Method and apparatus for monitoring metabolism in body organs

• US 4,281,645 A
• Filed: 06/28/1977
• Issued: 08/04/1981
• Est. Priority Date: 06/28/1977
• Status: Expired due to Term

• Current Assignee: Duke University Inc (Duke University)
• Original Assignee: Duke University Inc (Duke University)
• Inventors: Jobsis, Frans F.
• Primary Examiner(s): Kamm, William E.
• Application Number:
  US05/810,777
• Time in Patent Office: 1,498 Days
• Field of Search: 128/2 R, 128/2 L, 128/2.05 F, 128/2.05 P, 128/2.05 V, 128/633, 128/634, 128/664, 128/665, 128/2.06 R, 356/43-45, 356/39, 356/432
• US Class Current: 600/324
• CPC Class Codes: A61B 5/0059 using light, e.g. diagnosis by transillumination, diascopy, fluorescence A61B5/0093, A61B5/1455, A61B5/02416 and A61B5/0261 take precedence
• CPC Class Codes: A61B 5/0073 by tomography, i.e. reconstruction of 3D images from 2D projections A61B5/0066 takes precedence
• CPC Class Codes: A61B 5/14551 for measuring blood gases
• CPC Class Codes: A61B 5/14552 Details of sensors specially adapted therefor
• CPC Class Codes: A61B 5/14553 specially adapted for cerebral tissue
• CPC Class Codes: A61B 5/6833 Adhesive patches
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions

Abstract

A spectrophotometric transillumination method and apparatus are directed to non-invasive, continuous, atraumatic, in vivo, in situ monitoring of metabolism in a body organ. In the described applications, measuring and reference wavelengths within the near infrared region, i.e., 700-1300 nm, are utilized for non-invasive, continuous, atraumatic, in situ, in vivo monitoring of oxidative metabolism by monitoring oxygen sufficiency in an internal organ, e.g., the brain or heart, of a human or animal body. Advantage is taken of the critical characteristic of cellular enzyme cytochrome a, a₃ within the optical path and within the radiated portion of the selected organ for absorbing the selected measuring wavelength and for light of this measuring wavelength, as well as at least one reference wavelength within the same defined infrared region and at a low, non-hazardous level of intensity to travel through and be detectable at the end of a relatively long path, e.g., of several centimeters length, which may include substantial content of bone as well as soft tissue. The selection of wavelengths, circuitry and method also provide techniques for compensating for changes in blood volume in the organ being monitored, for continuous monitoring of hemoglobin oxygenation and blood volume and for intermittent monitoring of blood flow rate.

Claims

1. A spectrophotometric method for measuring local metabolism of a body organ such as the brain in situ, in vivo, non-invasively, atraumatically, harmlessly, rapidly and continuously, said method comprising the steps:

(a) with the organ positioned in the body in vivo, selecting an optical path intersecting said organ and extending for several centimeters between points of light entry and exit on the surface of the body;

(b) establishing a plurality of near infrared light sources located external of the body and having light emissions of different wavelength in the 700 to 1300 nanometer spectral range and of an intensity below the level damaging to the body and said organ as positioned in the body in vivo but sufficient to be detectable by a light sensor after transmission along said path, said emissions including at least one measuring wavelength and at least one reference wavelength within said spectral range, each said measuring wavelength being selected such that said organ in vivo exhibits a selective absorption therefor, the extent of which is dependent upon a specific state of metabolic activity of said organ in vivo;

(c) directing said light emissions at said measuring and reference wavelengths sequentially along said path and through said organ and receiving the transmitted light emissions at a light sensor and circuit means to produce an electrical output signal representing the difference in absorption of said measuring and reference wavelengths by the organ as a function of the state of said metabolic activity in vivo; and

(d) converting said electrical output signal to a signal providing a substantially continuous and rapid measure of said activity.

2. The method of claim 1 wherein each respective said measuring wavelength is selected within an absorption band of a metabolite, enzyme or other cellular biochemical entity controlling said state of activity and wherein each said reference wavelength to which a respective measuring wavelength is referred is selected so as to be more distant from the peak of the respective said band within which such respective wavelength resides.

