Abstract:
An optical biological measuring device includes a light transmission/reception element  30  having a plurality of light transmission probes  12 , light reception probes  13  and reference probes  14 ; a second observation signal acquiring element  25  for acquiring a second observation signal indicating a time-course variation relating to a cerebral activity; a first observation signal acquiring element  24  for acquiring a first observation signal indicating a time-course variation relating to the blood flow in the skin; and an analysis control element  40  for generating a removal target component removal observation signal based on the first and second observation signals.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims priority from and relates to International App. Ser. No. PCT/JP2012/069209 filed Jul. 27, 2012, the entire contents of which are incorporated herein by reference. 
     
    
     FIGURE SELECTED FOR PUBLICATION 
       [0002]    
       FIG. 7 
     
       BACKGROUND OF THE INVENTION 
       [0003]    1. Field of the Invention 
         [0004]    The present invention relates to an optical biological measuring device using light and analysis method for acquiring an observation signal indicating time-course (chronological) variations in terms of a measurement site. Particularly, the present invention is used as an optical cerebral function imaging apparatus for measuring an activity situation of a cerebral measurement site in a noninvasive manner using near-infrared rays, and an oxygen monitor for monitoring oxygen consumption in a measurement site in a living body. 
         [0005]    2. Description of the Related Art 
         [0006]    In recent years, in order to observe a cerebral activity situation, optical cerebral function imaging apparatuses for conducting a measurement in a simple and noninvasive manner using light have been developed. In such optical cerebral function imaging apparatuses, the brain is irradiated with near infrared rays with three different wavelengths of λ1, λ2 and λ3 (for example, 780 nm, 805 nm and 830 nm) from a light transmission probe arranged on the scalp surface of a subject, and intensity variations (information of an amount of received light) ΔA(λ1), ΔA(λ2) and ΔA(λ3) of the near infrared rays with wavelengths of λ1, λ2 and λ3 emitted from the brain are detected by light reception probes arranged on the scalp surface. 
         [0007]    In order to obtain a product [oxyHb] of oxyhemoglobin concentration change and optical path length and a product [deoxyHb] of deoxyhemoglobin concentration change and optical path length in the cerebral blood flow from ΔA(λ1), ΔA(λ2), ΔA(λ3), the information of the amount of received light obtained in this manner, for example, simultaneous equations shown by the relational equations (1), (2) and (3) are formulated by using, for example, Modified Beer Lambert Law, and then the simultaneous equations are solved. Further, a product ([oxyHb]+[deoxyHb]) of total hemoglobin concentration change and optical path length is calculated from the product [oxyHb] of oxyhemoglobin concentration change and optical path length and the product [deoxyHb] of deoxyhemoglobin concentration change and optical path length. 
         [0000]      Δ A (λ 1 )= E   O (λ 1 )×[oxyHb]+ E   d (λ 1 )×[deoxyHb]  (1)
 
         [0000]      Δ A (λ 2 )= E   O (λ 2 )×[oxyHb]+ E   d (λ 2 )×[deoxyHb]  (2)
 
         [0000]      Δ A (λ 3 )= E   O (λ 3 )×[oxyHb]+ E   d (λ 3 )×[deoxyHb]  (3)
 
         [0008]    E O  (λm) represents an absorbance coefficient of oxyhemoglobin at the light with wavelength λm, and E d (λm) represents an absorbance coefficient of deoxyhemoglobin at the light with wavelength λm. 
         [0009]    Here, a relationship between distance (channel) between the light transmission probe and the light reception probe and a measurement site is described.  FIGS. 8A and 8B  are diagrams illustrating a relationship between a pair of a light transmission probe and a light reception probe and a measurement site. A light transmission probe  12  is pressed against a light transmitting point T of the scalp surface of a subject, and a light reception probe  13  is pressed against a light receiving point R of the scalp surface of the subject. Light is irradiated from the light transmission probe  12 , and then light emitted from the scalp surface is incident on the light reception probe  13 . At this time, light that is radiated and passes through a banana-like shape region (measurement region) of the light radiated from the light transmitting point T of the scalp surface reaches the light receiving point R of the scalp surface. 
         [0010]    Further, in the optical cerebral function imaging apparatuses, for example, a near-infrared spectrometer is used in order to measure the product [oxyHb] of oxyhemoglobin concentration change and optical path length, the product [deoxyHb] of deoxyhemoglobin concentration change and optical path length, and the product ([oxyHb]+[deoxyHb]) of total hemoglobin concentration change and optical path length related to a plurality of measurement sites in the brain. 
         [0011]    In such a near-infrared spectrometer, a holder (transmission/reception portion)  130  is used in order to allow the eight light transmission probes  12  and the eight light reception probes  13  to contact with the scalp surface of a subject in a predetermined arrangement.  FIG. 9  is a plan diagram illustrating one example of the holder  130  into which the eight light transmission probes and the eight light reception probes are inserted. 
         [0012]    Light transmission probes  12   T1  to  12   T8  and light reception probes  13   R1  to  13   R8  are alternately arranged to make four in the vertical direction and the horizontal direction. At this time, a second setting distance r 2  that is an interval (channel) between each of the light transmission probes  12   T1  to  12   T8  and each of the light reception probes  13   R1  to  13   R8  is 30 mm. As a result, the information of the amount of received light ΔA2 n (λ 1 ), ΔA2 n (λ 2 ) and ΔA2 n (λ 3 ) (n=1, 2, . . . , 24) concerning twenty-four measurement positions of the brain are obtained. 
