Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
  • A61B5/4076—Diagnosing or monitoring particular conditions of the nervous system
  • A61B5/4088—Diagnosing of monitoring cognitive diseases, e.g. Alzheimer, prion diseases or dementia

Definitions

• the present invention irradiates a human head surface with light, detects light reflected near the surface and light transmitted near the surface (hereinafter collectively referred to as transmitted light), and detects the functions and functions of the human brain.
• the present invention relates to a biological optical measurement device for measuring and diagnosing a disease, and particularly to a biological optical measurement device useful for determining dementia such as Alzheimer's disease.
• a biological light measurement device is a device for observing blood dynamics of a living body by using transmitted light from a living body such as a human being or an animal, and particularly detects a change in hemoglobin amount at a plurality of points on a head. This makes it possible to non-invasively measure brain functions and diagnose diseases. For measuring and diagnosing brain functions, various techniques for analyzing data measured as hemoglobin change signals at a plurality of measurement points have been developed.
• Patent Document 1 describes that a correlation between a feature of a change pattern of hemoglobin and a reference template is calculated to thereby determine a disease, and as a feature, a hemoglobin change pattern curve is described as a feature. And the use of differential values and integral values of change.
• dementia includes various types such as mild cognitive impairment, Alzheimer's disease, and vascular dementia, and their causes and treatment methods are different, but accurate diagnosis is made only by observing the symptoms. It is difficult, and other diagnostic methods using measuring instruments are also used.
• diagnosis for the purpose of diagnosing Aluno and Ima's disease measurement methods using PET and cerebral blood flow SPECT are used.
• PET and cerebral blood flow SPECT are used.
• Patent Document 1 JP-A-2003-275191
• an object of the present invention is to provide a biological optical measurement device that can provide important parameters in the diagnosis of dementia including Alzheimer's disease.
• Another object of the present invention is to provide a bio-optical measurement device that can determine dementia using measurement results of different measurement sites.
• the living body light measuring device of the present invention irradiates a predetermined part of the subject with light, detects living body light measuring means for detecting light transmitted through the part or reflected / scattered by the part, and the living body light.
• the signal waveform of the hemoglobin change signal is modeled using a predetermined basic waveform, and the feature amount is automatically calculated from the modeled measurement signal waveform, and is compared with a previously obtained feature amount of a known dementia. Strength The feature is to determine specific dementia.
• the biological optical measurement device of the present invention includes a probe attached to a subject, and a means for receiving an optical signal of a plurality of measurement point forces obtained through the probe, and converting the optical signal into a hemoglobin change signal.
• a feature amount extracting means for analyzing the hemoglobin change signals at the plurality of measurement points and extracting a feature amount specific to dementia, a feature amount for each type of dementia as a database Storage means for storing, and a determination means for comparing the feature quantity extracted by the feature quantity extraction means with the feature quantity of dementia accumulated as a database to determine specific dementia;
• the characteristic amount extracting means is characterized in that the signal waveform of the hemoglobin change signal is modeled, and the characteristic amount is automatically calculated from the modeled measurement signal waveform.
• Modeling substitutes a known coordinate value of a predetermined point on the signal waveform into a coordinate of a corresponding point of a model (basic waveform) to form a model waveform, and the model waveform and the signal
• An evaluation function representing a square error with a waveform is determined, a simplex is formed using points representing a plurality of combinations of unknown coordinate values, and a procedure of finding a combination of coordinate values that minimizes the evaluation function is repeated. Including that.
• the coordinate values obtained by such repetition are substituted into the initial model waveform.
• a trapezoidal model can be used as a signal waveform model, and an optimization technique can be used as a modeling technique.
• the known coordinate value of a predetermined point on the signal waveform is substituted into the coordinates of the corresponding point of the basic waveform to obtain a model waveform, and an evaluation function representing a square error between the model waveform and the signal waveform.
• a simplex is constructed using points representing a plurality of combinations of unknown coordinate values, and a procedure for finding a combination of coordinate values that minimizes the evaluation function is repeated, and the obtained coordinate values are converted to the coordinate values of the model waveform. Is determined.
