Measuring Upper Extremity Activity of Children With Unilateral Cerebral Palsy Using Wrist-Worn Accelerometers: A Pilot Study.

IMPORTANCE: Children with unilateral cerebral palsy (UCP) have poor strength and movement control on one side of their body, leading to impaired bimanual coordination skills. OBJECTIVE: To compare duration and intensity of all-day habitual movement of the dominant and nondominant upper extremities (UEs) in typically developing (TD) children and children with UCP. DESIGN: Two-group observational study. SETTING: Children's naturalistic settings. PARTICIPANTS: Convenience sample of 9 TD children and 9 children with UCP. INTERVENTION: Children wore accelerometers on both wrists all day and night for 1 wk. OUTCOMES AND MEASURES: We compared the extent of asymmetry in bilateral arm use (intensity and duration) between the 2 groups. RESULTS: Compared with TD children who use both UEs equally, children with UCP were more likely to use their dominant or unaffected UE than their nondominant or affected UE during daily activities. There were no differences between groups in dominant UE activity. However, children with UCP engaged in lower levels of moderate to vigorous activity and greater levels of light activity with their nondominant or affected UE than their TD peers. CONCLUSIONS AND RELEVANCE: Wrist-worn accelerometry can provide objective information on real-world habitual activity with both arms in children. Accelerometers are nonintrusive, easy to use, and well tolerated by children, and they allow prolonged monitoring of UE activity outside therapeutic contexts. Occupational therapists can use wrist-worn accelerometers as sensitive tools to assess asymmetries in UE use at baseline and as an outcome measure to assess the efficacy of behavioral interventions and carryover into real-world settings among children with UCP. Plain-Language Summary: This pilot study provides promising evidence that supports the use of wrist-worn accelerometry as an accurate, easy-to-use, and objective assessment tool for children with unilateral cerebral palsy (UCP) to detect asymmetries in bilateral real-world arm activity at baseline and after intensive occupational therapy interventions to improve arm function. The authors used wrist-worn accelerometry for one week with 9 typically developing (TD) children and 9 children with UCP to compare dominant or unaffected versus nondominant or affected upper extremity (UE) use for intensity and duration of activity. Compared with TD children, children with UCP had lower relative intensity of activity in the nondominant UE than the dominant UE. Wrist-worn accelerometers seem to be a sensitive measure to detect asymmetries in bilateral all-day UE use in children with UCP. The findings have implications for the use of wrist-worn accelerometers as an outcome measure to assess the efficacy of intensive therapies to improve real-world affected UE activity and bimanual function among children with UCP.

Low-cost compact multispectral spatial frequency domain imaging prototype for tissue characterization.

We present a low-cost, compact, and multispectral spatial frequency domain imaging prototype. Illumination components, including 9 LEDs (660 nm - 950 nm) placed on a custom-designed printed circuit board, linear and rotational motors, a printed sinusoidal pattern, and collimation and projection optics as well as the detection components are incorporated in a compact custom-designed 3D-printed probe. Reconstruction of absorption and reduced scattering coefficients is evaluated via imaging tissue mimicking phantoms and potentials of the probe for biological tissue imaging are evaluated via imaging human ovarian tissue ex vivo.

Laser scanning laser diode photoacoustic microscopy system.

The development of low-cost and fast photoacoustic microscopy systems enhances the clinical applicability of photoacoustic imaging systems. To this end, we present a laser scanning laser diode-based photoacoustic microscopy system. In this system, a 905 nm, 325 W maximum output peak power pulsed laser diode with 50 ns pulsewidth is utilized as the light source. A combination of aspheric and cylindrical lenses is used for collimation of the laser diode beam. Two galvanometer scanning mirrors steer the beam across a focusing aspheric lens. The lateral resolution of the system was measured to be ∼21 µm using edge spread function estimation. No averaging was performed during data acquisition. The imaging speed is ∼370 A-lines per second. Photoacoustic microscopy images of human hairs, ex vivo mouse ear, and ex vivo porcine ovary are presented to demonstrate the feasibility and potentials of the proposed system.

Coregistered photoacoustic and ultrasound imaging and classification of ovarian cancer: ex vivo and in vivo studies.