         [0013]    The twenty-four information of the amount of received light ΔA2 n (λ 1 ), ΔA2 n (λ 2 ) and ΔA2 n (λ 3 ) are obtained at a predetermined time interval Δt so that time-course (chronological) variations (second observation signal) X n (t) of the product [oxyHb] of oxyhemoglobin concentration change and optical path length, time-course variations (second observation signal) Y n (t) of the [deoxyHb] of deoxyhemoglobin concentration change and optical path length, and time-course variations (second observation signal) Z n (t) of the product ([oxyHb]+[deoxyHb]) of total hemoglobin concentration change and optical path length (n=1, 2, . . . , 24) are obtained by using the relational equations (1), (2) and (3). 
         [0014]      FIG. 5  is a diagram illustrating a monitor screen where twenty-four time-course variations (second observation signals) X n (t) of the product [oxyHb] of oxyhemoglobin concentration change and optical path length are being displayed. Further, the vertical axis in one of second observation signal X n (t) represents the product [oxyHb] of oxyhemoglobin concentration change and optical path length, and the horizontal axis represents time t. 
         [0015]    Incidentally, as shown in  FIG. 5 , the displayed twenty-four of second observation signals X n (t) include overlapping signals based on the fluctuations in the blood flow in the skin, the heart rate, variations in pulsation and respiration and so forth, in addition to signals based on the blood flow according to the brain activity. 
         [0016]    Therefore, in order to easily diagnose whether or not symptoms such as cerebral ischemia are generated, a biological light measuring method for surely discriminating the signals based on the blood flow according to the brain activity from signals other than these signals in the second observation signal X n (t) is disclosed (for example, see Patent Document 1). Such a biological light measuring method includes a step (a) of obtaining an N×N mixing matrix and numerical N independent component signals S n  (t) based on observation signals X n (t) on numerical N detection positions through independent component analysis (ICA) according to the following formula (4); a step (b) of substituting 0 for a column vector corresponding to a removal target component in the N×N mixing matrix as expressed in the following formula (5); and a step (c) of calculating a product of the N×N removal target component removal mixing matrix and numerical N independent component signals S n (t) so as to obtain numerical N removal target component removal observation signals X n ′(t). 
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         [0017]    The column vector in the mixing matrix represents a weight of a specific independent component signal S n (t) in a measurement site. That is to say, the observation signals X n (t) are a linear combination of numerical N independent component signals S n (t) from independent signal generating sources with respective elements in the mixing matrix as a weight coefficient. 
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         [0018]    The expression (5) shows a case where an independent component signal S 1 (t) is determined as a removal target component, 0 is substituted for a first column vector corresponding to the removal target component, and a removal target component removal mixing matrix is generated. 
         [0019]    According to such a biological light measuring method, the removal target component removal observation signals X n ′(t) can be restored, in which the signal S 1 (t) based on the removal target component from the observation signals X n (t) is removed. 
         [0020]    On the other hand, in order to acquire the information of the amount of received light ΔA only based on a blood vessel in the brain, that having a distance (channel) between the light transmission probe  12  and the light reception probe  13  is set as both a short distance r 1  and a long distance r 2  is disclosed (for example, see Patent Document 2 and Non-Patent Document 1.)  FIG. 10  is a cross-sectional diagram illustrating a relationship between the light transmission probe  12  to make a short distance r 1  with a reference probe  14  and a long distance r 2  with the light reception probe  13  and a measurement site. As a result, second information of the amount of received light ΔA2 about a blood vessel present in the skin near the light transmitting point T, a blood vessel present in the brain and a blood vessel present in the skin in proximity to the light receiving point R 2  is acquired at the long distance r 2  channel, and first information of the amount of received light ΔA1 about only a blood vessel present in the skin in proximity to the light transmitting point T (blood vessel present in the skin in proximity to a light receiving point R 1 ) is acquired at the short distance r 1  channel. 
         [0021]    The information of the amount of received light ΔA about only the blood vessel present in the brain is obtained based on the information of the amount of received light ΔA1 and ΔA2 by using the equation (6). 
         [0000]      Δ A=ΔA 2− KΔA 1  (6)
 
         [0022]    Incidentally, in the equation (6), a coefficient K should be determined in order to obtain the information of the amount of received light ΔA, and a method for calculating the coefficient K is disclosed (for example, see Non-Patent Document 2.) In this calculating method, the coefficient K is calculated by using least square error. 
       PRIOR ART DOCUMENT 
     Patent Documents 
       [0000]    
       
         Patent Document 1: JP 2005-245636 A 
         Patent Document 2: JP 2009-136434 A 
       
     
       Non-Patent Documents 
       [0000]    
       
         Non-Patent Document 1: Rolf B. Saager, and Andrew J. Berger “Direct characterization and removal of interfering absorption trends in two-layer turbid media” J. Opt. Soc. Am. A/Vol. 22, No. 9/September 2005. 
         Non-Patent Document 2: Francesco Fabbri, Angelo Sassaroli, Michael e Henry, and Sergio Fantini “Optical measurements of absorption changes in two-layered diffusive media” Phys. Med. Biol. 49(2004) 1183-1201. 
       
     
       ASPECTS AND SUMMARY OF THE INVENTION 
     Aspects to be Solved 
       [0027]    The optical biological measuring device using above independent component analysis, however, utilizes signals based on the blood flow in the skin, which are not localized, it is effective only on the wide range measurement of the brain but no precise diagnosis whether a cerebral ischemia have taken place or not might be achieved when the local cerebral area was measured. 
         [0028]    Further in the above calculation method using information of an amount of received light ΔA1, ΔA2 and the coefficient K, the calculated information of the amount of received light ΔA was obtained under consideration of the combination of a pair of a light transmission probe  12  and a light reception probe  13  but not under consideration of the combination of a plurality of light transmission probes  12   T1  to  12   T8  and a plurality of light reception probes  13   R1  to  13   R8  as the holder  130  of the above optical cerebral function imaging apparatus. Further, the first information of the amount of received light ΔA1 includes most of signals based on the blood flow in the skin but also includes signals based on the blood flow along with brain activities despite an extremely small amount. Accordingly, an object of the present invention is to provide an optical biological measuring device and a method of analysis using the same, in which a signal corresponding to a removal target component can be removed from the observed signals even when a local area of brain is measured. 
