Investigation of the Effect of the Skull in Transcranial Photoacoustic Imaging: A Preliminary Ex Vivo Study.

Although transcranial photoacoustic imaging (TCPAI) has been used in small animal brain imaging, in animals with thicker skull bones or in humans both light illumination and ultrasound propagation paths are affected. Hence, the PA image is largely degraded and in some cases completely distorted. This study aims to investigate and determine the maximum thickness of the skull through which photoacoustic imaging is feasible in terms of retaining the imaging target structure without incorporating any post processing. We identify the effect of the skull on both the illumination path and acoustic propagation path separately and combined. In the experimental phase, the distorting effect of ex vivo sheep skull bones with thicknesses in the range of 0.7~1.3 mm are explored. We believe that the findings in this study facilitate the clinical translation of TCPAI.

Photoacoustic/Ultrasound/Optical Coherence Tomography Evaluation of Melanoma Lesion and Healthy Skin in a Swine Model.

The marked increase in the incidence of melanoma coupled with the rapid drop in the survival rate after metastasis has promoted the investigation into improved diagnostic methods for melanoma. High-frequency ultrasound (US), optical coherence tomography (OCT), and photoacoustic imaging (PAI) are three potential modalities that can assist a dermatologist by providing extra information beyond dermoscopic features. In this study, we imaged a swine model with spontaneous melanoma using these modalities and compared the images with images of nearby healthy skin. Histology images were used for validation.

Photoacoustic Signal Enhancement: Towards Utilization of Low Energy Laser Diodes in Real-Time Photoacoustic Imaging.

In practice, photoacoustic (PA) waves generated with cost-effective and low-energy laser diodes, are weak and almost buried in noise. Reconstruction of an artifact-free PA image from noisy measurements requires an effective denoising technique. Averaging is widely used to increase the signal-to-noise ratio (SNR) of PA signals; however, it is time consuming and in the case of very low SNR signals, hundreds to thousands of data acquisition epochs are needed. In this study, we explored the feasibility of using an adaptive and time-efficient filtering method to improve the SNR of PA signals. Our results show that the proposed method increases the SNR of PA signals more efficiently and with much fewer acquisitions, compared to common averaging techniques. Consequently, PA imaging is conducted considerably faster.

Adaptive coherent weighted averaging algorithm for enhancement of photoacoustic tomography images of brain.

One common method to improve the low signal-to-noise ratio of the photoacoustic (PA) signal generated from weak absorbers or absorbers located in deep tissue is to acquire signal multiple times from the same region and perform averaging. However, pulse-to-pulse laser fluctuations together with differences in the beam profile of the pulses create undeterministic multiple scattering processes in the tissue. This phenomenon consequently induces a spatiotemporal displacement in the PA signal samples which in turn deteriorates the effectiveness of signal averaging. Here, we present an adaptive coherent weighted averaging algorithm to adjust the locations and values of PA signal samples for more efficient signal averaging. The proposed method is evaluated in a linear array-based PA imaging setup of ex vivo sheep brain.

Development and characterization of transfontanelle photoacoustic imaging system for detection of intracranial hemorrhages and measurement of brain oxygenation: Ex-vivo.

We have developed and optimized an imaging system to study and improve the detection of brain hemorrhage and to quantify oxygenation. Since this system is intended to be used for brain imaging in neonates through the skull opening, i.e., fontanelle, we called it, Transfontanelle Photoacoustic Imaging (TFPAI) system. The system is optimized in terms of optical and acoustic designs, thermal safety, and mechanical stability. The lower limit of quantification of TFPAI to detect the location of hemorrhage and its size is evaluated using in-vitro and ex-vivo experiments. The capability of TFPAI in measuring the tissue oxygenation and detection of vasogenic edema due to brain blood barrier disruption are demonstrated. The results obtained from our experimental evaluations strongly suggest the potential utility of TFPAI, as a portable imaging modality in the neonatal intensive care unit. Confirmation of these findings in-vivo could facilitate the translation of this promising technology to the clinic.

Ultrasound and Photoacoustic Imaging of Breast Cancer: Clinical Systems, Challenges, and Future Outlook.

