Hugang Ren

Cocaine-induced cortical microischemia in the rodent brain: clinical implications

Cocaine-induced stroke is among the most serious medical complications associated with its abuse. However, the extent to which acute cocaine may induce silent microischemia predisposing the cerebral tissue to neurotoxicity has not been investigated; in part, because of limitations of current neuroimaging tools, that is, lack of high spatiotemporal resolution and sensitivity to simultaneously measure cerebral blood flow (CBF) in vessels of different calibers (including capillaries) quantitatively and over a large field of view. Here we combine ultrahigh-resolution optical coherence tomography to enable tracker-free three-dimensional (3D) microvascular angiography and a new phase-intensity-mapping algorithm to enhance the sensitivity of 3D optical Doppler tomography for simultaneous capillary CBF quantization. We apply the technique to study the responses of cerebral microvascular networks to single and repeated cocaine administration in the mouse somatosensory cortex. We show that within 2–3 min after cocaine administration CBF markedly decreased (for example, ∼70%), but the magnitude and recovery differed for the various types of vessels; arterioles had the fastest recovery (∼5 min), capillaries varied drastically (from 4–20 min) and venules showed relatively slower recovery (∼12 min). More importantly, we showed that cocaine interrupted CBF in some arteriolar branches for over 45 min and this effect was exacerbated with repeated cocaine administration. These results provide evidence that cocaine doses within the range administered by drug abusers induces cerebral microischemia and that these effects are exacerbated with repeated use. Thus, cocaine-induced microischemia is likely to be a contributor to its neurotoxic effects.

Early Detection of Carcinoma In Situ of the Bladder: A Comparative Study of White Light Cystoscopy, Narrow Band Imaging, 5-ALA Fluorescence Cystoscopy and 3-Dimensional Optical Coherence Tomography

PURPOSE We compared the efficacy and potential limitations of white light cystoscopy, narrow band imaging, 5-ALA fluorescence cystoscopy and 3-dimensional optical coherence tomography for early diagnosis of bladder carcinoma in situ. MATERIALS AND METHODS By expressing simian virus 40T antigen in the urothelium carcinoma in situ typically develops in SV40T transgenic mice in about 8 to 20 weeks and then frank high grade papillary urothelial carcinoma starts to emerge. A total of 18 control and 29 SV40T mice were examined during weeks 8 to 22 by white light cystoscopy, fluorescence cystoscopy, narrow band imaging and 3-dimensional optical coherence tomography. Results were validated by histology. Newly improved algorithms for computer aided detection were applied to acquired 3-dimensional optical coherence tomography images to enhance the quantitative diagnosis of carcinoma in situ in near real time. RESULTS Of 29 carcinoma in situ samples 27 were detected by 3-dimensional optical coherence tomography, 1 by white light cystoscopy, 26 by narrow band imaging and 13 by fluorescence cystoscopy. Of the 18 histologically confirmed benign cases 17 were detected by 3-dimensional optical coherence tomography, 14 by white light cystoscopy, 5 by narrow band imaging and 18 by fluorescence cystoscopy. The diagnostic sensitivity of white light cystoscopy (3.4%) and fluorescence cystoscopy (44.8%), and the specificity of narrow band imaging (27.8%) were significantly enhanced by 3-dimensional optical coherence tomography to 93.1% and 94.4%, respectively (p <0.01). CONCLUSIONS Three-dimensional optical coherence tomography with quantitative computer aided detection can significantly enhance the sensitivity of white light cystoscopy and fluorescence cystoscopy, and the specificity of narrow band imaging for early diagnosis of carcinoma in situ. This suggests the potential of narrow band imaging guided 3-dimensional optical coherence tomography for future clinical detection of carcinoma in situ when effective image guidance is desirable.

A digital frequency ramping method for enhancing Doppler flow imaging in Fourier-domain optical coherence tomography.

A digital frequency ramping method (DFRM) is proposed to improve the signal-to-noise ratio (SNR) of Doppler flow imaging in Fourier-domain optical coherence tomography (FDOCT). To examine the efficacy of DFRM for enhancing flow detection, computer simulation and tissue phantom study were conducted for phase noise reduction and flow quantification. In addition, the utility of this technique was validated in our in vivo clinical bladder imaging with endoscopic FDOCT. The Doppler flow images reconstructed by DFRM were compared with the counterparts by traditional Doppler FDOCT. The results demonstrate that DFRM enables real-time Doppler FDOCT imaging at significantly enhanced sensitivity without hardware modification, thus rendering it uniquely suitable for endoscopic subsurface blood flow imaging and diagnosis.

