cerebral-blood-flow-based-resting-state-functional-connectivity-human

Cerebral Blood Flow-Based Resting State Functional Connectivity of the Human Brain using Optical Diffuse Correlation Spectroscopy

To obtain a comprehensive understanding of the human brain, utilization of cerebral blood flow (CBF) as a source of contrast is desired because it is a ...

Wright State University

The efficacy of chemotherapy is related, in large part, to the concentration of drug that reaches tumor sites. Doxorubicin (DOX) is a common anti-cancer drug that is also approved for use in liposomal form for the treatment of ovarian cancer. We recently developed a porphyrin-phospholipid (PoP)-liposome system that enables on demand release of DOX from liposomes using near infrared irradiation to improve DOX bioavailability. Owing to its intrinsic fluorescence, it is possible, and desirable, to quantify DOX concentration and distribution, preferably noninvasively. Here we quantified DOX distribution following light-triggered drug release in phantoms and an animal carcass using spatial frequency domain imaging. This study demonstrates the feasibility of non-invasive quantitative mapping of DOX distributions in target areas. 

Quantitative imaging of light-triggered doxorubicin release.

Stealth liposomes can be used to extend the blood circulation time of encapsulated therapeutics. Inclusion of 2 molar % porphyrin-phospholipid (PoP) imparted optimal near infrared (NIR) light-triggered release of doxorubicin (Dox) from conventional sterically stabilized stealth liposomes. The type and amount of PoP affected drug loading, serum stability and drug release induced by NIR light. Cholesterol and PEGylation were required for Dox loading, but slowed light-triggered release. Dox in stealth PoP liposomes had a long circulation half-life in mice of 21.9 h and was stable in storage for months. Following intravenous injection and NIR irradiation, Dox deposition increased ∼ 7 fold in treated subcutaneous human pancreatic xenografts. Phototreatment induced mild tumor heating and complex tumor hemodynamics. A single chemophototherapy treatment with Dox-loaded stealth PoP liposomes (at 5-7 mg/kg Dox) eradicated tumors while corresponding chemo- or photodynamic therapies were ineffective. A low dose 3 mg/kg Dox phototreatment with stealth PoP liposomes was more effective than a maximum tolerated dose of free (7 mg/kg) or conventional long-circulating liposomal Dox (21 mg/kg). To our knowledge, Dox-loaded stealth PoP liposomes represent the first reported long-circulating nanoparticle capable of light-triggered drug release.

Doxorubicin encapsulated in stealth liposomes conferred with light-triggered drug release.

Functional near-infrared spectroscopy (fNIRS) was used to investigate spontaneous hemodynamic activity in the temporal cortex for typically developing (TD) children and children with autism spectrum disorder (ASD). Forty-seven children participated in the experiments including twenty-five with ASD. Compared with TD children, children with ASD showed weaker bilateral resting-state functional connectivity (RSFC), but much stronger fluctuation magnitude in terms of oxy-hemoglobin (HbO2) and deoxy-hemoglobin (Hb). Differentiating between ASD and TD based on a support vector machine (SVM) model including bilateral RSFC and the fluctuation power of HbO2 and Hb as variables could achieve high accurate classification with sensitivity of 81.6% and specificity of 94.6%. This study demonstrates optical brain imaging has the potential for screening children with risk of ASD.

Characterization of autism spectrum disorder with spontaneous hemodynamic activity.

Bronchoscopic procedures have been increasingly used for the diagnosis of peripheral lung cancers, but the yield remains moderately low. The aim of this study is to assess the feasibility and ability of a custom-built bimodal optical spectroscopy system to enhance the on-site discrimination between malignant and benign specimens obtained from the transbronchial lung biopsies (TBLB) of peripheral lung lesions.

Optical imaging of tissue obtained by transbronchial biopsies of peripheral lung lesions.

For prevention and accurate intervention planning, it is crucial to predict if lesions will progress towards cancer. In this study, we investigated the change in optical properties and vascular parameters to characterize skin tissue from mild photodamage to actinic keratosis (AK). Multi-wavelength spatial frequency domain imaging (SFDI) measurements were performed on three patients with clinically normal skin, as well as pre-cancerous actinic keratosis lesions. Our results indicate that there exist significant differences in both optical and vascular parameters between these patients, and that these parameters can be early biomarkers of neoplasia. Ultimately, clinicians can use this noninvasive approach for frequent monitoring of high-risk population.

Noninvasive mesoscopic imaging of actinic skin damage using spatial frequency domain imaging.

Image Characteristics of Lung Abscess by Convex-Probe Endobronchial Ultrasound.