3. The method of claim 1 wherein said optical path is linear and said points of light entry and exit are at opposed positions on said body.

4. The method of claim 1 wherein said activity is one of cellular metabolism.

5. The method of claim 4 wherein said activity is that of the redox state of enzyme cytochrome a, a₃.

6. The method of claim 1 wherein said activity is that of hemoglobin oxygenation in said organ.

7. The method of claim 1 wherein said activity relates to local changes in blood volume in said organ.

8. The method of claim 1 including the step of periodically interrupting normal measuring of said metabolism by admitting an agent to said body in a manner enabling such agent to reach said organ and designed to effect a fluctuating change of the absorption properties within said organ over a period of time effecting a corresponding change in said electrical output signal during such time, and recording the intensity of said fluctuating change and the time interval between the beginning and end of said change in the output signal brought about by said agent within said organ as a measure of the blood flow rate to said organ.

9. The method of claim 8 wherein said agent comprises a dye agent.

10. The method of claim 8 wherein said agent comprises a gaseous agent.

11. The method of claim 1 wherein said organ is the heart.

12. The method of claim 1 wherein said activity is that of hemoglobin oxygenation in said organ.

13. The method of claim 1 wherein said activity is that of the redox state of enzyme cytochrome a, a₃ in said organ.

14. The method of claim 1 wherein said activity includes both the redox state of enzyme cytochrome a, a₃ in said organ and the state of hemoglobin oxygenation in said organ, said plural light sources including one measuring wavelength in an absorption band having a peak related to said redox state of enzyme cytochrome a, a₃ and another measuring wavelength in an absorption band having a peak related to said hemoglobin oxygenation and at least one said reference wavelength referable to both measuring wavelengths and operating said sensor and circuit means to produce one electrical output signal for conversion and recording as a measure of said redox state of enzyme cytochrome a, a₃ and another electrical output signal for conversion and recording as a measure of said hemoglobin oxygenation.

15. The method of claim 14 wherein one said measuring length is 840±

15 nanometers for purposes of measuring said redox state of enzyme cytochrome a, a₃ and another said measuring length is 760±

20 nanometers for purposes of measuring said state of hemoglobin oxygenation.

16. The method of claim 1 wherein at least one said measuring wavelength is 760±

20 nanometers and at least one said reference wavelength is an isobestic point for oxygenated and disoxygenated hemoglobin and including the steps of producing said electrical output signal from prior signals corresponding to the respective optical densities of each wavelength and maintaining substantially constant the level of signal corresponding to the optical density of said reference wavelength by voltage feedback to said sensor means and converting the fluctuating voltage of said feedback to an additional signal for recording as a measure of the blood volume to said organ.

17. The method of claim 1 including at least two said reference wavelengths comprising a contrabestic pair or series.

18. The method of claim 1 including the step of introducing into said body during said measuring a compound having the characteristic of differential optical properties in said spectral range affected by the state of said activity when in said organ.

19. The method of claim 1 wherein said organ is the brain.

20. The spectrophotometric method of measuring a local metabolic function of an organ such as the brain of a body in vivo, in situ, non-invasively, harmlessly, rapidly, continuously and atraumatically comprising the steps:

(a) with the organ positioned in the body in vivo, selecting an optical path intersecting said organ and extending for several centimeters between fixed points of light entry and exit on the surface of the body;

(b) establishing a plurality of light sources located externally of the body and having light emissions of different wavelength including at least one measuring wavelength and one reference wavelength, said measuring wavelength characterized by being selected such that said organ in vivo exhibits a selective absorption therefor, the extent of which is dependent upon a specific state of metabolic activity of said organ in vivo and said reference wavelength being selected sufficiently close to said measuring wavelength to be useful as a reference therefor;

(c) directing said light emissions at said measuring and reference wavelengths sequentially to said point of entry to be transmitted along said path to said point of exit and at a level of intensity below the level damaging to the body and said organ in vivo but sufficient to be detectable by a light sensor after transmission along said path;

(d) receiving the transmitted light emissions at a light sensor and circuit means to produce an electrical output signal representing the difference in absorption of said measuring and reference wavelengths by the organ as a function of the state of said metabolic activity in vivo; and

(e) converting said electrical output signal to a signal providing a substantially continuous and rapid measure of said function.

