Title: Examination of subjects using photon migration with high directionality techniques
Abstract: A spectroscopic method and system for examination of biological tissue includes multiple input ports optically connected to at least one light source, multiple detection ports optically connected to at least one detector, a radiation pattern controller coupled to the light source and detector, and a processor. The multiple input ports are arranged to introduce light at input locations into biological tissue and the multiple detection ports are arranged to collect light from detection locations of the biological tissue. The radiation pattern controller is constructed to control patterns of light introduced from the multiple input ports and constructed to control detection of light migrating to the multiple detection ports. The processor is operatively connected to the radiation pattern controller and connected to receive detector signals from the detector, and is constructed to examine a tissue region based on the introduced and detected light patterns.
Patent Number: 7,010,341 Issued on 03/07/2006 to Chance
| Inventors:
|
Chance; Britton (Marathon, FL)
|
| Assignee:
|
NonInvasive Technology, Inc. (Philadelphia, PA)
|
| Appl. No.:
|
924152 |
| Filed:
|
August 7, 2001 |
| Current U.S. Class: |
600/476; 600/473 |
| Current Intern'l Class: |
A61B 5/00 (20060101) |
| Field of Search: |
600/473,476,407
356/317,318,319,450,451,456,484
|
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|
Primary Examiner: Mercader; Eleni Mantis
Attorney, Agent or Firm: Zitkovsky; Ivan David
Parent Case Text
This application is a continuation and claims the benefit of priority under
35 USC 120 of U.S. application Ser. No. 09/153,051, filed Sep. 15, 1998, now U.S.
Pat. No. 6,272,367, which is a continuation of U.S. application Ser. No. 08/356,162,
filed Dec. 16, 1994, now U.S. Pat. No. 5,807,263, which is a 371 of PCT/US93/05868,
filed Jun. 17, 1993, which is a CIP of U.S. application Ser. No. 07/900,197, filed
Jun. 17, 1992, now U.S. Pat. No. 5,353,799. The disclosures of the prior applications
are considered part of (and are incorporated by reference in) the disclosure of
this application.
Claims
What is claimed is:
1. A spectroscopic system for imaging biological tissue comprising:
multiple input ports arranged to introduce light at input locations into biological
tissue and multiple detection ports arranged to collect light from detection locations
of the biological tissue,
at least one light source, operatively connected to a radiation pattern controller,
constructed to generate light of a wavelength in a range from visible to infrared,
said light source optically coupled to at least one of said input ports;
at least one detector, operatively connected to said radiation pattern controller,
constructed and arranged to detect light of said wavelength that has migrated in
the tissue region to at least one detection location and corresponding at least
one of said detection ports; and
a processor operatively connected to received detector signal from said detector
and provided and image.
2. The spectroscopic system of claim 1 wherein said radiation pattern controller
is constructed to control intensity of said introduced light.
3. The spectroscopic system of claim 1 wherein said radiation pattern controller
is constructed to control phase of said introduced light.
4. The spectroscopic system of claim 3 including an amplitude detector for detecting
amplitude of said fluorescent light.
5. The spectroscopic system of claim 1 wherein said radiation pattern controller
is cooperatively constructed and arranged with said light source to generate said
light modulated at a frequency on the order of 10
8 Hz.
6. The spectroscopic system of claim 1, wherein said excitation wavelength is
selected to be absorbed by an endogenous pigment in the examined tissue emitting
said fluorescent light.
7. The spectroscopic system of claim 1, wherein said excitation wavelength is
selected to be absorbed by an exogenous pigment emitting said fluorescent light.
8. The spectroscopic system of claim 1 further including an interference filter,
said filter being arranged to pass to said detector mainly said fluorescent light
excited in the examined tissue.
9. The spectroscopic system of claim 1, wherein said light source includes a
laser diode.
10. The spectroscopic system of claim 1, wherein said light source includes a
light emitting diode (LED).
11. The spectroscopic system of claim 1, wherein said detector includes a diode detector.
12. The spectroscopic system of claim 1, wherein said detector includes a photomultiplier.
13. A method of spectroscopic examination and imaging of biological tissue, comprising:
providing a radiation pattern controller coupled to a light source, and a detector,
introducing into the biological tissue electromagnetic non-ionizing radiation
of an excitation wavelength, said radiation having a known time-varying pattern
of photon density,
detecting over time fluorescent radiation emitted from a fluorescent constituent
located in the tissue,
processing signals of said detected fluorescent radiation in relation to said
introduced radiation to create processed data indicative of location of said fluorescent
constituent, including determining location of said fluorescent constituent of
the subject by correlating said fluorescent radiation with irradiation and detection
locations, and
providing an image.
