obtain the distribution of resonant frequencies within the spectrum, and then an inverse Fourier transform can be performed to generate a curve of the brain pulsation, for example, in real time.

[0092] Yet another embodiment of the present invention is a device 10 for noninvasively measuring (and / or recursively monitoring) mean intracranial pressure (ICP) in a person's head, comprising at least one probe 20 (e.g., at least one ultrasound probe 20) positioned adjacent to an outer tissue layer of the person's head and configured to emit energy and receive reflected signals upon pulsation of one or more brain tissues, cerebral blood vessels, and ventricles of the person's head; a processing unit 30 configured to derive an ICP waveform (e.g., having a discernible amplitude) from the signals or from images associated with these signals; and a pressure mechanism 40 in communication with the processing unit 30 and configured to apply intermittent external pressure to the outer surface of the head. In some embodiments, the processing unit 30 is configured to detect a decrease in the amplitude of the ICP waveform, the decrease starting from an initial amplitude value A1 (e.g., as a result of increasing external pressure) and detecting a final amplitude value A2. In some embodiments, the processing unit 30 is configured to communicate a command to the pressure mechanism 40 to stop the external pressure when the amplitude reaches the final value, or such stopping can occur due to intervention by an operator or another component. In some embodiments, processing unit 30 is configured to determine the person's ICP from the sum of applied external pressures, or from an extrapolated sum of applied external pressures, for a period beginning at a time of initial value A1 and ending by a time of final value A2. In an embodiment, processing unit 30 is also configured to detect an ICRS interim period and to detect any decrease in the amplitude of the ICP waveform that occurs after the ICRS interim period is completed.

[0093] A further embodiment of the present invention is an apparatus for non-invasive measurement of a person's mean intracranial pressure (ICP), comprising at least one probe positioned on an exterior of the person's head and configured to radiate energy into pulsating tissue (e.g., pulsating one or more of brain tissue, cerebral blood vessels, and ventricles of the person's head) or cavities of the brain or head and receive reflected signals; a processing unit configured to derive an ICP waveform from the signals or from images associated with the signals; and a pressure mechanism in communication with the processing unit and configured to apply external pressure to the exterior of the head (and in some embodiments, measure the applied external pressure). The processing unit is configured to detect a decrease in the amplitude of the ICP waveform. The decrease has a beginning and an end point. The processing unit determines the ICP, such as the person's mean ICP, from a sum of the external pressures applied during the decrease, or from an extrapolated sum of the external pressures applied during the decrease.

[0094] Any implementation of at least one probe 20, processing unit 30, or pressure mechanism 40 described herein may be used in the apparatus 10.

[0095] Furthermore, the method 100 may be implemented using any version of the apparatus 10 mentioned in this patent application.

[0096] While the invention has been described with respect to a limited number of embodiments, it will be understood that the invention is susceptible to many variations, modifications, and other applications. Accordingly, the invention as set forth in the following claims is not limited to the embodiments described herein.

Claims

1. 1. An apparatus for non-invasively measuring intracranial pressure (ICP) in a human, comprising: at least one probe configured for placement adjacent to the person's head and for emitting energy at pulsating tissue or cavities within the brain and receiving reflected signals; a processor configured to derive an ICP waveform from the signal or from an image associated with the signal; a pressure mechanism in communication with the processor, the pressure mechanism being configured to apply an external pressure to the person's skull when a surface of the mechanism contacts the person's skull, the pressure mechanism comprising a manometer; the processor is configured to detect a decrease in amplitude of the ICP waveform occurring after one or more of a baseline shift, a phase shift, and completion of an intracranial reserve space (ICRS) intermediate period, the decrease starting from an initial amplitude value A1, and to detect a final amplitude value A2; The processor is configured to determine the person's ICP calculated as a function of the value of the applied external pressure beginning at or after the initial value A1 time and ending no later than the final value A2 time.

2. (i) the final value A2 is the value at which the amplitude reaches a predetermined absolute or relative amount with additional increases in the applied external pressure, or 2. The apparatus of claim 1, wherein (ii) the final value A2 is a value to which the amplitude is reduced from the initial value A1, the amplitude at the final value being toward but not reaching a predetermined absolute or relative amount, and wherein the apparatus is configured to determine ICP or estimated ICP with additional increases in applied external pressure.

3. The apparatus of claim 1 , wherein the at least one probe comprises an ultrasound probe configured to emit ultrasound energy and receive reflected signals.

4. 10. The device of claim 1, wherein the processor is configured to execute an image processing algorithm that measures at least three of a baseline, an amplitude value, a phase shift, and a change in resonant frequency of an ICP waveform.