21. The method of measuring according to claim 20, including the step of monitoring the level of sensor signal intensity of said reference wavelength, developing with said light sensor and circuit means a voltage signal corresponding thereto, utilizing said voltage signal as a feedback control for maintaining said reference wavelength sensor signal intensity at some predetermined level and monitoring said feedback voltage signal as a substantially continuous and rapid measure of blood volume of said organ.

22. The method of claim 20 including the step of periodically interrupting normal measuring of said metabolism by admitting an agent to said body in a manner enabling such agent to reach said organ and designed to effect a fluctuating change of the absorption properties within said organ over a period of time effecting a corresponding change in said electrical output signal during such time, and recording the intensity of said fluctuating change and the time interval between the beginning and end of said change in the output signal brought about by said agent within said organ as a measure of the blood flow rate to said organ.

23. A spectrophotometric method for monitoring the local oxygen sufficiency of a body organ such as the brain in vivo, in situ, non-invasively, atraumatically, harmlessly, rapidly and continuously, said method comprising the steps:

(a) providing means for producing near infrared light at different wavelengths in the 700 to 1300 nanometer range and of sufficient intensity to be detectable after transmission along an optical path of several centimeters extending through the body and intersecting said organ but with said intensity being below that which would damage any in vivo body material included in said path;

(b) selecting at least two measuring wavelengths and at least one reference wavelength within said spectral region for transmission through the body organ to be monitored, each said measuring wavelength being selected from within one of the absorption bands of oxidized cytochrome a, a₃ and disoxygenated hemoglobin, and each said reference wavelength being selected from a spectral region within from about 75 nanometers on either side of a measuring wavelength;

(c) with the organ positioned in the body in vivo, locating and fixing the body and said organ with relation to said light means in a position suited for transillumination therethrough along an optical path of several centimeters extending through said body and intersecting said organ;

(d) causing beams of light at each measuring and reference wavelength to be focused in alternating sequence on one side of the body so as to effect entry therein and passage along said path through said body intersecting said organ and then to a point of exit from said body;

(e) detecting the light emerging from said body at the point of exit therefrom and electrically converting the received light intensity to an output signal for each measuring wavelength compared to a selected reference wavelength and representing the difference in absorption as a function of the different wavelengths compared; and

(f) electrically converting each such output signal to a signal as a substantially continuous and rapid representation of said oxygen sufficiency of said organ in vivo.

24. The method in accordance with claim 23 wherein the Hb-HbO₂ isobestic point at 815±

5 nanometers is selected as the reference wavelength.

25. The method in accordance with claim 23 wherein a measuring wavelength at 840±

15 nanometers and a reference wavelength at 815±

5 nanometers are used to monitor the redox state of the cellular enzyme cytochrome a, a₃.

26. The method in accordance with claim 23 wherein a measuring wavelength at 760±

20 nanometers and a reference wavelength at 815±

5 nanometers are used to monitor the oxygenation state of hemoglobin.

27. The method in accordance with claim 23 including at least two said reference wavelengths comprising a contrabestic pair or series.

28. A spectrophotometric method for monitoring local changes in blood volume and in metabolism as indicated in the redox state of cytochrome a, a₃ and the oxygenation state of homoglobin in an intact organ such as the brain of the human or animal body and wherein said monitoring is accomplished in vivo, in situ, harmlessly, rapidly, continuously and atraumatically, said method comprising:

(a) providing a first source of near infrared light having a wavelength in the absorption band of oxidized cytochrome a, a₃, a second source of such light having a wavelength in the absorption band of disoxygenated hemoglobin and a third source having a wavelength at the 815±

5 nanometers isobestic point of hemoglobin, the latter wavelength being selected to provide a reference against which the others may be measured;

(b) with the organ positioned in the body in vivo, directing the separate wavelengths of said near infrared light in alternating sequence and at a level of intensity below that which would be damaging to the body and organ in vivo at one fixed entry point on the body under test so as to effect an optical pathway into and through the organ and then to a fixed point of exit several centimeters therefrom elsewhere on the body;

(c) detecting the light emerging from said body after passage through said organ by means of electrically operated photon sensor means having a voltage supply controlled by a feedback circuit;

(d) converting the detected light energy into electrical signals for each wavelength while regulating changes in the voltage supply of said photon sensor means to maintain a constant signal at the reference wavelength;

(e) measuring the intensity of said electrical signals and determining the quantitative differences in intensity between the measuring and reference signals;

(f) converting said differences to corresponding optical density values; and

(g) continuously recording said optical density values as a substantially continuous and rapid measure of said metabolism in vivo together with the changes in the voltage supplied to said photon sensor means as a substantially continuous and rapid measure of said blood volume in vivo.