Presently, breast cancer diagnostic methods are dominated by mammography. Although drawbacks of mammography are present including ionizing radiation and patient discomfort, not many alternatives are available. Ultrasound (US) is another method used in the diagnosis of breast cancer, commonly performed on women with dense breasts or in differentiating cysts from solid tumors. Handheld ultrasound (HHUS) and automated breast ultrasound (ABUS) are presently used to generate reflection images which do not contain quantitative information about the tissue. This limitation leads to a subjective interpretation from the sonographer. To rectify the subjective nature of ultrasound, ultrasound tomography (UST) systems have been developed to acquire both reflection and transmission UST (TUST) images. This allows for quantitative assessment of tissue sound speed (SS) and acoustic attenuation which can be used to evaluate the stiffness of the lesions. Another imaging modality being used to detect breast cancer is photoacoustic tomography (PAT). Utilizing much of the same hardware as ultrasound tomography, PAT receives acoustic waves generated from tissue chromophores that are optically excited by a high energy pulsed laser. This allows the user to ideally produce chromophore concentration maps or extract other tissue parameters through spectroscopic PAT. Here, several systems in the area of TUST and PAT are discussed along with their advantages and disadvantages in breast cancer diagnosis. This overview of available systems can provide a landscape of possible intersections and future refinements in cancer diagnosis.

Feasibility of ultrasound tomography-guided localized mild hyperthermia using a ring transducer: Ex vivo and in silico studies.

BACKGROUND: As of 2022, breast cancer continues to be the most diagnosed cancer worldwide. This problem persists within the United States as well, as the American Cancer Society has reported that ∼12.5% of women will be diagnosed with invasive breast cancer over the course of their lifetime. Therefore, a clinical need continues to exist to address this disease from a treatment and therapeutic perspective. Current treatments for breast cancer and cancers more broadly include surgery, radiation, and chemotherapy. Adjuncts to these methods have been developed to improve the clinical outcomes for patients. One such adjunctive treatment is mild hyperthermia therapy (MHTh), which has been shown to be successful in the treatment of cancers by increasing effectiveness and reduced dosage requirements for radiation and chemotherapies. MHTh-assisted treatments can be performed with invasive thermal devices, noninvasive microwave induction, heating and recirculation of extracted patient blood, or whole-body hyperthermia with hot blankets. PURPOSE: One common method for inducing MHTh is by using microwave for heat induction and magnetic resonance imaging for temperature monitoring. However, this leads to a complex, expensive, and inaccessible therapy platform. Therefore, in this work we aim to show the feasibility of a novel all-acoustic MHTh system that uses focused ultrasound (US) to induce heating while also using US tomography (UST) to provide temperature estimates. Changes in sound speed (SS) have been shown to be strongly correlated with temperature changes and can therefore be used to indirectly monitor heating throughout the therapy. Additionally, these SS estimates allow for heterogeneous SS-corrected phase delays when heating complex and heterogeneous tissue structures. METHODS: Feasibility to induce localized heat in tissue was investigated in silico with a simulated breast model, including an embedded tumor using continuous wave US. Here, both heterogenous acoustic and thermal properties were modeled in addition to blood perfusion. We further demonstrate, with ex vivo tissue phantoms, the feasibility of using ring-based UST to monitor temperature by tracking changes in SS. Two phantoms (lamb tissue and human abdominal fat) with latex tubes containing varied temperature flowing water were imaged. The measured SS of the water at each temperature were compared against values that are reported in literature. RESULTS: Results from ex vivo tissue studies indicate successful tracking of temperature under various phantom configurations and ranges of water temperature. The results of in silico studies show that the proposed system can heat an acoustically and thermally heterogenous breast model to the clinically relevant temperature of 42°C while accounting for a reasonable time needed to image the current cross section (200 ms). Further, we have performed an initial in silico study demonstrating the feasibility of adjusting the transmit waveform frequency to modify the effective heating height at the focused region. Lastly, we have shown in a simpler 2D breast model that MHTh level temperatures can be maintained by adjusting the transmit pressure intensity of the US ring. CONCLUSIONS: This work has demonstrated the feasibility of using a 256-element ring array transducer for temperature monitoring; however, future work will investigate minimizing the difference between measured SS and the values shown in literature. A hypothesis attributes this bias to potential volumetric average artifacts from the ray-based SS inversion algorithm that was used, and that moving to a waveform-based SS inversion algorithm will greatly improve the SS estimates. Additionally, we have shown that an all-acoustic MHTh system is feasible via in silico studies. These studies have indicated that the proposed system can heat a tumor within a heterogenous breast model to 42°C within a narrow time frame. This holds great promise for increasing the accessibility and reducing the complexity of a future all-acoustic MHTh system.