• the analysis means compares, for example, the characteristic amount obtained as a result of measurement for a plurality of parts with the characteristic amount of a healthy person stored in a database.
• the specific dementia can be determined based on the combination of the feature amount and the difference. In the determination of dementia, one feature amount or a combination of a plurality of feature amounts is used.
• the analysis means obtains, for example, a hemoglobin change signal force principal component waveform obtained for each measurement point, and corrects the principal component waveform according to the number of measurement points (normalization). ) And then model.
• the display means operates a user interface for inputting selection of conditions and setting of each processing performed by the analysis means. Display as a screen.
• the biological light measurement device of the present invention is suitable for diagnosing dementia, especially Alzheimer's disease.
• the method for determining dementia of the present invention is a method for determining dementia based on a hemoglobin change waveform obtained by measuring the strength of a plurality of parts of a head by measuring living body light.
• the hemoglobin change waveform includes change waveforms of a plurality of measurement channels
• the step of modeling includes: The method includes a step of creating a waveform and a step of correcting the created principal component waveform according to the number of measurement channels of each part.
• the method for determining dementia of the present invention is a method for determining dementia based on a hemoglobin change waveform obtained by measuring the strength of a plurality of parts of a head by measuring living body light, wherein the hemoglobin change waveform is determined.
• pre-processing including fitting processing and averaging processing on the data, performing principal component analysis on the pre-processed data for each region, and applying the data after principal component analysis to the measurement channel of each region. Correcting according to the number, modeling the data for each part, extracting the modeled changed waveform force of each of the plurality of parts, and extracting the characteristic amount for each of the plurality of parts. And a step of comparing the feature amounts accumulated for each type of dementia, and a step of displaying a result of the comparison.
• the method for determining dementia is a method for determining dementia based on characteristics of a hemoglobin change waveform obtained by measuring the strength of a plurality of parts of a head by measuring living body light, wherein the hemoglobin change waveform is used. Modeling, and extracting a feature from the modeled waveform.
• the modeling includes setting an initial value to coordinate values of a plurality of points defining a model figure, and changing a hemoglobin change to be modeled.
• the step of optimizing the simplex includes, for example, calculating a point having a minimum evaluation function value and a point having a maximum evaluation function value at points constituting the simplex.
• the method includes a sub-step 3 for searching for a certain improvement value, and a step of repeating the above sub-steps 11 to 13 until a convergence condition is reached.
• a characteristic is obtained by praying hemoglobin change signals at a plurality of measurement points, extracting characteristic amounts specific to dementia, and modeling a signal waveform. Quantities can be calculated automatically and compared to the database. By all means, everything from measurement to diagnosis can be realized with a biological light measurement device.
• FIG. 1 is a diagram showing an overall outline of a biological optical measurement device to which the present invention is applied.
• the living body light measuring device mainly includes a light measuring unit 101 that irradiates a living body with light and detects light transmitted through the living body, and a signal from the light measuring unit 101. And a signal processing unit 108 for calculating and displaying in-vivo information such as the amount of hemoglobin in the blood.
• the optical measurement unit 101 includes a light source unit 102 for irradiating a living body with light having a predetermined wavelength to a test site of a subject, and light reflected or scattered by light transmitted through the test site of the subject or the test site. did A light detector 105-107 having a light receiving element for detecting light (hereinafter collectively referred to as transmitted light); an optical fiber 103 for transmitting light from the light source 102 to a predetermined portion of the subject; It comprises an attachment (probe) 104 for fixing each end of an optical fiber 103 for transmitting transmitted light to a light detection unit and attaching the tip to an object.
• a light detector 105-107 having a light receiving element for detecting light (hereinafter collectively referred to as transmitted light)
• an optical fiber 103 for transmitting light from the light source 102 to a predetermined portion of the subject
• It comprises an attachment (probe) 104 for fixing each end of an optical fiber 103 for transmitting transmitted light to a light detection unit and attaching the tip
• the light source unit 101 includes a plurality of optical modules, and each optical module includes two semiconductors that emit light of a predetermined wavelength in a wavelength range from visible light to infrared light, for example, two wavelengths of 780 nm and 830 nm. It has a laser.
