Evaluating a new generation of wearable high-density diffuse optical tomography technology via retinotopic mapping of the adult visual cortex.

Significance: High-density diffuse optical tomography (HD-DOT) has been shown to approach the resolution and localization accuracy of blood oxygen level dependent-functional magnetic resonance imaging in the adult brain by exploiting densely spaced, overlapping samples of the probed tissue volume, but the technique has to date required large and cumbersome optical fiber arrays. Aim: To evaluate a wearable HD-DOT system that provides a comparable sampling density to large, fiber-based HD-DOT systems, but with vastly improved ergonomics. Approach: We investigated the performance of this system by replicating a series of classic visual stimulation paradigms, carried out in one highly sampled participant during 15 sessions to assess imaging performance and repeatability. Results: Hemodynamic response functions and cortical activation maps replicate the results obtained with larger fiber-based systems. Our results demonstrate focal activations in both oxyhemoglobin and deoxyhemoglobin with a high degree of repeatability observed across all sessions. A comparison with a simulated low-density array explicitly demonstrates the improvements in spatial localization, resolution, repeatability, and image contrast that can be obtained with this high-density technology. Conclusions: The system offers the possibility for minimally constrained, spatially resolved functional imaging of the human brain in almost any environment and holds particular promise in enabling neuroscience applications outside of the laboratory setting. It also opens up new opportunities to investigate populations unsuited to traditional imaging technologies.

Functional imaging of the developing brain with wearable high-density diffuse optical tomography: A new benchmark for infant neuroimaging outside the scanner environment.

Studies of cortical function in the awake infant are extremely challenging to undertake with traditional neuroimaging approaches. Partly in response to this challenge, functional near-infrared spectroscopy (fNIRS) has become increasingly common in developmental neuroscience, but has significant limitations including resolution, spatial specificity and ergonomics. In adults, high-density arrays of near-infrared sources and detectors have recently been shown to yield dramatic improvements in spatial resolution and specificity when compared to typical fNIRS approaches. However, most existing fNIRS devices only permit the acquisition of ~20-100 sparsely distributed fNIRS channels, and increasing the number of optodes presents significant mechanical challenges, particularly for infant applications. A new generation of wearable, modular, high-density diffuse optical tomography (HD-DOT) technologies has recently emerged that overcomes many of the limitations of traditional, fibre-based and low-density fNIRS measurements. Driven by the development of this new technology, we have undertaken the first study of the infant brain using wearable HD-DOT. Using a well-established social stimulus paradigm, and combining this new imaging technology with advances in cap design and spatial registration, we show that it is now possible to obtain high-quality, functional images of the infant brain with minimal constraints on either the environment or on the infant participants. Our results are consistent with prior low-density fNIRS measures based on similar paradigms, but demonstrate superior spatial localization, improved depth specificity, higher SNR and a dramatic improvement in the consistency of the responses across participants. Our data retention rates also demonstrate that this new generation of wearable technology is well tolerated by the infant population.

Targeting Proteotoxic Stress in Cancer: A Review of the Role that Protein Quality Control Pathways Play in Oncogenesis.

Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging "Achilles heel" of malignancy. This review highlights the importance of managing proteotoxic stress for cancer cell survival and provides an overview of the integral role proteostasis pathways play in the maintenance of protein homeostasis. We further review the efforts undertaken to exploit proteotoxic stress in multiple myeloma (as an example of a hematologic malignancy) and triple negative breast cancer (as an example of a solid tumor), and give examples of: (1) FDA-approved therapies in routine clinical use; and (2) promising therapies currently in clinical trials. Finally, we provide new insights gleaned from the use of emerging technologies to disrupt the protein secretory pathway and repurpose E3 ligases to achieve targeted protein degradation.

MAESTROS: A Multiwavelength Time-Domain NIRS System to Monitor Changes in Oxygenation and Oxidation State of Cytochrome-C-Oxidase.

We present a multiwavelength, multichannel, time-domain near-infrared spectroscopy system named MAESTROS. This instrument can measure absorption and scattering coefficients and can quantify the concentrations of oxy- and deoxy-haemoglobin ([HbO2], [HHb]), and oxidation state of cytochrome-c-oxidase ([oxCCO]). This system is composed of a supercontinuum laser source coupled with two acousto-optic tuneable filters. The light is collected by four photomultipliers tubes, connected to a router to redirect the signal to a single time-correlated single-photon counting card. The interface between the system and the tissue is based on optical fibres. This arrangement allows us to resolve up to 16 wavelengths, within the range of 650-900 nm, at a sampling rate compatible with the physiology (from 0.5 to 2 Hz). In this paper, we describe the system and assess its performance based on two specifically designed protocols for photon migration instruments, the basic instrument protocol and nEUROPt protocols, and on a well characterized liquid phantom based on Intralipid and water. Then, the ability to resolve [HbO2 ], [HHb], and [oxCCO] is demonstrated on a homogeneous liquid phantom, based on blood for [HbO2], [HHb], and yeast for [oxCCO]. In the future, the system could be used to monitor brain tissue physiology.

Evaluation of Haemoglobin and Cytochrome Responses During Forearm Ischaemia Using Multi-wavelength Time Domain NIRS.

We demonstrate the ability of a 16-wavelength time domain near-infrared spectroscopy system to monitor changes in oxy- and deoxy haemoglobin ([HbO2] [HHb]) and the oxidation of cytochrome-c-oxidase ([oxCCO]), during forearm ischaemia. We tested two methods to retrieve the concentration changes. The first uses the measured changes in light attenuation and the modified Beer-Lambert law, and the second uses the absorption and scattering estimated by the measured time-point spread function. The system is able to retrieve the concentration changes with both methods, giving similar results. At the end of forearm ischaemia (t = 5 min), we measured an increase in [HHb] of 16.77 ± 2.52 and 16.37 ± 2.33 µMol, and a decrease in [HbO2] of -6.12 ± 1.62 and -5.57 ± 2.02 µMol for method 1 and 2, respectively. At that same time, the changes in [oxCCO] were -0.36 ± 0.33 and -1.40 ± 1.20 µMol, for method 1 and 2, respectively. These small changes in [oxCCO], despite a huge change in haemoglobin, demonstrate the absence of crosstalk and are comparable to previous measurements using broadband NIRS.

Development of a near infrared multi-wavelength, multi-channel, time-resolved spectrometer for measuring brain tissue haemodynamics and metabolism.

We present a novel time domain functional near infrared spectroscopy system using a supercontinuum laser allowing us to measure the coefficient of absorption and scattering of up to 16 multiplexed wavelengths in the near infrared region. This is a four detector system that generates up to 3 mW of light for each wavelength with a narrow 2-3 nm FWHM bandwidth between 650 and 890 nm; each measurement of 16 wavelengths per channel can be performed up to a rate of 1 Hz. We can therefore quantify absolute haemoglobin changes in tissue and are currently investigating which and how many wavelengths are needed to resolve additional chromophores in tissue, such as water and the oxidation state of cytochrome-c-oxidase.