Frequency-domain optical tomographic imaging of arthritic finger joints.

Abstract

We are presenting data from the largest clinical trial on optical tomographic imaging of finger joints to date. Overall we evaluated 99 fingers of patients affected by rheumatoid arthritis (RA) and 120 fingers from healthy volunteers. Using frequency-domain imaging techniques we show that sensitivities and specificities of 0.85 and higher can be achieved in detecting RA. This is accomplished by deriving multiple optical parameters from the optical tomographic images and combining them for the statistical analysis. Parameters derived from the scattering coefficient perform slightly better than absorption derived parameters. Furthermore we found that data obtained at 600 MHz leads to better classification results than data obtained at 0 or 300 MHz.

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IEEE TRANSACTIONS ON MEDICAL IMAGING, VOL. 30, NO. 10, OCTOBER 2011 1725
Frequency-Domain Optical Tomographic
Imaging of Arthritic Finger Joints
Andreas H. Hielscher*, Member, IEEE, Hyun Keol Kim, Ludguier D. Montejo, Member, IEEE, Sabine Blaschke,
Uwe J. Netz, Paul A. Zwaka, Gerd Illing, Gerhard A. Müller, and Jürgen Beuthan
Abstract—We are presenting data from the largest clinical trial
on optical tomographic imaging of finger joints to date. Overall we
evaluated 99 fingers of patients affected by rheumatoid arthritis
(RA)and120fingersfromhealthyvolunteers.Usingfrequency-do-
mainimagingtechniquesweshowthatsensitivitiesandspecificities
of 0.85 and higher can be achieved in detecting RA. This is accom-
plished by deriving multiple optical parameters from the optical
tomographic images and combining them for the statistical anal-
ysis. Parameters derived from the scattering coefficient perform
slightly better than absorption derived parameters. Furthermore
we found that data obtained at 600 MHz leads to better classifica-
tion results than data obtained at 0 or 300 MHz.
Index Terms—Computer aided diagnostics, light propagation in
tissue, optical tomography, rheumatoid arthritis (RA).
I. INTRODUCTION
O
and other joint diseases. Jiang et al. have performed extensive
studies to show the potential of optical tomography to detect
osteoarthritis (OA). In 2001 they introduced a continuous-wave
(CW) system for reconstructing absorption and scattering co-
efficients of joints [1]. Using experimental data from a human
finger and several chicken bones, this group subsequently
showed that 3-D volumetric reconstructions can provide details
of the joint structure and composition that would be impossible
from 2-D imaging methods [2]. For this study they employed
VER the last decade several groups have pursued the
use of optical tomographic methods to image arthritis
Manuscript received February 06, 2011; accepted March 08, 2011. Date of
publication April 05, 2011; date of current version September 30, 2011. This
work was supported in part by a grant from the National Institute of Arthritis
andMusculoskeletalandSkinDiseases(NIAMS-2R01AR46255),whichispart
of the National Institutes of Health. Asterisk indicates corresponding author.
*A. H. Hielscher is with the Departments of Biomedical Engineering, Radi-
ology,andElectricalEngineering,ColumbiaUniversity,NewYork,10027USA
(e-mail: ahh2004@columbia.edu).
H. K. Kim and L. D. Montejo are with the Department of Biomedical En-
gineering, Columbia University, New York 10027 USA (e-mail: hkk2107@
columbia.edu; ldm2106@columbia.edu).
S. Blaschke and G. A. Müller are with the Department of Nephrology
and Rheumatology, Georg-August-University, University Medical Center
Göttingen, 37075 Göttingen, Germany.
U. J. Netz is with the Laser- und Medizin-Technologie GmbH Berlin, 14195
Berlin-Dahlem, Germany and with the Department of Medical Physics and
Laser Medicine, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
P. A. Zwaka is with the Department of Radiology, Georg-August-University,
University Medical Center Göttingen, 37075 Göttingen, Germany.
G. Illing is with Laser- und Medizin-Technologie GmbH Berlin, 14195
Berlin-Dahlem, Germany.
J. Beuthan is with the Department of Medical Physics and Laser Medicine,
Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Color versions of one or more of the figures in this paper are available online
at http://ieeexplore.ieee.org.