Near-infrared diffuse correlation spectroscopy (DCS) is used to record spontaneous cerebral blood flow fluctuations in the frontal cortex. Nine adult subjects participated in the experiments, in which 8-minute spontaneous fluctuations were simultaneously recorded from the left and right dorsolateral and inferior frontal regions. Resting-state functional connectivity (RSFC) was measured by the temporal correlation of the low frequency fluctuations. Our data shows the RSFC within the dorsolateral region is significantly stronger than that between the inferior and dorsolateral regions, in line with previous observations with functional near-infrared spectroscopy. This indicates that DCS is capable of investigating brain functional connectivity in terms of cerebral blood flow.

Resting-state functional connectivity measured by diffuse correlation spectroscopy.

Doxorubicin (Dox) is approved for use in liposomal form for the treatment of ovarian cancer. We previously developed a long-circulating Dox formulation in liposomes containing small amounts of porphyrin-phospholipid, which enables on-demand drug release with near-infrared irradiation. In this study, we present and evaluate a dual-modal, dual-channel light endoscope that allows quantitative reflectance and fluorescence imaging for monitoring of local Dox concentrations in target areas. The endoscope consists of two flexible imaging fibers; one to transmit diagnostic and therapeutic light to the target, and the other to detect fluorescent and reflected light. Thus, the endoscope serves for imaging, for light delivery to trigger drug release, and for monitoring drug concentration kinetics during drug release. We characterized the performance of this endoscope in tissue phantoms and in an in vivo model of ovarian cancer. This study demonstrates the feasibility of non-invasive, quantitative mapping of Dox distribution in vivo via endoscopic imaging.

A dual-channel endoscope for quantitative imaging, monitoring, and triggering of doxorubicin release from liposomes in living mice.

A novel approach for time-domain diffuse correlation spectroscopy (TD-DCS) has been recently proposed, which has the unique advantage by simultaneous measurements of optical and dynamical properties in a scattering medium. In this study, analytical models for calculating the time-resolved electric-field autocorrelation function is presented for a multi-layer turbid sample, as well as a semi-infinite medium embedded with a small dynamic heterogeneity. To verify the analytical models, we used Monte Carlo simulations, which demonstrated that the theoretical prediction for the time-resolved autocorrelation function was highly consistent with the Monte Carlo simulation, validating the proposed analytical models. Using these analytical models, we also showed that TD-DCS has a higher sensitivity compared to conventional continuous-wave (CW) DCS for detecting the deeper dynamics. The presented analytical models and simulations can be utilized for quantification of optical and dynamical properties from future TD-DCS experimental data as well as for optimization of the experimental design to achieve maximum contrast for deep tissue dynamics.

Analytical models for time-domain diffuse correlation spectroscopy for multi-layer and heterogeneous turbid media.

Early knowledge about burn severity and depth can lead to improved outcome for patients. In this study, we investigated the change in optical properties in ex vivo human skin following thermal burn injuries. Human skin removed during body contouring procedures was subjected to thermal burn injury for either 10 or 60 s. Multi-wavelength spatial frequency domain imaging (SFDI) measurements were performed on each sample and the optical properties (absorption and scattering parameters) were obtained at each wavelength. Multi-wavelength fitting was used to quantify absorption and scattering parameters, and these parameters were compared to histologic assessments of burn depth related to burn severity. Our results indicated substantial changes in optical scattering parameters and these changes correlated well with the burn severity and depth, and fit closely with previously reported studies using porcine in vivo models. This study provides the characterization of thermal burn injury on human skin ex vivo by using the optical method of SFDI with high sensitivity and specificity. This preclinical human model system without live animals could have uses in testing the imaging parameters of other skin injuries, including from caustic agents.

Early assessment of burn severity in human tissue ex vivo with multi-wavelength spatial frequency domain imaging.

Photodynamic therapy (PDT) of cancer is dependent on three primary components: photosensitizer (PS), light and oxygen. Because these components are interdependent and vary during the dynamic process of PDT, assessing PDT efficacy may not be trivial. Therefore, it has become necessary to develop pre-treatment planning, on-line monitoring and dosimetry strategies during PDT, which become more critical for two or more chromophore systems, for example, PS-CD (Photosensitizer-Cyanine dye) conjugates developed in our laboratory for fluorescence-imaging and PDT of cancer. In this study, we observed a significant impact of variable light dosimetry; (i) high light fluence and fluence rate (light dose: 135 J/cm², fluence rate: 75 mW/cm²) and (ii) low light fluence and fluence rate (128 J/cm² and 14 mW/cm² and 128 J/cm² and 7 mW/cm²) in photobleaching of the individual chromophores of PS-CD conjugates and their long-term tumor response. The fluorescence at the near-infrared (NIR) region of the PS-NIR fluorophore conjugate was assessed intermittently via fluorescence imaging. The loss of fluorescence, photobleaching, caused by singlet oxygen from the PS was mapped continuously during PDT. The tumor responses (BALB/c mice bearing Colon26 tumors) were assessed after PDT by measuring tumor sizes daily. Our results showed distinctive photobleaching kinetics rates between the PS and CD. Interestingly, compared to higher light fluence, the tumors exposed at low light fluence showed reduced photobleaching and enhanced long-term PDT efficacy. The presence of NIR fluorophore in PS-CD conjugates provides an opportunity of fluorescence imaging and monitoring the photobleaching rate of the CD moiety for large and deeply seated tumors and assessing PDT tumor response in real-time.