       Means to Solve the Concerns 
       [0029]    In one aspect of the invention, disclosed is an optical biological measuring device including a light transmission/reception element  30  having a plurality of light transmission probes  12 , light reception probes  13  and reference probes  14 ; a second observation signal acquiring element  25  for acquiring a second observation signal indicating a time-course variation relating to a cerebral activity; a first observation signal acquiring element  24  for acquiring a first observation signal indicating a time-course variation relating to the blood flow in the skin; and an analysis control element  40  for generating a removal target component removal observation signal based on the first and second observation signals, the analysis control element  40  includes a second mixing matrix generating element  44  for separating a plurality of second observation signal into products of a second mixing matrix and a plurality of second independent component signals through independent component analysis, a removal target second independent component signal determination element  46  for extracting a removal target second independent component signal from among the plurality of second independent component signals using the first observation signal, and a restructuring element  47  for removing a removal target second observation signal so as to generate a plurality of removal target component removal observation signals. 
         [0030]    In order to solve the above problem, the optical biological measuring device of the present invention includes a light transmission/reception element having a plurality of light transmission probes arranged on the scalp surface of a subject, a plurality of light reception probes arranged on positions separated from the light transmission probes on the scalp surface by a second setting distance r 2 , and reference probes arranged on positions separated from the light transmission probes or the light reception probes on the scalp surface by a first setting distance r 1  shorter than the second setting distance r 2 ; a second observation signal acquiring element for acquiring second information of an amount of received light ΔA2 from the light transmission probes to the light reception probes so as to acquire a second observation signal indicating a time-course (chronological) variation relating to a cerebral activity; a first observation signal acquiring section for acquiring first information of an amount of received light ΔA1 from the light transmission probes or the light reception probes to the reference probes so as to acquire a first observation signal indicating a time-course variation relating to the blood flow in the skin; and an analysis control element for generating a removal target component removal observation signal based on the first observation signal and the second observation signal, wherein the analysis control element includes a second mixing matrix generating element for separating a plurality of second observation signals into products of a second mixing matrix and a plurality of second independent component signals through independent component analysis, a removal target second independent component signal determination element for finding a removal target second independent component signal from among the plurality of second independent component signals using the first observation signal, and a restructuring element for removing the removal target second independent component signal from the second observation signal so as to generate a plurality of removal target component removal observation signals. 
         [0031]    Herein, “the second setting distance r 2 ” is a distance for acquiring information of an amount of received light about a blood vessel present in the skin in proximity to the light transmitting point T, a blood vessel present in the brain and a blood vessel present in the skin in proximity to the light receiving point R, and “the first setting distance r 1 ” is a distance for acquiring information of an amount of received light about the blood vessel present in the skin in proximity to the light sending point T or the light receiving point R. 
         [0032]    Further, “the observation signal” may be a time-course variation itself in the information of the amount of received light detected by the light reception probes, or may be a time-course variation in oxyhemoglobin concentration calculated based on the information of the amount of received light, or a time-course variation in deoxyhemoglobin concentration or a time-course variation in total hemoglobin concentration. 
         [0033]    Furthermore, “the signal corresponding to the removal target component” refers to a signal other than the signal based on the blood flow according to the brain activity, and for example, refers to the signal based on the blood flow in the skin, the signal based on the fluctuations in the heart rate, and the signal based on pulsation and respiration and so forth. 
         [0034]    In the optical biological measuring device of the present invention, the second observation signal acquiring element allows the light transmission probe to irradiate the scalp surface with light and control the light reception probe in order to detect light emitted from the scalp surface, and thus numerical N second observation signals X n (t) concerning numerical N measurement sites are acquired. Here, the second observation signals X n (t) include overlapping signals based on the fluctuations in the blood flow in the skin and the heart rate and variations in pulsation and respiration and so forth, in addition to signals based on the blood flow according to the brain activity. 
         [0035]    Therefore, the analysis control element removes the signal corresponding to the removal target component from the second observation signals X n (t). First, the second mixing matrix generating element, as shown by the formula (4), separates numerical N second observation signals X n (t) into products of an N×N second mixing matrix and numerical N second independent component signals S n (t) through independent component analysis. Herein, when there is a signal generating source of the signal based on the blood flow in the skin, which is irrelevant of the signal based on the blood flow according to the brain activity, it is considered that any of numerical N second independent component signals S n (t) is the signal based on the blood flow in the skin from the signal generating source. The number of signals to be determined as the signals corresponding to the removal target component is not limited to one, and may be two or more. 
         [0036]    Next, in order to find the signal based on the blood flow in the skin from among numerical N second independent component signals S n (t), the first observation signal acquiring element allows the light transmission probe to irradiate the scalp surface with light and control the reference probe in order to detect light emitted from the scalp surface, and thus at least one first observation signal H(t) concerning at least one measurement site is acquired. The first observation signal H(t) mostly includes the signal based on the blood flow in the skin. 
         [0037]    The removal target second independent component signal determination element compares at least one first observation signal H(t) with numerical N second independent component signals S n (t), so as to find the removal target second independent component signal from among numerical N second independent component signals S n (t). For example, the second independent component signal S 1 (t) is found as the removal target second independent component signal. 
         [0038]    Finally, as shown by the formula (5), the restructuring element generates an N×N removal target component removal mixing matrix where 0 is substituted for a column vector corresponding to a removal target second independent component signal S 1 (t) in the N×N mixing matrix, and calculates the products of the N×N removal target component removal mixing matrix and numerical N second independent component signals S n (t) so as to obtain numerical N removal target component removal observation signals X n ′(t). 
