Patent Grant
11880989
The present invention relates to methods for imaging an abnormality of vascular reactivity, for example, cerebrovascular reactivity (CVR), broadly defined as an abnormality in a vascular response relative to a control population, as evident from high resolution imaging.
The measurement of cerebrovascular reactivity (CVR), whereby a strong vasoactive stimulus is applied to expose occult clinical limitations in regional cerebral blood flow (CBF) reactivity constitutes a cerebrovascular stress test. Quantitatively, CVR is defined as the change in CBF in response to a measurable stimulus. A surrogate high resolution measure of changes in CBF can be obtained by exploiting the Blood Oxygen Level Dependent (BOLD) effect of magnetic resonance imaging (MRI); and a measurable increase in the end-tidal (end-exhaled) partial pressure of CO2 (PETCO2) may be used as a surrogate measure for the true independent stimulus, the partial pressure of CO2 in arterial blood (PaCO2). CVR is can then optionally be defined as the percent change in BOLD signal (arbitrary units) per mmHg change in PaCO2. CVR values can be color coded and superimposed, on the corresponding voxel on an anatomical scan to generate CVR maps. Of particular interest in the CVR maps are the detection of areas of paradoxical reductions in flow following the application of a vasodilatory stimulus, termed ‘steal’. Steal has been shown to exist in deep white matter in healthy people [Mandell, 2008] as well as associated with pathology such as arteriovenous malformations [Fierstra, 2011], vasculitis [Han, 2008], steno-occlusive vascular disease [Han, 2011]; and associated with disease in the form of cortical thinning [Fierstra, 2010], cognitive decline [Balucani, 2012; Silvestrini, 2011], and enhanced risk of stroke [Silvestrini, 2000; Markus, 2001].
Whereas the presence of steal is highly specific for identifying compromised CVR, the absence of steal does not necessarily imply normal CVR. For example, CVR may be considerably reduced, but steal is absent if the stimulated demand fails to exceed its supply capacity. Alternatively, if the reduction of CVR is widespread and uniform, rather than localized, a differential in vasodilatory capacity between vascular territories may not exist and therefore, steal may not occur [Sobczyk 2014]. Steal may also not occur if compromised vessels maintain greater than some threshold vasodilatory reserve. Under these conditions, the absolute value of CVR may be less than ‘normal’ but the extent of reduction cannot be assessed unless the normal range of CVR is known for each anatomical location.
The range of CVR in healthy subjects is large and varies from region to region. Thus, even substantial reductions in CVR in one region will overlap with normal values in another resulting in difficulty in distinguishing reduced CVR due to pathophysiology from normally low CVR. Because the interpretation and assessment of CVR maps currently relies on subjective assessments, it is difficult to identify reduced CVR short of that causing ‘steal’.
Currently however, the interpretation and assessment of CVR maps relies on a qualitative review of possible abnormalities, viewed as inhomogeneities in the CVR maps that appear to differ from the CVR maps of healthy individuals. Such qualitative comparisons require considerable experience for correct interpretation; areas where blunted CVR is present may be misinterpreted as healthy responses.
We describe a method of assessing the severity and distribution of an abnormality or reduction in a subject's vascular response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain.
The vasoactive stimulus is in the form of at least one change in a subject's arterial partial pressure of carbon dioxide (each arterial partial termed a PaCO2T). Measured PetCO2 values are used as a surrogate measure of the true stimulus.
The targeted PaCO2T(s) is maintained during the course of obtaining input of MR signals. Accordingly, the stimulus is standardized, allowing the severity and distribution of abnormal or reduced vascular response values to be assessed by using statistical scores such as z scores which reveal the severity and distribution of abnormal or reduced surrogate measures of blood flow as revealed by MRI.
According to one aspect, the invention is directed to method of assessing the severity and distribution of an abnormality or reduction in a subject's vascular response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain.
An MRI scanner and a selected MR imaging protocol are used to generate for members of a group of control subjects, a set of vascular response signals representing a non-pathological vascular response to at least one change in the subject's arterial partial pressure of carbon dioxide (each arterial partial pressure of carbon dioxide a PaCO2T) in at least one common ROI of each control subject's brain.
It will be appreciated that the control group need not represent a non-pathological response since any type of status/criterion/parameter can be controlled for for the purposes evaluating a test subject.
The vascular response is quantifiable, from a surrogate measure of blood flow, on a voxel by voxel basis, with reference to the voxel coordinates, from MR signals corresponding respectively to each PaCO2T in the form of a response value per voxel.
The control subject's respective voxel coordinates are co-registered to a standardized space based on a set of anatomic landmarks.
A measure of variability of the vascular response values are computed on a voxel by voxel basis. The vascular response values measure at least one of the amplitude of the vascular response and the time course of the vascular response.
For example, a mean and standard deviation of the vascular response values for voxels corresponding to the at least one ROI are computed to define, for the control group as a whole, a set of statistical values respectively associated with individual voxels corresponding to the ROI (an atlas).
The MR scanner and the selected MR imaging protocol are used to obtain MR signals per voxel corresponding to the surrogate measure of blood flow for each PaCO2T for a test subject.
By scoring (e.g. as z values) the test subject's response values for individual voxels in the at least one ROI (each voxel co-registered to the standardized space based on the set of anatomic landmarks), relative to the respective computed statistical values e.g. means and standard deviations per corresponding voxel, the severity and distribution of the abnormal or reduced vascular response is revealed.
The method may be implemented using a MR scanner and a stand alone CPU or dedicated MR image processor.
The processor obtains input of the “abnormal voxel” (pre-defined or user defined via a user interface) coordinates and scores.
The processor may employ program code to define a new to ROI.
The processor may employ program code to compare the scores to a threshold value.
The processor may employ program code to compare the scores to scores associated with a disease.
According to another aspect, the invention is directed to an imaging system for detecting an abnormality in a subject's response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain. The vascular response values may measure at least one of the amplitude and time course of the vascular response.
In one embodiment, the imaging system comprises an MR scanner configurable, using a pre-selected MR protocol, to capture spatially resolved MR signals corresponding to the subject's vasoactive response to a standardized cerebrovascular stimulus comprising at least one targeted change in the subject's arterial partial pressure of carbon dioxide (each arterial PCO2 a PaCO2T). Optionally, at least one PaCO2T is attained from an initial steady state PaCO2 value. Optionally, the at least one change in PaCO2 is at least one of a series of increments or decrements in the subject's arterial partial pressure of carbon dioxide.
The imaging system also comprises a computer programmed to obtain input of the MR signals and implement an algorithm for analyzing the MR signals with reference to a pre-determined surrogate measure of blood flow in the at least one ROI, the pre-determined surrogate measure of blood flow optionally quantifying at least one of the amplitude of the subject's vascular response and a time constant of the subject's vascular response to the at least one PetCO2T (at least one change from a steady value or two targeted values) The algorithm includes program code for processing the MR signals with reference to the selected surrogate measure of blood flow for each PetCO2T including computing a vasoactive response value per voxel, each voxel co-registered into a standardized space, and scoring the subject's vascular response values for respective individual voxels in the ROI, relative to statistical reference values, optionally using scores, for example z scores.