Most ovarian cancers are diagnosed at advanced stages due to the lack of efficacious screening techniques. Photoacoustic tomography (PAT) has a potential to image tumor angiogenesis and detect early neovascular changes of the ovary. We have developed a coregistered PAT and ultrasound (US) prototype system for real-time assessment of ovarian masses. Features extracted from PAT and US angular beams, envelopes, and images were input to a logistic classifier and a support vector machine (SVM) classifier to diagnose ovaries as benign or malignant. A total of 25 excised ovaries of 15 patients were studied and the logistic and SVM classifiers achieved sensitivities of 70.4 and 87.7%, and specificities of 95.6 and 97.9%, respectively. Furthermore, the ovaries of two patients were noninvasively imaged using the PAT/US system before surgical excision. By using five significant features and the logistic classifier, 12 out of 14 images (86% sensitivity) from a malignant ovarian mass and all 17 images (100% specificity) from a benign mass were accurately classified; the SVM correctly classified 10 out of 14 malignant images (71% sensitivity) and all 17 benign images (100% specificity). These initial results demonstrate the clinical potential of the PAT/US technique for ovarian cancer diagnosis.

Characterizing optical properties and spatial heterogeneity of human ovarian tissue using spatial frequency domain imaging.

A spatial frequency domain imaging (SFDI) system was developed for characterizing ex vivo human ovarian tissue using wide-field absorption and scattering properties and their spatial heterogeneities. Based on the observed differences between absorption and scattering images of different ovarian tissue groups, six parameters were quantitatively extracted. These are the mean absorption and scattering, spatial heterogeneities of both absorption and scattering maps measured by a standard deviation, and a fitting error of a Gaussian model fitted to normalized mean Radon transform of the absorption and scattering maps. A logistic regression model was used for classification of malignant and normal ovarian tissues. A sensitivity of 95%, specificity of 100%, and area under the curve of 0.98 were obtained using six parameters extracted from the SFDI images. The preliminary results demonstrate the diagnostic potential of the SFDI method for quantitative characterization of wide-field optical properties and the spatial distribution heterogeneity of human ovarian tissue. SFDI could be an extremely robust and valuable tool for evaluation of the ovary and detection of neoplastic changes of ovarian cancer.

Design of optimal light delivery system for co-registered transvaginal ultrasound and photoacoustic imaging of ovarian tissue.

A hand-held transvaginal probe suitable for co-registered photoacoustic and ultrasound imaging of ovarian tissue was designed and evaluated. The imaging probe consists of an ultrasound transducer and four 1-mm-core multi-mode optical fibers both housed in a custom-made sheath. The probe was optimized for the highest light delivery output and best beam uniformity on tissue surface, by simulating the light fluence and power output for different design parameters. The laser fluence profiles were experimentally measured through chicken breast tissue and calibrated intralipid solution at various imaging depths. Polyethylene tubing filled with rat blood mimicking a blood vessel was successfully imaged up to ∼30 mm depth through porcine vaginal tissue at 750 nm. This imaging depth was achieved with a laser fluence on the tissue surface of 20 mJ/cm(2), which is below the maximum permissible exposure (MPE) of 25 mJ/cm(2) recommended by the American National Standards Institute (ANSI). Furthermore, the probe imaging capability was verified with ex vivo imaging of benign and malignant human ovaries. The co-registered images clearly showed different vasculature distributions on the surface of the benign cyst and the malignant ovary. These results suggest that our imaging system has the clinical potential for in vivo imaging and characterization of ovarian tissues.

A low-cost photoacoustic microscopy system with a laser diode excitation.

Photoacoustic microscopy (PAM) is capable of mapping microvasculature networks in biological tissue and has demonstrated great potential for biomedical applications. However, the clinical application of the PAM system is limited due to the use of bulky and expensive pulsed laser sources. In this paper, a low-cost optical-resolution PAM system with a pulsed laser diode excitation has been introduced. The lateral resolution of this PAM system was estimated to be 7 µm by imaging a carbon fiber. The phantoms made of polyethylene tubes filled with blood and a mouse ear were imaged to demonstrate the feasibility of this PAM system for imaging biological tissues.

Design of miniaturized illumination for transvaginal co-registered photoacoustic and ultrasound imaging.