Digital Object Identifier 10.1109/TMI.2011.2135374
a finite-element algorithm that was based on the diffusion
equation of light transport in tissue. Refining the imaging
hardware and software further, they presented first clinical
results involving data from two OA patients and three healthy
volunteers in 2007 [3]–[5]. They found that the reconstructed
images demonstrated differences in optical properties in the
joint region between the OA and healthy joints. Since then
this group has further improved their system by introducing a
combined X-ray optical-imaging system [6], developed a new
instrument based on photo-acoustic imaging [7], and moved be-
yond the diffusion model to include higher-order reconstruction
schemes that account for light-transport effects not previously
covered [8]. The X-ray system was used to image the distal
inter-phalangeal (DIP) joints of 22 patients and 18 healthy
volunteers, while the photo-acoustic system was explored by
imaging DIP joints of 2 OA patients and four healthy subjects.
In 2007, Wang et al. showed the potential of photo-acoustic
tomography (PAT) for imaging of human peripheral joints by
studying the method’s resolution in cadaver human fingers and
small animals [9], [10]. More recently, several researchers have
suggested molecular imaging approaches that involved bio-
luminescence and fluorescence markers [11]–[13]. However,
they did not apply tomographic imaging methods.
Our research team has focused in the past on application of
optical tomographic imaging for detecting and characterizing
inflammation in rheumatoid arthritis (RA). RA is an autoim-
mune disease characterized by chronic inflammation of the syn-
ovial membrane of joints [14], [15]. The etiology of RA is un-
known, however, it affects an estimated 1.5 million Americans.
PatientswithRA cansuffer from cripplingpainandlack ofjoint
mobility. These handicaps can result in large financial costs due
to health care expenses and loss of productivity at work. De-
spite recent advances in therapeutic intervention including bi-
ological therapies, there is currently no cure of RA. However,
early treatment of RA has been shown to significantly improve
clinical outcome and management of the disease. It is therefore
important to diagnose a patient with RA as early as possible.
Inpreviousstudiesweshowedthattheabsorptioncoefficients
inside the joint cavity are elevated in patients with RA com-
paredtohealthysubjects[16]–[18].However,usingjustasingle
parameter [for example, the smallest or the largest absorption
coefficient,
or
ties (Se) and specificities (Sp) of only 0.71 were achieved. Sub-
sequently, Klose et al. [19], showed that if optically derived pa-
rameters, such as
and and
the classification process, sensitivities and specificities can be
increased to 0.76 and 0.78, respectively.
] for classification, sensitivi-
, are combined for
0278-0062/$26.00 © 2011 IEEE

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1726 IEEE TRANSACTIONS ON MEDICAL IMAGING, VOL. 30, NO. 10, OCTOBER 2011
In these previous studies a continuous wave (CW) instru-
ment was used that measured the amplitude of transmitted light
intensities. However, it is known that CW systems have diffi-
culties separating absorption and scattering effects, which may
limit the achievable sensitivities and specificities. In this work
we present first clinical results obtained with a frequency-do-
main imaging system. In addition to amplitude information,
frequency-domain data contains phase information, which has
been shown to improve the separation of scattering and absorp-
tion effects [20]. By imaging over 200 fingers at three different
modulation frequencies (0, 300, and 600 MHz) and comparing
the results to established clinical criteria, ultrasound (US) and
magnetic resonance imaging (MRI), we sought to demonstrate
that frequency-domain imaging leads to higher sensitivities
and specificities. Furthermore, by combining a multitude of
optically derived parameters, we explored the possibility of
using computer aided diagnostic tools that could assist in the
diagnosis of rheumatoid arthritis.
II. PATIENTS AND METHODS
A. Introduction
In this study 36 patients, previously diagnosed with rheuma-
toid arthritis (RA), were enrolled at the Department of
Nephrology and Rheumatology, University Medicine of Göet-
tingen, Germany. Data from three patients was discarded
because the optical tomographic imaging system failed to
operate correctly during the exam. Of the remaining 33 RA
patients, 24 were female and 9 male, which reflects the fact that
RA is 2–3 times more common in women than in men. The
mean age of these patients was 51.5
years). All patients met the criteria for the diagnosis of RA
established by the American College of Rheumatology (ACR)
and the European League Against Rheumatism (EULAR) [21],
[22]. Most of the patients (21/33; 63.6%) received standard
disease-modifying anti-rheumatic drug therapy (methotrexate,
leflunomide, adalimumab) and low-dose prednisone ( 10
mg/d). Positivity for the rheumatoid factor was found in 8 out
of 33 cases (24%). All patients had active disease, defined as
at least three swollen and tender peripheral joints and morning
stiffness for
1 hour, with or without an elevated erythrocyte
sedimentation rate
level
mg/l . The mean clinical disease activity,
assessed according to the method previously defined by van der
Heijde et al. [23], was 4.6 (range 1.59–8.02).