The imaging system optionally includes a user interface operable to initiate the aforesaid algorithm and optionally to map the scores back onto an anatomical representation of the standardized space to generate a statistical map of the subject's vascular response to a standardized cerebrovascular stimulus, wherein the probability that subject's vascular response to the standardized cerebrovascular stimulus is pathological is depicted, on a voxel by voxel basis, on the statistical map (e.g. a z map) for example using a color scheme wherein different colors are assigned to different scores such that each color pixel is mapped onto its anatomical 3 dimensional origin. The probability that the vascular response is part of the normal range may be represented by a z score, where high z scores represent lower probability that they are in the normal range and correspondingly higher probability of resulting from underlying pathology.
The reference values are a measure of the amount and variability of the vasoactive response and optionally comprise a mean and standard deviation of vascular response values per voxel for a corresponding ROI in a group of control subjects, the vascular response values generated using the pre-selected MR protocol for each same PaCO2T and quantifying, on a voxel by voxel basis, the statistical scores e.g. the mean and standard deviation of the selected surrogate measure of blood flow (amplitude or tau or both). The vascular response values are generated from a set of MR signals corresponding to the control subjects' respective vascular responses per voxel, the respective voxel coordinates per subject co-registered to a standardized space based on a set of anatomic landmarks.
The MR scanner captures MR signals from the brain, as surrogates of brain blood flow, wherein the change in signal corresponds to the subject's vasoactive response to the stimulus. The stimulus is standardized with respect to strength preferably via induction of at least two levels of arterial partial pressure of carbon dioxide (PaCO2), at least one of which is hypercapnic, or greater than the baseline resting level of the subject, and the level of which can be determined directly by arterial blood sampling or noninvasively by its surrogate, the end tidal, or end exhaled partial pressure of carbon dioxide.
For example, where the MR signals quantify the subject's vasoactive response to each of a series of targeted increments in the subject's end tidal partial pressure of carbon dioxide, each a PetCO2T, the reference values include a statistical summary of the control subjects' respective vascular response values to each PetCO2T.
Optionally, the images represent a change in the blood oxygen level dependent (BOLD) effect of a MR response to a targeted change in a subject's end tidal PCO2 (P
Optionally, the images depict a change in the blood flow as measured by arterial spin labeling MR response to a targeted change in a subject's end tidal PaCO2.
Optionally, the program code is operable on a dedicated image processor connected to or forming part of the MR scanner hardware. Alternatively, the MR signals are recorded in a file, optionally a file according to the DICOM standard and processed by a separate computer.
Optionally, the statistical scores are optionally further compared to threshold values per voxel associated with a particular disease, on a voxel by voxel basis.
The statistical scores e.g. z scores may be used to identify a new ROI, for example a smaller ROI within an ROI of the subject's brain that was of interest, a priori, in virtue of the pathology being assessed or in virtue of a prior, concurrent or later assessment. Optionally, the algorithm includes program code for identifying the new ROI.
In another aspect, the invention is directed to a computer program product comprising program code/instructions for executing the above-described algorithm, and optionally the reference values and/or program code for accessing the computer remotely to compare a subject's MR signals corresponding to the selected surrogate measure of blood flow with reference values and same targeted arterial partial pressures of carbon dioxide. Optionally, the computer program product comprises program code for producing a color coded statistical map and/or program code for identifying a new ROI.
In another aspect, the invention is directed to a non-transitory computer readable medium comprising program code for executing the above-described algorithm, and optionally the reference values and/or program code for accessing the computer remotely to compare a subject's MR signals corresponding to the selected surrogate measure of blood flow with reference values and same targeted arterial partial pressures of carbon dioxide. Optionally, the computer program product comprises program code for producing a color coded statistical map and/or program code for identifying a new ROI.
In one embodiment the reference scores are part of an atlas prepared for each a series of targeted increments in a subject's arterial partial pressure of carbon dioxide.
Thus, according to another aspect, the invention is directed to a method of characterizing an abnormality in a subject's vascular response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain comprising the steps of:
Optionally, the method further comprises the step of color-coding the z values and mapping the color-coded values back onto an anatomical representation of the standardized space to produce a z map. The invention is also directed to such z maps and their use as a diagnostic tool.
Optionally, the co-registered MR images are full brain images defining a substantially full set of potential ROIs.
Optionally, the standardized cerebrovascular stimulus is a vasodilatory stimulus.
Optionally, the vasodilatory stimulus is at least one targeted increase in the subject's end tidal PCO2, optionally from a steady state PetCO2 or a previously targeted value.
Optionally, the stimulus is a series of increment or decrements in a subject's arterial partial pressure of carbon dioxide (a so-called ramp sequence).
Optionally, the reference values in an atlas are generated using a ramp sequence.
As described below, statistical maps such as z maps can be used to interpret interval differences and values for gain, phase and coherence emerging from a transfer function analysis.
Optionally, the images represent a change in a blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) response to a targeted increase in a subject's end tidal PCO2 (P
Optionally, the set of control subjects are selected on the basis that they report being free of neurological disease.
Optionally, the control subjects are matched for a parameter that is appropriate for the condition being examined in a patient. The term patient is used broadly to define a subject being tested with reference a selected control population.
Optionally, the set of control subjects are matched for at least one of age and gender.
According to one embodiment, the invention is directed to a method of assessing the severity and distribution of an abnormality or reduction in a subject's vascular response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain, comprising the steps of:
In one embodiment, the method excludes the MR scans (for one of or for both the test and control subjects) and optionally also excludes preparation of the reference value atlas from the MR signal data (DICOM), the method comprising, for example, the steps required to compute z scores, namely: (a) obtaining input of the test subject's vascular response values per voxel; (b) obtaining input of the statistical values per voxel (the reference values); and (c) computing the z values.
The reference values comprise statistical values, for example, a mean and standard deviation of respective control subject's vascular response values per voxel for a corresponding ROI in each member of the group of control subjects, the reference values and the test subject's vascular response values per voxel derived from MR signals obtained from an MR scanner using a pre-selected MR protocol and including respective voxel coordinates co-registered to a standardized space based on a set of anatomic landmarks; the vascular response values corresponding to and quantifying an individual subject's (control or test subject) vascular response to at least one change in the individual subject's arterial partial pressure of carbon dioxide (each arterial partial pressure of carbon dioxide a PaCO2T) in at least one common ROI of each individual subject's brain, wherein the vascular response is quantified, from a surrogate measure of blood flow, on a voxel by voxel basis, the MR signals quantifying at least one of the amplitude of the individual subject's vascular response and a time constant of the individual subject's vascular response to the each PaCO2T, wherein the scores e.g. z scores, identify the severity and distribution of an abnormality or reduction in the test subject's vascular response to the vasoactive stimulus.
After obtaining input of the test-subject's vascular response values corresponding to at least one region of interest (ROI) of the test subject's brain, obtaining input of reference values for each voxel in the ROI (an atlas) for a group of control subjects (e.g. by interrogating a database), and scoring the test subject's vascular response values for respective individual voxels in the ROI, relative to the corresponding reference values per voxel using the scores, the scores and voxel coordinates may be compared to a threshold value, for example to define the extent and distribution of an abnormality.