• the light source unit includes an oscillation unit including a plurality of oscillators having different oscillation frequencies, and applies different modulations to the respective semiconductor lasers.
• Light of, for example, two wavelengths from a semiconductor laser is mixed for each optical module and introduced into one irradiation optical fiber 103.
• one optical fiber 103 is shown.
• the number of optical fins 103 for irradiation is provided as many as the number of optical modules.
• light having different modulation applied to each optical module is irradiated onto the surface of the subject from the ends of the plurality of optical fibers.
• the ends of the irradiation and reception optical fibers 103 are, for example, 3
• the probe 104 It is fixed to the probe 104 so as to be located at the intersection of a square lattice such as X3, 4X4, or the like.
• the area between the irradiation optical fiber tip and the light receiving optical fiber tip is a measurement point measured by optical measurement.
• the light detection unit is connected to each of the light receiving optical fibers 103, and converts a light guided by the light receiving optical fiber 103 into an electric signal corresponding to a light amount.
• a modulation signal detection circuit for inputting an electric signal from the element 105 and selectively detecting a modulation signal corresponding to an irradiation position (position of the irradiation optical fiber tip) and a wavelength, for example, a lock-in amplifier 106, and A variable amplifier 107 is provided.
• a photomultiplier tube may be used.
• a photodiode an avalanche photodiode that can realize high-sensitivity optical measurement is preferable.
• the modulation signal detection circuit 106 selectively detects a modulation signal corresponding to an irradiation position and a wavelength.
• a lock-in amplifier 106 is used.
• a digital filter or digital signal processor is used.
• light of two wavelengths is used as irradiation light, so that the number of signals to be measured (ch Is the number of [measurement points] X [2], and has the same number of lock-in amplifiers.
• the signal detected for each measurement channel is amplified by a continuously variable amplifier 107, converted into a digital signal by A / D conversion (not shown), and sent to a signal processing unit 108.
• the signal processing unit 108 processes a signal from the light detection unit, a memory 109 for recording a signal from the light detection unit 105-107, calculates a change in blood hemoglobin, and calculates a change in blood hemoglobin.
• a display unit (monitor) 112 for displaying a time course of a measurement signal and a topography image as a calculation result.
• an input unit for inputting conditions in optical measurement, patient information, and the like is provided, and the monitor 112 displays a GUI for input.
• the signal processing unit 108 having such a configuration can be constructed on a general-purpose personal computer, and may be directly connected to the biological optical measurement device by a cable, or may be connected to a communication network, a portable medium, or the like. May be transmitted and received.
• FIG. 2 is a diagram showing an embodiment of an operation flow in the living body light measurement device of the present invention.
• the basic operations are (1) living body light measurement (201), (2) pre-processing of measurement data (202), (3) Data selection for diagnosis of dementia (203), (4) Principal component analysis (204), (5) Correction of number of measurement channels (205), (6) Modeling of measurement data (206), (7) ) Calculation of feature quantity (207), (8) comparison with database of each case (208), and (9) display of results (209).
• living body light measurement 201
• pre-processing of measurement data 202
• Data selection for diagnosis of dementia 203
• Principal component analysis 204
• Correction of number of measurement channels 205
• Modeling of measurement data 206
• Calculation of feature quantity 207
• comparison with database of each case 208
• 9 display of results (209).
• each step will be described in detail.
• a task such as a word fluency test is given while irradiating and receiving light with the probe 104 attached to the subject, and the amount of change in hemoglobin at that time is measured.
• the measurement site is the forehead, left head, and right head. There are four locations at the same time, depending on the type of probe! /, Are measured separately.
• the hemoglobin change signal measured at each measurement point of the probe is given as a time course graph with the horizontal axis representing time and the vertical axis representing hemoglobin change. Respectively Is obtained. By repeating a predetermined task with a fixed repetition time, a hemoglobin change amount at each repetition interval can be obtained.
• the pre-processing mainly includes a fitting process for calculating the amount of change before and after the task, and an adding process for improving the SN of the measurement result.