All patients were subjected to clinical examination (CE), ul-
trasound (US) imaging and low-field MRI of the clinically pre-
dominant hand. Furthermore, proximal interphalangeal (PIP)
joints II-IV were subjected to frequency-domain optical tomog-
raphy (FDOT), resulting in 99 images of fingers from RA pa-
tients. As controls 20 healthy persons male:female
with a mean age of 38.814.1 years (range 22–60 years) were
included and subjected to FDOT analysis of PIP joints II–IV
of both hands (resulting in
of healthy finger joints). The study was approved by the Institu-
tional Review Board (IRB) and each patient and healthy control
gave informed consent prior to study entry.
13.9 years (range 21–77
mm/h or C-reactive protein
FDOT images
B. Gold Standard
To establish a gold standard for classification results CE,
MRI, and US were used to determine if a finger was affected
by RA or not. The CE of each PIP joint was performed by
bi-manual palpation to assess the degree of swelling, tender-
ness and warmth. The joints were classified according to a
clinical synovitis score (CSS) [24], [25]. To assess the overall
state of the disease, laboratory tests included the erythrocyte
sedimentation rate (ESR) and C-reactive protein (CRP). Both
blood tests used to detect inflammation within the body. Higher
sedimentation rates indicate the presence of inflammation and
occur in inflammatory disease, such as RA. The CRP is a
protein built in liver tissue and also considered a parameter
of inflammation as part of activating the immune system.
Although not specific, both parameters show a good correlation
to RA disease activity. Finally, an overall disease activity score
(DAS) was assessed as part of the clinical exam. The DAS28
is a combined index that has been developed to measure the
disease activity in patients with RA [26], [27]. It includes a
classification of 28 joints according to the degree of swelling
and tenderness, the ESR, and a patient self-assessment ac-
cording to the visual analogue scale (VAS). The DAS28 results
in a number between 0 and 10, indicating how active the RA
is at this moment. Using the DAS28, several thresholds have
been developed for high disease activity, low disease activity,
or disease inactivity. Disease activity is defined as inactive
when
, moderately active if
and highly active if
MRI was performed using a dedicated low-field (0.2 T) MRI
system (C-scan, ESAOTE, Genova, Italy) equipped with a
specifically designed hand coil. Imaging sequences included
native gradient-echo short-tau inversion-recovery (STIR) se-
quence in coronal slice orientation, T1-weighted spin-echo
high resolution sequence in transversal and coronal orienta-
tions, and T1-weighted 3-D gradient-echo sequence in coronal
slice orientation before and after bolus administration of the
paramagnetic contrast medium gadolinium diethylenetriamine-
pentaacetic acid (Gd-DTPA, Magnevist, Schering, Berlin,
Germany) at a dose of 0.2 mmol/kg body weight. The data set
acquired with the T1-weighted 3-D gradient echo sequence was
used for reconstruction of axial views. Examples are shown
in Fig. 1, which display how synovitis [Fig. 1(a) and (b)] and
joint erosions [Fig. 1(c) and (d)] appear in MR images before
and after administration of the contrast agent. Synovitis is
clearly apparent in the contrast-enhanced image, while erosion
is visible even before the administration of a Gd-DTPA bolus.
Scoring of synovitis and erosions was performed according to
the EULAR OMERACT criteria [24], using a semi-quantitative
scoring system as previously described by Schirmer et al. [25].
Ultrasound imaging (US) was performed with an Esaote
Technos MPX ultrasound system. We used a 14-8 MHz hockey
stick linear array transducer for examination of the PIP joints.
ExamplesofUSimagestakenfromthepalmarsideareshownin
Fig. 2. A healthy joint is shown in Fig. 2(a), while Fig. 2(b)–(d)
show joints with inflammation. In US, two criteria of active
inflammation were evaluated following Szkudlarek et al. [28].
Joint effusion (E) was visible as an anechoic area between the
capsule and the bone in the proximal part from the palmar side
.

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HIELSCHER et al.: FREQUENCY-DOMAIN OPTICAL TOMOGRAPHIC IMAGING OF ARTHRITIC FINGER JOINTS1727
Fig. 1. (a), (b) The two figures show T1-weighted images (a) before and (b) after administration of a bolus of Gd-DTPA. The region marked with a white circle
shows synovitis in a PIP joint. (c), (d) The two figures show T1-weighted images (c) before and (d) after administration of a bolus of Gd-DTPA. The region marked
with a white circle shows erosions in all three joints inside the circle.
of the hand [Fig. 2(b)–(d)]. Second, thickening of the synovial
membrane (S, synovitis) could be visualized as hyper-echoic
structures within the region affected by effusion [Fig. 2(d)]. We
performed US from palmar because we found that synovitis
and effusion can best be evaluated from the palmar as opposed
to the dorsal side. This is probably due to the small amount of
tissue overlying the joint from the dorsal side.