Optionally, the vascular response values are a measure of a delay in vascular response to the at least one change in the subject's arterial partial pressure of carbon dioxide, wherein at least one statistical value is determined for each respective voxel using a transfer function analysis. For example, a polynomial function may be computed to match the MR signals constituting the vascular response.
Optionally, the at least one statistical value is tau, a standardized transfer function analysis for all subjects optionally employing a mono-exponential dispersion function to generate an atlas of tau values.
Optionally, the atlas response values are rank ordered on a voxel by voxel basis. For example, the test subject response values per voxel are assigned a rank score following the rank order to generate a rank score map.
Optionally, a log transformation of the respective (voxel by voxel) vascular response values for the individual control subjects shows that the values are generally normally distributed. The individual control subject vascular response values and patient vascular response values are transformed, on a voxel by voxel basis, by taking the log of the values, and wherein a mean and SD of the control subjects respective vascular responses log transformed values is computed on a voxel by voxel basis to generate an atlas, and wherein the patient's respective vascular responses log transformed values are respectively scored with a z value.
Optionally, the method further comprises the step of color coding the scores and mapping the color-coded scores back onto an anatomical representation of the standardized space.
Optionally, the test subject and the control subjects are each scanned on one occasion to obtain a set of response values per voxel (A) and then each re-scanned at least once after an interval to obtain another set of response values per voxel (B). Optionally, a voxel mean and standard deviation with respect the quantum and variability of the respective differences (e.g. consistently A image values per voxel minus B image values per voxel, or consistently B image values minus A image values) between the test and re-test vascular response values for the control group of subjects, wherein the differences between the patient's test response and re-test response for respective voxels corresponding to the at least one ROI are scored, relative to the voxel means and standard deviations (optionally the means and standard deviation per voxel of the respective computed differences), using z values.
Thus, according to another aspect, the invention is directed to a method of assessing the severity and distribution of an abnormality or reduction in a subject's vascular response to a vasoactive stimulus, in at least one region of interest (ROI) of the subject's brain, comprising the steps of:
In one embodiment, the method excludes the scans (test and control subjects) and optionally also excludes preparation of the reference value atlas, the method comprising the steps required to compute z scores, namely: (a) obtaining input of the A and B values per voxel (or at least the differences per voxel) for the test subject; (b) obtaining input of means and standard deviations per voxel of the differences between the A and B scores for the control group (the reference values); and computing the z values.
Optionally, the method further comprises the step of color-coding the z values and mapping the color-coded values back onto an anatomical representation of the standardized space to produce a z map.
Optionally, the co-registered voxel coordinates represent full brain images defining a substantially full set of potential ROIs.
Optionally, the standardized cerebrovascular stimulus is a vasodilatory stimulus. A vasoactive stimulus can optionally be a vasoconstrictive stimulus
Optionally, the vasodilatory stimulus is at least one targeted increase in the subject's end tidal PCO2 relative to an steady state baseline PaCO2 or a previous targeted value which may optionally be an initial reduction in PCO2.
Optionally, the images represent a change in a blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) response to a targeted increase in a subject's end tidal PCO2 (P
Optionally, the set of control subjects are selected on the basis that they report being free of neurological disease.
Optionally, the set of control subjects are matched for at least one additional parameter that that defines a preferred subset of control subjects for the patient population for whom an assessment of an abnormality in vascular response is needed.
Optionally, the set of control subjects are matched for at least one of age and gender.
Optionally, the set of control subjects are selected on the basis that they report being non-smokers.
In another aspect, the invention is directed to a reference atlas of response values as generated in any manner defined above using a series of increments in a subject's arterial partial pressure of carbon dioxide as a stimulus, and to the use of such an atlas as a diagnostic tool in aiding of diagnosing a condition associated with an abnormal vascular response, for example a vascular disease or disease manifesting an abnormality in a vascular response. Optionally, the atlas is generated using a sequential gas delivery circuit (physical or virtual) wherein end tidal partial pressure of carbon dioxide are used as surrogates for targeted arterial partial pressures of carbon dioxide.
According to another aspect, the invention is directed to a neuro-imaging assessment method in aid of diagnosing at least one of the existence, location, deterioration and amelioration of a brain disorder associated with abnormal vascular reactivity (i.e. any abnormal vascular response including an abnormality in the amplitude and/or time course of the response), for example a cerebrovascular disorder.
The neuro-imaging assessment protocol of the present invention, including any permutations of the steps defined above or below, enables images to be produced from which such diagnostic assessments may be carried out and/or confirmed. According to one embodiment the invention, the organ is brain and the invention provides a novel cerebrovascular reactivity assessment protocol for producing a reference atlas, for example an atlas of non-pathological cerebrovascular reactivity.
Accordingly in a further embodiment, the invention provides for a method and for the use such an atlas of non-pathological cerebrovascular reactivity to produce brain imaging results e.g. neuro-imaging results from which a subject in need of assessment of abnormal cerebrovascular reactivity can be assessed for the abnormality. The method optionally comprises producing a reference atlas and comparing voxel by voxel test vascular response value of a patient to the corresponding reference atlas value by scoring those values, preferably in a manner that accounts for relative departure of the test value from a quantity describing a characteristic value (e.g. mean/SD for normal distributions of value or normal distributions of log values) such as to account for the variability or distribution of the control values.
According to another aspect the invention is directed to a diagnostic tools in the form of a neuro-image and other visual depictions such as graphs derived from such images that incorporate statistical transformations of MR signals generated in response to at least one targeted change in a subject end-tidal PCO2. According to one embodiment the invention is directed to a cerebrovascular reactivity response map e.g. in the form a z map, tau z map or ID z map as described herein.
For example, according to one embodiment the organ is brain and the invention is directed to a diagnostic tool comprising color-coded z values mapped onto an anatomical representation of a standardized 3D map of at least one region of interest (ROI) of the brain, the z values and 3D map characterized in that a standardized set of MR imaging protocols are employed to generate for members of a group of control subjects, a set of CVR response signals depicting a non-pathological CVR response, in at least one common ROI of each control subject's brain, wherein the CVR response is a reaction to a standardized vasoactive stimulus, and wherein the CVR response is quantifiable from images corresponding to the response signals, on a voxel-by-voxel basis, in the form of CVR response value per voxel; and wherein
Optionally, z values can be generated for test subjects that are based on a measurement of a plurality of CVR test values, on a voxel by voxel basis, for each respective control subject. Multiple CVR values per control subject are obtained from a plurality of imaging tests generated using a standardized stimulus and therefore reflect expected test/re-test variability in CVR measurements. The successive tests are preferably conducted on different days and optionally at different times of day, such that the plurality of variant values reflect primarily the inevitable variations corresponding to normal variations in physiology and in the technology (even despite using a single scanner), over time. The different values may also reflect in minor part differences due to other categories influences (e.g. unidentified sources of small variation or, identifiable sources of small variation of the type not generally subject to practical control).