A novel lens-array based illumination design for a compact co-registered photoacoustic/ultrasound transvaginal probe has been demonstrated. The lens array consists of four cylindrical lenses that couple the laser beams into four 1-mm-core multi-mode optical fibers with optical coupling efficiency of ~87%. The feasibility of our lens array was investigated by simulating the lenses and laser beam profiles using Zemax. The laser fluence on the tissue surface was experimentally measured and was below the American National Standards Institute (ANSI) safety limit. Spatial distribution of hemoglobin oxygen saturation (sO2) of a mouse tumor was obtained in vivo using photoacoustic measurements at multiple wavelengths. Furthermore, benign and malignant ovaries were imaged ex vivo and evaluated histologically. The co-registered images clearly showed different patterns of blood vasculature. These results highlight the clinical potential of our system for noninvasive photoacoustic and ultrasound imaging of ovarian tissue and cancer detection and diagnosis.

Indocyanine green enhanced co-registered diffuse optical tomography and photoacoustic tomography.

To overcome the intensive light scattering in biological tissue, diffuse optical tomography (DOT) in the near-infrared range for breast lesion detection is usually combined with other imaging modalities, such as ultrasound, x-ray, and magnetic resonance imaging, to provide guidance. However, these guiding imaging modalities may depend on different contrast mechanisms compared to the optical contrast in the DOT. As a result, they cannot provide reliable guidance for DOT because some lesions may not be detectable by a nonoptical modality but may have a high optical contrast. An imaging modality that relies on optical contrast to provide guidance is desirable for DOT. We present a system that combines a frequency-domain DOT and real-time photoacoustic tomography (PAT) systems to detect and characterize deeply seated targets embedded in a turbid medium. To further improve the contrast, the exogenous contrast agent, indocyanine green (ICG), is used. Our experimental results show that the combined system can detect a tumor-mimicking phantom, which is immersed in intralipid solution with the concentrations ranging from 100 to 10 µM and with the dimensions of 0.8 cm × 0.8 cm × 0.6 cm, up to 2.5 cm in depth. Mice experiments also confirmed that the combined system can detect tumors and monitor the ICG uptake and washout in the tumor region. This method can potentially improve the accuracy to detect small breast lesions as well as lesions that are sensitive to background tissue changes, such as the lesions located just above the chest wall.

Photoacoustic imaging enhanced by indocyanine green-conjugated single-wall carbon nanotubes.

A photoacoustic contrast agent that is based on bis-carboxylic acid derivative of indocyanine green (ICG) covalently conjugated to single-wall carbon nanotubes (ICG/SWCNT) is presented. Covalently attaching ICG to the functionalized SWCNT provides a more robust system that delivers much more ICG to the tumor site. The detection sensitivity of the new contrast agent in a mouse tumor model is demonstrated in vivo by our custom-built photoacoustic imaging system. The summation of the photoacoustic tomography (PAT) beam envelope, referred to as the "PAT summation," is used to demonstrate the postinjection light absorption of tumor areas in ICG- and ICG/SWCNT-injected mice. It is shown that ICG is able to provide 33% enhancement at approximately 20 min peak response time with reference to the preinjection PAT level, while ICG/SWCNT provides 128% enhancement at 80 min and even higher enhancement of 196% at the end point of experiments (120 min on average). Additionally, the ICG/SWCNT enhancement was mainly observed at the tumor periphery, which was confirmed by fluorescence images of the tumor samples. This feature is highly valuable in guiding surgeons to assess tumor boundaries and dimensions in vivo and to achieve clean tumor margins to improve surgical resection of tumors.

Co-registered pulse-echo/photoacoustic transvaginal probe for real time imaging of ovarian tissue.

We present the design and construction of a prototype imaging probe capable of co-registered pulse-echo ultrasound and photoacoustic (optoacoustic) imaging in real time. The probe consists of 36 fibers of 200 micron core diameter each that are distributed around a commercial transvaginal ultrasound transducer, and housed in a protective shield. Its performance was demonstrated by two sets of experiments. The first set involved imaging of blood flowing through a tube mimicking a blood vessel, the second set involved imaging of human ovaries ex vivo. The results suggest that the system along with the probe has great potential for imaging and characterizing of ovarian tissue in vivo.

Characterization of ovarian tissue based on quantitative analysis of photoacoustic microscopy images.

