TRAUMATIC BRAIN INJURY DETECTION

Abstract

Apparatus for the non-invasive in-vivo determination of changes in tissue, e.g. the myelination, of the optic nerve (ON) in a biological subject, said apparatus comprising: a laser source for generating an excitation laser beam; an optical system including a fundus camera operatively associated with the laser source for use in obtaining a fundus image for illuminating the optic nerve (ON) of a subject with the excitation laser beam; a detector (13) operatively associated with the optical system and configured to detect a Raman spectrum from the optic nerve (ON) and/or surrounding cerebral spinal fluid; and a processor provided with a computer program for comparing the detected Raman spectrum to at least one reference spectrum. The reference spectrum may correspond to the myelination of the optic nerve in a normal, healthy subject, for determining the changes in the myelination of the optic nerve of the subject based on the detecting and comparing steps from the Raman spectrum.

Claims

1-22. (canceled)

23. Apparatus for the non-invasive in-vivo determination of changes in tissue, e.g., the myelination, of the optic nerve in a biological subject, said apparatus comprising: i. a laser source for generating an excitation laser beam; ii. an optical system including a fundus camera operatively associated with the laser source for use in obtaining a fundus image for illuminating the optic nerve of a subject with the excitation laser beam; iii. a detector operatively associated with the optical system and configured to detect a Raman spectrum from the optic nerve and/or surrounding cerebral spinal fluid; and a processor operable to compare the detected Raman spectrum to at least one reference Raman spectrum of an optic nerve and/or surrounding cerebral spinal fluid of a healthy subject, the reference spectrum preferably corresponding to the myelination of the optic nerve in a normal, healthy subject, for determining the changes in the myelination of the optic nerve of the subject based on the detecting and comparing steps from the Raman spectrum, wherein the optical system further comprises: a short pass dichroic mirror filter configured to transmit visible light for obtaining the fundus image whilst reflecting laser and Raman scattered light; and a long pass dichroic mirror filter configured to reflect light emitted from the excitation laser source and to transmit resonance Raman scattered light.

24. Apparatus according to claim 23, wherein the laser source comprises a class I laser capable of emitting laser light above 400 nm wavelength.

25. Apparatus according to claim 23, wherein the optical system comprises a hand-held computing device with a fundus camera attachment, and the hand-held computing device is one of a tablet computer and a smartphone.

26. Apparatus according to claim 25, wherein the hand-held computing device is operable to provide white light illumination.

27. Apparatus according to claim 23, wherein the optical system comprises at least one further short pass filters, and at least one further long pass filters.

28. Apparatus according to claim 23, further comprising a support configured to hold the laser source, the optical system including the fundus camera and the detector.

29. Apparatus according to claim 23, further comprising a head mount to mount at least the optical system and a fundus camera to the head of a patient.

30. Apparatus according to claim 23, comprising a controller operable to move the excitation laser beam across the optic nerve of the subject.

31. Apparatus according to claim 30, wherein the controller is operable to move the excitation laser beam across the optic nerve of the subject by reference to an image obtained by the fundus camera.

32. A method of analyzing an optic nerve of a subject, the method comprising: a. generating an excitation laser beam; b. causing the excitation laser beam to illuminate an optic nerve of a subject; c. detecting a Raman spectrum from the illuminated region of the optic nerve, wherein the method further comprises, simultaneously: using a fundus camera to obtain an image of the retina and/or optic nerve of the eye of the subject; and using the fundus image to guide illumination the optic nerve of the subject with the laser beam.

33. A method according to claim 32, comprising illuminating the optic nerve with laser light having a wavelength of from 400 to 1000 nm.

34. An in-vivo non-invasive method for determining changes in the tissue of the optic nerve in a biological subject, the method comprising: a. generating an excitation laser beam; b. causing the excitation laser beam to illuminate an optic nerve of a subject; c. detecting a Raman spectrum from the illuminated region of the eye; d. comparing the Raman spectrum from step c to at least one predetermined reference spectrum corresponding to the tissue of the optic nerve in a healthy subject; e. determining changes to the optic nerve of the subject based on step d, wherein the method further comprises, simultaneously: using a fundus camera to obtain an image of the retina and/or optic nerve of the eye of the subject; and using the fundus image to guide illumination the optic nerve of the subject with the laser beam.

35. A method according to claim 34, comprising a further step f of determining changes in the myelination of the optic nerve.

36. A method according to claim 34, comprising qualitatively or quantitatively determining changes in the tissue of the optic nerve in a biological subject.

37. A method according to claim 34, comprising using the fundus image to focus the excitation laser beam through a short pass filter and into the eye of the subject to illuminate the optic nerve.

38. A method according to claim 34, comprising rastering the excitation laser beam across the optic nerve to obtain Raman spectra from different locations on the optic nerve.

39. A method according to claim 38, comprising controlling the rastering of the excitation laser beam using electric control circuitry.

40. A method according to claim 39, wherein the electric control circuitry is operable to control the rastering in reference to a fundus image of the optic nerve.

41. A method according to claim 34, comprising illuminating the optic nerve with laser light having a wavelength of from 400 to 1000 nm.

42. A method according to claim 34, comprising a further step of comparing Raman bands between 2000 to 3500 cm.sup.−1 within the Raman spectrum from the detecting step to at least one predetermined reference spectrum.

Description

[0073] Embodiments of the invention will now be described by way of example only with reference to the accompanying drawings in which:

[0074] FIG. 1 is a schematic representation of an apparatus according to an embodiment of the invention; and

[0075] FIG. 2 is a schematic representation of an apparatus according to a further embodiment of the invention;

[0076] FIG. 3A is shown an eye model comprising bacon fat for testing the method and apparatus of the invention;

[0077] FIG. 3B is a fundus image of the bacon fat of FIG. 3A;

[0078] FIG. 4 is a Raman spectrum of the bacon fat of FIG. 3A, recorded with the apparatus of FIG. 2.