The standard CVR atlas may reflect this retest values in the means and standard deviation per voxel. Alternative the probative value of such re-test values can be accentuated by generating a specialized reference atlas (an Interval Difference atlas) in which the control group means and standard deviations are calculated with respect to intra-subject differences e.g. say between the two test values for a subject which are subtracted from one another. The intra-subject test/re-test variability, however quantified or accounted for, both from an intra-control subject perspective and across a group of control subjects, is important for assessing a patient's change in CVR per voxel against a backdrop of normal re-test variability.
These so-called Interval Difference (ID) variations may be used to compute ID z values for a given control or diseased subject, and for creating for the group of subjects, an atlas of test-retest value differences, on a voxel by voxel basis. This enables an attribution of the statistical probability that changes in CVR to true interval change in pathophysiology. Optionally resulting ID-z values may be as reference maps to monitor progression of the disease over time or responses to treatment.
Optionally, the standardized cerebrovascular stimulus is a vasodilatory stimulus.
Optionally, the method is used in aid of diagnosing a neurological disorder
Optionally, the vasodilatory stimulus is a surrogate measure of the subject's arterial PCO2 (PetCO2), the surrogate measure optionally an end tidal partial pressure of carbon dioxide measured on a breath by breath basis. The stimulus is preferably controlled by targeting at least one increase (relative to a subject's baseline steady state value or a previously targeted value), in a subject's end tidal PCO2.
As described herein, in any of the methods the standardized stimulus optionally provides for a subjects baseline PetCO2 to be increased to a targeted value and returned to baseline, and optionally increased again to the same targeted value. Variations on such standardized protocols would be apparent to those skilled in the art of manipulating arterial blood gases.
Several surrogate measures of cerebral blood flow (CBF) are known to persons skilled in the art.
Optionally, the images represent a change in a Blood Oxygen Level Dependent (BOLD) magnetic resonance imaging (MRI) response to a targeted increase in a subject's end tidal PCO2.
Optionally, the images depict a change in the blood flow as measured by arterial spin labeling MR response to a targeted change in a subject's end tidal PaCO2.
The control subjects are preferably free of neurological disease and optionally also non-smokers.
Optionally, the control subjects are age and/or gender matched.
The subjects can be matched with respect to a wide variety of parameters including underlying disease, the use or non-use of certain medications etc.
The z maps or ID standardized z values are optionally employed for the detection of areas of paradoxical reductions in blood flow following the application of the vasodilatory stimulus (‘steal’). In the same connection, parallel increases in blood flow elsewhere may also be indicative of an abnormality in a vascular bed.
Optionally, for non-parametric data one can rank order the voxel value in the reference atlas and then score the test voxel in terms of rank. Also, data can be transformed by taking the log of a measure and tested for normal distribution. If the logs are normally distributed, then the mean and SD of the logs are computed. The test voxel is then also transformed to log value and then scored with a z value.
In a further general aspect, the invention is directed to a method of using blood flow correlated high resolution imaging signals for characterizing an abnormality in a vascular response to a standardized vasoactive stimulus in at least one region of interest (ROI) in an organ, the method comprising the steps of:
Optionally, the method further comprises the step of color-coding the scores and mapping the color-coded scores back onto an anatomical representation of the standardized space to produce a vascular response map of the at least on ROI.
Optionally, the scores are z-scores and wherein the map is a z-map.
Optionally, the organ is brain.
Optionally, the high resolution imaging device is an MRI device, wherein the co-registered images are magnetic resonance images.
Optionally, the co-registered MR images are full brain images defining a substantially full set of potential ROIs.
Optionally, the standardized cerebrovascular stimulus is a vasodilatory stimulus.
Optionally, the vasodilatory stimulus is at least one targeted increase in the subject's end tidal PCO2 from a steady state PetCO2.
Optionally, the images correspond to signals representing a change in a blood oxygen level dependent (BOLD) MRI response to a targeted increase in a subject's end tidal PCO2 (P
Optionally, the vascular response values are a measure of a delay in the vascular response to the standardized vasoactive stimulus, the at least one statistical value determined for each respective voxel using a standardized transfer function analysis wherein a polynomial function is computed to match the vascular response signal data.
Optionally, the at least one statistical value is tau, the standardized transfer function analysis employing a mono-exponential dispersion function (exemplified herein) to generate an atlas of tau values.
Optionally, the atlas response values are rank ordered on a voxel by voxel basis and wherein the corresponding patient response values are assigned a rank score following the rank order to generate a rank score map.
Optionally, a log transformation of the respective (voxel by voxel) vascular response values for the individual control subjects shows that the values are generally normally distributed and wherein the individual control subject vascular response values and patient vascular response values are transformed, on a voxel by voxel basis, by taking the log of the values, and wherein a mean and SD of the control subjects respective vascular responses log transformed values is computed on a voxel by voxel basis to generate an atlas, and wherein the patient's respective vascular responses log-transformed values are respectively scored with a z value.
Optionally, each of the members of the group of control subjects are selected to represent healthy individuals exhibiting a non-pathological vascular response to the standardized vasoactive stimulus in the at least one ROI. Alternatively, the control group can be represented by any number of different criteria.
According to another aspect, the invention is directed to a neuro-imaging assessment method in aid of diagnosing at least one of the existence, location, deterioration and amelioration of a brain disorder associated with abnormal vascular reactivity, for example a cerebrovascular disorder.
The neuro-imaging assessment protocol of the present invention, including any permutations of the steps defined above, enables images to be produced from which such diagnostic assessments may be carried out and/or confirmed. According to one embodiment the invention provides a novel cerebrovascular reactivity assessment protocol for producing an atlas of non-pathological cerebrovascular reactivity. Accordingly, in a further embodiment, the invention provides a method of using such an atlas of non-pathological cerebrovascular reactivity to produce neuro-imaging results from which a subject in need of assessment of abnormal cerebrovascular reactivity can be assessed for the abnormality.
According to another aspect the invention is directed to a diagnostic tool in the form of a neuro-image and other visual depictions such as graphs derived from such images that incorporate statistical values derived from MR signals generated in response to at least one targeted change in a subject's end-tidal PCO2.
According to one embodiment the invention is directed to a cerebrovascular reactivity response map in the form a z map or ID z map, or tau z map as described herein.
For example, according to one embodiment the invention is directed to a diagnostic tool comprising color-coded z values mapped onto an anatomical representation of a standardized 3D map of at least one region of interest (ROI) of an organ e.g. brain, the z values and 3D map characterized in that a standardized set of imaging protocols are employed to generate for members of a group of control subjects, a set of vascular response signals depicting a non-pathological CVR response, in at least one common ROI of each control subject's organ of interest, wherein the vascular response is a reaction to a standardized vasoactive stimulus, and wherein the vascular response is quantifiable from images corresponding to the response signals, on a voxel-by-voxel basis, in the form of vascular response value per voxel;
According to another aspect the invention is directed a method of assessing the severity and distribution of an abnormality or reduction in a test subject's vascular response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain, comprising the steps of:
The distribution of changes in both positive and negative directions consistent with the history, and the magnitude of voxelwise divergence in interval differences from the sample ID atlas, establish that these changes were not due to technical or physiologic variability.
