Diffuse optical tomography for mapping cerebral hemodynamics and functional connectivity in delirium.

INTRODUCTION: Delirium is associated with mortality and new onset dementia, yet the underlying pathophysiology remains poorly understood. Development of imaging biomarkers has been difficult given the challenging nature of imaging delirious patients. Diffuse optical tomography (DOT) offers a promising approach for investigating delirium given its portability and three-dimensional capabilities. METHODS: Twenty-five delirious and matched non-delirious patients (n = 50) were examined using DOT, comparing cerebral oxygenation and functional connectivity in the prefrontal cortex during and after an episode of delirium. RESULTS: Total hemoglobin values were significantly decreased in the delirium group, even after delirium resolution. Functional connectivity between the dorsolateral prefrontal cortex and dorsomedial prefrontal cortex was strengthened post-resolution compared to during an episode; however, this relationship was still significantly weaker compared to controls. DISCUSSION: These findings highlight DOT's potential as an imaging biomarker to measure impaired cerebral oxygenation and functional dysconnectivity during and after delirium. Future studies should focus on the role of cerebral oxygenation in delirium pathogenesis and exploring the etiological link between delirium and dementias. HIGHLIGHTS: We developed a portable diffuse optical tomography (DOT) system for bedside three-dimensional functional neuroimaging to study delirium in the hospital. We implemented a novel DOT task-focused seed-based correlation analysis. DOT revealed decreased cerebral oxygenation and functional connectivity strength in the delirium group, even after resolution of delirium.

A one-step method for quantitative microwave-induced thermoacoustic tomography.

BACKGROUND: Electrical conductivity directly correlates with tissue functional information such as blood and water contents, and quantitative extraction of tissue conductivity is of significant importance for disease detection and diagnosis using microwave-induced thermoacoustic tomography (TAT). OBJECTIVE: The existing quantitative TAT (qTAT) approaches capable of extracting tissue conductivity require two steps for the recovery of conductivity. Such two steps approaches depend on an accurate knowledge of the microwave energy loss distribution in tissue and offer a slow computational convergence rate. The purpose of this study is to develop a new algorithm to reconstruct tissue conductivity with higher reconstruction accuracy and greater computational efficiency. METHODS: We propose an improved qTAT method for direct recovery of tissue conductivity from thermoacoustic data measured along the boundary with only one step without the dependence of microwave energy loss information. The feasibility of our one-step qTAT method is validated in both simulated and tissue-mimicking phantom experiments with single-target and multi-target configurations with different contrast levels. RESULTS: Compared with the previous two-step methods, our one-step qTAT method improves the accuracy of conductivity recovery with approximately one-fold reduction in the mean absolute error (MAE) and root mean square error (RMSE) with p-values greater than 0.05. In addition, the convergence rate is improved by more than two folds for the one-step method. CONCLUSIONS: The study demonstrates that new method can quantitatively reconstruct conductivity of tissue more accurately and efficiently over the existing qTAT methods, leading to potentially enhanced accuracy for disease detection and diagnosis.

Development of Dual-Frequency PMUT Arrays Based on Thin Ceramic PZT for Endoscopic Photoacoustic Imaging.

This paper presents a dual-frequency piezoelectric micromachined ultrasonic transducer (pMUT) array based on thin ceramic PZT for endoscopic photoacoustic imaging (PAI) applications. With a chip size of 7 × 7 mm2, the pMUT array consists of 256 elements, half of which have a lower resonant frequency of 1.2 MHz and the other half have a higher resonant frequency of 3.4 MHz. Ceramic PZT, with outstanding piezoelectric coefficients, has been successfully thinned down to a thickness of only 4 µ by using wafer bonding and chemical mechanical polishing (CMP) techniques and employed as the piezoelectric layer of the pMUT elements. The diaphragm diameters of the lower-frequency and higher-frequency elements are 220 µm and 120 µm, respectively. The design methodology, multiphysics modeling, fabrication process, and characterization of the pMUTs are presented in detail. The fabricated pMUT array has been fully characterized via electrical, mechanical, and acoustic measurements. The measured maximum responsivities of the lower- and higher- frequency elements reach 110 nm/V and 30 nm/V at their respective resonances. The measured cross-couplings of the lower-frequency elements and higher-frequency elements are about 9% and 5%, respectively. Furthermore, PAI experiments with pencil leads embedded into an agar phantom have been conducted, which clearly shows the advantages of using dual-frequency pMUT arrays to provide comprehensive photoacoustic images with high spatial resolution and large signal-to-noise ratio simultaneously.