14. The spectroscopic method of claim 13, including introducing said excitation
wavelength being selected to be absorbed by an endogenous pigment in the examined
tissue comprising said fluorescent constituent emitting said fluorescent radiation.
15. The spectroscopic method of claim 13, including introducing an exogenous
pigment into the tissue, said exogenous pigment comprising said fluorescent constituent
emitting said fluorescent radiation.
16. The spectroscopic method of claim 13 including controlling intensity of said
introduced radiation utilizing said radiation pattern controller.
17. The spectroscopic method of claim 16, including detecting amplitude of said
fluorescent radiation using an amplitude detector.
18. The spectroscopic method of claim 13 including controlling a phase of said
introduced radiation utilizing said radiation pattern controller.
19. The spectroscopic method of claim 18, including detecting phase of said fluorescent radiation.
20. The spectroscopic method of claim 13, wherein said radiation pattern controller
said radiation pattern controller is cooperatively constructed and arranged with
said light source to generate said introduced radiation being modulated at a frequency
on the order of 10
8 Hz.
Description
BACKGROUND OF THE INVENTION
This invention relates to examination and imaging of biological tissue using
visible or infra-red radiation.
Traditionally, potentially harmful ionizing radiation (for example,
X-ray or γ-ray) has been used to image biological tissue. This radiation
propagates in the tissue on straight, ballistic tracks, i.e., scattering of the
radiation is negligible. Thus, imaging is based on evaluation of the absorption
levels of different tissue types. For example, in roentgenography the X-ray film
contains darker and lighter spots. In more complicated systems, such as computerized
tomography (CT), a cross-sectional picture of human organs is created by transmitting
X-ray radiation through a section of the human body at different angles and by
electronically detecting the variation in X-ray transmission. The detected intensity
information is digitally stored in a computer which reconstructs the X-ray absorption
of the tissue at a multiplicity of points located in one cross-sectional plane.
Near infra-red radiation (NIR) has been used to study non-invasively the oxygen
metabolism in tissue (for example, the brain, finger, or ear lobe). Using visible,
NIR and infra-red (IR) radiation for medical imaging could bring several advantages.
In the NIR or IR range the contrast factor between a tumor and a tissue is much
larger than in the X-ray range. In addition, the visible to IR radiation is preferred
over the X-ray radiation since it is non-ionizing; thus, it potentially causes
fewer side effects. However, with lower energy radiation, such as visible or infra-red
radiation, the radiation is strongly scattered and absorbed in biological tissue,
and the migration path cannot be approximated by a straight line, making inapplicable
certain aspects of cross-sectional imaging techniques.
Recently, certain approaches to NIR imaging have been suggested. One approach
undertaken by Oda et al. in "Non-Invasive Hemoglobin Oxygenation Monitor and Computerized
Tomography of NIR Spectrometry," SPIE Vol. 1431, p. 284, 1991, utilizes NIR radiation
in an analogous way to the use of X-ray radiation in an X-ray CT. In this device,
the X-ray source is replaced by three laser diodes emitting light in the NIR range.
The NIR-CT uses a set of photomultipliers to detect the light of the three laser
diodes transmitted through the imaged tissue. The detected data are manipulated
by a computer of the original X-ray CT scanner system in the same way as the detected
X-ray data would be.
Different approaches were suggested by S. R. Arriadge et al. in "Reconstruction
Methods for Infra-red Absorption Imaging," SPIE Vol. 1431, p. 204, 1991; F. A.
Grünbaum et al. in "Diffuse Tomography," SPIE Vol. 1431, p. 232, 1991; B.
Chance et al., SPIE Vol. 1431 (1991), p. 84, p. 180, and p. 264; and others who
recognized the scattering aspect of the non-ionizing radiation and its importance
in imaging. None of those techniques have fully satisfied all situations.
In summary, there continues to be a need for an improved imaging system which
utilizes visible or IR radiation of wavelengths sensitive to endogenous or exogenous pigments.
SUMMARY OF THE INVENTION
The invention relates to systems and methods for spectroscopic examination of
a subject positioned between input and detection ports of the spectroscopic system
applied to the subject.