Co-registration of such maps for a reference cohort (sometimes described herein as a healthy or normal cohort) is accomplished as described below.
Means and SD are computed and then a z map is generated for our test subject of gain and lag phase. Theoretically, these values should correspond to CVR and T respectively.
The approach as illustrated in
A reference atlas can be made for each the vascular response values exemplified herein, the values matched to a set of particular targeted arterial partial pressures of carbon dioxide. For example, the reference atlases can be made from τ and phase lag, for amplitude of CVR, for interval differences etc. Each can be used to generate a z map.
The terms “vasoactive response” and “vascular response” are used interchangeably.
The term “co-register” means transforming image data onto common coordinates of a standard brain using an alignment algorithm that standardizes brain size while optimizing alignment of a set of key anatomical structures.
The term “vascular reactivity” and the related term cerebrovascular reactivity (CVR) is used broadly to refer any vascular response to a standardized vasoactive stimulus, which vascular response may be a change in amplitude of the response, the time course of the response etc. Vascular response values may be a measure of the amplitude of the response (i.e. a measure of amplitude alone, wherein amplitude is revealed, for example, by allowing 3 time constants in the progress of the response to be attained before modifying the PaCO2T or where a ramp stimulus is employed e.g. equal size increments in PaCO2T and equal time intervals, the true amplitude of the response will be substantially revealed where, for example, two time constants in the progress of the response are attained before the next incremental change in PaCO2T.
A user may prospectively or retrospectively define a voxel as “abnormal” with reference to at least one of: (1) the size of the vasoactive stimulus or change in stimulus (e.g. the degree of upward departure of the PaCO2T from a normal baseline value for the subject) used to reveal the abnormality; (2) the size of the z score (e.g. 2 to 3 standard deviations relative to the mean). The smaller the stimulus required to generate a deviation from the normal distribution of signals for the voxel, or the greater the signal change for a given stimulus, the more indicative of abnormality.
The time course of the response may be revealed with a step change (e.g. a targeted increase within the range of approximately 5 to 12 mm of Hg, for example 10 mm of Hg in PetCO2) in the standardized vasoactive stimulus by monitoring the time course of the response to the step change.
Similarly, with respect to the amplitude of the vasoactive response at least one step change within this range or a ramp with small increments in PaCO2T from baseline e.g. to baseline+10 mm of Hg may be used to assess the amplitude of the response.
Importantly, each PaCO2T is maintained in the course of obtaining input of the MR signals. Accordingly the stimulus is standardized for control and test subjects and the true nature of the response is revealed. In this manner, comparing test subjects with a control subject atlas reveals the severity and distribution of an abnormal or reduced vascular response. Thus while a CVR map might show a mildly abnormal response for a voxel that is hard to judge as a probable indicator of disease, the precision of the stimulus allows a more conclusive determination of abnormality to be revealed. Herein, statistical maps such as z maps reveal the paramount importance of this standardized PaCO2T stimulus. Furthermore a reduction in the vasoactive response, not visible in a CVR map, will be be revealed as abnormal and hence as a region that might harbour an underlying pathology.
The term “high resolution” with used with reference to imaging modality or device refers to an imaging modality enjoying a spatial resolution of 1 cubic centimeter or smaller. The term includes MRI imaging modalities (for example BOLD, T2*, ASL) and other imaging modalities well known as being useful to quantify surrogate measures of blood flow (CT, SPECT, PET). Proprietary and non-proprietary software for analyzing images in available to persons skilled in the
Importantly, a standardized vasoactive stimulus is accomplished in the manner described herein.
Preferably, the standardized vasoactive stimulus is one or more targeted arterial partial pressures of carbon dioxide. Optionally, the standardized vasoactive stimulus is a series of increments or decrements in a subject's arterial partial pressure of carbon dioxide as described in our co-pending U.S. patent application Ser. No. 14/398,034 originally published as WO/2013/163735. One or more targeted increases in a subject's arterial partial pressure of carbon dioxide may also be accomplished in larger steps as described in the examples herein and more generally in our co-pending U.S. application Ser. No. 14/363,259, originally published as WO/2013/082703.
A measurable increase in the end-tidal (end-exhaled) partial pressure of CO2 (PETCO2) may be used as a surrogate measure for the true independent stimulus, the partial pressure of CO2 in arterial blood (PaCO2). Optionally, a targeted end tidal partial pressure of carbon dioxide is achieved via sequential gas delivery using a specialized re-breathing circuit or a virtual sequential gas delivery circuit (see our co-pending application No. US/2015/0034085, originally published as WO/2013/138910).
CVR may be defined as the percent change in BOLD signal (arbitrary units) per mmHg change in PaCO2.
CVR values for subjects in need of assessment of cerebrovascular reactivity in at least one ROI are assigned color-coded z values based on computations of mean (+/−SD) CVR values, preferably computed on a voxel by voxel basis, for a group of control individuals using images co-registered to a standardized space based on anatomical markers and standardized parameters. The color-coded Z values representing the number of standard deviations from the mean are then superimposed, on the corresponding voxel on an anatomical scan to generate Z maps.
In one embodiment of the method, CVR was measured as the blood oxygen level dependent (BOLD), magnetic resonance imaging (MRI) response to a standardized hypercapnic stimulus. CVR maps from 46 healthy subjects were co-registered into a standard space and mean and standard deviation (SD) was measured for each voxel to form the normal CVR atlas. CVR maps from 9 patients were assigned a z-score according to the mean and SD of the corresponding voxel of the atlas. The z-scores were color coded and superimposed on their anatomical scans to form z-maps, which were assessed to determine whether they enhanced the interpretation of CVR maps.
The z-maps display of the voxel-by-voxel statistical deviation of CVR from the mean of the atlas enabled detection of reductions in CVR not apparent in CVR scans. They identified generalized, symmetrical reductions in CVR as well as quantifying the extent of abnormality in focal lesions evident on CVR maps.
The inventors have found that z-maps complement CVR maps by detecting, localizing, and assessing, the deviation from normal vascular responses.
In order to excessive repetition, it is to be understood that the various optional features described in connection with one of the various aspects and more particularized embodiments of the invention described herein, apply to other aspects/embodiments subject matter described herein including a method as defined herein, an imaging system as defined herein, an atlas as defined herein, a computer program product as defined herein, a non-transitory computer memory as defined herein etc.
The present invention extends the analytic methods of CVR measurement to determine the region by region normal range of CVR and thereby enable quantification of abnormality by the assessment of CVR in terms of its deviation from a statistical mean. The inventors took an approach similar to that of Guimond et al. [Guimond A, 2000] and Seitz et al. [Seitz, 1990] who co-registered scans of healthy subjects into a standard space and determined the normal mean and variance of CVR, voxel-by-voxel. In one aspect, the present invention is directed to generating an atlas of images for non-pathological CVR response by co-registering CO2 stimulated BOLD MRI CVR maps from a healthy cohort into a standard space, and calculating the mean and SD of the CVR for each voxel.
