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OBJECTIVE Intracranial pressure (ICP) is an important therapeutic target in many critical neuropathologies. The current tools for ICP measurements are invasive; hence, these are only selectively applied in critical cases where the benefits surpass the risks. To address the need for low-risk ICP monitoring, the authors developed a noninvasive alternative. METHODS The authors recently demonstrated noninvasive quantification of ICP in an animal model by using morphological analysis of microvascular cerebral blood flow (CBF) measured with diffuse correlation spectroscopy (DCS). The current prospective observational study expanded on this preclinical study by translating the method to pediatric patients. Here, the CBF features, along with mean arterial pressure (MAP) and heart rate (HR) data, were used to build a random decision forest, machine learning model for estimation of ICP; the results of this model were compared with those of invasive monitoring. RESULTS Fifteen patients (mean age ± SD [range] 9.8 ± 5.1 [0.3–17.5] years; median age [interquartile range] 11 [7.4] years; 10 males and 5 females) who underwent invasive neuromonitoring for any purpose were enrolled. Estimated ICP (ICPest) very closely matched invasive ICP (ICPinv), with a root mean square error (RMSE) of 1.01 mm Hg and 95% limit of agreement of ≤ 1.99 mm Hg for ICPinv 0.01–41.25 mm Hg. When the ICP range (ICPinv 0.01–29.05 mm Hg) was narrowed on the basis of the sample population, both RMSE and limit of agreement improved to 0.81 mm Hg and ≤ 1.6 mm Hg, respectively. In addition, 0.3% of the test samples for ICPinv ≤ 20 mm Hg and 5.4% of the test samples for ICPinv > 20 mm Hg had a limit of agreement > 5 mm Hg, which may be considered the acceptable limit of agreement for clinical validity of ICP sensing. For the narrower case, 0.1% of test samples for ICPinv ≤ 20 mm Hg and 1.1% of the test samples for ICPinv > 20 mm Hg had a limit of agreement > 5 mm Hg. Although the CBF features were crucial, the best prediction accuracy was achieved when these features were combined with MAP and HR data. Lastly, preliminary leave-one-out analysis showed model accuracy with an RMSE of 6 mm Hg and limit of agreement of ≤ 7 mm Hg. CONCLUSIONS The authors have shown that DCS may enable ICP monitoring with additional clinical validation. The lower risk of such monitoring would allow ICP to be estimated for a wide spectrum of indications, thereby both reducing the use of invasive monitors and increasing the types of patients who may benefit from ICP-directed therapies.

Intracranial pressure (ICP) measurements are important for patient treatment but are invasive and prone to complications. Noninvasive ICP monitoring methods exist, but they suffer from poor accuracy, lack of generalizability, or high cost.We previously showed that cerebral blood flow (CBF) cardiac waveforms measured with diffuse correlation spectroscopy can be used for noninvasive ICP monitoring. Here we extend the approach to cardiac waveforms measured with near-infrared spectroscopy (NIRS).Changes in hemoglobin concentrations were measured in eight nonhuman primates, in addition to invasive ICP, arterial blood pressure, and CBF changes. Features of average cardiac waveforms in hemoglobin and CBF signals were used to train a random forest (RF) regressor.The RF regressor achieves a cross-validated ICP estimation ofThis study provides a proof of concept for the use of NIRS in noninvasive ICP estimation.

The current technology for monitoring fetal wellbeing during child birth is cardiotocography. However, CTG has high false positive rates that lead to unnecessary emergency Cesarean deliveries and false negatives that result in birth injuries. To curtail these issues, fetal pulse oximetery has been a topic of interest for many decades. Fetal pulse oximetry would yield the oxygen saturation of the fetus in utero and provide a more robust marker for clinicians to make decisions about performing emergency Cesarean deliveries. Here, we present a review of biomedical optical developments related to transabdominal fetal pulse oximetery in the biophotonics field and the challenges that must be overcome to make transabdominal pulse oximetry a clinical reality.