According to one aspect of the invention, a spectroscopic system includes
at least one light source adapted to introduce, at multiple input ports, electromagnetic
non-ionizing radiation of a known time-varying pattern of photon density and of
a wavelength selected to be scattered and absorbed while migrating in the subject,
the input ports being placed at selected locations on the subject to probe a selected
quality of the subject; and radiation pattern control means adapted to achieve
selected a time relationship of the introduced patterns to form resulting radiation
that possesses a substantial gradient in photon density as a result of the interaction
of the introduced patterns emanating from the input ports, the radiation being
scattered and absorbed in migration paths in the subject. The gradient in photon
density may be achieved by encoding the introduced radiation patterns with a selected
difference in their relative amplitude, relative phase, relative frequency or relative
time. The system also includes a detector adapted to detect over time, at a detection
port placed at a selected location on the subject, the radiation that has migrated
in the subject; processing means adapted to process signals of the detected radiation
in relation to the introduced radiation to create processed data indicative of
the influence of the subject upon the gradient of photon density; and evaluation
means adapted to examine the subject by correlating the processed data with the
locations of the input and output ports.
Preferred embodiments of this aspect of the invention include displacement
means adapted to move synchronously all the optical input ports or move the detection
ports to another location on a predetermined geometric pattern; at this location
the examination of the subject is performed.
According to another aspect of the invention, a spectroscopic system includes
at least one light source adapted to introduce, at multiple input ports, electromagnetic
non-ionizing radiation of a known time-varying pattern of photon density and of
a wavelength selected to be scattered and absorbed while migrating in the subject,
the input ports being placed at selected locations on the subject to probe a selected
quality of the subject; radiation pattern control means adapted to achieve a selected
time relationship of the introduced patterns to form resulting radiation that possesses
a substantial gradient in photon density as a result of the interaction of the
introduced patterns emanating from the input ports, the radiation being scattered
and absorbed in migration paths in the subject. The system also includes a detector
adapted to detect over time, at a detection port placed at a selected location
on the subject, the radiation that has migrated in the subject; displacement means
adapted to move the detection port to various locations on a predetermined geometric
pattern, the various locations being used to detect over time radiation that has
migrated in the subject; processing means adapted to process signals of the detected
radiation in relation to the introduced radiation to create processed data indicative
of the influence of the subject upon the gradient of photon density; and evaluation
means adapted to examine the subject by correlating the processed data with the
locations of the input and output ports.
According to another aspect of the invention, a spectroscopic system includes
at least one light source adapted to introduce, at multiple input ports, electromagnetic
non-ionizing radiation of a known time-varying pattern of photon density and of
a wavelength selected to be scattered and absorbed while migrating in the subject,
the input ports being placed at selected locations on the subject to probe a selected
quality of the subject; radiation pattern control means adapted to achieve a selected
time relationship of the introduced patterns to form resulting radiation that possesses
a substantial gradient in photon density as a result of the interaction of the
introduced patterns emanating from the input ports, the radiation being scattered
and absorbed in migration paths in the subject. The system also includes at least
one detector adapted to detect over time, at multiple detection ports placed at
selected locations on the subject, the radiation that has migrated in the subject;
processing means adapted to process signals of the detected radiation in relation
to the introduced radiation to create processed data indicative of the influence
of the subject upon the gradient of photon density, and evaluation means adapted
to examine the subject by correlating the processed data with the locations of
the input and output ports.
Preferred embodiments of this aspect of the invention include displacement
means adapted to move at least one of the detection ports to another location on
a predetermined geometric pattern, the other location being used to perform the
examination of the subject.
Preferred embodiments of this aspect of the invention include rotation
means adapted to rotate synchronously the optical input ports while introducing
the resulting radiation along a predetermined geometric pattern, the input port
rotation being used to perform the examination of a region of the subject.
Preferred embodiments of the above described aspects of the invention are
also used to locate a fluorescent constituent of interest in the subject; the wavelength
of the introduced radiation is selected to be absorbed in the fluorescent constituent,
the detected radiation is emitted from the fluorescent constituent and processed
to determine location of the fluorescent constituent.
According to another aspect of the invention, a spectroscopic system includes
a light source adapted to introduce, at an input port, electromagnetic non-ionizing
radiation of a known time-varying pattern of photon density and of a wavelength
selected to be scattered and absorbed while migrating in the subject, the input
port being placed at a selected location on the subject to probe a selected quality
of the subject; detectors adapted to detect over time, at multiple detection ports
placed at selected locations on the subject, the radiation that has migrated in
the subject; the time relationship of the detection over time, at the detection
ports, being selected to observe a gradient in photon density formed as a result
of the interaction of the introduced radiation with the subject. The system also
includes processing means adapted to process signals of the detected radiation
in relation to the introduced radiation to create processed data indicative of
the influence of the subject upon the gradient of photon density, and evaluation
means adapted to examine the subject by correlating the processed data with the
locations of the input and output ports.