Patient CVR maps were then also co-registered into standard space and each voxel scored positive or negative relative to the mean, and quantified by a z-score of the corresponding voxel in the atlas. These z-scores were then colour coded and superimposed on the patient's anatomical scan to generate a z-map. The inventors determined that z-maps enhance the interpretation of BOLD MRI CVR maps and highlight brain areas where vessels may have residual reactivity above the threshold for the development of steal. In particular, by comparing CVR maps and z-maps in 8 patients with symptomatic cerebrovascular steno-occlusive disease and one patient with increased intracranial hypertension it was determined that z-maps enhance the interpretation of CVR maps.
Studies conformed to the standards set by the latest revision of the Declaration of Helsinki and were approved by the Research Ethics Board (REB) of the University Health Network, Toronto, Ontario and all subjects gave written informed consent. Forty-six healthy volunteers were recruited for the creation of a normal CVR atlas by advertisement and word of mouth. This cohort consisted of subjects of both sexes and any age who claimed to be in good health, denied a history of neurological disease, were non-smokers, and were taking no medication. They were asked not to engage in heavy exercise or drink caffeinated drinks on the day of the scan. The characteristics of these subjects are presented in Table 1 (
Experimental Protocol
Hypercapnic Stimulus
The implementation of prospective end-tidal gas control has been described in detail elsewhere [Fierstra, 2013]. In brief, subjects were fitted with a face mask, and connected to a sequential gas delivery breathing circuit [Somogyi, 2005]. The patterns of P
MRI Protocol and CVR Map Generation
Magnetic resonance imaging was performed with a 3.0-Tesla HDx scanner using an 8-channel phased-array receiver coil (Signa; GE Healthcare, Milwaukee, Wisconsin), and consisted of BOLD acquisitions with echo planar imaging (EPI) gradient echo (TR/TE=2000/30 ms, 3.75×3.75×5 mm voxels, field of view 24×24 cm, 39 slices, slice thickness 5 mm, matrix size 64×64, number of frames=254, flip angle (FA)=85°).
The acquired MRI and P
BOLD images were then volume registered and slice-time corrected and co-registered to an axial 3-D T1-weighted Inversion-Recovery prepared Fast Spoiled Gradient-Echo (IR-FSPGR) volume (TI/TR/TE=450/8/3 ms, voxel size 0.86×0.86×1.0 mm, matrix size 256×256, field of view 22×22 cm, slice thickness=1 mm, FA=15°) that was acquired at the same time [Saad, 2009]. This method has been described in greater detail elsewhere [Fierstra, 2010].
Analysis of CVR Maps
Constructing the Atlas (see also Guimond, A 2000, and Seitz, 1990).
Analytical processing software (SPMS; Wellcome Department of Imaging Neuroscience, University College, London, UK; http://www.fil.ion.ucl.ac.uk/spm/software/spm5), was used to co-register each of the individual brain volumes from the healthy cohort into MNI (Montreal Neurologic Institute) standard space using a 12-parameter [Ashburner,1997] affine transformation followed by nonlinear deformations to warp the brain volume of interest into an MNI template of identical weighting contrast. The T1-weighted FSPGR volume was used to estimate the transformation normalization into standard space, as defined by a T1-weighted MNI152 standard template [Ashburner,1999].
A spatial smoothing of Full-Width Half-Maximum (FWHM) 5 mm was applied to each voxel. Assumption for normality was tested using the Anderson-Darling test (the statistical test for normality provided in AFNI) with p values greater than 0.05 assumed to pass the test. As most voxels (60%) did pass this threshold, and these were diffusely distributed throughout the brain, the simplifying assumption was made that the CVR for each voxel was normally distributed. The mean (μ) and associated standard deviation (σ) of CVR was calculated (AFNI software [Cox, 1996]). Maps were then constructed for μ and coefficient of variation (σ/μ) to characterize the atlas.
CVR Z-Map Generation
The generation of an individual's CVR z-map consisted of three steps. First, a spatial normalization of the individual's anatomical scan and CVR map [Ashburner,1999] using a MNI152 SPM distributed template was produced. Second, the CVR of each voxel (x) was scored in terms of a z value (i.e., z=(x−μ/σ). Finally, a color was assigned to each z score (see scale in
To clarify the colour coding used, it is pointed out that in the resulting z-map: (1) Patient CVR map voxels that are negative (blue) where the corresponding atlas CVR map voxels are positive, will have negative z-scores coded light blue to purple. (2) Patient CVR voxels that are positive but lower than the atlas CVR voxels will also have negative z-scores. (3) However, negative CVR voxels that are greater (towards the positive direction) than the corresponding atlas CVR voxel will nevertheless have a positive z-score. Greater specificity is connoted by greater z scores (for z-maps) and the confluence of similarly scored voxels (both CVR and z-maps).
Z-Map
Normal Cohort CVR Characteristics
With respect to variability, GM areas had the lowest CV values, ranging between 30-40%, whereas higher CV values, between 50-60%, were found in WM. The high CV values calculated at the outer margin of the brain result from the variation in CVR measured where that voxel is predominantly GM, CSF, bone, WM, and blood vessels in different subjects. Similarly, venous sinuses were difficult to localize consistently.
The spatial distribution of the results of the Anderson-Darling statistical test of normality applied to the 46 healthy subjects CVRs graphed into the MNI standard brain is shown in
For comparison purposes,
Z-scoring the CVR studies in our sample patient cohort provided an objective, graded demarcation of the reduction in CVR, quantified relative to the normal range for the region. The z-map therefore emphasized the CVR changes attributable to underlying vascular pathophysiology. This approach diverges significantly from previous practice where CVR was divided into ‘steal and non-steal’ territories [Fierstra, 2010] [Balucani, 2012] or compared to normal atlases where thresholded CVR values of 2 [Commowick, 2008] and 3 [Kemp, 1995] standard deviations were required to identify significant differences from normal.
Our method identifies a graded range of reductions in CVR that do not meet all of the conditions required for steal, yet nevertheless represent vascular pathophysiology [Sobczyk 2014]. Furthermore, we minimized the inter-subject variability (i.e., ‘noise’) due to diversity of technical specifications and brain physiology by standardizing both MRI sequences and the provocative stimulus across the atlas and patient studies. A secondary outcome of the study is that the calculation of the voxelwise mean and variance, characterizes the magnitude and variance of normal CVR in humans, as represented by our sample cohort.
Previous studies examined the deviation from steady state, and therefore reflected only the combined subject-to-subject, and the test-to-test variability [Seitz, 1990]. In contrast, CVR requires the application of a stimulus and the measurement of a response to that stimulus, both potentially adding variations to the CVR values in the atlas. Of these, we can only address the issue of variability in the stimulus, leaving the variation of response to be reflected as a characteristic of the atlas.