Technical considerations in the Verasonics research ultrasound platform for developing a photoacoustic imaging system.

Photoacoustic imaging (PAI) is an emerging functional and molecular imaging technology that has attracted much attention in the past decade. Recently, many researchers have used the vantage system from Verasonics for simultaneous ultrasound (US) and photoacoustic (PA) imaging. This was the motivation to write on the details of US/PA imaging system implementation and characterization using Verasonics platform. We have discussed the experimental considerations for linear array based PAI due to its popularity, simple setup, and high potential for clinical translatability. Specifically, we describe the strategies of US/PA imaging system setup, signal generation, amplification, data processing and study the system performance.

Wavelength and pulse energy optimization for detecting hypoxia in photoacoustic imaging of the neonatal brain: a simulation study.

Cerebral hypoxia is a severe injury caused by oxygen deprivation to the brain. Hypoxia in the neonatal period increases the risk for the development of neurological disorders, including hypoxic-ischemic encephalopathy, cerebral palsy, periventricular leukomalacia, and hydrocephalus. It is crucial to recognize hypoxia as soon as possible because early intervention improves outcomes. Photoacoustic imaging, using at least two wavelengths, through a spectroscopic analysis, can measure brain oxygen saturation. Due to the spectral coloring effect arising from the dependency of optical properties of biological tissues to the wavelength of light, choosing the right wavelength-pair for efficient and most accurate oxygen saturation measurement and consequently quantifying hypoxia at a specific depth is critical. Using a realistic neonate head model and Monte Carlo simulations, we found practical wavelength-pairs that quantified regions with hypoxia most accurately at different depths down to 22 mm into the cortex neighboring the lateral ventricle. We also demonstrated, for the first time, that the accuracy of the sO2 measurement can be increased by adjusting the level of light energy for each wavelength-pair. Considering the growing interest in photoacoustic imaging of the brain, this work will assist in a more accurate use of photoacoustic spectroscopy and help in the clinical translation of this promising imaging modality. Please note that explaining the effect of acoustic aberration of the skull is not in the scope of this study.

Direct measurement of neuronal ensemble activity using photoacoustic imaging in the stimulated Fos-LacZ transgenic rat brain: A proof-of-principle study.

Measuring neuroactivity underlying complex behaviors facilitates understanding the microcircuitry that supports these behaviors. We have developed a functional and molecular photoacoustic tomography (F/M-PAT) system which allows direct imaging of Fos-expressing neuronal ensembles in Fos-LacZ transgenic rats with a large field-of-view and high spatial resolution. F/M-PAT measures the beta-galactosidase catalyzed enzymatic product of exogenous chromophore X-gal within ensemble neurons. We used an ex vivo imaging method in the Wistar Fos-LacZ transgenic rat, to detect neuronal ensembles in medial prefrontal cortex (mPFC) following cocaine administration or a shock-tone paired stimulus. Robust and selective F/M-PAT signal was detected in mPFC neurons after both conditions (compare to naive controls) demonstrating successful and direct detection of Fos-expressing neuronal ensembles using this approach. The results of this study indicate that F/M-PAT can be used in conjunction with Fos-LacZ rats to monitor neuronal ensembles that underlie a range of behavioral processes, such as fear learning or addiction.

Overview of Ultrasound Detection Technologies for Photoacoustic Imaging.

Ultrasound detection is one of the major components of photoacoustic imaging systems. Advancement in ultrasound transducer technology has a significant impact on the translation of photoacoustic imaging to the clinic. Here, we present an overview on various ultrasound transducer technologies including conventional piezoelectric and micromachined transducers, as well as optical ultrasound detection technology. We explain the core components of each technology, their working principle, and describe their manufacturing process. We then quantitatively compare their performance when they are used in the receive mode of a photoacoustic imaging system.