       Effects of the Invention 
       [0039]    As described above, in the optical biological measuring device of the present invention, since the removal target second independent component signal S 1 (t) is found from among numerical N second independent component signals S n (t) by using the first observation signals H(t) almost all of which includes the signal based on the blood flow in the skin, it is possible to accurately diagnose whether or not symptoms such as cerebral ischemia are generated also in the case of regionally measuring the brain. 
         [0040]    Further, in the optical biological measuring device of the present invention, a plurality of reference probes is arranged in the light transmission/reception element, and the analysis control element includes a first mixing matrix generating element for separating a plurality of first observation signals into products of a first mixing matrix and a plurality of first independent component signals through independent component analysis, and a removal target first independent component signal determination element for finding a removal target first independent component signal from among the plurality of first independent component signals. The removal target second independent component signal determination element calculates correlation coefficients between the removal target first independent component signals and the second independent component signals, and may determine a signal where the correlation coefficient is a threshold or more as the removal target second independent component signal. 
         [0041]    In the optical biological measuring device of the present invention, the first observation signal acquiring element allows the light transmission probe to irradiate the scalp surface with light and control the reference probe in order to detect light emitted from the scalp surface, and thus numerical M first observation signals H m (t) concerning numerical M measurement sites are acquired. The first observation signals H m (t) mostly include the signal based on the blood flow in the skin, but few of them include the signal based on the blood flow according to the brain activity. 
         [0042]    Therefore, the analysis control element finds the signal corresponding to the removal target component from among the first observation signals H m (t). Also at this time, the independent component analysis is used. First, the first mixing matrix generating element, as shown by the following formula (7), separates numerical M first observation signals H m (t) into products of an M×M first mixing matrix and numerical M first independent component signals U m (t) through independent component analysis. Herein, when there is a signal generating source of the signal based on the blood flow in the skin, which is irrelevant of the signal based on the blood flow according to the brain activity, it is considered that any of numerical M second independent component signals U m (t) is the signal based on the blood flow in the skin from the signal generating source. The number of signals to be determined as the signals corresponding to the removal target component is not limited to one, and may be two or more. 
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         [0043]    Next, the removal target first independent component signal determination element finds a removal target first independent component signal from among numerical M first independent component signals U m (t). For example, as shown by the following formula (8), the maximum mixing coefficient b max  is found from among each line vector in the M×M first mixing matrix so as to be circled, and the removal target first independent component signal is found based on the number of the maximum mixing coefficients b max  present in each column vector (for example, 2 or more), and threshold mixing coefficients b over  that are a threshold b th  or more is found from among each line vector in the M×M first mixing matrix. The removal target first independent component signal is found based on the number of the threshold mixing coefficients b over  present in each column vector (for example, 2 or more). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0044]    The formula (8) shows a case where the number of the maximum mixing coefficients b max  present in the second column vector is two or more and a first independent component signal U 2 (t) is the removal target first independent component signal. 
         [0045]    The removal target second independent component signal determination element calculates correlation coefficients α n  between a removal target first independent component signal U 2 (t) and numerical N second independent component signals S n (t), and determines signals where correlation coefficients α n  are a threshold α th  or more as the removal target second independent component signal. For example, when the correlation coefficients α n  between the second independent component signal S 1 (t) and the removal target first independent component signal U 2 (t) is the threshold α th  or more, the second independent component signal S 1 (t) is found as the removal target second independent component signal. 
         [0046]    As described above, in the optical biological measuring device of the present invention, the independent component analysis is conducted on numerical M first observation signals H m (t) so that the removal target first independent component signal U 2 (t) is found from among numerical M first independent component signals U m (t), and further, the removal target second independent component signal S 1 (t) is found from among numerical N second independent component signals S n (t) by using the removal target first independent component signal U 2 (t). For this reason, it is possible to accurately diagnose whether or not symptoms such as cerebral ischemia are generated also in the case of regionally measuring the brain. 
         [0047]    Further, in the optical biological measuring device of the present invention, the removal target first independent component signal determination element may find the maximum mixing coefficient from among each line vector in the first mixing matrix, and may find the removal target first independent component signal based on the number of the maximum mixing coefficients present in each column vector. 
         [0048]    Further, in the optical biological measuring device of the present invention, the removal target first independent component signal determination element may find the threshold mixing coefficient that is the threshold or more from among each line vector in the first mixing matrix, and may find the removal target first independent component signal based on the number of the threshold mixing coefficients present in each column vector. 
         [0049]    Further, in the optical biological measuring device of the present invention, the restructuring element substitutes 0 for a column vector corresponding to the removal target second independent component signal in the second mixing matrix so as to generate the removal target component removal mixing matrix, and multiplies the removal target component removal mixing matrix by the plurality of second independent component signals, so as to generate a plurality of removal target component removal observation signals. 
         [0050]    The analysis method of the present invention for generating a removal target component removal observation signal based on a first observation signal and a second observation signal using an optical biological measuring device including a light transmission/reception element having a plurality of light transmission probes arranged on the scalp surface of a subject, a plurality of light reception probes arranged on positions separated from the light transmission probes on the scalp surface by a second setting distance r 2 , and reference probes arranged on positions separated from the light transmission probes or the light reception probes on the scalp surface by a first setting distance r 1  shorter than the second setting distance r 2 ; a second observation signal acquiring element for acquiring second information of an amount of received light ΔA2 from the light transmission probes to the light reception probes so as to acquire the second observation signal indicating a time-course variation relating to a cerebral activity; and a first observation signal acquiring element for acquiring first information of an amount of received light ΔA1 from the light transmission probes or the light reception probes to the reference probes so as to acquire the first observation signal indicating a time-course variation relating to the blood flow in the skin, wherein the analysis method includes a second mixing matrix generating step of separating a plurality of second observation signals into products of a second mixing matrix and a plurality of second independent component signals through independent component analysis; a removal target second independent component signal determining step of finding a removal target second independent component signal from among the plurality of second independent component signals using the first observation signal; and a restructuring step of removing the removal target second independent component signal from the second observation signal so as to generate a plurality of removal target component removal observation signals. 