MRI and US images of patients with RA were analyzed by
two independent investigators including a radiologist and a
rheumatologist. According to US and MRI findings, PIP joints
were classified into joints affected by RA (Group A) and joints
unaffected by RA (Group U). To be classified as affected by
RA, joints had to show either signs of effusion, synovitis or
erosions. Joints classified as unaffected by RA did not show
any of these signs. In almost all cases consensus was reached in
classification results. In the few case of discrepant evaluations
of the two initial reviewers a third reviewer was consulted and
his finding was used to determine group membership. This
classification was used as ground truth for the evaluation of the
frequency-domain optical tomography (FDOT) images.
C. Optical Tomographic Imaging
1) Optical Tomographic Instrument: As optical imaging
system we employed a recently developed frequency-domain
system that allows for source-modulation frequencies up to
1 GHz [29]. A laser beam (wavelength
power
, beam diameter 1.0 mm) was directed onto the
back of a finger and scanned across the PIP joint in a sagittal
plane (Fig. 3). Transmitted light intensities were measured
with an intensified CCD (ICCD) camera. The ICCD camera
was operated in homodyne mode, i.e., the gain of the ICCD is
modulated by a slave signal generator at the same frequency as
thelaser.Asaresult,asteadystateimageattheintensifieroutput
nm, optical
is imaged to the CCD. The signal in every pixel depends on
the phase between source and detector modulation. Master and
slavesignalgeneratorsarelinkedtogetherandthephasedelayis
adjustable. To detect the complete oscillation of the modulation
multiple images are taken at phase delays covering the range of
and are transferred to a computer. From the stack of images
2-Damplitudeandphaseimagesarederivedbydataprocessing.
More details concerning this setup can be found in [29].
In addition to the transmission measurements, accurate sur-
face coordinates of the finger were generated by a newly in-
troduced laser scanner unit. The finger was scanned simulta-
neously by two red laser lines (wavelength
tical power
, line width
the palm (Fig. 4). In this setup the diode lasers are mounted
on a gear-wheel each. Slight rotation of the gear-wheel by a
stepping motor yields a step of the laser line on the finger sur-
face. Both gear-wheels are driven by one stepping motor to ac-
complish simultaneous scanning of the two lines. The shapes of
the deformed laser lines on the finger surface are imaged with
a fast video camera (SPC 900 NC, Philips, The Netherlands),
which is controlled by the DAVID laser-scanner software (ver.
1.6b, TU-Braunschweig, Germany). Two thin walls besides the
finger arranged in certain angle serve as calibration background
to adjust the coordinate system of the camera. According to the
camera coordinate system the line shapes are transformed into
3-D surface coordinates in real-time. These coordinates were
employed to generate a surface mesh of the scanned part of
thefinger usingGIDsoftwarepackage(MicromechatornicsInc.
http://www.mmech.com/) [Fig. 4(b)], which is input into the re-
constructionproceduretogether withthetransmission data.Test
onstandardsurfacephantomsshowedthatthissetupcanresolve
surface details with an accuracy of at least 0.4 mm. Both the to-
mographic unit and the laser-scanning unit are equipped with
nm, op-
mm) at the back and

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1728IEEE TRANSACTIONS ON MEDICAL IMAGING, VOL. 30, NO. 10, OCTOBER 2011
Fig. 2. Ultrasound images of a healthy joint (a), and joints affected by RA (b),
(c), (d). The larger the anechoic area and/or extent of synovial hypertrophy, the
higherwastheultrasoundscore(USS)(
extensive effusion/hypertrophy). Images were produced by placing a
hockey stick linear array transducer on the palmar side of the PIP joint. (
effusion,synovitis,tendon,
minimal, moderate,
joint cavity).
identical, ergonomic hand and arm rest in the same height to
allow for identical positioning of the patient’s arm and hand.
2) Optical Imaging Protocol: Before the measurement was
started, the fingers were marked with a small black dot on the
back of the finger in the sagittal plane, 17 mm distal from the
PIP joint. This mark was used to position the finger identically
in both the tomographic and laser scanner unit. Once the finger
was placed inside the tomographic unit on a hand rest, the laser
beam was moved to the marked position. The finger axis was
aligned with the scanning plane of the laser. Then, the laser
moved to the first tomographic source position, 10 mm distal
from the PIP joint and subsequently scanned over a range of
20 mm. Images were acquired at 11 equally spaced source po-
sitions. At every source position the oscillation was sampled in
16 phase steps with an exposure time of 80 ms each. The scan
was performed twice, at first in the forward direction with mod-
ulation frequency of 600 MHz, and then in the reverse direction
with a frequency of 300 MHz.