Improving vascular imaging with co-planar mutually guided photoacoustic and diffuse optical tomography: a simulation study.

Diffuse optical tomography (DOT) and photoacoustic tomography (PAT) are functional imaging modalities that provide absorption coefficient maps of the tissue. Spatial resolution of DOT is relatively low due to light scattering characteristics of the tissue. On the other hand, although PAT can resolve regions of different absorptions with a high spatial resolution, measuring the absolute value of optical absorptions using PAT is challenging due to unknown light fluence distribution in the tissue. Development of image guidance techniques using a priori information of imaging target structure has been shown to increase the accuracy of DOT. PAT is one such method that can be used as a complementary modality to serve as a guide for DOT image reconstruction. On the other hand, estimated fluence map provided by DOT can be used to quantitatively correct PAT images. In this study we introduce a mutually-guided imaging system for fast and simultaneous optical and photoacoustic measurements of tissue absorption map, where DOT is guided by the PAT image and vice versa. Using the obtained absorption map of the tissue, we then estimate the tissue scattering map. We conducted this study using a series of simulations on digital phantoms and demonstrated the effectiveness of the proposed method.

Review of cost reduction methods in photoacoustic computed tomography.

Photoacoustic Computed Tomography (PACT) is a major configuration of photoacoustic imaging, a hybrid noninvasive modality for both functional and molecular imaging. PACT has rapidly gained importance in the field of biomedical imaging due to superior performance as compared to conventional optical imaging counterparts. However, the overall cost of developing a PACT system is one of the challenges towards clinical translation of this novel technique. The cost of a typical commercial PACT system originates from optical source, ultrasound detector, and data acquisition unit. With growing applications of photoacoustic imaging, there is a tremendous demand towards reducing its cost. In this review article, we have discussed various approaches to reduce the overall cost of a PACT system, and provided a cost estimation to build a low-cost PACT system.

Linear-array photoacoustic imaging using minimum variance-based delay multiply and sum adaptive beamforming algorithm.

In photoacoustic imaging, delay-and-sum (DAS) beamformer is a common beamforming algorithm having a simple implementation. However, it results in a poor resolution and high sidelobes. To address these challenges, a new algorithm namely delay-multiply-and-sum (DMAS) was introduced having lower sidelobes compared to DAS. To improve the resolution of DMAS, a beamformer is introduced using minimum variance (MV) adaptive beamforming combined with DMAS, so-called minimum variance-based DMAS (MVB-DMAS). It is shown that expanding the DMAS equation results in multiple terms representing a DAS algebra. It is proposed to use the MV adaptive beamformer instead of the existing DAS. MVB-DMAS is evaluated numerically and experimentally. In particular, at the depth of 45 mm MVB-DMAS results in about 31, 18, and 8 dB sidelobes reduction compared to DAS, MV, and DMAS, respectively. The quantitative results of the simulations show that MVB-DMAS leads to improvement in full-width-half-maximum about 96%, 94%, and 45% and signal-to-noise ratio about 89%, 15%, and 35% compared to DAS, DMAS, MV, respectively. In particular, at the depth of 33 mm of the experimental images, MVB-DMAS results in about 20 dB sidelobes reduction in comparison with other beamformers.

Development and Optimization of a Fluorescent Imaging System to Detect Amyloid-ß Proteins: Phantom Study.

Alzheimer disease is the most common form of dementia, affecting more than 5 million people in the United States. During the progression of Alzheimer disease, a particular protein begins to accumulate in the brain and also in extensions of the brain, ie, the retina. This protein, amyloid-ß (Aß), exhibits fluorescent properties. The purpose of this research article is to explore the implications of designing a fluorescent imaging system able to detect Aß proteins in the retina. We designed and implemented a fluorescent imaging system with a range of applications that can be reconfigured on a fluorophore to fluorophore basis and tested its feasibility and capabilities using Cy5 and CRANAD-2 imaging probes. The results indicate a promising potential for the imaging system to be used to study the Aß biomarker. A performance evaluation involving ex vivo and in vivo experiments is planned for future study.