         [0051]    The above and other aspects, features and advantages of the present invention will become apparent from the following description read in conjunction with the accompanying drawings, in which like reference numerals designate the same elements. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0052]      FIG. 1  is a block diagram illustrating a schematic structure of an optical biological measuring device according to one embodiment of the present invention. 
           [0053]      FIG. 2  is a plan diagram illustrating one example of a holder into which eight light transmission probes, eight light reception probes and twelve reference probes are inserted. 
           [0054]      FIG. 3  is a diagram for describing positions where first information of an amount of received light is obtained. 
           [0055]      FIG. 4  is a diagram for describing one example of a control table. 
           [0056]      FIG. 5  is a diagram illustrating a monitor screen on which time-course (chronological) variations (second observation signals) X n (t) of a product [oxyHb] of concentration change of twenty-four oxyhemoglobins and optical path length are displayed. 
           [0057]      FIG. 6  is a diagram illustrating a monitor screen on which twenty-four removal target component removal observation signals X n ′(t) are displayed. 
           [0058]      FIG. 7  is a flowchart for describing one example of an analysis method for the optical biological measuring device. 
           [0059]      FIGS. 8A and 8B  are diagrams illustrating a relationship between a pair of the light transmission probe and the light reception probe, and a measurement site. 
           [0060]      FIG. 9  is a plan diagram illustrating one example of a holder into which the eight light transmission probes and the eight light reception probes are inserted. 
           [0061]      FIG. 10  is a cross-sectional diagram illustrating a relationship between the light transmission probe, the reference probe for a short distance r 1  and the light reception probe for a long distance r 2 , and the measurement site. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0062]    Reference will now be made in detail to embodiments of the invention. Wherever possible, same or similar reference numerals are used in the drawings and the description to refer to the same or like parts or steps. The drawings are in simplified form and are not to precise scale. The words ‘couple’ connected ‘linked’ and similar terms do not necessarily denote direct and immediate connections, but also include connections through intermediate elements or devices. For purposes of convenience and clarity only, directional (up/down, etc.) or motional (forward/back, etc.) terms may be used with respect to the drawings. It will be further understood that certain terms, such as ‘data’ may be plural or singular a suited to the circumstance, and that there shall be no limitation on such use, so that ‘a data’ or ‘the data’ or simply ‘data’ may be plural or singular. It will also be understood that the phrases ‘time-course’ or ‘chronological’ will be understood as relative terms of the process and steps discussed herein and are not to be construed in a limiting manner. All these and the related terms used in the application should not be construed to limit or narrow the scope in any manner. It will also be understood that other embodiments may be utilized without departing from the scope of the present invention, and that the detailed description is not to be taken in a limiting sense, and that elements may be differently positioned, or remotely located (and operable via distant electronic connection) or otherwise noted as in the appended claims without need of the written description being required thereto. 
         [0063]    In the following, the embodiments of the present invention are described in reference to the drawings. Here, the present invention is not limited to the following embodiments, but includes various aspects within the range that does not deviate from the gist of the present invention. 
         [0064]      FIG. 1  is a block diagram illustrating a schematic structure of an optical biological measuring device according to one embodiment of the present invention. Further,  FIG. 2  is a plan diagram illustrating one example of a holder (light transmission/reception element) into which eight light transmission probes, eight light reception probes and twelve reference probes are inserted. 
         [0065]    An optical biological measurement device  1  includes a light source  2  for emitting light, a light source driving mechanism  4  for driving the light source  2 , a light detector  3  for detecting light, an A/D (A/D converter)  5 , a light transmission/reception control element  21 , a first observation signal acquiring element  24  for calculating first observation signals U m (t), a second observation signal acquiring element  25  for calculating second observation signals X n (t), an analysis control element  40 , and a memory  23 , as well as eight light transmission probes  12 , eight light reception probes  13 , twelve reference probes  14 , a holder  30 , a display device  26  having a monitor screen  26   a , etc., and a keyboard  27 . 
         [0066]    The light source driving mechanism  4  drives the light source  2  based on a driving signal input from the light transmission/reception control element  21 . The light source  2  is, for example, semiconductor lasers LD 1 , LD 2  and LD 3  that can emit three different kinds of near infrared rays with wavelengths of λ 1 , λ 2  and λ 3 . 
         [0067]    The light detector  3  is, for example, a photo multiplier, and detects near infrared rays received by the eight light reception probes  13   R1  to  13   R8  individually, so as to output eight second information of an amount of received light ΔA2(λ 1 ), ΔA2(λ 2 ) and ΔA2(λ 3 ) to the light transmission/reception control element  21  via the A/D  5 . The light detector  3  also detects near infrared rays received by the twelve reference probes  14  individually, so as to output twelve first information of an amount of received light ΔA1(λ 1 ), ΔA1(λ 2 ) and ΔA1(λ 3 ) to the light transmission/reception control element  21  via the A/D  5 . 
         [0068]    The holder  30  has the eight light transmission probes  12   T1  to  12   T8 , the eight light reception probes  13   R1  to  13   R8 , and the twelve reference probes  14   B1  to  14   B12 . 
         [0069]    The light transmission probes  12   T1  to  12   T8  and the light reception probes  13   R1  to  13   R8  are arranged into a square lattice pattern alternately in a line direction and a column direction. At this time, a second setting distance r 2  that is an interval (channel) between each of the light transmission probes  12   T1  to  12   T8  and each of the light reception probes  13   R1  to  13   R8  is 30 mm. 