29. The method in accordance with claim 28 wherein a wavelength at about 840 nanometers is used to monitor the redox state of cytochrome a, a₃.

30. The method in accordance with claim 28 wherein a wavelength at about 760 nanometers is used to monitor the oxygenation state of hemoglobin.

31. The method in accordance with claim 28 wherein the organ monitored is the heart.

32. The method in accordance with claim 28 wherein the organ monitored is the brain.

33. A spectrophotometric method for continuously, in vivo, in situ, harmlessly, rapidly and atraumatically monitoring local changes in blood volume and in metabolism as indicated in the redox state of cytochrome a, a₃ and the oxygenation state of hemoglobin in an intact organ such as the brain of the human or animal body, said method comprising:

(a) providing a first source of near infrared light having a wavelength in the absorption band of oxidized cytochrome a, a₃, a second source of such light having a wavelength in the absorption band of disoxygenated hemoglobin and a third source having a wavelength at the 815±

5 nanometers isobestic point of hemoglobin, the latter wavelength being selected to provide a reference against which the others may be measured;

(b) with the organ positioned in the body in vivo, directing the separate wavelengths of said near infrared light in alternating sequence at a level of intensity below that which would be damaging to the organ in vivo and to a fixed point of entry on the body under test so as to effect an optical pathway of at least 4 centimeters in length into and through the organ and to a fixed point of exit elsewhere on the body;

(c) detecting the light emerging from said body after passage through said organ;

(d) measuring the detected light for each of the separate wavelengths by means of photon counter means;

(e) determining the quantitative differences in intensity between the light measured at the measuring and reference wavelengths;

(f) converting said differences to corresponding optical density values; and

(g) recording said optical density values together with the changes in the optical density values at the reference wavelength.

34. The method in accordance with claim 33 wherein a wavelength at about 840 nanometers is used to monitor the redox state of cytochrome a, a₃.

35. The method in accordance with claim 33, wherein a wavelength at about 760 nm is used to monitor the oxygenation state of hemoglobin.

36. The method in accordance with claim 33 wherein the organ monitored is the heart.

37. The method in accordance with claim 33 wherein the organ monitored is the brain.

51. The apparatus of claim 37 wherein said light sources and means for operating said light sources are adapted to produce a pair of said reference wavelengths comprising a contrabestic pair.

38. Apparatus for measuring metabolism of a body organ such as the brain in situ, in vivo, non-invasively, atraumatically, harmlessly, rapidly and continuously comprising:

(a) a plurality of near infrared light sources located external of the body and having light emissions of different wavelength in the 700 to 1300 nanometer spectral range and of an intensity below the level damaging to the body and said organ in vivo but sufficient to be detectable by a light sensor after transmission along an optical path extending for several centimeters between a pair of points of light source attachment and sensor attachment on the surface of the body and intersecting said organ;

(b) means for sequentially operating said light sources to produce at least one measuring wavelength and at least one reference wavelength within said spectral range for transmission along said path and through said organ and at levels of intensity below that which would be damaging to the body and said organ in vivo, each said measuring length being of a value for which said organ in vivo exhibits an absorption band for a specific state of metabolic activity, the absorption peak of which changes as said in vivo state of activity changes, said measuring wavelength being of a value to reside within said band and closer to said peak than said reference wavelength;

(c) attachment means for fixing the output of said light sources to a selected fixed light entry point on said body enabling transmission of said light emissions from said light sources along said path and through said organ such that the absorption thereof becomes dependent upon the in vivo state of said metabolic activity of said organ;

(d) means for receiving the transmitted light emissions including a light sensor fixed to a selected fixed light exit point on said body spaced along said path several centimeters from said entry point and circuit means to produce for each wavelength a reference signal corresponding to the optical density thereof at said sensor and to produce from such reference signals an electrical output representing the difference in absorption of the organ as a function of each respective set of compared measuring and reference wavelengths and the in vivo state of said metabolic activity in said organ; and

(e) means for receiving said electrical output and converting the same to a signal providing a substantially continuous and rapid measure of said activity.