Three-dimensional optical imaging of brain activation during transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) of the brain is an effective clinical treatment for psychiatric disorders. Noninvasive neuroimaging during rTMS allows visualization of cortical brain activations and responses, and it is a potential tool for investigating the neurophysiological response occurring actively during stimulation. In this paper, we present a fast diffuse optical tomography (DOT) approach for three-dimensional brain mapping of hemodynamics during rTMS. Eight healthy subjects were enrolled in the study. These subjects received 10 Hz stimulation with 80%and 100%of resting motor threshold (rMT), respectively, for 4 seconds for each stimulation. Significant hemodynamic activation was observed in all cases with the strongest response when 100%rMT stimulation was applied. This work demonstrates that fast DOT has the potential to become a powerful tool for noninvasive three-dimensional imaging of the brain during rTMS.

A Ceramic PZT-based PMUT Array for Endoscopic Photoacoustic Imaging.

In this paper, we present the design, fabrication, and characterization of a compact 4 × 4 piezoelectric micromachined ultrasonic transducer (pMUT) array and its application to photoacoustic imaging. The uniqueness of this pMUT array is the integration of a 4 µm-thick ceramic PZT, having significantly higher piezoelectric coefficient and lower stress than sol-gel or sputtered PZT. The fabricated pMUT array has a small chip size of only 1.8 × 1.6 mm2 with each pMUT element having a diameter of 210 µm. The fabricated device was characterized with electrical impedance measurement and acoustic sensing test. Photoacoustic imaging has also been successfully demonstrated on an agar phantom with a pencil lead embedded using the fabricated pMUT array.

In Vivo Evaluation of a Miniaturized Fluorescence Molecular Tomography (FMT) Endoscope for Breast Cancer Detection Using Targeted Nanoprobes.

In this study, in vivo animal experiments with 12 nude mice bearing breast-cancer-patient-tissue-derived xenograft (PDX) tumors were performed aiming to verify the imaging capability of a novel miniaturized fluorescence molecular tomography (FMT) endoscope, in combination with targeted nanoparticle-near-infrared (NIR) dye conjugates. Tumor-bearing mice were divided into two groups by systematic injection with urokinase plasminogen activator receptor-targeted (n = 7) and nontargeted (n = 5) imaging nanoprobes as a contrast agent, respectively. Each mouse was imaged at 6, 24, and 48 h following the injection of nanoprobes using the FMT endoscope. The results show that systemic delivery of targeted nanoprobes produced a 4-fold enhancement in fluorescence signals from tumors, compared with tumors that received nontargeted nanoprobes. This study indicates that our miniaturized FMT endoscope, coupled with the targeted nanoparticle-NIR dye conjugates as a contrast agent, has high sensitivity and specificity, and thus great potential to be used for image-guided detection and removal of a primary tumor and local metastatic tumors during surgery.

Thermoacoustic tomography of germinal matrix hemorrhage in neonatal mouse cerebrum.

BACKGROUND: Microwave-induced thermoacoustic tomography (TAT) has potential for detecting germinal matrix hemorrhage (GMH). However, it has not been demonstrated in vivo. OBJECTIVE: To demonstrate the feasibility of TAT for in vivo detecting GMH by using neonatal mouse. METHODS: A cylindrical-scanning TAT system was developed with optimized microwave irradiation and ultrasound detection for neonatal mouse imaging. Neonatal mice were used to develop GMH model by injection of autologous blood into the periventricular region. After TAT experiments, the animals were sacrificed, frozen and excised to validate the TAT findings. The detailed comparative analyses of the TAT images and corresponding photographs of the excised brain tissues were conducted. RESULTS: Satisfactory matches are identified between the TAT images and corresponding histological sections, in terms of the shape and size of the brain tissues. Some organs and tissues were also identified. Particularly, comparing to the corresponding histological sections, using TAT enables to more accurately detect the hematoma region at different depths in the neonatal mouse brain. CONCLUSIONS: This study demonstrates for the first time that TAT can detect GMH in neonatal mouse cerebrum in vivo. This represents the first important step towards the in vivo diagnosis and grading of hemorrhage in the infant human brain.

An improved method for quantitative recovery of conductivity using tomographically measured thermoacoustic data.