Fig. 3. Setup of tomographic scanning unit, (a) schematic and (b) photograph.
The hardware parts shown are the (1) laser diode, (2) laser diode driver, (3,7)
signal generator, (4) finger, (5) focusing lens, (6) ICCD camera, (8) high rate
imager, and (9) computer.
We scanned three fingers from the hand of each patient; the
index, middle, and the ring finger (PIP II to PIP IV). To avoid
movement artifacts in the image reconstruction, the examiner
controlled the correct position of the finger again after the to-
mographic scan was finished. Acquisition time for one finger
including laser movement, image acquisition, and data storage
was about 35 s for one frequency. Positioning of the finger av-
eraged another 80 s. Thus, the complete tomographic scanning
time needed for six fingers and two modulation frequencies was
about 15 min.
Inthelaserscannerunit,thepositioningofthefingeriscarried
out by using the mark on the finger as a reference. An additional
laser line, across the finger as a pilot beam, helps to find the
correct axial position for the mark. The finger is angled parallel
to the scanning direction. The scan starts approximately 3 mm
before the mark and ends after a distance of 40 mm on both
sides. One step of the stepping motor yields a step of the laser
line on the finger surface of approximately 0.05 mm and takes
about 10 ms. Both cameras are in a free running mode and take
images with 30 frames/s. A waiting time of 20 ms is inserted
between the steps to get approximately one step per frame. The
scanning over 40 mm takes about 25 s, positioning averages
another 60 s. Thus the complete time for scanning six fingers
is about 7 min.

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HIELSCHER et al.: FREQUENCY-DOMAIN OPTICAL TOMOGRAPHIC IMAGING OF ARTHRITIC FINGER JOINTS 1729
Fig. 4. (a) Surface registration and (b) 3-D mesh generation. The surface scan-
ning unit detects the shape of the laser line on the finger surface and determines
the 3-D-surface coordinates while the laser line is scanned over the finger. The
background serves for calibration of the camera coordinate system. Surface reg-
istration and 3-D mesh generation. (a) 3-D laser scanning to obtain a finger joint
geometry and (b) 3-D finite volume mesh generated using the laser scanned sur-
face mesh.
After acquisition, the raw imaging data was processed. In
every stack of images a fast Fourier transformation (FFT) was
performed through the stack in every pixel. The FFT yielded
values for the amplitude, phase and the dc components. By this
means 2-D dc, amplitude and phase images were calculated for
every distinct source position.
3) OpticalTomographicReconstruction: Three-dimensional
image reconstructions were performed using the PDE-con-
strained reduced-Hessian SQP method [30], that solves the
forward and inverse problems simultaneously. As a forward
model this code employs the frequency-domain equation of
radiative transfer (FD-ERT) [31], [32]
(1)
where
is the complex-valued radiance in unit
andare the absorption and scattering
coefficients, respectively, in units of
source modulation frequency,
the medium, and
is the scattering phase function
that describes scattering from incoming direction
tering direction
. In this work we employed the widely used
Henyey–Greenstein phase function with
Furthermore, to be able to consider the refractive index mis-
match at air-tissue interface [34], [35], we implemented a par-
tially-reflective boundary condition
,
,is the external
is the speed of light inside
into scat-
[33].
(2)
where
rection
sity due to the external source function, subscript
the boundary surface of the medium, and
vector pointing outwards at the boundary surface.
Given the spatial distribution of optical properties inside the
medium, we solve the radiative transfer equation [(1)] with
a discrete ordinates method [34], which provides the predic-
tion of measurements obtained on the surface of the medium
is the reflectivity at Fresnel interface from di-
to direction, is the radiation inten-
denotes
is the unit normal
. Here is the measurement
operator that projects the radiance vector
forward model onto the image plane of a CCD camera.
In PDE-constrained optimization, an image reconstruction
problem is to find the radiation intensity vector
of a
(3)
and the optical property vector
(4)
such that
(5)
where
for measurements and predictions,
surements and the predictions for source-detector pairs
and the operator denotes the complex conjugate of the com-
plex vector.
Given the current estimate of forward and inverse variables
, the rSQP scheme makes the new iterate for both for-
ward and inverse variables
andare the numbers of sources and detectors used
, andare the mea-
(6)
where a step length
merit function, and a search direction
obtained by solving the quadratic programming problem
provides a sufficient decrease in the
can be
(7)