(e) means for receiving said electrical output and converting the same to a signal to be displayed as a measure of said activity.

39. The apparatus of claim 38 wherein said optical path is intended to be linear and said light source attachment means and said light sensor fixation are adapted for opposed positions on said body.

40. The apparatus of claim 38 wherein said activity is one of cellular metabolism and said wavelengths operate in reference.

41. The apparatus of claim 38 wherein said activity is one of cellular oxidative metabolism and said wavelengths operate in reference thereto.

42. The apparatus of claim 41 wherein said activity is that of the redox state of enzyme cytochrome a, a₃ and said wavelengths operate in reference thereto.

43. The apparatus of claim 38 wherein said activity is that of hemoglobin oxygenation in said organ and said wavelengths operate in reference thereto.

44. The apparatus of claim 38 wherein said activity is that of local changes in blood volume in said organ, including means for establishing a feedback voltage to maintain at some predetermined level the said reference signal corresponding to a selected said reference wavelength and monitoring said voltage as a measure of said volume.

45. The apparatus of claim 38 wherein said organ is the heart of said body and including means for monitoring the heart beat of said body and triggering said light sources such that said transmitting is accomplished at selected times in rhythm with a selected state of the heart of said body.

46. The apparatus of claim 38 wherein said measured activity is that of the redox state of enzyme cytochrome a, a₃ in said organ.

47. The apparatus of claim 38 wherein said measured activity is that of hemoglobin oxygenation in said organ.

48. The apparatus of claim 38 wherein said measured activity includes both the redox state of enzyme cytochrome a, a₃ and the state of hemoglobin oxygenation in said organ, said plural light sources include one measuring wavelength in an absorption band related to said redox state of enzyme cytochrome a, a₃ and another measuring wavelength in an absorption band related to said hemoglobin oxygenation and at least one said reference wavelength referable to both measuring wavelengths, said signal receiving and converting means being adapted to producing one output signal for conversion to provide a substantially continuous and rapid measure of said redox state of enzyme cytochrome a, a₃ and another output signal for conversion to provide a substantially continuous and rapid measure of said hemoglobin oxygenation.

49. The apparatus of claim 48 wherein one said measuring wavelength is 840±

15 nanometers for purposes of measuring said redox state of enzyme cytochrome a, a₃ and another said measuring wavelength is 760±

20 nanometers for purposes of measuring said hemoglobin oxygenation.

50. The apparatus of claim 50 wherein said measuring wavelength is 760±

20 nanometers and said reference wavelength corresponds with an isobestic point for oxygenated and disoxygenated hemoglobin and including means for maintaining substantially constant the level of received signal corresponding to said reference wavelength by voltage feedback to said sensor means and converting the fluctuating voltage of said feedback to an additional signal for display as a measure of the blood volume to said organ.

54. The apparatus of claim 50 wherein the Hb-HbO₂ isobestic point at 815+5 nanometers comprises a said reference wavelength.

55. The apparatus of claim 54 wherein one said measuring wavelength comprises 840+15 nanometers and one said reference wavelength comprises 815+5 nanometers and being operative to monitor the redox state of the cellular enzyme cytochrome a, a₃.

56. The apparatus of claim 54 wherein one said measuring wavelength comprises 760+20 nanometers and one said reference wavelength comprises 815+5 nanometers and being operative to monitor the oxygenation state of hemoglobin.