Cerebral autoregulation ensures a stable average blood supply to brain tissue across steady state cerebral perfusion pressure (CPP) levels. Neurovascular coupling, in turn, relies on sufficient blood flow to meet neuronal demands during activation. These mechanisms break down in pathologies where extreme levels of CPP can cause dysregulation in cerebral blood flow. Here, we experimentally tested the influence of changes in CPP on neurovascular coupling in a hydrocephalus-type non-human primate model (n = 3). We recorded local neural and vascular evoked responses to a checkerboard visual stimulus, non-invasively, using electroencephalography and near-infrared spectroscopy respectively. The evoked signals showed changes in various waveform features in the visual evoked potentials and the hemodynamic responses, with CPP. We further used these signals to fit for a hemodynamic response function (HRF) to describe neurovascular coupling. We estimated n = 26 distinct HRFs at a subset of CPP values ranging from 40–120 mmHg across all subjects. The HRFs, when compared to a subject dependent healthy baseline (CPP 70–90 mmHg) HRF, showed significant changes in shape with increasing CPP (ρCPP = −0.55, p-valueCPP = 0.0049). Our study provides preliminary experimental evidence on the relationship between neurovascular coupling and CPP changes, especially when beyond the limits of static autoregulation.

This project was partially funded by the Department for Business, Energy and Industrial Strategy Offshore Energy Strategic Environmental Assessment Programme. Supplementary funding supporting JM was provided by the US Office of Naval Research (ONR) grant nos. N00014-18-1-2062 and N00014-20-1-2709. Supplementary funding supporting AF and JM was provided by the US Office of Naval Research (ONR) grant no. N00014-19-1-2560. Supplementary funding supporting BS-C, JK, and AR was provided by the US Office of Naval Research (ONR) grant no. N00014-19-1-1223. Developments in wearable human medical and sports health trackers has offered new solutions to challenges encountered by eco-physiologists attempting to measure physiological attributes in freely moving animals. Near-infrared spectroscopy (NIRS) is one such solution that has potential as a powerful physio-logging tool to assess physiology in freely moving animals. NIRS is a non-invasive optics-based technology, that uses non-ionizing radiation to illuminate biological tissue and measures changes in oxygenated and deoxygenated hemoglobin concentrations inside tissues such as skin, muscle, and the brain. The overall footprint of the device is small enough to be deployed in wearable physio-logging devices. We show that changes in hemoglobin concentration can be recorded from bottlenose dolphins and gray seals with signal quality comparable to that achieved in human recordings. We further discuss functionality, benefits, and limitations of NIRS as a standard tool for animal care and wildlife tracking for the marine mammal research community. Publisher PDF

This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions.

Funding Information: We would like to thank all volunteers for their kind participation. The studies were funded by a donation from Jennifer and Peter Francis, and by the Swedish Centre for Research in Sports. Further funding was received from the Office of Naval Research (N00014-19-1-1223). Near-infrared spectroscopy was used to observe the cerebral hemodynamic response of freedivers during single breath-hold training dives. We observed variability in hemodynamic progression, and heartbeat shape changes with diving depth. Publisher PDF

Acute stroke is associated with high morbidity and mortality. In the last decades, new therapies have been investigated with the aim of improving clinical outcomes in the acute phase post stroke onset. However, despite such advances, a large number of patients do not demonstrate improvement, furthermore, some unfortunately deteriorate. Thus, there is a need for additional treatments targeted to the individual patient. A potential therapeutic target is interventions to optimize cerebral perfusion guided by cerebral hemodynamic parameters such as dynamic cerebral autoregulation (dCA). This narrative led to the development of the INFOMATAS (Identifying New targets FOr Management And Therapy in Acute Stroke) project, designed to foster interventions directed towards understanding and improving hemodynamic aspects of the cerebral circulation in acute cerebrovascular disease states. This comprehensive review aims to summarize relevant studies on assessing dCA in patients suffering acute ischemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage. The review will provide to the reader the most consistent findings, the inconsistent findings which still need to be explored further and discuss the main limitations of these studies. This will allow for the creation of a research agenda for the use of bedside dCA information for prognostication and targeted perfusion interventions.