Preferred embodiments of this aspect of the invention of the invention
include displacement means adapted to move at least one of the detection ports
to another location on a predetermined geometric pattern, the other location being
used to perform the examination of the subject.
According to another aspect of the invention, a spectroscopic system includes
a light source adapted to introduce, at an input port, electromagnetic non-ionizing
radiation of a known time-varying pattern of photon density and of a wavelength
selected to be scattered and absorbed by a fluorescent constituent while migrating
in the subject, the input port being placed at a selected location on the subject
to locate the fluorescent constituent of the subject; detectors adapted to detect
over time, at multiple detection ports placed at selected locations on the subject,
fluorescent radiation that has migrated in the subject. The system also includes
processing means adapted to process signals of the detected radiation in relation
to the introduced radiation to create processed data indicative of location of
the fluorescent constituent of the subject, and evaluation means adapted to examine
the subject by correlating the processed data with the locations of the input and
output ports.
Preferred embodiments of this aspect of the invention include displacement
means adapted to move at least one of the detection ports to another location on
a predetermined geometric pattern, the other location being used to locate the
fluorescent constituent of the subject.
Preferred embodiments of the above-described aspects of the invention use
one or more of the following features:
The time-varying pattern comprises radiation of a selected wavelength intensity
modulated at a selected frequency. The radiation pattern control means are further
adapted to control a selected phase relationship between the modulated radiation
patterns introduced from each of the input ports having to produce in at least
one direction a steep phase change and a sharp minimum in the intensity of the radiation.
The radiation pattern control means are further adapted to impose on all the
introduced radiation patterns an identical time-varying phase component thereby
changing the spatial orientation of the direction of the steep phase change and
the sharp minimum in the intensity of the radiation.
The time-varying pattern comprises radiation of a selected wavelength intensity
modulated at a selected frequency. The radiation pattern control means are further
adapted to control a selected frequency relationship between the modulated radiation
patterns introduced from each of the input ports having to produce in at least
one direction a steep phase change and a sharp minimum in the intensity of the radiation.
The time-varying pattern comprises radiation of a selected wavelength intensity
modulated at a selected frequency. The radiation pattern control means are further
adapted to control a selected amplitude relationship between the modulated radiation
patterns introduced from each of the input ports having to produce in at least
one direction a steep phase change and a sharp minimum in the intensity of the radiation.
The radiation pattern control means are further adapted to add to all the introduced
radiation patterns an identical time-varying amplitude component thereby changing
the spatial orientation of the direction of the steep phase change and the sharp
minimum in the intensity of the radiation.
The radiation is modulated at a frequency that enables resolution of the phase
shift that originates during migration of photons in the subject.
The frequency is on the order of 10
8 Hz.
The processing means further adapted to determine the phase or the intensity
of the radiation altered by scattering and absorption in the subject.
The wavelength of the radiation is susceptible to changes in an endogenous or
exogenous tissue pigment of the subject.
The gradient in photon density may also be achieved by encoding the introduced
radiation patterns with a selected difference in their relative amplitude, relative
phase, relative frequency or relative time.
Other advantages and features of the invention will be apparent from the following
description of the preferred embodiment and from the claims.
BRIEF DESCRIPTION OF THE DRAWING
FIGS. 1, 1A and 1B show diagrammatically phase modulation imaging
systems employing several input ports and one detection port in accordance with
the present invention.
FIG. 2 is a block diagram of the phase modulation imaging system including several
input ports and several detection ports in accordance with the present invention.
FIG. 2A depicts a phased array transmitter that radiates a directional beam.
FIG. 2B depicts sequencing of the phases of an antiphase multi-element array
to achieve an electronic scan of the photon density gradient in accordance with
the present invention.
FIG. 2C depicts four element antiphased array designed for a conical scan of
the photon density gradient in accordance with the present invention.
FIG. 2D depicts the input and output port arrangement of an imaging system in
accordance with the present invention.
FIGS. 3 and 3A depict an imaging system for detection of a hidden fluorescing
object in accordance with the present invention.
FIG. 4 is a block diagram of an alternative embodiment of a dual wavelength
PMS system.
FIG. 4A is a schematic diagram of an oscillator circuit of FIG. 4.
FIG. 4B is a schematic diagram of a PMT heterodyne modulation and mixing network
shown in FIG. 4.
FIG. 4C is a schematic diagram of an AGC circuit shown in FIG. 4.
FIG. 4D is a schematic diagram of a phase detector circuit shown in FIG. 4.
FIGS. 5A, 5B, and 5C illustrate changes in optical field propagating
in a strongly scattering medium which includes a strongly absorbing component.
FIG. 6 shows an experimental arrangement of a two element phased array used
in an interference experiment.