Measurement of Cyanine Dye Photobleaching in Photosensitizer Cyanine Dye Conjugates Could Help in Optimizing Light Dosimetry for Improved Photodynamic Therapy of Cancer.

Diffuse optical imaging probes deep living tissue enabling structural, functional, metabolic, and molecular imaging. Recently, due to the availability of spatial light modulators, wide-field quantitative diffuse optical techniques have been implemented, which benefit greatly from structured light methodologies. Such implementations facilitate the quantification and characterization of depth-resolved optical and physiological properties of thick and deep tissue at fast acquisition speeds. We summarize the current state of work and applications in the three main techniques leveraging structured light: spatial frequency-domain imaging, optical tomography, and single-pixel imaging. The theory, measurement, and analysis of spatial frequency-domain imaging are described. Then, advanced theories, processing, and imaging systems are summarized. Preclinical and clinical applications on physiological measurements for guidance and diagnosis are summarized. General theory and method development of tomographic approaches as well as applications including fluorescence molecular tomography are introduced. Lastly, recent developments of single-pixel imaging methodologies and applications are reviewed.

Review of structured light in diffuse optical imaging.

We investigated the change in optical properties and vascular parameters to characterize skin tissue from mild photodamage to actinic keratosis (AK) with comparison to a published photodamage scale. Multi-wavelength spatial frequency domain imaging (SFDI) measurements were performed on the dorsal forearms of 55 adult subjects with various amounts of photodamage. Dermatologists rated the levels of photodamage based upon the photographs in blinded fashion to allow comparison with SFDI data. For characterization of statistical data, we used artificial neural networks. Our results indicate that optical and vascular parameters can be used to quantify photodamage and can discriminate between the stages as low, medium, and high grades, with the best performance of ∼70%, ∼76% and 80% for characterization of low- medium- and high-grade lesions, respectively. Ultimately, clinicians can use this noninvasive approach for risk assessment and frequent monitoring of high-risk populations.

Article	Year
Quantitative imaging of light-triggered doxorubicin release. Biomedical optics express\| PubMed ID: 26417522	2015
Doxorubicin encapsulated in stealth liposomes conferred with light-triggered drug release. Biomaterials\| PubMed ID: 26513413	2016
Characterization of autism spectrum disorder with spontaneous hemodynamic activity. Biomedical optics express\| PubMed ID: 27867699	2016
Optical imaging of tissue obtained by transbronchial biopsies of peripheral lung lesions. Journal of thoracic disease\| PubMed ID: 28616294	2017
Noninvasive mesoscopic imaging of actinic skin damage using spatial frequency domain imaging. Biomedical optics express\| PubMed ID: 28663925	2017
Image Characteristics of Lung Abscess by Convex-Probe Endobronchial Ultrasound. Journal of bronchology & interventional pulmonology\| PubMed ID: 28696970	2017
Resting-state functional connectivity measured by diffuse correlation spectroscopy. Journal of biophotonics\| PubMed ID: 28708329	2018
A dual-channel endoscope for quantitative imaging, monitoring, and triggering of doxorubicin release from liposomes in living mice. Scientific reports\| PubMed ID: 29138489	2017
Analytical models for time-domain diffuse correlation spectroscopy for multi-layer and heterogeneous turbid media. Biomedical optics express\| PubMed ID: 29296485	2017
Early assessment of burn severity in human tissue ex vivo with multi-wavelength spatial frequency domain imaging. Toxicology in vitro : an international journal published in association with BIBRA\| PubMed ID: 29859991	2018
Measurement of Cyanine Dye Photobleaching in Photosensitizer Cyanine Dye Conjugates Could Help in Optimizing Light Dosimetry for Improved Photodynamic Therapy of Cancer. Molecules (Basel, Switzerland)\| PubMed ID: 30042350	2018
Review of structured light in diffuse optical imaging. Journal of biomedical optics\| PubMed ID: 30218503	2018
Quantifying skin photodamage with spatial frequency domain imaging: statistical results. Biomedical optics express\| PubMed ID: 31565518	2019

Ulas Sunar

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