Quantitative imaging of red blood cell velocity invivo using optical coherence Doppler tomography

We present particle counting ultrahigh-resolution optical Doppler tomography (pc-μODT) that enables accurate imaging of red blood cell velocities (ν(RBC)) of cerebrovascular networks by detecting the Doppler phase transients induced by the passage of a RBC through a capillary. We apply pc-μODT to image the response of capillary ν(RBC) to mild hypercapnia in mouse cortex. The results show that ν(RBC) in normocapnia (ν(N) = 0.72 ± 0.15 mm/s) increased 36.1% ± 5.3% (ν(H) = 0.98 ± 0.29 mm/s) in response to hypercapnia. Due to uncorrected angle effect and low hematocrit (e.g., ∼10%), ν(RBC) directly measured by μODT were markedly underestimated (ν(N) ≈ 0.27 ± 0.03 mm/s, ν(H) ≈ 0.37± 0.05 mm/s). Nevertheless, the measured ν(RBC) increase (35.3%) matched that (36.1% ± 5.3%) by pc-μODT.

Enhancing Detection of Bladder Carcinoma In Situ by 3-Dimensional Optical Coherence Tomography

PURPOSE We examined the usefulness of 3-dimensional optical coherence tomography to enhance the diagnosis of urothelial carcinoma in situ. MATERIALS AND METHODS By expressing SV40T antigen with uroplakin II promoter, carcinoma in situ readily develops in SV40T transgenic mice at about ages 8 to 20 weeks and then frank high grade papillary carcinoma develops in bladder epithelium. We examined 10 control and 40 SV40T mice during weeks 8 to 20 after birth by parallel en face white light imaging and 3-dimensional optical coherence tomography, and compared results with histology findings. We applied quantitative analysis of computer aided detection to 3-dimensional tomography images to enhance the diagnosis of carcinoma in situ, including 3-dimensional segmentation, speckle reduction, fast Fourier transform analysis, and standard deviation and histogram evaluation. RESULTS We identified carcinoma in situ in 23 SV40T mice by histology. Most carcinoma could not be detected by en face imaging and 2-dimensional optical coherence tomography but was well differentiated by 3-dimensional optical coherence tomography. The 56.5% sensitivity and 61.5% specificity of 2-dimensional optical coherence tomography for carcinoma in situ diagnosis were significantly enhanced by 3-dimensional optical coherence tomography to 95.7% and 92.3%, respectively (p ≤0.031). CONCLUSIONS On quantitative analysis of increased urothelial heterogeneity induced by carcinogenesis we noted that 3-dimensional optical coherence tomography enabled accurate differentiation of carcinoma in situ from normal bladder and benign lesions. Results reveal the potential of cystoscopic 3-dimensional optical coherence tomography to significantly enhance the clinical diagnosis of nonmuscle invasive bladder cancer, particularly carcinoma in situ.

OPTICAL COHERENCE TOMOGRAPHY FOR BLADDER CANCER DIAGNOSIS: FROM ANIMAL STUDY TO CLINICAL DIAGNOSIS

This paper summarizes the recent technological development in our lab on cystoscopic optical coherence tomography (COCT) by integrating time-domain OCT (TDOCT) and spectral-domain OCT (SDOCT) with advanced MEMS-mirror technology for endoscopic laser scanning imaging. The COCT catheter can be integrated into the instrument channel of a commercial 22Fr rigid cystoscopic sheath for in vivo imaging of human bladder under the cystosocopic visual guidance; the axial/transverse resolutions of the COCT catheter are roughly 9 μm and 12 μm, respectively, and 2D COCT imaging can be performed with over 110dB dynamic range at 4–8 fps. To examine the utility and potential limitations of OCT for bladder cancer diagnosis, systemic ex vivo rat bladder carcinogenesis studies were performed to follow various morphological changes induced by tumor growth and in vivo porcine study was performed to examine the feasibility of COCT for in vivo imaging. Justified by promising results of the animal studies, preliminary clinical study was conducted on patients scheduled for operating-room cystoscopy for bladder cancers. Double-blind clinical results reveal that COCT can delineate detailed bladder architectures (e.g., urothelium, lamina propria, muscularis) at high resolution and detect bladder cancers based on enhanced urothelial heterogeneity as a result of excessive growing nature of bladder cancers. The diagnostic sensitivity and specificity can be enhanced to 92% and 85%, respectively. Results also suggest that due to reduced imaging depth of COCT in cancerous lesions, staging of bladder cancers may be limited to Ta or T1 for non-outgrowing cancerous lesions.