FIGS. 6A, 6B, and 6C show detected interference patterns of two
diffusive waves.
FIG. 7 displays the phase shifts measured for a two element array (curve A),
and for a single source (curve B).
FIG. 8A depicts an experimental arrangement of sources of a four element phased
array and a detector.
FIGS. 8B and 8C display the intensities and the phase shifts measured for the
four element array of FIG. 8A, respectively.
FIG. 9A depicts an experimental arrangement of sources of a four element phased
array, a detector, and a strongly absorbing object.
FIGS. 9B, 9C display respectively the intensities and the phase shifts
measured for the four element array of FIG. 9A scanning absorbing objects of different sizes.
FIG. 9D displays the phase shifts measured for the four element array of FIG.
9A scanning absorbing objects of different absorption coefficients.
FIG. 10A an experimental arrangement of sources of a four element phased array,
a detector, and two strongly absorbing objects.
FIG. 10B displays the phase shifts measured for he four element array of FIG.
10A scanning two absorbing objects of different sizes.
FIG. 11 depict diagrammatically a single wavelength localization system utilizing
a conical scanner.
FIGS. 11A and 11B depict diagrammatically imaging systems utilizing one or
two dimensional phased array transmitters.
FIGS. 12A and 12B depict an imaging system comprising a two dimensional phased
array transmitter and detection array.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Imaging system embodiments of the present invention based upon interference
effects of radiation migrating in a subject having scattering and absorptive properties
are shown in FIGS. 1,
2, and
3. The systems effectively utilize,
in this scattering medium, a directional beam of visible or IR radiation generated
and/or detected by an array of sources and/or detectors, respectively. For instance,
in the case of an array of sources, each source is placed at a selected location
in the array and emits intensity modulated radiation, preferably coherent radiation
from a laser diode, of a selected intensity and phase. The criteria for selecting
the source locations, the intensities, and the phases of the respective sources
is the shape of the desired beam that at any time point possesses a substantial
photon density gradient produced by interference effects of radiation from the
various sources. This gradient of photon density is localized and has directional
properties. Overall, the resulting radiation formed by interference of the radiation
of the individual sources migrates in a selected direction in the subject. In an
antiphase system, the wavefront of the beam has sections of equal photon density
separated by a sharp localized change in photon density. Selected different locations
of the photon density gradient are shown in FIG. 2B.
In general, the wavefront propagates in the selected direction in the subject
and the gradient of photon density is localized in one or more planes extending
from the source array in a selected direction. If the subject includes a localized
object having different scattering and absorptive properties from those of the
surrounding environment, the propagating radiated field is perturbed. This perturbation
is detected and from the source detector geometry the perturbing object can be located.
Referring to the embodiment of FIGS. 1 and 1A, the imaging system utilizes
an array of laser diodes
12,
14,
16, and
18 for introducing
light into the tissue at selected locations. The geometry of optical input ports
11,
13,
15,
17 and of an optical output port
19
is selected to examine a specific part of the tissue. From the known geometry of
the optical input ports and the detection port and from the shape of the introduced
and detected radiation, a computer can locate a hidden object
9 of examined
tissue
8 (for example, a head or breast). A master oscillator
22,
which operates at 200 MHz, excites laser diodes
12 through
18, that
emit light of a selected wavelength (e.g., 760 nm). The light from each laser diode
is conducted to the respective input port placed on a subject via a set optical
fibers , A detector
24 detects the light that has migrated through the examined
tissue. Preferably, detector
24 includes a photomultiplier tube (e.g., Hamamatsu
R928) powered by a high voltage supply which outputs about 900 V in order to ensure
a high gain. A local oscillator
26 operating at a convenient offset frequency
(e.g., 25 kHz) sends a signal to a mixer
28 and a reference signal to detector
24. Accordingly, an output waveform
25 from detector
24 is
at a carrier frequency equal to the difference of the detected and reference frequency,
i.e., 25 kHz.
Detector
24 (for example, PMT Hamamatsu R928 or Hamamatsu R1645u)
detects the scattered and absorbed light that has migrated through the subject.
Detection port
19 is located several centimeters from the location of the
input ports. The PMT detector is connected to the subject by the fiber optic guide,
or, alternatively, may be directly placed on the subject. It has been found that
the most cost-effective detector for measuring signals of frequencies on the order
of 10
8 Hz is Hamamatsu R928. However, the Hamamatsu R1645u detector
is preferred due to its high precision. The second dynode of the PMT of detector
24 is modulated by 200.025 MHz signal
27 so that the 25 kHz hetrodyned
signal
25 is received by a phase detector
30. Phase detector
30
also receives reference signal
29 from mixer
28. If phase detector
30 is a lock-in amplifier then the output signals are the phase shift and
the intensity of the detected signal. Both the phase shift and the intensity of
the detected light characterize the migration path of photons in the subject (e.g.,
the brain tissue).