This research was funded as part of the Department for Business, Energy and Industrial Strategy Offshore Energy Strategic Environmental Assessment Programme. National Capability funding was provided by the Natural Environment Research Council to the Sea Mammal Research Unit grant number: NE/R015007/1. Supplementary funding supporting K.A.B. was provided by the Natural Environment Research Council grant numbers: NE/M013723/1 and NE/M01357X/1. Chemical immobilisation of pinnipeds is a routine procedure in research and veterinary practice. Yet, there are inevitable risks associated with chemical immobilisation, and the physiological response to anaesthetic agents in pinnipeds remains poorly understood. The current study used wearable continuous-wave near-infrared spectroscopy (NIRS) data from 10 trials of prolonged anaesthesia (0.5 to 1.4 h) induced through ketamine and midazolam in five grey seals (Halichoerus grypus) involved in other procedures. The aim of this study was to (1) analyse the effect of each compound on heart rate, arterial oxygen saturation (SpO2), and relative concentration changes in oxygenated [ΔO2Hb] and deoxygenated haemoglobin [ΔHHb] in cerebral tissue and (2) to investigate the use of NIRS as a real-time physiological monitoring tool during chemical immobilisation. Average group responses of ketamine (n = 27) and midazolam (n = 11) administrations were modelled using generalised additive mixed models (GAMM) for each dependent variable. Following ketamine and midazolam administration, [ΔHHb] increased and [ΔO2Hb] remained relatively stable, which was indicative of apnoea. Periods of apnoea were confirmed from respiratory band data, which were simultaneously collected during drugging trials. Given that SpO2 remained at 97% during apnoea, we hypothesized that increasing cerebral [ΔHHb] was a result of venous congestion as opposed to decreased oxygen delivery. Changes in heart rate were limited and appeared to be driven by the individual pharmacological actions of each drug. Future research could include simultaneous measures of metabolic rate, such as the relative change in concentration of cytochrome-c-oxidase, to guide operators in determining when apnoea should be considered prolonged if changes in [ΔHHb] and [ΔO2Hb] occur beyond the limits recorded in this study. Our findings support the use of NIRS as real-time physiological monitoring tool during pinniped chemical immobilisation, which could assist veterinarians and researchers in performing safe anaesthetic procedures. Publisher PDF

As 3D bioprinting has grown as a fabrication technology, so too has the need for improved analytical methods to characterize engineered constructs. This is especially challenging for engineered tissues composed of hydrogels and cells, as these materials readily deform when trying to assess print fidelity and other properties non-destructively. Establishing that the 3D architecture of the bioprinted construct matches its intended anatomic design is critical given the importance of structure-function relationships in most tissue types. Here we report development of a multimaterial bioprinting platform with integrated optical coherence tomography for in situ volumetric imaging, error detection, and 3D reconstruction. We also report improvements to the freeform reversible embedding of suspended hydrogels bioprinting process through new collagen bioink compositions, gelatin microparticle support bath optical clearing, and optimized machine pathing. This enables quantitative 3D volumetric imaging with micron resolution over centimeter length scales, the ability to detect a range of print defect types within a 3D volume, and real-time imaging of the printing process at each print layer. These advances provide a comprehensive methodology for print quality assessment, paving the way toward the production and process control required for achieving regulatory approval and ultimately clinical translation of engineered tissues.

As 3D bioprinting has grown as a fabrication technology, so too has the need for improved analytical methods to characterize these engineered constructs. This is especially challenging for soft tissues composed of hydrogels and cells as these materials readily deform, posing a barrier when trying to assess print fidelity and other properties non- destructively. Indeed, given the importance of structure-function relationships in most tissue types, establishing that the 3D architecture of the bioprinted construct matches its intended anatomic design is critical. Here we report development of a multimaterial bioprinting platform with integrated optical coherence tomography (OCT) for in situ volumetric imaging, error detection, and 3D reconstruction. While generally applicable to extrusion-based 3D bioprinting, we also report improvements to the Freeform Reversible Embedding of Suspended Hydrogels (FRESH) bioprinting process through new collagen bioink compositions, support bath optical clearing, and machine pathing. This enables high-fidelity 3D volumetric imaging with micron scale resolution over centimeter length scales, the ability to detect a range of print defect types within a 3D volume, and real-time imaging of the printing process at each print layer. These advances provide FRESH and other extrusion-based 3D bioprinting approaches with a comprehensive methodology for quality assessment that has been absent in the field to date, paving the way for translation of these engineered tissues to the clinic and ultimately to achieving regulatory approval.TeaserTransparent FRESH support bath enables in situ 3D volumetric imaging and validation of patient-derived tissue constructs.