Noninvasive extraction of tissue conductivity distribution is important in brain imaging and cancer detection. Here we present an improved method that can accurately image tissue conductivity using tomographically measured microwave-induced thermoacoustic data. Our reconstruction algorithm is first tested using simulations, and then validated using tissue phantom experiments where saline-containing tubes are used as target(s) with various target sizes, positions and conductivities. The average error of reconstruction for the simulations is reduced from 4.87% to 1.38% compared with the previous algorithm. The experimental results obtained suggest that accurate quantitative thermoacoustic imaging would provide a potential tool for precision medicine.

In vivo hemodynamic visualization of berberine-induced effect on the cerebral cortex of a mouse by photoacoustic tomography.

While berberine, a traditional Oriental herbal drug commonly used for treatment of diarrhea, has recently been used to treat a number of brain disorders, such as stroke and Alzheimer's disease, berberine-induced changes in hemodynamics are largely unknown. Here, we utilize photoacoustic tomography (PAT) to study hemodynamic effects of berberine in mice. In vivo photoacoustic images are obtained in ten functional regions of a mouse brain. Cortical vascular network and dynamic changes in total hemoglobin (HbT) concentration are acquired at 532 nm. Functional atlas and statistical data are also obtained at low-dose and high-dose berberine. Our results provide compelling evidence that both low-dose and high-dose berberine can increase the HbT concentration to a varied extent in certain brain regions. This study also suggests that PAT provides a powerful tool for visualizing brain hemodynamic changes induced by drugs.

[Thermoacoustic imaging and its application in breast cancer detection and therapy].

Thermoacoustic imaging (TAI) is a new non-invasive, non-ionization and nondestructive modality capable of high microwave contrast and high ultrasound resolution, and it has attracted extensive attention in recent years. This review introduces the technical principle, imaging system and imaging characteristics of TAI, and then introduces the application of TAI for breast cancer detection as an example. This review introduces the advantages of TAI in solving corresponding clinical problems in view of its high resolution and high contrast. In addition, it also explains the roles of TAI in medical diagnosis and treatment. Finally, the potential applications of TAI in medical diagnosis is introduced from many aspects and multiple perspectives. The future development of TAI in the challenges of current medical diagnosis is also prospected.

Full density fluorescence molecular tomography (FD-FMT) based on a dichroic mirror.

We present a novel method called full density fluorescence molecular tomography (FD-FMT) that can considerably improve the performance of conventional FMT. By converting each source (or detector) to a detector (or source) through the use of a dichroic mirror, FD-FMT not only increases the amount of optical projections by more than fourfold (compared to conventional FMT) to achieve high-resolution image reconstruction, but also offers the possibility to realize miniaturized FMT systems.

Near-Infrared Optical Imaging Noninvasively Detects Acutely Damaged Muscle.

Muscle damage is currently assessed through methods such as muscle biopsy, serum biomarkers, functional testing, and imaging procedures, each with its own inherent limitations, and a pressing need for a safe, repeatable, inexpensive, and noninvasive modality to assess the state of muscle health remains. Our aim was to develop and assess near-infrared (NIR) optical imaging as a novel noninvasive method of detecting and quantifying muscle damage. An immobilization-reambulation model was used for inducing muscle damage and recovery in the lower hindlimbs in mice. Confirmation of muscle damage was obtained using in vivo indocyanine green-enhanced NIR optical imaging, magnetic resonance imaging, and ex vivo tissue analysis. The soleus of the immobilized-reambulated hindlimb was found to have a greater amount of muscle damage compared to that in the contralateral nonimmobilized limb, confirmed by in vivo indocyanine green-enhanced NIR optical imaging (3.86-fold increase in radiant efficiency), magnetic resonance imaging (1.41-fold increase in T2), and an ex vivo spectrophotometric assay of indocyanine green uptake (1.87-fold increase in normalized absorbance). Contrast-enhanced NIR optical imaging provides a sensitive, rapid, and noninvasive screening method that can be used for imaging and quantifying muscle damage and recovery in vivo.

Finite-element-based photoacoustic imaging of absolute temperature in tissue: retraction.

The referenced article [Opt. Lett.39, 5355 (2014)OPLEDP0146-959210.1364/OL.39.005355] has been retracted.

In vivo photoacoustic imaging of vasculature with a low-cost miniature light emitting diode excitation.