In this paper, human ovarian tissue with malignant and benign features was imaged ex vivo using an optical-resolution photoacoustic microscopy (OR-PAM) system. The feasibility of PAM to differentiate malignant from normal ovarian tissues was explored by comparing the PAM images morphologically. Based on the observed differences between PAM images of normal and malignant ovarian tissues in microvasculature features and distributions, seven features were quantitatively extracted from the PAM images, and a logistic model was used to classify ovaries as normal or malignant. 106 PAM images from 18 ovaries were studied. 57 images were used to train the seven-parameter logistic model, and a specificity of 92.1% and a sensitivity of 89.5% were achieved; 49 images were then tested, and a specificity of 81.3% and a sensitivity of 88.2% were achieved. These preliminary results demonstrate the feasibility of our PAM system in mapping microvasculature networks as well as characterizing the ovarian tissue, and could be extremely valuable in assisting surgeons for in vivo evaluation of ovarian tissue during minimally invasive surgery.

Investigation of a diffuse optical measurements-assisted quantitative photoacoustic tomographic method in reflection geometry.

Photoacoustic tomography provides the distribution of absorbed optical energy density, which is the product of optical absorption coefficient and optical fluence distribution. We report the experimental investigation of a novel fitting procedure that quantitatively determines the optical absorption coefficient of chromophores. The experimental setup consisted of a hybrid system of a 64-channel photoacoustic imaging system with a frequency-domain diffused optical measurement system. The fitting procedure included a complete photoacoustic forward model and an analytical solution of a target chromophore using the diffusion approximation. The fitting procedure combines the information from the photoacoustic image and the background information from the diffuse optical measurements to minimize the photoacoustic measurements and forward model data and recover the target absorption coefficient quantitatively. 1-cm-cube phantom absorbers of high and low contrasts were imaged at depths of up to 3.0 cm. The fitted absorption coefficient results were at least 80% of their true values. The sensitivities of this fitting procedure to target location, target radius, and background optical properties were also investigated. We found that this fitting procedure was most sensitive to the accurate determination of the target radius and depth. Blood sample in a thin tube of radius 0.58 mm, simulating a blood vessel, was also studied. The photoacoustic images and fitted absorption coefficients are presented. These results demonstrate the clinical potential of this fitting procedure to quantitatively characterize small lesions in breast imaging.

Application of laser pulse stretching scheme for efficiently delivering laser energy in photoacoustic imaging.

High-energy and short-duration laser pulses are desirable to improve the photoacoustic image quality when imaging deeply seated lesions. In many clinical applications, the high-energy pulses are coupled to tissue using optical fibers. These pulses can damage fibers if the damage threshold is exceeded. While keeping the total energy under the Food and Drug Administration limit for avoiding tissue damage, it is necessary to reduce the peak intensity and increase the pulse duration for minimizing fiber damage and delivering sufficient light for imaging. We use laser-pulse-stretching to address this problem. An initial 17-ns pulse was stretched to 27 and 37 ns by a ring-cavity laser-pulse-stretching system. The peak power of the 37-ns stretched pulse reduced to 42% of the original, while the fiber damage threshold was increased by 1.5-fold. Three ultrasound transducers centered at 1.3-, 3.5-, and 6-MHz frequencies were simulated, and the results showed that the photoacoustic signal of a 0.5-mm-diameter target obtained with 37-ns pulse was about 98, 91, and 80%, respectively, using the same energy as the 17-ns pulse. Simulations were validated using a broadband hydrophone. Quantitative comparisons of photoacoustic images obtained with three corresponding transducers showed that the image quality was not affected by stretching the pulse.

Integrated optical coherence tomography, ultrasound and photoacoustic imaging for ovarian tissue characterization.

Ovarian cancer has the lowest survival rate of the gynecologic cancers because it is predominantly diagnosed in Stages III or IV due to the lack of reliable symptoms, as well as the lack of efficacious screening techniques. Detection before the malignancy spreads or at the early stage would greatly improve the survival and benefit patient health. In this report, we present an integrated optical coherence tomography (OCT), ultrasound (US) and photoacoustic imaging (PAI) prototype endoscopy system for ovarian tissue characterization. The overall diameter of the prototype endoscope is 5 mm which is suitable for insertion through a standard 5-12.5mm endoscopic laparoscopic port during minimally invasive surgery. It consists of a ball-lensed OCT sample arm probe, a multimode fiber having the output end polished at 45 degree angle so as to deliver the light perpendicularly for PAI, and a high frequency ultrasound transducer with 35MHz center frequency. System characterizations of OCT, US and PAI are presented. In addition, results obtained from ex vivo porcine and human ovarian tissues are presented. The optical absorption contrast provided by PAI, the high resolution subsurface morphology provided by OCT, and the deeper tissue structure imaged by US demonstrate the synergy of the combined endoscopy and the superior performance of this hybrid device over each modality alone in ovarian tissue characterization.