         [0070]    Further, the reference probe  14   B1  is arranged on a position between the light transmission probe  12   T1  and the light reception probe  13   R3 , the reference probe  14   B1  being separated from the light transmission probe  12   T1  by a first setting distance r 1 . A first setting distance r 1  that is an interval between the light transmission probe  12   T1  and the reference probes  14   B1  is 15 mm. The respective reference probes  14  are arranged on positions separated from the respective light transmission probes  12  by the first setting distance r 1  such that the reference probe  14   B2  is arranged on a position separated from the light transmission probe  12   T3  by the first setting distance r 1 , and the reference probes  14   B3  is arranged on a position separated from the light transmission probe  12   T2  by the first setting distance r 1 . 
         [0071]    The memory  23  is formed with a control table storage region  23   a  to store a control table in which control forms for controlling transmission/reception of light are set in advance for the holder  30  in order to acquire twenty-four second information of an amount of received light ΔA2 n (λ 1 ), ΔA2 n (λ 2 ) and ΔA2 n  and twelve first information of an amount of received light ΔA1 m (λ 1 ), ΔA1 m (λ 2 ) and ΔA1 m (λ 3 ); and a data storage region  23   b  for storing the twenty-four second information of the amount of received light ΔA2 n (λ 1 ), ΔA2 n (λ 2 ) and ΔA2 n , the twelve first information of the amount of received light ΔA1 m (λ 1 ), ΔA1 m (λ 2 ) and ΔA1 m (λ 3 ), etc. 
         [0072]    Here,  FIG. 3  is a diagram for describing a position where the first information of the amount of received light is obtained, and  FIG. 4  is a diagram for describing one example of the control table. According to such a control table, light is sequentially transmitted to each of the light transmission probes  12   T1  to  12   T8  at predetermined timing such that light with a wavelength of 780 nm is transmitted to the light transmission probe  12   T1  for first 5 milliseconds, light with a wavelength of 805 nm is transmitted to the light transmission probe  12   T1  for next 5 milliseconds, light with a wavelength of 830 nm is transmitted to the light transmission probe  12   T1  for next 5 milliseconds, and light with a wavelength of 780 nm is transmitted to the light transmission probe  12   T2  for next 5 milliseconds. At this time, every time when light is transmitted to any one of the light transmission probes  12   T1  to  12   T8 , the eight light reception probes  13   R1  to  13   R8  and the twelve reference probes  14   B1  to  14   B12  detect information of an amount of received light, but predetermined information of an amount of received light about the light reception probes  13   R1  to  13   R8  and predetermined information of an amount of received light about the reference probes  14   B1  to  14   B12  that are detected at predetermined timing are stored in the data storage region  23   b  of the memory  23 . Concretely, the predetermined information of the amount of received light about the light reception probes  13   R1  to  13   R8  and the predetermined information of the amount of received light about the reference probes  14   B1  to  14   B12  that are detected at predetermined timing are stored in the data storage region  23   b  such that information of an amount of received light about the light reception probe  13   R1 , the light reception probe  13   R3 , and the reference probe  14   B1  that detect light from the light transmission probe  12   T1  is stored in the data storage region  23   b , and information of an amount of received light about the light reception probe  13   R1 , the light reception probe  13   R2 , the light reception probe  13   R4 , and the reference probe  14   B3  that detect light from the light transmission probe  12   T2  is stored in the data storage region  23   b . As a result, the twenty-four second information of the amount of received light ΔA2 n (λ 1 ), ΔA2 n (λ 2 ), and ΔA2 n (λ 3 ) in total are collected, and the twelve first information of the amount of received light ΔA1 m (λ 1 ), ΔA1 m (λ 2 ), and ΔA1 m (λ 3 ) in total are collected. 
         [0073]    The light transmission/reception control element  21  controls output of a driving signal for transmitting light to one light transmission probe  12  to the light source driving mechanism  4  at a predetermined time based on the control table, and detection of the information of the amount of received light ΔA1 m (λ 1 ), ΔA1 m (λ 2 ), ΔA1 m (λ 3 ), ΔA2 n (λ 1 ), ΔA2 n (λ 2 ), and ΔA2 n (λ 3 ) (m=1, 2, . . . , 12, and n=1, 2, . . . , 24), with the photodetector  3 , received by the light reception probes  13  and the reference probes  14 . 
         [0074]    The first observation signal acquiring element  24  controls obtainment of time-course variations (first observation signal) H m (t) of a product [oxyHb] of oxyhemoglobin concentration change and optical path length, time-course variations (first observation signal) I m (t) of a product [deoxyHb] of deoxyhemoglobin concentration change and optical path length, and time-course variations (first observation signal) J m (t) of a product ([oxyHb]+[deoxyHb]) of total hemoglobin concentration change and optical path length (m=1, 2, . . . , 12) based on the twelve first information of the amount of received light ΔA1 m (λ 1 ), ΔA1 m (λ 2 ) and ΔA1 m (λ 3 ) stored in the data storage region  23   b  by using the relational equations (1), (2) and (3). 
         [0075]    The second observation signal acquiring element  25  controls obtainment of time-course variations (second observation signal) X n (t) of a product [oxyHb] of oxyhemoglobin concentration change and optical path length, time-course variations (second observation signal) Y n (t) of a product [deoxyHb] of deoxyhemoglobin concentration change and optical path length, and time-course variations (second observation signal) Z n (t) of a product ([oxyHb]+[deoxyHb]) of total hemoglobin concentration change and optical path length (n=1, 2, . . . , 24) based on the twenty-four second information of the amount of received light ΔA2 n (λ 1 ), ΔA2 n (λ 2 ), and ΔA2 n (λ 3 ) stored in the data storage region  23   b  by using the relational equations (1), (2) and (3). 