In this Letter, we present a photoacoustic imaging (PAI) system based on a low-cost high-power miniature light emitting diode (LED) that is capable of in vivo mapping vasculature networks in biological tissue. Overdriving with 200 ns pulses and operating at a repetition rate of 40 kHz, a 1.2 W 405 nm LED with a radiation area of 1000 µm×1000 µm and a size of 3.5 mm×3.5 mm was used to excite photoacoustic signals in tissue. Phantoms including black stripes, lead, and hair were used to validate the system in which a volumetric PAI image was obtained by scanning the transducer and the light beam in a two-dimensional x-y plane over the object. In vivo imaging of the vasculature of a mouse ear shows that LED-based PAI could have great potential for label-free biomedical imaging applications where the use of bulky and expensive pulsed lasers is impractical.

Portable optical resolution photoacoustic microscopy (pORPAM) for human oral imaging.

Optical resolution photoacoustic microscopy (ORPAM) represents one of the fastest evolving optical microscopic techniques. However, due to the bulky size and complicated system configuration of conventional ORPAM, it is largely limited to small animal experiments. In this Letter, we present the design and evaluation of a portable ORPAM with a high spatiotemporal resolution and a large field of view. In this system, we utilize a rotatory scanning mechanism instead of the conventional raster scanning to achieve translationless imaging of the probe/samples, making it accessible to the human oral lip and tongue. After phantom evaluation, we applied this system to monitor longitudinal neo-angiogenesis of tumor growth and, for the first time, to the best of our knowledge, image the oral vascular network of humans to show its potential in clinical detection of early-stage oral cancer.

GPU-based acceleration and mesh optimization of finite-element-method-based quantitative photoacoustic tomography: a step towards clinical applications.

Finite element method (FEM)-based time-domain quantitative photoacoustic tomography (TD-qPAT) is a powerful approach, as it provides highly accurate quantitative imaging capability by recovering absolute tissue absorption coefficients for functional imaging. However, this approach is extremely computationally demanding, and requires days for the reconstruction of one set of images, making it impractical to be used in clinical applications, where a large amount of data needs to be processed in a limited time scale. To address this challenge, here we present a graphic processing unit (GPU)-based parallelization method to accelerate the image reconstruction using FEM-based TD-qPAT. In addition, to further optimize FEM-based TD-qPAT reconstruction, an adaptive meshing technique, along with mesh density optimization, is adopted. Phantom experimental data are used in our study to evaluate the GPU-based TD-qPAT algorithm, as well as the adaptive meshing technique. The results show that our new approach can considerably reduce the computation time by at least 136-fold over the current central processing unit (CPU)-based algorithm. The quality of image reconstruction is also improved significantly when adaptive meshing and mesh density optimization are applied.

Miniature probe integrating optical-resolution photoacoustic microscopy, optical coherence tomography, and ultrasound imaging: proof-of-concept.

In this Letter, we present a novel tri-modal miniature side-view probe, through which optical-resolution photoacoustic microscopy (OR-PAM), optical coherence tomography (OCT), and pulse-echo ultrasound (US) images can be coaxially acquired and displayed simultaneously. The probe consists of a common optical path for OR-PAM (light delivery) and OCT (light delivery/detection), and a 40-MHz unfocused ultrasound transducer for OR-PAM (photoacoustic detection) and US (ultrasound transmission/receiving) with an overall diameter of 2 mm. Combining OR-PAM, OCT, and US would provide complementary information including optical absorption (OR-PAM), optical back-scattering (OCT), and deep tissue structures (US) about biological tissue. Based on an integrated imaging system consisting of OR-PAM, time-domain OCT, and US, phantom images and in vivo images of rat ear were acquired to demonstrate the capabilities of the integrated tri-modality imaging probe. The probe yields a lateral resolution of 13.6 µm for OR-PAM and OCT, and an axial resolution of 43 µm for OR-PAM and US. Currently, for a scanning area of 1 ×1 mm, it took ∼25 min to acquire data for tri-modal volumetric imaging.

In vivo imaging of epileptic foci in rats using a miniature probe integrating diffuse optical tomography and electroencephalographic source localization.