Alternatively, a tunable dye laser or other laser source connected
to a wide band acousto-optical modulator operating at the carrier frequency, e.g.,
200 MHz can be used instead of the laser diode. The acousto-optical modulator modulates
the intensity of the light emitted by the laser at the selected carrier frequency.
The invention also envisions using only one source of coherent light that irradiates
one end of several optical fibers at the same time. The other end of each fiber
is placed on the subject at a selected input port location. This source radiates
light of a selected time varying pattern. The phase relationship and the intensity
of the light carried by each fiber is varied by creating a time delay (e.g., different
fiber length) and by coupling different amounts of light into each fiber.
FIG. 1B shows diagrammatically an imaging system of FIG. 1 further adapted to
encode the transmitted light sing an offset frequency. Oscillators
22a,
22b,
22c and
22d drive four laser diodes
at frequencies 30.025 MHz, 30.035 MHz, 30.045 MHz and 30.055 MHz, respectively.
The laser diodes introduce the light that migrates in tissue
8 and is collected
at detection port
19 and detected by PMT detector
24. Local oscillator
26 provides a 30 MHz reference signal to detector
24 that outputs
a detection signal having 25 kHz, 35 kHz, 45 kHz and 55 kHz frequency components.
Each component signal is phase detected at a corresponding phase detector (
30a,
30b,
30c and
30d) having a suitable frequency
filter. The phase detectors provide a phase shift, migration pathlength and amplitude
for each frequency.
The imaging systems of FIGS. 1,
2, and
3 are shown to have a light
source of a single wavelength; however, a dual wavelength imaging system is also
envisioned according to this invention. In the dual wavelength imaging system two
laser diodes or a tunable wavelength laser generate light of two wavelengths that
is coupled to an optical fiber. Such a system will now be described.
A dual wavelength operation is shown in FIG. 4. The system includes a master
oscillator
60 operating at 200 MHz and an oscillator
62 operating at 200.025
MHz which is offset 25 kHz from the master oscillator frequency. The offset frequency
of 25 kHz is a convenient frequency for phase detection in this system; however,
other offset frequencies as high as a few megahertz can be used. Oscillator
60
alternatively drives two sets of laser diodes
64a,
64b,
. . . ,
64n and
66a,
66b, . . . ,
66n
using switches
61a,
61b, . . . ,
66n.
These switches are driven electronically to couple a selected wavelength into the
optical fiber and also to achieve a selected radiation pattern resulting from the
radiation emanating from the individual fibers. An output 8 mm fiber coupler
72
collects photons for an R928 PMT detector
74. The second dynode (shown in
FIG. 3B) of PMT
74 is modulated with a 200.025 MHz reference signal generated
by oscillator
62 and amplified by an amplifier
63. Thus, the output
signal of the PMT detector has a frequency of 25 kHz. PMT detector
74 alternately
detects light of the two laser diodes that has migrated in the tissue and produces
corresponding output signals, which are filtered by a filter
76 and leveled
by an automatic gain control (AGC) circuit
79. A reference signal of 25
kHz is produced in a mixer
65 by mixing the 200 and 200.025 MHz oscillator
signals. The reference 25 kHz signal is also leveled using the second AGC
77
and fed into a phase detector
79. Phase detector
79 generates a signal
indicative of the phase of each output signal relative to the phase of the reference
signal. The outputs of phase detector
79 are alternately selected by an
electronic switch
80, filtered, and then input to an adder
82 and
a subtractor
81 to produce sum and difference signals proportional to <L>
λ1+<L>
λ2
and <L>
λ1-<L>
λ2. The difference
and sum signals are then used to calculate changes in the probed pigment and in
the blood volume, respectively.
A schematic diagram of preferred oscillator
60 or
62 is shown in
FIG. 4A. This circuit has a drift of only 0.03 degrees/hr. (Weng, et al., "Measurement
of Biological Tissue Metabolism Using Phase Modulation Spectroscopic Measurement,"
SPIE, Vol. 143, p. 161, 1991, which is incorporated herein by reference). The crystal
is neutralized, which enables operation at resonance, and thus achieves long-term
stability. The respective crystals of oscillators
60 and
62 are offset
from each other by 25 kHz. This circuit provides a sufficient output to directly
drive a 5 mW laser diode.
A modulation circuit
75 for the second dynode of the PMT is shown in FIG.