5. 10. The apparatus of claim 1, wherein the at least one probe is a steerable one-dimensional ultrasound probe configured to be placed on the person's forehead and to focus on an area in the brain where brain tissue pulsates.

6. The apparatus of claim 5, wherein the one-dimensional ultrasound probe is configured to operate at a frequency of 0.5 to 1.5 MHz.

7. 6. The device of claim 5, wherein the region in the brain is at least one of the third ventricle, the lateral ventricles, the thalamic-striatal veins and the central cerebral veins of the third ventricle cavity, the edges of the third ventricle and lateral ventricles, the fourth ventricle, the choroid plexus veins of the ventricles, and the cortical pulsation.

8. 6. The apparatus of claim 5, wherein the signals are aligned on a sagittal plane at 20 to 50 degrees relative to the horizontal (axial) plane.

9. 10. The device of claim 1, wherein the at least one probe is a steerable two-dimensional USB ultrasound probe configured to be attached to the temporal region of the head or to obtain at least one of (i) axial slices, (ii) coronal slices, and (iii) oblique slices, and the two-dimensional USB ultrasound probe focuses on areas in the brain where pulsations occur in one or more of brain tissue, cerebral blood vessels, and ventricles.

10. 10. The apparatus of claim 9, wherein the two-dimensional USB ultrasound probe is configured to operate at a frequency of 1.5 to 2.5 MHz.

11. 10. The device of claim 9, wherein the region in the brain is one of the rim of the third ventricle, the central cerebral vein, and the thalamostriatal vein.

12. 10. The device of claim 1, wherein the external pressure is applied to both sides of the person's head in a bitemporal direction, or in a coronal, axial, or oblique direction.

13. 10. The device of claim 1, wherein the pressure mechanism comprises one of: (i) a pressure applicator including an inflatable sleeve that is applied to the person's head; or (ii) a helmet configured to apply pressure to specific locations on the person's skull.

14. 2. The apparatus of claim 1, wherein the processor is configured to derive the ICP waveform from signals derived from the one or more pulsating tissues in the brain using a fast Fourier transform performed on the signals to obtain a distribution of resonant frequencies in a spectrum, and an inverse Fourier transform is performed to generate a non-invasive ICP waveform of the one or more pulsating tissues.

15. The device of claim 1 , wherein the value of the external pressure increases incrementally.

16. 1. A non-invasive method for measuring intracranial pressure (ICP) in a human, comprising: using at least one probe configured to be placed on the person's head to emit energy into pulsating tissue or cavities within the person's brain and to receive reflected signals; deriving an ICP waveform from the signal or from an image associated with the signal using a processor; applying external pressure to the person's skull using a pressure mechanism in communication with the processor, the mechanism including a manometer, and a surface of the mechanism configured to apply external pressure to the person's skull upon contact with the person's skull; The method includes: detecting a decrease in the amplitude of an ICP waveform occurring after one or more of a baseline shift, a phase shift, and completion of an intracranial reserve space (ICRS) intermediate period, the decrease beginning from an initial value A1 of amplitude and detecting a final value A2 of the amplitude; and determining the person's ICP calculated as a function of the value of the applied external pressure beginning at or after a time of the initial value A1 and ending by a time of the final value A2.

17. One of the following is true: (i) the final value A2 is the value at which the amplitude reaches a predetermined absolute or relative amount with an additional increase in the applied external pressure, or 17. The method of claim 16, wherein (ii) the final value A2 is a value at which the amplitude is reduced from the initial value A1 such that the amplitude tends toward the initial value A1 but has not yet reached an amplitude that is a predetermined absolute or relative amount with additional increases in the applied external pressure.

18. 17. The method of claim 16, wherein the energy is applied using a steerable one-dimensional ultrasound probe that is placed on the person's forehead and focused on the area in the brain where the pulsations originate.

19. The method of claim 18, wherein the one-dimensional ultrasound probe is operated at a frequency of 0.5 to 1.5 MHz.

20. 19. The method of claim 18, wherein the region in the brain is at least one of the third ventricle, the lateral ventricles, the thalamic-striatal veins and the central cerebral veins of the third ventricle cavity, the edges of the third ventricle and lateral ventricles, the fourth ventricle, the choroid plexus veins of the ventricles, and the cortical pulsation.

21. 19. The method of claim 18, wherein the signals are ultrasound signals recorded on a sagittal plane at 20 to 50 degrees relative to the horizontal (axial) plane.

22. 17. The method of claim 16, wherein the energy is applied using a steerable two-dimensional (2D) ultrasound probe attached to the temporal region of the head or mounted to obtain at least one of (i) axial slices, (ii) coronal slices, and (iii) oblique slices, and the 2D probe is focused on regions in the brain where pulsations occur in one or more of brain tissue, cerebral blood vessels, and ventricles.