High-resolution imaging diagnosis of human fetal membrane by three-dimensional optical coherence tomography

Microscopic chorionic pseudocyst (MCP) arising in the chorion leave of the human fetal membrane (FM) is a clinical precursor for preeclampsia which may progress to fatal medical conditions (e.g., abortion) if left untreated. To examine the utility of three-dimensional (3D) optical coherence tomography (OCT) for noninvasive delineation of the morphology of human fetal membranes and early clinical detection of MCP, 60 human FM specimens were acquired from 10 different subjects undergoing term cesarean delivery for an ex vivo feasibility study. Our results showed that OCT was able to identify the four-layer architectures of human FMs consisting of high-scattering decidua vera (DV, average thickness d(DV) ≈ 92±38 μm), low-scattering chorion and trophoblast (CT, d(CT) ≈ 150±67 μm), high-scattering subepithelial amnion (A, d(A) ≈ 95±36 μm), and low-scattering epithelium (E, d(E) ≈ 29±8 μm). Importantly, 3D OCT was able to instantaneously detect MCPs (low scattering due to edema, fluid buildup, vasodilatation) and track (staging) their thicknesses d(MCP) ranging from 24 to 615 μm. It was also shown that high-frequency ultrasound was able to compliment OCT for detecting more advanced thicker MCPs (e.g., d(MCP)>615 μm) because of its increased imaging depth.

Multichannel optical brain imaging to separate cerebral vascular, tissue metabolic, and neuronal effects of cocaine

Characterization of cerebral hemodynamic and oxygenation metabolic changes, as well neuronal function is of great importance to study of brain functions and the relevant brain disorders such as drug addiction. Compared with other neuroimaging modalities, optical imaging techniques have the potential for high spatiotemporal resolution and dissection of the changes in cerebral blood flow (CBF), blood volume (CBV), and hemoglobing oxygenation and intracellular Ca ([Ca2+]i), which serves as markers of vascular function, tissue metabolism and neuronal activity, respectively. Recently, we developed a multiwavelength imaging system and integrated it into a surgical microscope. Three LEDs of λ1=530nm, λ2=570nm and λ3=630nm were used for exciting [Ca2+]i fluorescence labeled by Rhod2 (AM) and sensitizing total hemoglobin (i.e., CBV), and deoxygenated-hemoglobin, whereas one LD of λ1=830nm was used for laser speckle imaging to form a CBF mapping of the brain. These light sources were time-sharing for illumination on the brain and synchronized with the exposure of CCD camera for multichannel images of the brain. Our animal studies indicated that this optical approach enabled simultaneous mapping of cocaine-induced changes in CBF, CBV and oxygenated- and deoxygenated hemoglobin as well as [Ca2+]i in the cortical brain. Its high spatiotemporal resolution (30μm, 10Hz) and large field of view (4x5 mm2) are advanced as a neuroimaging tool for brain functional study.

Image guided 3D OCT for early diagnosis of carcinoma in situ of the bladder

Bladder carcinoma in situ (CIS) remains a clinical challenge. We compare the efficacies and potential limitations of surface imaging modalities, e.g., white light (WL), fluorescence (FC), blue-light imaging (BL) and 3D optical coherence tomography (3D OCT) for early diagnosis of bladder CIS. SV40T transgenic mice, which develop carcinoma in situ in about 8 to 20 weeks then high grade papillary tumor in the bladder, were employed as the rodent carcinogenesis model to closely mimic human bladder CIS. A total of 30 mice (i.e., SV40T mice blinded with its back strain Balb/c mice) were enrolled in the study, including 20 with CIS and 10 with normal or benign lesions of the bladder mucosa. Our results show that the low diagnostic sensitivities and specificities of WL, FC and BL for early CIS were significantly enhanced by quantitative 3D OCT to 95.0% and 90.0%, suggesting the value of image-guided 3D OCT for future clinical diagnosis of CIS in vivo.

Characterization of dynamic physiology of the bladder by optical coherence tomography

Because of its high spatial resolution and noninvasive imaging capabilities, optical coherence tomography has been used to characterize the morphological details of various biological tissues including urinary bladder and to diagnose their alternations (e.g., cancers). In addition to static morphology, the dynamic features of tissue morphology can provide important information that can be used to diagnose the physiological and functional characteristics of biological tissues. Here, we present the imaging studies based on optical coherence tomography to characterize motion related physiology and functions of rat bladder detrusor muscles and compared the results with traditional biomechanical measurements. Our results suggest that optical coherence tomography is capable of providing quantitative evaluation of contractile functions of intact bladder (without removing bladder epithelium and connective tissue), which is potentially of more clinical relevance for future clinical diagnosis - if incorporated with cystoscopic optical coherence tomography.