4B. This circuit -uses a resonant circuit
75a with an impedance of
20,000 ohms instead of the usual 50 Ω load with very high power dissipation,
providing a 50 V drive of the photomultiplier dynode while dissipating only a few
watts of power.
To obtain stable operation of the phase detector, a stable input signal is required.
The 25 kHz AGC circuit
77,
78 illustrated in FIG. 4C includes an
MC 1350 integrated circuit U
1, featuring wide range AGC for use as an amplifier.
The signal amplitude is controlled by a feedback network, as shown. A major reason
for the accurate detection of phase changes by the PMT system is that the phase
detector input signal level is kept nearly constant by the AGC circuit. Since the
input voltage change of between 2 and 6 volts causes variation in the phase shift
of only 0.2%, the AGC circuit eliminates the need for a very stable high voltage
power supply.
A preferred phase detector circuit is shown in FIG. 4D. Two sinusoidal signals
(the measurement signal and the reference signal) are transformed to a square wave
signal by a Schmitt trigger circuit
79a. The phase of the square
wave signal is shifted by an RC change (composed of R
11, R
12, C
8),
which makes it possible to change the measuring range. The detector further includes
a 74HC221 integrated circuit. The lock-in amplifier technique obtained to derive
the difference of the phase and amplitude of the two signals has the highest signal
to noise ratio possible for this type of equipment.
The above-described systems utilize the carrier frequency on the order of 10
8
Hz which is sufficiently fast to resolve the phase shift of the detected
light. The characteristic time, the time it takes for a photon to migrate between
an input port and an output port, is several nanoseconds. The sensitivity of the
system is high, approximately 70° per nanosecond or 3° per centimeter
change of pathlength, as observed in experimental models. Selection of the modulation
frequency also depends on the desired penetration depth and resolution of the imaging
system that will be described below. If deep penetration is desired, a low modulation
frequency (e.g., 40 MHz) is selected, and if shallow penetration is needed, modulation
frequencies as high as 10
9 Hz can be used.
Referring to FIGS. 1 and 1A, a master oscillator
22 operates at
a modulation frequency in the range of 40 to 400 MHz selected according to the
desired penetration depth of the optical field. The array of laser diodes
12,
14,
16, and
18 generates a highly directional radiation pattern,
which is employed in the tissue examination.
In one preferred mode of operation, laser diodes
12 to
18 operate
in a phased array pattern which is introduced into the tissue and detected by a
single PMT detector
30. Master oscillator
22 operating at 200 MHz
drives a multi-channel phased splitter which gives outputs at predetermined phases.
Input ports
11 through
17 are located at selected distances and an
appropriate phasing of the array creates a directional beam and enables scanning
of the optical field in two dimensions across the tissue, as shown in FIGS. 2A,
2B, and
2D. After migrating through the tissue, the optical field
is collected in a large area fiber on selected locations
19. The detected
signals are heterodyned in the PMT detector
24 by utilizing the output of
local oscillator
26, operating at a 25 kHz offset frequency, to detector
24. The resulting 25 kHz signal is phase detected with respect to the output
signal
29 of mixer
28 and detector
24. Phase detector
30
outputs the phase and the intensity of signal
25. The detected phase shifts
and intensities are stored and used for construction of an image of the subject.
This is performed by computer control
34, which governs the operation of
the system.
FIG. 2 depicts a phase modulation imaging system comprising an input port array
for introducing radiation and a detection port array for detecting radiation that
has migrated in the subject. The operation of the system is controlled by computer
control
34, which coordinates a Transmitter unit
32 with a receiver
unit
42. Transmitter unit
32 comprises several sources of visible
or IR radiation adapted to introduce a selected time-varying pattern of photon
density into subject
8 by array of input ports
31,
33,
35,
and
37. Receiver unit
42 detects radiation that has migrated in the
subject from the input port array to an array of detectors
39,
41,
42, and
47.
The radiation sources of transmitter unit
32 are intensity modulated at
a frequency in the range of 40 MHz to 200 MHz, as described for the imaging system
of FIG. 1. Receiver unit
42 detects and processes the radiation using the
same principles of the phase and amplitude detection as described above. The signal
detected at individual ports can be phased using appropriate delays.
Several modes of operation of the transmitter array and receiver array are
described in FIGS. 2A,
2B,
2C, and
2D. Referring to FIG. 2A,
it has been known, that for a simple horizontal linear array of N identical elements
radiating amplitude modulated light spaced a distance, d, apart. The radiating
wavefront is created by the interference effect. If all elements radiate in phase
the wavefront propagates in a direction perpendicular to the array. However, by
appropriately phasing the radiating elements, the resulting beam can scan space
in two dimensions. We consider the phases of the signal along the plane A—A
whose normal makes an angle θ
0 with respect to the array normal.