23. The method of claim 22, wherein the two-dimensional ultrasound probe is operated at a frequency of 1.5 to 2.5 MHz.

24. 23. The method of claim 22, wherein the region in the brain is one of the following: the rim of the third ventricle, the central cerebral vein, and the thalamostriatal vein.

25. 17. The method of claim 16, wherein the external pressure is applied in uniform, stepwise increments.

26. 17. The method of claim 16, wherein the external pressure is applied to both sides of the person's head in a bitemporal direction.

27. 17. The method of claim 16, wherein deriving the ICP waveform from the signals is achieved by a Fast Fourier Transform performed on the signals derived from the pulsations of the one or more of the brain tissue, cerebral blood vessels, and ventricles in the region within the brain where the brain tissue pulsates to obtain a distribution of resonant frequencies in a spectrum, and performing an Inverse Fourier Transform to reconstruct the ICP waveform from the pulsations.

28. 17. The method of claim 16, wherein the value of the external pressure is increased incrementally.

29. 1. An apparatus for non-invasive measurement of intracranial pressure (ICP) in a human, comprising: at least one probe configured to be positioned to emit energy at pulsating tissue or cavities within the brain and receive reflected signals; a processor configured to derive an ICP waveform from the signal or from an image associated with the signal; a pressure mechanism in communication with a processor, the pressure mechanism configured to apply external pressure in graduated increments to the person's skull using at least one surface of the pressure mechanism; the processor is configured to detect a decrease in amplitude of the ICP waveform occurring after one or more of a baseline shift, a phase shift, and completion of an intracranial reserve space (ICRS) intermediate period, the decrease starting from an initial amplitude value A1, and to detect a final amplitude value A2; The processor is configured to determine the person's ICP by calculating it as a function of the value of incremental steps of applied external pressure starting at or after an initial value A1 and ending no later than a final value A2.

30. 30. The apparatus of claim 29, wherein the at least one probe comprises an ultrasound probe configured to emit ultrasound energy and receive reflected signals.

31. 30. The apparatus of claim 29, wherein the processor is configured to execute an image processing algorithm that measures at least three of the following: baseline, amplitude, phase shift, and change in resonant frequency of the ICP waveform.

32. 30. The apparatus of claim 29, wherein the at least one probe is a steerable one-dimensional ultrasound probe configured to be placed on the person's forehead and to focus on an area in the brain where brain tissue pulsates.

33. 33. The apparatus of claim 32, wherein the one-dimensional ultrasound probe is configured to operate at a frequency of 0.5 to 1.5 MHz.

34. 33. The device of claim 32, wherein the region in the brain is at least one of the third ventricle, the lateral ventricles, the thalamic-striatal veins and central cerebral veins of the third ventricle cavity, the edges of the third ventricle and lateral ventricles, the fourth ventricle, the choroid plexus veins of the ventricles, and the cortical pulsation.

35. 33. The apparatus of claim 32, wherein the signals are aligned in a sagittal plane at 20 to 50 degrees relative to the horizontal (axial) plane.

36. 30. The apparatus of claim 29, wherein the at least one probe is a steerable two-dimensional USB ultrasound probe configured to be attached to the person's temporal region or to obtain at least one of (i) axial slices, (ii) coronal slices, and (iii) oblique slices, and the two-dimensional USB ultrasound probe focuses on areas in the brain where pulsations occur in one or more of brain tissue, cerebral blood vessels, and ventricles.

37. 37. The apparatus of claim 36, wherein the two-dimensional USB ultrasound probe is configured to operate at a frequency of 1.5 to 2.5 MHz.

38. 37. The device of claim 36, wherein the region in the brain is one of the rim of the third ventricle, the central cerebral vein, and the thalamostriatal vein.

39. 30. The device of claim 29, wherein the external pressure is applied to both sides of the person's head, in a bitemporal direction, or in a coronal, axial, or oblique direction.

40. 30. The apparatus of claim 29, wherein the pressure mechanism comprises one of: (i) a pressure applicator including an inflatable sleeve that is applied to the person's head; or (ii) a helmet configured to apply pressure to specific locations on the person's skull.

41. 30. The apparatus of claim 29, wherein the processor is configured to derive the ICP waveform from the signal by a Fast Fourier Transform performed on cerebral pulsations in a region in the brain where brain tissue pulsates to obtain a distribution of resonant frequencies in a spectrum, and an inverse Fourier transform is performed to generate a non-invasive ICP waveform of the cerebral pulsations.

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