• the fitting process when the wavelength of the irradiation light is given, the irradiation light amount R Q (e), the detected light amount R S (e) before the task is executed (when not executed), and the detected light amount R (e) ),
• the change in the concentration of oxygenated and deoxygenated hemoglobin is calculated using the molecular extinction coefficients of oxygenated and deoxygenated hemoglobin at the wavelength. Details of the calculation method are described in, for example, Patent Document 2.
• the addition process is a process of averaging a plurality of results.
• Patent Document 2 JP-A-2003-10188
• FIG. 3 shows data 301 after performing the above preprocessing.
• FIG. 3A is a diagram showing a display example 301 of the measurement result when the number of channels is 24.
• a graph is displayed for each channel, where the horizontal axis represents time and the vertical axis represents hemoglobin change.
• the graph of channel 24 (Ch24) is shown as a representative in FIG.
• As the hemoglobin change amount each of the amount of oxygenated hemoglobin, the amount of deoxygenated hemoglobin, and the total amount of hemoglobin is displayed.
• the graph also shows two vertical lines indicating the start and end of the task. Before and after that are the waiting time before the task starts and the rest time after the task ends.
• Select clinically necessary data from the oxygenated hemoglobin amount data, deoxygenated hemoglobin amount data, and hemoglobin total amount data after the pretreatment This may be determined by the user from the graph displayed on the monitor 112, or when the diagnosis target is dementia, for example, the amount of oxygenated hemoglobin may be automatically selected.
• the eigenvectors W are columns of eigenvectors V from the first principal component to the Mth principal component.
• FIG. 4 shows a representative waveform 401 obtained by the above principal component analysis.
• the vertical axis represents the hemoglobin change amount
• the horizontal axis represents time, with the task start time being 0.
• independent component analysis may be supplementarily used in addition to the above-described principal component analysis.
• Figure 501 is shown in Figure 5. Also in FIG. 5, the vertical axis is hemoglobin and the horizontal axis is time, and the start and end points of the task are indicated by two lines 503 and 505, respectively. The interval between the two lines corresponds to the task duration 504. In addition, points on the waveform 501, measurement start time 506, task start time 507, task end time 508, and measurement end time 509 necessary for calculating parameters (features) described below are shown. The coordinates of these points will be used for automatic calculation in the next modelling.
• Modeling of Measurement Data (206) Modeling is performed on the representative waveform obtained for each measurement site in order to obtain important parameters for the diagnosis of dementia.
• Some models such as polygons that are considered to correspond to biological signals can be used for the model dani, but in the present embodiment, a model dani using a trapezoidal model will be described with reference to FIG.
• FIG. 6A shows a waveform 601 showing a trapezoid model, and a task start time 603, a task end time 605, and a task duration 604 are also shown in the figure.
• This trapezoid model waveform 601 can be defined by the coordinates of six points AF. These coordinates of A—F are (t y), (t
• Modeling using such a trapezoidal model is a process of finding a trapezoidal waveform 611 that best matches the representative waveform 501, as shown in FIG. 6B, and is an automatic process using a known optimization method. It can be done by calculation.
• a modeling method that minimizes the square error using the Simplex method will be described.
• Figure 7 shows the optimization procedure. The details of the Simplex method are introduced in, for example, non-patent literature.
• Non-Patent Document 1 Nelder, J.A. and R. Mead, ⁇ A Simplex Method for Function
• the coordinates of the following points of the representative waveform (501 in FIG. 5) to be modeled are also calculated.
• Point X 4 (508): Coordinate value at the end of the task on the representative waveform
• the variables t, t, t, t, y, y, y, y, y for which the estimated values have not yet been determined the variables t, t, t, t, y, y, y for which the estimated values have not yet been determined.
• a trapezoidal model waveform composed of t, t, t, y, y, y and constants t *, t *, and a pair of modeling
• An evaluation function representing a square error with a representative waveform as an elephant is defined as the following equation.
• the evaluation function f is used as a function representing the square error between the trapezoidal model waveform composed of the estimated values at that time and the representative waveform to be modeled in the iterative process of the optimization calculation.