The phase of the signal from the first radiator lags the phase of the second radiator
by a phase angle (2π/λ)d sin θ
0 because the signal
from the second radiator has to travel a distance d sin θ
0 longer
than the signal from the first radiator to reach plane A—A. Similarly, the
phase of the signal from the n
th radiator leads that from the first
radiator by an angle n(2π/λ))d sin θ
0. Thus, the signals
from the various radiators can be adjusted to be in-phase along the A—A plane,
if the phase of each radiator is increased by (2π/λ)d sin θ
0.
Consequently, at a point on the wavefront in the far field of the transmitter array
the signals from the N radiators will add up in phase, i.e., the intensity of the
total normalized signal is a sum of the signals from the individual sources. The
constructed pattern has a well defined directional characteristic and a well pronounced
angular dependence, i.e., the transmitter pattern has a well defined transfer characteristic
of the transmitter with respect to the angle θ
0.
FIG. 2B depicts an arrangement of phases for the sources the system of FIG.
2 operating in one preferred mode of operation. The array of five sources is divided
into two or more portions that are phased 180° apart. Each portion has at
least one source. The sources of each portion radiate amplitude modulated light
of equal intensity and are spaced so that the resulting beam of two or more equally
phased sources has a substantially flat wavefront, i.e., no gradient of photon
density. on the other hand, there is a sharp 180° phase transition, a large
gradient in photon density between two antiphased portions of the array. Thus,
the radiated field possesses an amplitude null and a phase transition of 180°
(i.e. crossover phase), which is due to the large gradient of photon density.
Electronic scanning is performed by appropriately varying the apportionment
of 0° and 180° phases on the sources. The five element array of FIG.
2B can have the 180° phase transition along four different parallel planes
extending from the array. Scanning is achieved by electronically switching the
sources by 180°, so that the photon density gradient moves in the direction
parallel to the location of the sources.
Using the principles described in FIGS. 2A and 2B, a conical scan of a directional
beam possessing at least one substantial photon density gradient can be accomplished
using a four element antiphased array, as shown in FIG. 2C. The laser diodes are
antiphased using a push pull transformer. The phasing and amplitude of four laser
diodes S
1, S
2, S
3, and S
4 arranged
into a two dimensional array is modified sequentially using the switches Sw
1,
Sw
2, Sw
3, and Sw
6 and inductances L
1,
L
2, L
3, and L
4.
FIG. 2D shows a possible arrangement of the transmitter array and the receiver
array. The above described directional beam enters subject
8 at the transmitter
array location and is pointed to hidden absorber
9 which perturbs the migrating
beam. The field perturbation is measured by the receiver array. Scanning of the
transmitter array or the receiver array is envisioned by the present invention.
A hidden absorber that includes a fluorescent constituent is detected using a
selected
excitation wavelength of the laser sources of the transmitter array. Then, the
radiation is absorbed, and almost instantly a fluorescent radiation of a different
wavelength is re-emitted. The re-emitted radiation propagating in all directions
is detected by the receiver array.
FIG. 3 depicts a phase modulation imaging system comprising one input port and
several arrays of detection ports. This system operates comparably to the systems
of FIGS. 1 and 2. The 754 nm light of a laser diode
48 is amplitude modulated
using master oscillator
22. The light is coupled to subject
8 using
an input port
49. The amplitude modulated light migrates in the subject
and is scattered from hidden object
9. It is also expected that hidden object
9 has a different effective index of refraction than subject
8. The
migrating radiation is governed by the laws of diffusional wave optics that are
described below. The scattered radiation migrates in several directions and is
detected by detection systems
50,
52, and
54.
Ports
51,
53, and
55 of the detection systems can include
either large area fibers or arrays of detection ports. If large area fibers are
used then detector systems
50,
52, and
54 correspond to detector
24 of FIG. 1. If arrays detection ports are used, then each of detector
systems
50,
52, and
54 includes several individual PMT detectors.
The PMT detectors of each detector system are phased utilizing a selected phase
mode, as described above. The phasing is controlled by the computer control. The
detected signals are heterodyned at the PMT detectors and sent to a phase detector
58. Phase detector
58 detects alternatively the heterodyned signals
using a switch
56. Operation of phase detector
58 is similar to the
operation of phase detector
30 of FIG. 1. The detected phase and amplitude
are alternatively sent to the computer control using a switch
56a.
Even thought only one phase detector is show