First, we wished to retain the advantage of the high spatial and temporal resolution provided by BOLD signal [van der Zande, 2005] as the surrogate for CBF; for this, the application of the stimulus had to be MRI compatible. Second, whereas the magnitude of the stimulus—i.e., the change in PaCO2—is unknown with other hypercapnic methods (Fierstra, 2013), it is precisely known with our method of stimulus generation [Ito, 2008 #14395]. This methodology therefore enables the reduction of the effects of variations in the stimulus on CBF by (a) normalizing the change in BOLD signal for the change in PaCO2 and (b) implementing a uniform change in PaCO2 [Fierstra, 2013] between patients and atlas.
Characteristics of the Patient Cohort
The examination of our patient data illustrated the value added to CVR interpretation by z-maps surprisingly underscoring the importance of a standardized vasoactive stimulus. Subjects 3, 6, 8, and 10, in
We also note that most of the patients presented with protean transient symptoms and were otherwise remarkably asymptomatic. We are impressed that the extent of the neurovascular changes that were provoked by the hypercapnic challenge are very much out of proportion to the clinical symptoms, indicating the considerably greater sensitivity of neuroimaging, including CVR, in detecting occult neurovascular disease compared to clinical assessment.
Characteristics of the Reference Atlas
The CVR atlas represents the distribution of CVR and its variance in the human brain, as reflected in our sample. It incorporates and reflects the regional anatomical differences in the response of the BOLD signal resulting from (a) tissue factors, such as age, sex, O2 consumption, capillary density, changes in blood volume, differences in blood arrival time, and vascular response time; (b) physiologic factors such as genetic makeup, variations in diet, sleep pattern, time of day, hormonal level, physical fitness, blood pressure and blood pressure response to hypercapnia, state of mind; and (c) unknown technical and mechanical changes in the MRI system over time. These form the background “noise”, from which a patient's abnormal voxels, their distribution and the extent of their deviation, must be discerned.
To optimize sensitivity, the subject-to-subject variability in the atlas can be minimized by targeting the atlas to a particular patient group. For example, matching age, sex, medication, and other physiologic features to the target study group (for example young men with multiple sclerosis), and reducing all technical and methodological sources of variability—would leave the disease process as the dominant source of divergence of CVR from that of the reference cohort.
Z-Maps to Compare CVR Across Platforms
An important feature that favours the normal atlas and z-map approach is that its value does not depend on the MRI sequence used or the actual method of administering the vasodilatory stimulus—dose of acetazolamide, inspired concentration of CO2, or breath hold time—rather it is the consistency of the acquisition sequence and the stimulus within the atlas population and between the atlas and the target subjects that is revealed to be important (see [Fierstra, 2013]). Under these conditions, z values should be comparable across platforms.
Pooling atlases from multiple scanners may also address this issue but would also increase the atlas variability and therefore reduce its sensitivity. We therefore suggest that at least initially, it is safest to generate a unique atlas for each scanner. On the positive side, doing so can be seen as a one time ‘calibration’. Since it accounts for between-subject variability the, z-map approach provides a robust control group that can be referenced for several studies, and thereby maximize the statistical power of the subject cohort, and minimizing the number of subjects required.
We accepted the large age range in our atlas. Nevertheless, it was characteristic of the age range of our patient database. Any discrepancies in matching would optimize the specificity. Sensitivity in picking up pathology in our patient cohort was not a concern as our experiences lead us to expect that the changes in CVR due to cerebrovascular disease will greatly exceed that between healthy subjects in an atlas, regardless of the sex and age distribution [Oudegeest-Sander, 2013]. We did however minimize the variability by using a single scanner, running the same MRI acquisition sequence for all subjects and patients, and implementing a uniform stimulus.
These example patients we chose were not intended to represent typical findings for any particular pathology, but to illustrate the range of images produced by z-score analysis relative to a reference atlas. We anticipate that different neurological diseases may call for different stimulus patterns, and so specific normal atlases to reveal their pathophysiology. It will be appreciated that certain patterns (square wave, sinusoidal, ramp, pulse, and others) may be optimum to study certain conditions (vasculitis, traumatic brain injury, subarachnoid hemorrhage and others). The overarching approach nevertheless would be the same: compare patient CVR maps to that of a reference atlas.
Construction of the Interval Difference (ID) Atlas
Twelve males with a mean (SD) age of 35(14.3), were selected from the healthy cohort to repeat their CVR measurement within a two week timeframe, within which it is assumed that no disease process was initiated and all physiologic differences are those that occur in healthy people day to day. Construction of the ID-atlas proceeded as described for the normal atlas except that in this case we first calculated a voxel-by-voxel difference in CVR between the repeated studies in each of the 12 subjects.
MRI Protocol and CVR Map Generation
Magnetic resonance imaging was performed with a 3.0-Tesla scanner (Signa; GE Healthcare, Milwaukee, Wisconsin) and consisted of BOLD acquisitions with echo planar imaging (EPI) gradient echo (TR 2000, TE 30 ms, 3.75×3.75×5 mm voxels).
The acquired MRI and P
Analytical processing software (SPMS; Wellcome Department of Imaging Neuroscience, University College, London, UK; http://www.fil.ion.ucl.ac.uk/spm/software/spm5), was used to co-register each of the healthy individual cohort brain volumes into MNI (Montreal Neurologic Institute) standard space using a 12-parameter (Ashburner and Friston, 1997) affine transformation followed by nonlinear deformations to warp the brain volume of interest into an MNI template of identical weighting contrast. The T1-weighted FSPGR volume was used to estimate the transformation normalization into standard space, as defined by a T1-weighted MNI152 standard template (Ashburner and Friston, 1999). A spatial smoothing of FWHM 5 mm was applied to each. Finally, the mean CVR (
Repeatability and Construction of the Interval Test Difference (ID) Atlas
Twelve males with a mean (SD) age of 35(14.3), were selected from the healthy cohort to repeat their CVR measurement within a two week timeframe. To obtain regional measures of CVR, we segmented the anatomical images into gray matter and white matter (SPMS; Wellcome Department of Imaging Neuroscience, Institute of Neurology, University College, London, UK) regions and spatially normalized to CVR maps. Time comparisons were evaluated by Bland-Altman plots and the coefficient of variation (CV) for grey and white matter as estimates of repeatability (SigmaPlot 12.5, Systat Software, California).
Construction of the ID-atlas proceed as described for the normal atlas except that in this case we first calculated a difference CVR map from the two time points in each of the 12 subjects. Then from the difference maps, we calculated a difference mean, and associated standard deviation for each voxel to produce the test-retest difference probability atlas (ID-atlas).
Z-Maps
To compare an individual CVR map with that of the normal or temporal atlas the spatial CVR information was further analyzed by comparing the direction and magnitude of the change in BOLD signal of each voxel to that of the corresponding voxel in the atlas; the resulting map was called a z-map. This comparison consisted of three steps. First, a spatial normalization of the patient anatomical and CVR scan (Ashburner and Friston, 1999) using a MNI152 SPM distributed template supplied by the Montreal Neurological Institute was produced. Second, the CVR of each voxel was scored in terms of a z value (i.e., the value expressed in standard deviations (SD) of the CVR scores of the corresponding voxel in the atlas,
Finally, a color was assigned to each z-score; AFNI software (Cox, 1996) to indicate a magnitude and direction of the differences in z-scores compared to the atlas population. Positive scores (where the CVR is greater than the mean of the atlas) were coloured green with 15 different shades ranging in intensity between 0 to 3.0 SD. Negative scores (where CVR is less than the mean) were coloured purple with 15 shades ranging in intensity between 0 and −3 SD.