• the points P and P representing the initial values of the initial Simplex are set as follows.
• Figure 8 shows the flow of the optimization calculation.
• Points P — P are betats with 7 variables each
• Point P The evaluation function value f-f at that point is the point that has the minimum value.
• the point having the maximum value is designated as point H (step 802).
• the vector representing the point S is expressed as SV (where SV is synonymous with the character with the right arrow above the character "S", the same applies hereinafter), and the evaluation function value f , F, the evaluation function value at point S, which is the minimum value, is f (SV), and the vector representing point H is HV
• the value of the evaluation function at point H which is the maximum value among the valence function values f-f, is f (HV)
• Point P P force also determines a point O that represents the position of the center of gravity of seven points excluding point H (step 803). Heavy
• the vector representing the center point o can be expressed by the following equation.
• a search is made for an improvement value that may reduce the evaluation function value (step 804). For this reason, first, a vector representing the mirror image point R is obtained using the mirror image parameter ⁇ (a is any value larger than 0; here, it is assumed that hi 0.1) as in the following equation.
• the vector representing the contraction point C is calculated as follows.
• Evaluation function value f (C) at contraction point C [0052] The relationship between the evaluation function value at R at the mirror image point, the evaluation function value at point H, and the evaluation function value at point S is
• point C is adopted as a new candidate point, and 7 points excluding point H out of point P-P
• a new simplex is composed of a total of eight points, C and C.
• a new simplex is composed of a total of eight points in E.
• a total of eight points of R form a new simplex.
• the convergence condition is checked (step 805). First, a point S at which the value of the evaluation function is minimum among the eight points constituting the updated new simplex is determined. Then, a vector representing the point S and an evaluation function value at the point S are obtained.
• Condition 1 The number of repetitions of the calculation processing from step 801 to 804 exceeds a certain number (for example, 2000).
• Condition 2 The evaluation function value at the point S is less than a certain value (for example, 0.05).
• step 801 If the conditions 1 and 2 are satisfied, if not, the process returns to the calculation process in step 801 using the new simplex updated in step 804. If condition 1 or condition 2 is satisfied, the iterative calculation is terminated, and point S is set as a combination that represents the optimal parameter.
• FIG. 9 shows an example of a feature value that can be used for diagnosing dementia.
• the slope of the modeled waveform during the task 901 the slope of the modeled waveform after the task is completed 902, the height of the maximum flat portion of the modeled waveform 903, the maximum flat portion of the modeled waveform during the task
• the duration 904, the duration 905 of the maximum flat part of the modeled waveform after the task ends, etc. can be used as the feature amount, and the size of the representative waveform (( ⁇ / ⁇ )) is also used.
• the height 903 of the maximum flat portion of the modeled waveform is effective for diagnosing Aln's disease.
• the feature amount of each case is stored as a database, and the comparative power with this database diagnoses the case of the subject.
• the database is to store data obtained by performing light measurement on patients with dementia and healthy persons whose diagnosis has been confirmed in advance by another diagnostic method, and processing the results in the above-described procedure. It can be created from a box.
• Figure 10 shows an example of “the height of the maximum flat part of the modeled waveform”. As shown in the figure, the average value 1002 and the variance ⁇ 1003 of each measurement site are stored for each of healthy subjects, mild cognitive impairment, Alzheimer's disease, vascular dementia, alcoholic dementia, and frontal temporal lobe dementia. Have been. Fig.
• FIG. 11 shows this graphically, where (a) shows the forehead, (b) shows the left head, and (c) shows the right head.
• the vertical axis indicates the height of the maximum flat portion of the waveform
• the center of the box is the average value 1102
• the variance 1103 is shown above and below it.
• the horizontal axis corresponds to six types of cases including healthy subjects. Specifically, A is a healthy individual, B is mild cognitive impairment, C is Alzheimer's disease, D is vascular dementia, E is alcoholic dementia, and F is frontotemporal lobe dementia.
• the database of each case is compared with the feature amount of each measurement site calculated in step 208, here, the heights ⁇ and ⁇ of the maximum flat portions of the modeled shading waveform.