         [0076]    Here, for the sake of description, the function processed by the analysis control element  40  is divided into blocks: a first mixing matrix generating element  43 , a second mixing matrix generating element  44 , a removal target first independent component signal determination element  45 , a removal target second independent component signal determination element  46 , and a restructuring element  47  for generating removal target component removal observation signals X n ′(t). 
         [0077]    The first mixing matrix generating element  43  controls, as shown by the formula (7), separation of the twelve first observation signals U m (t) into products of a 12×12 first mixing matrix and twelve first independent component signals U m (t) through independent component analysis. 
         [0078]    The second mixing matrix generating element  44  controls, as shown by an expression (4), separation of the twenty-four second observation signals X n (t) into products of a 24×24 second mixing matrix and twenty-four second independent component signals S n (t) through independent component analysis. 
         [0079]    The removal target first independent component signal determination element  45  controls finding of maximum threshold mixing coefficients b max  from among each line vector in the 12×12 first mixing matrix, and finding of a removal target first independent component signal based on the number of maximum mixing coefficients b max  present in each column vector (for example, 2 or more). 
         [0080]    For example, twelve maximum mixing coefficients b max  in total are found in the 12×12 first mixing matrix such that the maximum mixing coefficient b max  is found from among mixing coefficients b 11  to b 1m  in a first line vector, and the maximum mixing coefficient b max  is found from among mixing coefficients b 21  to b 2m  in a second line vector. Then, the number of the maximum mixing coefficients b ma , present in each column vector is calculated such that the number of the maximum mixing coefficients b max  present in a first column vector is calculated and the number of the maximum mixing coefficients b max  present in a second column vector is calculated. The first independent component signals U m (t) corresponding to column vectors where the number of the maximum mixing coefficients b max  is, for example, two or more are determined as the removal target first independent component signal. For example, as shown by the formula (8), when the number of the maximum mixing coefficients b max  present in the second column vector is two or more and the number of the maximum mixing coefficients b max  present in the first column vector and a third column vector to a twelfth column vector are less than two, the signals are determined as a removal target first independent component signal U 2 (t). 
         [0081]    The removal target second independent component signal determination element  46  controls calculation of correlation coefficients α n  between the removal target first independent component signal U 2 (t) and each of the second independent component signals S n (t) (n=1, 2, . . . , 24), and determination of a signal where the correlation coefficient α n  is a threshold α th  or more as a removal target second independent component signal. 
         [0082]    For example, twenty-four correlation coefficients α n  in total are calculated such that a correlation coefficient α 1  between the removal target first independent component signal U 2 (t) and the second independent component signal S 1 (t) is calculated, and a correlation coefficient α 2  between the removal target first independent component signal U 2 (t) and the second independent component signal S 2 (t) is calculated. The second independent component signals S n (t) where the correlation coefficients α n  are the threshold α th  or more in the twenty-four second independent component signals S n (t) are determined as the removal target second independent component signal. For example, when the correlation coefficient α 1  is the threshold α th  or more and the correlation coefficients α 2  to α 24  are less than the threshold α th , the signals are determined as the removal target second independent component signal S 1 (t). 
         [0083]    The restructuring element  47  controls generation of a removal target component removal mixing matrix where 0 is substituted for a column vector corresponding to the removal target second independent component signal S 1 (t), and multiplication of a 24×24 removal target component removal mixing matrix by twenty-four independent component signals S n (t), so as to generate the twenty-four removal target component removal observation signals X n ′(t). 
         [0084]    For example, as shown by the formula (5), when such a signal is the removal target second independent component signal S 1 (t), a removal target component removal mixing matrix where 0 is substituted for the first column vector is generated. The 24×24 removal target component removal mixing matrix is multiplied with the twenty-four independent component signals S n (t) so that the twenty-four removal target component removal observation signals X n ′(t) are generated. As a result, the twenty-four removal target component removal observation signals X n ′(t) shown in  FIG. 6  are obtained. 
         [0085]    An analysis method for the optical biological measuring device  1  is described below.  FIG. 7  is a flowchart for describing one example of the analysis method for the optical biological measuring device  1 . 
         [0086]    First, the holder  30  is arranged on the scalp surface of a subject at step S 101 . 
         [0087]    Next, in processing at step S 102 , the light transmission/reception control element  21  outputs a driving signal for transmitting light to one light transmission probe  12  at a predetermined time based on the control table stored in the control table storage region  23   a  to the light source driving mechanism  4 , and detects, with the light detector  3 , the information of the amount of received light ΔA1 m (λ 1 ), ΔA1 m (λ 2 ), ΔA1 m (λ 3 ), ΔA2 n (λ 1 ), ΔA2 n (λ 2 ) and ΔA2 n (λ 3 ) (m=1, 2, . . . , 12, and n=1, 2, . . . , 24) received by the light reception probes  13  and the reference probes  14 . 
         [0088]    Next, in processing at step S 103 , the first observation signal acquiring element  24  obtains the time-course variations (first observation signals) H m (t) (m=1, 2, . . . , 12) of the product [oxyHb] of oxyhemoglobin concentration change and optical path length based on the twelve first information of the amount of received light ΔA1 m (λ 1 ), ΔA1 m (λ 2 ) and ΔA1 m (λ 3 ) stored in the data storage region  23   b  by using the relational equations (1), (2) and (3). 
         [0089]    Next, in processing at step S 104 , the second observation signal acquiring element  25  obtains the time-course variations (second observation signals) X n (t) (n=1, 2, . . . , 24) of the product [oxyHb] of oxyhemoglobin concentration change and optical path length based on the twenty-four second information of the amount of received light ΔA2 n (λ 1 ), ΔA2 n (λ 2 ) and ΔA2 n (λ 3 ) stored in the data storage region  23   b  by using the relational equations (1), (2) and (3). 
         [0090]    Next, in processing at step S 105 , the first mixing matrix generating element  43 , as shown by the formula (7), separates the twelve first observation signals H m (t) into products of the 12×12 first mixing matrix and the twelve first independent component signals U m (t) through independent component analysis. 