OBJECTIVE: The goal of this work is to establish a new dual-modal brain-mapping technique based on diffuse optical tomography (DOT) and electroencephalographic source localization (ESL) that can chronically/intracranially record optical/electroencephalography (EEG) data to precisely map seizures and localize the seizure-onset zone and associated epileptic brain network. METHODS: The dual-modal imaging system was employed to image seizures in an experimental acute bicuculline methiodide rat model of focal epilepsy. Depth information derived from DOT was used as constraint in ESL to enhance the image reconstruction. Groups of animals were compared based on localization of seizure foci, either at different positions or at different depths. RESULTS: This novel imaging technique successfully localized the seizure-onset zone in rat induced by bicuculline methiodide injected at a depth of 1, 2, and 3 mm, respectively. The results demonstrated that the incorporation of the depth information from DOT into the ESL image reconstruction resulted in more accurate and reliable ESL images. Although the ESL images showed a horizontal shift of the source localization, the DOT identified the seizure focus accurately. In one case, when the bicuculline methiodide (BMI) was injected at a site outside the field of view (FOV) of the DOT/ESL interface, ESL gave false-positive detection of the focus, while DOT showed negative detection. SIGNIFICANCE: This study represents the first to identify seizure-onset zone using implantable DOT. In addition, the combination of DOT/ESL has never been documented in neuroscience and epilepsy imaging. This technology will enable us to precisely measure the neural activity and hemodynamic response at exactly the same tissue site and at both cortical and subcortical levels.

Discovery of structure-based small molecular inhibitor of αB-crystallin against basal-like/triple-negative breast cancer development in vitro and in vivo.

αB-crystallin (CRYAB) is present at a high frequency in poor prognosis basal-like breast tumours, which are largely absent of oestrogen, progesterone receptors and HER2 known as triple-negative breast cancer (TNBC). CRYAB functions as a molecular chaperone to bind to and correct intracellular misfolded/unfolded proteins such as vascular endothelial growth factor (VEGF), preventing non-specific protein aggregations under the influence of the tumour microenvironment stress and/or anti-cancer treatments including bevacizumab therapy. Directly targeting CRYAB can sensitize tumour cells to chemotherapeutic agents and decrease tumour aggressiveness. However, growing evidence shows that CRYAB is a critical adaptive response element after ischemic heart disease and stroke, implying that directly targeting CRYAB might cause serious unwanted side effects. Here, we used structure-based molecular docking of CRYAB and identified a potent small molecular inhibitor, NCI-41356, which can strongly block the interaction between CRYAB and VEGF165 without affecting CRYAB levels. The disruption of the interaction between CRYAB and VEGF165 elicits in vitro anti-tumour cell proliferation and invasive effects through the down-regulation of VEGF signalling in the breast cancer cells. The observed in vitro anti-tumour angiogenesis of endothelial cells might be attributed to the down-regulation of paracrine VEGF signalling in the breast cancer cells after treatment with NCI-41356. Intraperitoneal injection of NCI-41356 greatly inhibits the tumour growth and vasculature development in in vivo human breast cancer xenograft models. Our findings provide 'proof-of-concept' for the development of highly specific structure-based alternative targeted therapy for the prevention and/or treatment of TNBC.

Photoacoustic and fluorescence image-guided surgery using a multifunctional targeted nanoprobe.

PURPOSE: A complete surgical excision with negative tumor margins is the single most important factor in the prediction of long-term survival for most cancer patients with solid tumors. We hypothesized that image-guided surgery using nanoparticle-enhanced photoacoustic and fluorescence imaging could significantly reduce the rate of local recurrence. METHODS: A murine model of invasive mammary carcinoma was utilized. Three experimental groups were included: (1) control; (2) tumor-bearing mice injected with non-targeted nanoprobe; and (3) tumor-bearing mice injected with targeted nanoprobe. The surgeon removed the primary tumor following the guidance of photoacoustic imaging (PAI), then inspected the surgical wound and removed the suspicious tissue using intraoperative near-infrared (NIR) fluorescence imaging. The mice were followed with bioluminescence imaging weekly to quantify local recurrence. RESULTS: Nanoprobe-enhanced photoacoustic contrast enabled PAI to map the volumetric tumor margins up to a depth of 31 mm. The targeted nanoparticles provided significantly greater enhancement than non-targeted nanoparticles. Seven mice in the group injected with the targeted nanoprobes underwent additional resections based upon NIR fluorescence imaging. Pathological analysis confirmed residual cancer cells in the re-resected specimens in 5/7 mice. Image-guided resection resulted in a significant reduction in local recurrence; 8.7 and 33.3 % of the mice in the targeted and control groups suffered recurrence, respectively. CONCLUSIONS: These results suggest that photoacoustic and NIR intraoperative imaging can effectively assist a surgeon to locate primary tumors and to identify residual disease in real-time. This technology has promise to overcome current clinical challenges that result in the need for second surgical procedures.