• the feature values ⁇ , j8, ⁇ for each measurement site of the subject and the values (average value and variance) of the database it is possible to determine whether or not there is Alzheimer's disease by a known statistical method such as ⁇ determination. Can do it.
• z —) Calculate the conventional metric from ⁇ , and ⁇ Calculate the risk factor using the statistical power normal distribution table. If the risk ratio is high for all parts and shows a value (for example, 50% or more), it is judged that the disease is Aln's disease. Set.
• FIG. 12 shows a display example including an operation screen for performing the above-described processing (steps 202 to 209 in FIG. 2).
• a subject information display unit 1201 is provided at the top of the screen, an operation button for inputting a command for each process is provided on the left side, and a display unit 1200 for displaying the results of light measurement, analysis, and determination is provided on the right side. Is provided.
• buttons for example, a button (Data Load) 1211 for reading out data (hemoglobin change signal) obtained by the biological light measurement stored in the storage unit 111 for analysis processing, and performing addition processing Buttons (Calculate Integral Hb) 1212, Selection buttons (Oxy, Deoxy, Total) 1213 for selecting data to be used for diagnosis among oxygenated hemoglobin amount data, deoxygenated hemoglobin amount data, and hemoglobin total amount data
• a principal component analysis start button (PCA) 1214, a modeling button (Model Fit) 1215, a feature value calculation button (Calculate Feature Parameter) 1216, and the like are displayed.
• a button corresponding to a process When a button corresponding to a process is selected by an input unit such as a mouse, the corresponding process is started. At this time, to indicate the processing status, it is possible to change the color of the corresponding button for the processing in progress, and to display a screen prompting the next processing after one processing is completed Is also possible. Further, an operation screen that allows the user to select and input parameters necessary for processing, such as input, may be displayed. For example, when the button (Model Fit) 1215 is selected, a menu for selecting a basic waveform used for modeling is displayed. It is possible to select a basic waveform other than the trapezoid model as shown in the figure.
• the display unit 1200 includes measurement result display units 1208 and 1209 for each measurement site.
• Each measurement result display unit includes a measurement site 1203, a measurement result 1204 for each channel, and a principal component analysis processing result 1205. , A modeled waveform 1206, a feature quantity 1207, and the like.
• the feature value display unit 1207 displays the average value and the variance of the database, the risk factor based on the calculated value, the determination result, and the like in addition to the calculated feature value.
• the biological optical measurement device of the present invention can be variously modified without being limited to these embodiments.
• features other than ⁇ flat portion height '' can be used depending on the case.
• Results may be displayed, and the user (physician) may make the determination.
• the averaging process in step 202 and the correction in step 205 are necessary. However, those steps are omitted from the scope of the present invention.
• the biological optical measurement device of the present invention is provided with a means for modeling the measured hemoglobin change waveform and automatically calculating parameters (features) suitable for the judgment of the case. Parameters can be provided. In particular, it can contribute to the accurate diagnosis of dementia.
• FIG. 1 is a diagram showing an overall outline of a biological optical measurement device to which the present invention is applied.
• FIG. 2 is a flowchart showing an embodiment of the operation of the biological light measurement device of the present invention.
• FIG. 3 is a diagram showing a result after fitting and averaging processing of a signal waveform obtained by biological light measurement.
• FIG. 4 is a diagram showing a result of further principal component analysis of the waveform in FIG. 3
• FIG. 5 is a diagram showing a result of correcting the number of channels of the waveform in FIG. 4
• FIG. 6 is a view for explaining the modeling of the waveform in FIG. 5; (a) is a trapezoidal model used for modeling;
• (b) is a diagram showing the waveform after modeling
• FIG. 7 is a flowchart showing a modeling process.
• FIG. 8 is a flowchart showing details of the optimization calculation in FIG. 7
• FIG. 9 is a view for explaining parameters (features) in the modeled dani waveform
• FIG. 10 is a diagram showing an example of a dementia database
• FIG. 12 is a display example of the biological light measurement device of the present invention.

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