52. Apparatus for measuring a local metabolic oxygen dependent function of an organ such as the brain of a body in situ, in vivo, non-invasively, atraumatically, harmlessly, rapidly and continuously where such function bears a measurable relation to an oxygen dependent absorption characteristic of the organ in vivo for a particular wavelength of light transmitted therethrough, comprising:

(a) a source of light productive of a wavelength within the range of 700 to 1300 nanometers and of a value for which said organ in vivo exhibits an absorption band for a specific state of an oxygen dependent metabolic activity the absorption peak of which changes as said in vivo state of activity changes with variations in oxygen supply to said organ, said light being of sufficient intensity to penetrate and pass through said body along an optical path of several centimeters length which includes such organ but below that level of intensity which would damage said organ in vivo or any in vivo portion of the body included in said path;

(b) means for directing said light along a said path of several centimeters length from a place of entry on said body through said organ and to another place of exit on said body; and

(c) means for receiving the transmitted light with sensor and circuit means and developing therewith for display a signal representative of the state of said oxygen dependent activity.

53. A spectrophotometric apparatus for monitoring the local oxygen sufficiency of a body organ such as the brain in vivo, in situ, non-invasively, atraumatically, harmlessly, rapidly and continuously, comprising:

(a) means for producing near infrared light at different wavelengths in the 700 to 1300 nanometer range and of sufficient intensity to be detectable after transmission for several centimeters along an optical path extending through the body and intersecting said organ but with said intensity being below that which would damage said organ in vivo or any in vivo portion of said body included in said path;

(b) means for selecting at least one measuring wavelength and at least one reference wavelength within said spectral region for transmission through the in vivo body organ to be monitored, each said measuring wavelength being selected from within one of the absorption bands of oxidized cytochrome a,a₃ and disoxygenated hemoglobin, and each said reference wavelength being selected from a spectral region withn from about 75 nanometers on either side of a measuring wavelength;

(c) means for locating and fixing the in vivo body and said organ with relation to said light means in a position suited for transillumination therethrough along an optical path of several centimeters length extending through said body and intersecting said organ;

(d) means for directing said light at each measuring and reference wavelength and in alternating sequence to one location on the body so as to effect entry therein and passage along a said path of several centimeters length through said body intersecting said organ and then to a point of exit from said body;

(e) means for detecting the light emerging from said body at the point of exit therefrom, comparing measuring and reference wavelength intensities and electrically converting the received light to an output signal for each measuring and reference wavelength compared and representing the difference in absorption thereof by said organ in vivo as a function of the different wavelengths; and

(f) means for converting each such output signal to a signal substantially continuously and rapidly representative of the changes in the absorption band to which the respective measuring-reference wavelengths are related.

57. A spectrophotometric apparatus for monitoring local changes in blood volume, the redox state of cytochrome a, a₃ and the oxygenation state of hemoglobin in an intact organ such as the brain of the human or animal body and wherein said monitoring is accomplished in vivo, in situ, harmlessly, rapidly, continuously and atraumatically, comprising:

(a) plural light sources including a first source of near infrared light having a wavelength in the absorption band of oxidized cytochrome a, a₃, a second source of such light having a wavelength in the absorption band of disoxygenated hemoglobin and a third source having a wavelength at the 815+5 nanometers isobestic point of hemoglobin, the latter wavelength being selected to provide a reference against which the others may be measured;

(b) means for directing the separate wavelengths of said near infrared light in alternating sequence to the in vivo body under test so as to effect an optical pathway of several centimeters length which enters the body, passes through the organ and emerges from the body

(c) means for detecting the light emerging from said body after passage through said organ including photon sensor means having a voltage supply controlled by a feedback circuit;

(d) means for converting the detected light energy into electrical signals while regulating changes in the voltage supply of said photon sensor means to maintain a constant signal at the reference wavelength;

(e) means for measuring the intensity of said electrical signals, determining the quantitative differences in intensity between the measuring and reference signals and converting said differences to corresponding optical density values; and

(f) means for recording said optical density values together with the changes in the voltage supplied to said photon sensor means.

58. The apparatus of claim 57 wherein said wavelength at about 840 nanometers is operative to monitor the redox state of cytochrome a, a₃.

59. The apparatus of claim 57 wherein said wavelength at about 760 nanometers is operative to monitor the oxygenation state of hemoglobin.

60. The apparatus of claim 57 wherein said light sources and said means are adapted for monitoring the heart as said organ.

61. The apparatus of claim 57 wherein said light sources and said means are adapted for monitoring the brain as said organ.