[0079] Referring now to FIG. 1, there is shown an apparatus 1 for obtaining a Raman spectrum of the optic nerve ON of an eye E according to an embodiment of the invention. The apparatus is for use in non-invasive in-vivo determination of changes in the myelination of the optic nerve in a biological subject.

[0080] The apparatus 1 comprises a laser source 10, a fundus camera 11, a white light source 12, and a detector 13. The apparatus 1 further comprises a mirror 14, a beam splitter 15, a first dichroic mirror filter 16, a second dichroic mirror filter 17, a laser line filter 18, and a Rayleigh filter 19.

[0081] There is shown a white light path ‘a’ from the white light source 12 to the optic nerve ON for use by the fundus camera 11. There is also shown a laser light path ‘b’ from the laser source 10, and a Raman light path ‘c’ from scattering of the excitation laser light from the laser source 10.

[0082] In use, the white light source 12 provides white light, which follows the path a. The white light is reflected from the mirror 14 and the beam splitter 15 sequentially to reach the optic nerve ON of the eye E. Simultaneously, the laser source 10 also provides an excitation laser beam, which follows path b. The white light is used by the fundus camera 11 to obtain an image (not shown) of the optic nerve ON of the eye E. The image (not shown) is used to focus the excitation laser beam into the eye E so that the optic nerve ON is illuminated. The Raman scattered light from the optic nerve ON, following path c, is then detected by the detector 13. A processor (not shown) is used to compare the recorded Raman spectrum to at least one predetermined reference spectrum corresponding to an ‘healthy’ state of the optic nerve, for example the myelination of the optic nerve in a normal, healthy subject. This information is usable to determine any changes in the state (e.g. myelination) of the optic nerve, which may be used to detect traumatic brain injury and to guide the need for or type of clinical intervention.

[0083] The inventors have found that obtaining a fundus image of the optic nerve is essential to recording a usable Raman spectrum. This is because fundus image enables the excitation laser beam to be accurately focused into the eye such that the optic nerve is illuminated.

[0084] Advantageously, this enables a Raman spectrum of the optic nerve and the surrounding cerebral spinal fluid to be recorded non-invasively and in real-time.

[0085] The processor (not shown) may undergo “machine learning”. The processor may have the ability to automatically categorize Raman spectra of an optic nerve of the same or different subjects, recorded in previous tests without being explicitly programmed.

[0086] Referring now to FIG. 2, there is shown an apparatus 2 according to a second embodiment of the invention.

[0087] In this embodiment, the apparatus 2 comprises a laser source 20, a smart phone 21 with a fundus camera attachment 22, and a detector 23.

[0088] The apparatus 2 further comprises a first dichroic mirror filter 24, a second dichroic mirror filter 25, a laser line filter 26, and a filter 27.

[0089] There is also shown the white light path ‘a’, the laser light path ‘b’, and the Raman light path ‘c’, as described for FIG. 1.

[0090] The laser source 20 is a 635 nm Class I eye-safe laser comprising an FC/PC FibrePort and mount. The smart phone 21 is an iPhone 7® and the fundus camera attachment 22 was purchased from D-EYE® (77 35131 Padova PD—Italy). The detector 23 comprises an SMA fibre port and mount lead to a QE Pro® 635 spectrometer.

[0091] The first dichroic mirror filter 24 is a 635 nm short pass dichroic mirror, the second dichroic mirror filter 25 is a 635 nm long pass dichroic mirror, the laser line filter 26 is a 635 nm laser line filter, and the filter 27 is a 650 nm long pass filter.

[0092] The apparatus 2 functions in a similar manner to that described for FIG. 1. The white light is provided by the smart phone 21 for the fundus camera attachment 22 to obtain an image of the optic nerve ON.

[0093] Advantageously, the first dichroic mirror filter (16; 24) is operable to allow the Raman spectrometer (detector 13, 23) and the fundus camera (12, 22) to be used together This is because the filter (16, 24) transmits the low wavelength, visible light used for fundus imaging whilst reflecting the high wavelength laser and Raman scattered light.

[0094] Referring now to FIG. 3A, there is shown an eye model 3A comprising bacon fat BF. This was designed to mimic the fatty tissue that makes up the optic disk. Referring also to FIG. 3B, there is shown a fundus image 3B obtained using the apparatus 2 of FIG. 2 of the bacon fat in the eye model 3A of FIG. 3A.

[0095] Referring now to FIG. 4, there is shown a Raman spectrum 4 obtained using the apparatus of FIG. 2. The Raman spectrum 4 was recorded using bacon fat in the eye model shown in FIG. 3 using 60 s acquisition with a 635 nm laser.

[0096] Once a Raman spectrum of the optic nerve of the eye is obtained using the apparatus it is possible to compare the spectrum, e.g. visually or automatically, with a library spectrum to determine if a specific signature signal (i.e. one or more characteristic Raman peaks) is present. Once the absence or presence of a specific signature signal has been detected methods may be deployed to quantify the reduction or increase in the specific signature signal to determine a deviation vis-à-vis the library spectrum and thence infer or calculate a condition.

[0097] It will be appreciated by those skilled in the art that several variations to the aforementioned embodiments are envisaged without departing from the scope of the invention.

[0098] It will also be appreciated by those skilled in the art that any number of combinations of the aforementioned features and/or those shown in the appended drawings provide clear advantages over the prior art and are therefore within the scope of the invention described herein.