Potential role of a hybrid intraoperative probe based on OCT and positron detection for ovarian cancer detection and characterization.

Ovarian cancer has the lowest survival rate of the gynecologic cancers because it is predominantly diagnosed in the late stages due to the lack of reliable symptoms and efficacious screening techniques. A novel hybrid intraoperative probe has been developed and evaluated for its potential role in detecting and characterizing ovarian tissue. The hybrid intraoperative dual-modality device consists of multiple scintillating fibers and an optical coherence tomography imaging probe for simultaneously mapping the local activities of (18)F-FDG uptake and imaging of local morphological changes of the ovary. Ten patients were recruited to the study and a total of 18 normal, abnormal and malignant ovaries were evaluated ex vivo using this device. Positron count rates of 7.5/8.8-fold higher were found between malignant and abnormal/normal ovaries. OCT imaging of malignant and abnormal ovaries revealed many detailed morphologic features that could be potentially valuable for evaluating local regions with high metabolic activities and detecting early malignant changes in the ovary. These initial results have demonstrated that our novel hybrid imager has great potential for ovarian cancer detection and characterization during minimally invasive endoscopic procedures.

Time-gating scheme based on a photodiode for single-photon counting.

A fast, simple, and low-cost optical time-gating scheme for counting single photons is presented. Its construction consists of a silicon photodiode connected in series with a 50 Ω resistor and that operates in the photoconductive mode. The temporal resolution at the FWHM of the photon counting system was measured to be 62 ps. The profile of a single-photon pulse measured with the counting system agreed well with analytical results. The system was also used to successfully resolve a pair of targets with 4 mm separation inside a highly scattering medium by the use of time-gated early-arriving photons.

Target detection and quantification using a hybrid hand-held diffuse optical tomography and photoacoustic tomography system.

We present a photoacoustic tomography-guided diffuse optical tomography approach using a hand-held probe for detection and characterization of deeply-seated targets embedded in a turbid medium. Diffuse optical tomography guided by coregistered ultrasound, MRI, and x ray has demonstrated a great clinical potential to overcome lesion location uncertainty and to improve light quantification accuracy. However, due to the different contrast mechanisms, some lesions may not be detectable by a nonoptical modality but yet have high optical contrast. Photoacoustic tomography utilizes a short-pulsed laser beam to diffusively penetrate into tissue. Upon absorption of the light by the target, photoacoustic waves are generated and used to reconstruct, at ultrasound resolution, the optical absorption distribution that reveals optical contrast. However, the robustness of optical property quantification of targets by photoacoustic tomography is complicated because of the wide range of ultrasound transducer sensitivity, the orientation and shape of the targets relative to the ultrasound array, and the uniformity of the laser beam. We show in this paper that the relative optical absorption map provided by photoacoustic tomography can potentially guide the diffuse optical tomography to accurately reconstruct target absorption maps.

Effect of ultrasound transducer face reflectivity on the light fluence inside a turbid medium in photoacoustic imaging.

Many endoscopic, intravascular, and transvaginal applications require light to be delivered through optical fibers in a reflection mode. For photoacoustic imaging in reflection geometry, the front-face reflectivity of the ultrasound transducer face imposes a boundary condition that affects the light fluence and its distribution inside a turbid medium. Understanding and characterizing this boundary condition is critical for maximizing tissue illumination and therefore the signal-to-noise ratio of the photoacoustic signal. We systematically analyze the light fluence under three typical commercial transducer faces having reflection coefficients of 1.4, 18, and 28%, and compare the results to a transducer face with 60% coefficient at the laser wavelength of 750 nm. Monte Carlo simulations and experimental results show that light fluence and distribution obtained inside a turbid medium with the use of the 60% reflection coefficient transducer face has a significant improvement over the others, especially at shallower depths.