The calculated z-scores were superimposed on the anatomical scans to allow comparison of the patient's CVR to the atlas CVR. As a result: (1) Patient CVR map voxels that are negative (blue) where the corresponding atlas CVR map voxels are positive, will have negative z-scores. (2) Patient CVR voxels that are positive but lower than the atlas CVR voxels will also have negative z-scores. (3) Negative CVR voxels that are higher than the corresponding atlas CVR voxel will have a positive z-score. Maps with z-score thresholds <0.5 SD provide highest sensitivity and those >2.0 SD greatest specificity.
CVR differences over time were calculated for two patients who underwent more than one CVR study in a year time span (ID z-maps). Z-scores were calculated voxel-by-voxel by comparing the difference CVR map of the patient to the temporal atlas. This allowed us to evaluated changes over time that differed significantly from changes over time found in a normal cohort.
We examined the ID z maps generated from our small trial atlas in the most recent 15 patients in our database that met the search criteria. We studies two illustrative cases in detail (one patient who had undergone several scans before undergoing extracranial-intracranial (EC-IC) bypass, and one patient with symptomatic Moyamoya disease that had undergone several CVR studies over a 2 year period).
On average the healthy subjects who participated in the testing for the temporal atlas were scanned 15 days apart.
The mean CVR and CV reproducibility measures for gray and white matter are presented in the Table immediately below. The reproducibility analysis demonstrates good reproducibility between-day CVR estimates in both gray (CV=10.25%) and white matter (CV=9.66%) on average.
The z-maps provide additional information, suggesting that the areas of impaired CVR on the left have in fact improved after surgery when compared to a normal cohort. The ID atlas was then applied to determine whether the z-map changes could be due to variability in the testing over time rather than the intervention (
Identifying pathophysiology and distinguishing changes over time is capable of determining the voxelwise probability of a true, clinical interval change in CVR between two scans. The above described z-maps consisted of a database of voxelwise mean and standard deviation of CVR suitable for identifying the probabilities and extent of abnormality of CVR. Z-maps can be thresholded to alter the balance of sensitivity and specificity in identifying abnormal voxels. Identifying significant changes in a single subject as the voxel statistic does not depend on when the scan is performed, and thus includes the test to test variability. Therefore according to one aspect of the invention, we separately determined, voxel-by-voxel, location-specific statistical probabilities for changes between scans not attributable to technological and physiological variability. This capability of identifying changes between scans is useful for carrying out longitudinal studies such as following the progress of disease and the effects of interventions. As with z-maps, the range of thresholds from 0.5 to 2.0 would provide a range of high sensitivity, low specificity to high specificity, low sensitivity. We used a sample atlas of scan-to-scan differences in 12 healthy male subjects which we used to evaluate 15 patients in our database with known cerebrovascular disease. Greater sensitivity would accrue the more the subjects used in the atlas reflect factors that affect CVR in the target population; greater specificity would accrue from larger cohort numbers and wider inclusion criteria in the atlas population.
Technical and Physiological Sources of Variability in Z Maps
The concept of a voxel-by-voxel comparison of the intensity of an image to that of a normal cohort has been extensively explored (Commowick et al., 2008; Kemp et al., 1995; Laliberte et al., 2004), but it has not been applied to CVR using BOLD MRI as a surrogate for cerebral blood flow.
Minimizing Variability in CVR Due to Variation in the Stimulus
The infusion of pharmacologic agents result in a variability of blood levels, even to a standard dose; there is also a variation of vasodilatory response to a given blood level of drug (see (Fierstra et al., 2013) for discussion). Hypercapnia may result in a more reliable response to a blood partial pressure of CO2 (PaCO2), the stimulus affecting cerebral blood flow (Kety and Schmidt, 1948); but attaining a repeatable PaCO2 is difficult. Infusing CO2 into a face mask, (Markus and Harrison, 1992) inhaling a fixed concentration of CO2, (van der Zande et al., 2005) or simply breath holding (Silvestrini et al., 1999) are not reproducible, and cannot even provide a reliable measure of the change in the PaCO2 (Hoskins, 1990; Mark et al., 2010; Prisman et al., 2007; Sasse et al., 1996). In this study we used a computer-controlled gas blender to prospectively target P
Accounting for the Variability in CVR Due to Variation in the Signal
Despite the precise designation of the MRI scanning sequences and data analysis, there are technical causes for variation in the CVR. During signal acquisition, the signal is affected in random ways due to drift; there may be a drift in signal over time affecting all voxels and separate drift in individual voxels. This drift is usually described by a polynomial and has no consistent pattern or direction with time over the long term. Thus ID z maps provide a confidence interval for identifying changes outside those attributable to technical and physiologic (day-to-day physiology or vasodilatory stimulus) signal changes. As the technical issues result in highly variable changes voxel by voxel, one would expect the observation of systematic changes in contiguous voxels—even if small compared to day-to-day variability—to reflect pathophysiologic changes. Thus, like with the z maps, different balance between sensitivity and specificity may occur at different thresholds.
Change in CVR over time in two patients with cerebrovascular disease We presented the clinical course of two patients with steno-occlusive disease in intracranial vessels. In both cases, the symptoms were mild and transient. In contrast, the stenosis of the intracranial vessels as seen by angiography, were relentlessly progressive. The CVR values were more nuanced, reflecting the balance of blood flow resulting from the establishment of spontaneously developing, and surgically established, collateral blood flow. The total blood flow in both patients apparently remained above the threshold required to sustain neuronal function and cellular integrity preventing an acute stroke as gauged by the absence of ischemia and absence symptoms during follow-up examination. In these patients, the advanced analysis of the CVR data the ID z maps introduced in this paper ostensibly improved the resolution of underlying subclinical pathophysiologic changes not apparent from angiography and CVR maps alone.
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This application is a Continuation of co-pending International Application No. PCT/CA2015/000274, filed Apr. 27, 2015, the disclosure of which is incorporated herein by reference. International Application No. PCT/CA2015/000274, in turn, claims the benefit, under 35 U.S.C. § 119(e), of U.S. provisional application Ser. No. 61/984,617, filed on Apr. 25, 2014, the disclosure of which is incorporated herein by reference in its entirety. This application is also a Continuation-in-Part of co-pending U.S. patent application Ser. No. 14/859,809, filed Sep. 21, 2015, which is a Continuation of U.S. patent application Ser. No. 14/614,310, filed Feb. 4, 2015, the disclosures of which are hereby incorporated by reference as if set forth in full herein.
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| Number | Date | Country | |
|---|---|---|---|
| 20170236294 A1 | Aug 2017 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61984617 | Apr 2014 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/CA2015/000274 | Apr 2015 | US |
| Child | 14859809 | US | |
| Parent | 14614310 | Feb 2015 | US |
| Child | 14859809 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14859809 | Sep 2015 | US |
| Child | 15332567 | US |