         [0091]    Next, in processing at step S 106 , the second mixing matrix generating element  44 , as shown by the formula (4), separates the twenty-four first observation signals X n (t) into products of the 24×24 first mixing matrix and the twenty-four second independent component signals S n (t) (second mixing matrix generating step) through independent component analysis. 
         [0092]    Next, in processing at step S 107 , the removal target first independent component signal determination element  45  finds the maximum threshold mixing coefficients b max  from among each line vector in the 12×12 first mixing matrix, and finds the removal target first independent component signal U 2 (t) based on the number of the maximum mixing coefficients b max  preset in each column vector (for example, two or more). 
         [0093]    Next, in processing at step S 108 , the removal target second independent component signal determination element  46  calculates the correlation coefficients α n  between the removal target first independent component signal U 2 (t) and each of the second independent component signals S n (t) (n=1, 2, . . . , 24). 
         [0094]    Next, in processing at step S 109 , the removal target second independent component signal determination element  46  determines a signal where the correlation coefficient α n  is the threshold α th  or more as the removal target second independent component signal S 1 (t) (removal target second independent component signal determining step). 
         [0095]    Next, in processing at step S 110 , the restructuring element  47 , as shown by the formula (5), generates the removal target component removal mixing matrix where 0 is substituted for a column vector corresponding to the removal target second independent component signal S 1 (t), and multiplies the 24×24 removal target component removal mixing matrix by the twenty-four independent component signals S n (t), so as to generate the twenty-four removal target component removal observation signals X n ′(t) (restructuring step). 
         [0096]    When step S 110  is finished, this flowchart will end. 
         [0097]    As described above, in the optical biological measuring device  1 , the independent component analysis is made on the twelve first observation signals H m (t) so that the removal target first independent component signal U 2 (t) is found from among the twelve first independent component signals U m (t). Further, the removal target second independent component signal S 1 (t) is found from among the twenty-four second independent component signals S n (t) by using the removal target first independent component signal U 2 (t). For this reason, it is possible to accurately diagnose whether or not symptoms such as cerebral ischemia are generated also in the case of regionally measuring the brain. 
       Another Alternative Embodiment(s) 
       [0098]    (1) The above optical biological measuring device  1  has the configuration such that the maximum threshold mixing coefficients b max  are found from among each line vector in the 12×12 first mixing matrix, and the removal target first independent component signal is found based on the number of the maximum mixing coefficients b max  present in each column vector (for example, two or more). However, it may have a configuration such that the threshold mixing coefficients b over  that are a threshold b th  or more are found from among each line vector in the 12×12 first mixing matrix, and the removal target first independent component signal is found based on the number of the threshold mixing coefficients b over  in each column vector (for example, two or more.) 
         [0099]    (2) The above optical biological measuring device  1  has the configuration such that the removal target component removal observation signals X n ′(t) are generated for the time-course (chronological) variations (second observation signal) X n (t) of the product [oxyHb] of oxyhemoglobin concentration change and optical path length. However, it may have a configuration such that removal target component removal observation signals Y n ′(t) are generated for time-course variations (second observation signal) Y n (t) of a product [deoxyHb] of deoxyhemoglobin concentration change and optical path length, or removal target component removal observation signals Z n ′(t) are generated for time-course variations (second observation signal) Z n (t) of a product ([oxyHb]+[deoxyHb]) of total hemoglobin concentration change and optical path length. 
         [0100]    (3) The above optical biological measuring device  1  has the configuration such that the holder  30  is used which has the eight light transmission probes  12   T1  to  12   T8 , the eight light reception probes  13   R1  to  13   R8 , and the twelve reference probes  14   B1  to  14   B12 , but may have a configuration such that a first holder is used which has the eight light transmission probes  12   T1  to  12   T8  and the eight light reception probes  13   R1  to  13   R8 , and a second holder is used which has the twelve reference probes  14   B1  to  14   B12 . 
         [0101]    (4) The above optical biological measuring device  1  has the configuration such that the independent component analysis is made on the twelve first observation signals H m (t), but may have a configuration such that one first observation signal H m (t) is used. 
       INDUSTRIAL APPLICABILITY 
       [0102]    The present invention can be applied for an optical biological measurement device and so forth, which measures noninvasively brain activities. 
         [0103]    It will be further understood by those of skill in the arts, after having studied the disclosure herein, that the modules, computer, and features herein shall be understood to contain all necessary components, features, processors, memory devices, and related elements shall be operative and effective to achieve the noted result without departing from the scope herein, whereby as a non-limiting example, a step of calculating shall be conducted in a suitable processor component for related signals and data contain and shall contain all the needed operative functions to achieve such goals and steps as discussed herein as will be recognized within the scope and skill of the art. As a non-limiting listing such as processor controls, memory devices, operative software, input/output features, and related elements shall be otherwise effective to render the proposed aspects, features, methods and or steps herein fully operative within the scope and spirit of the present invention and those of skill in the art. 
         [0104]    Having described at least one of the preferred embodiments of the present invention with reference to the accompanying drawings, it will be apparent to those skills that the invention is not limited to those precise embodiments, and that various modifications and variations can be made in the presently disclosed system without departing from the scope or spirit of the invention. Thus, it is intended that the present disclosure cover modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents. 
       REFERENCE OF SIGN 
       [0000]    
       
           1  Optical biological measurement device 
           12  Light transmission probe 
           13  Light reception probe 
           14  Reference probe 
           21  Light transmission/reception control element 
           23  Memory 
           24  First observation signal acquiring element 
           25  Second observation signal acquiring element 
           30  Holder (light transmission/reception element) 
           40  Analysis control element 
           44  Second mixing matrix generating element 
           46  Removal target second independent component signal determination element 
           47  Restructuring element