62. A spectrophotometric method for localization of an area of pathological change in metabolism of a body organ such as the brain by measuring local metabolism in selected areas thereof in situ, in vivo, non-invasively, atraumatically, harmlessly, rapidly and continuously, said method comprising the steps:

(a) with the organ positioned in the body in vivo, selecting a plurality of optical paths of several centimeters length intersecting various areas of said organ and extending between various separate three dimensionally located points of entry and exit on the surface of the body;

(b) establishing light source means external of the body and having light emissions of different wavelength and of an intensity below the level damaging to the body and said organ in vivo but sufficient to be detectable by a light sensor after transmission along a said path, said emissions including at least one measuring wavelength and at least one reference wavelength within some spectral range, each said measuring wavelength being selected such that said organ in vivo exhibits a selective absorption therefor, the extent of which is dependent upon a specific in vivo state of metabolic activity associated with said organ;

(c) directing said light emissions at said measuring and reference wavelengths along each of said paths in sequence and through the respective areas of said organ intersected thereby and sequentially receiving the transmitted light emissions at respective light sensor and circuit means associated with the said points of exit to produce an electrical output signal for each said path representing the difference in absorption of said measuring and reference wavelengths by the area of the organ transilluminated therewith as a function of the in vivo state of said metabolic activity in each said respective area thereof; and

(d) converting said electrical output signals to a representation of the localization of said area of change in said organ.

63. The method of claim 62 wherein said light emissions are all in the 700 to 1300 nanometer spectral range.

64. The method of claim 63 wherein said light source means are plural and at least one such light source means is fixed relative to said body at each said point of entry and said light sensor means are plural and at least one said light sensor means is fixed relative to said body at each said point of exit.

65. Apparatus for determining localization of an area of pathological change in metabolism of a body organ such as the brain by measuring local metabolism in selected areas thereof in situ, in vivo, non-invasively, atraumatically, harmlessly, rapidly and continuously, comprising:

(a) a near infrared light source means located external of the body and having light emissions of difference wavelength and of an intensity below the level damaging to the body and said organ in vivo but sufficient to be detectable by a light sensor after transmission along an optical path of several centimeters length extending between points of light source entry and exit on the surface of the body and intersecting an area of said organ;

(b) means for operating said light source means to produce in sequence at least one measuring wavelength and at least one reference wavelength suited for transmission along a selected said optical path and through a selected area of said organ and at levels of intensity below that which would be damaging to the body and said organ area in vivo, each said measuring wavelength being of a value for which said organ area in vivo exhibits an absorption band for a specific state of metabolic activity, the absorption peak of which changes as said in vivo state of activity changes, said measuring wavelength being of a value to reside within said band and closer to said peak than said reference wavelength;

(c) light directing means connected to said light source means and enabling the output of said light source means to be directed to a plurality of fixed three dimensionally spaced light entry points on said body in a predetermined sequence for transmission of said light emissions from said light source means for several centimeters along respective said optical paths and sequentially through said areas of said organ intersected by said paths and then from said body to respective points of exit such that the absorption thereof becomes dependent upon the respective in vivo state of said metabolic activity in the respective areas of said organ;

(d) light receiving means adapted for receiving the transmitted light emissions at said points of exit in a predetermined sequence coordinated with the sequential entry at said entry points, said light receiving means including for each point of exit a light sensor and circuit means to produce for each wavelength and sequentially for each point of exit a signal corresponding to the optical density thereof at the respective exit point sensor and to produce from such signals an electrical output for each exit point in sequence representing the difference in absorption of the organ area illuminated with the respective path as a function of each respective set of compared measuring and reference wavelengths transmitted therethrough and the in vivo state of said metabolic activity in the respective area of said organ; and

(e) means for sequentially storing and converting said outputs to a representation of location, size and shape of said area of pathological change.

66. The apparatus of claim 65 wherein said light emissions are all in the 700 to 1300 nanometer spectral range.

67. The apparatus of claim 65 wherein said light source means comprise plural light sources each productive of said measuring and reference wavelengths and including means to fix one of said light sources to said body at each said point of entry and wherein said light receiving means includes plural said light sensors and including means to fix one said sensor to said body at each said point of exit.