About a third of babies are delivered by Cesarean section. There has been an increase in maternal deaths during labor due to complications with subsequent births after a C-section. Therefore, there is a clinical motivation to reduce the C-section rate. Current techniques are, however, inefficient at determining fetal distress leading to a high false positive rate for complications and ultimately a C-section. For the current study, Monte Carlo simulations were used to calculate the amount of signal received on a model of a pregnant mother, as well as, the percent of the signal that comes from the fetal layer. Models with and without a 1 mm amniotic fluid were compared and showed differing trends.

Intracranial pressure (ICP) is typically measured invasively through a sensor placed inside the brain or a needle inserted into the spinal canal, limiting the patient population on which this assessment can be performed. Currently, non-invasive methods are limited due to lack of sensitivity and thus only apply to extreme cases of increased ICP, instead of use in general clinical practice. We demonstrate a novel application for near-infrared spectroscopy (NIRS) to accurately estimate ICP changes over time. Using a non-human primate (Rhesus Macaque) model, we collected optical data while we induced ICP oscillations at multiple ICP levels obtained by manipulating the height of a fluid column connected via a catheter to the lateral ventricle. Hemodynamic responses to ICP changes were measured at the occipital pole and compared to changes detected by a conventional intraparenchymal ICP probe. We demonstrate that hemoglobin concentrations are highly correlated with induced ICP oscillations and that this response is frequency dependent. We translated the NIRS data into non-invasive ICP measurements via a fitted non-parametric transfer function, demonstrating a match in both magnitude and time alignment with an invasively measured reference. Our results demonstrate that NIRS has the potential for non-invasive ICP monitoring.

Although shape perception is primarily considered a function of the ventral visual pathway, previous research has shown that both dorsal and ventral pathways represent shape information. Here, we examine whether the shape-selective electrophysiological signals observed in dorsal cortex are a product of the connectivity to ventral cortex or are independently computed. We conducted multiple EEG studies in which we manipulated the input parameters of the stimuli so as to bias processing to either the dorsal or ventral visual pathway. Participants viewed displays of common objects with shape information parametrically degraded across five levels. We measured shape sensitivity by regressing the amplitude of the evoked signal against the degree of stimulus scrambling. Experiment 1, which included grayscale versions of the stimuli, served as a benchmark establishing the temporal pattern of shape processing during typical object perception. These stimuli evoked broad and sustained patterns of shape sensitivity beginning as early as 50 msec after stimulus onset. In Experiments 2 and 3, we calibrated the stimuli such that visual information was delivered primarily through parvocellular inputs, which mainly project to the ventral pathway, or through koniocellular inputs, which mainly project to the dorsal pathway. In the second and third experiments, shape sensitivity was observed, but in distinct spatio-temporal configurations from each other and from that elicited by grayscale inputs. Of particular interest, in the koniocellular condition, shape selectivity emerged earlier than in the parvocellular condition. These findings support the conclusion of distinct dorsal pathway computations of object shape, independent from the ventral pathway.

We recently reported the use of optical imaging technology to quantify facial plethora in endogenous Cushing syndrome (CS). In the present study, we studied a larger cohort of patients with Cushing disease (CD) and examined water content fraction as well as blood volume fraction as bio-optic markers for determining the efficacy of this methodology as a predictor of lasting remission after surgery for CS. We imaged 49 patients before and after transsphenoidal surgery (TSS) for Cushing disease (CD); 22 patients were also seen at 3–6 months, and 13 patients 12 months post-operatively. On all patients, we used multi-spectral imaging (MSI) to evaluate hemodynamic distributions as well as water content at a specific area of the face. We found a decrease in blood volume fraction after vs. before surgical treatment in the tested facial area in 37 of the 40 patients, as determined with biochemical markers (p

Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) measure cerebral hemodynamics, which in turn can be used to assess the cerebral metabolic rate of oxygen (CMRO2) and cerebral autoregulation (CA). However, current mathematical models for CMRO2 estimation make assumptions that break down for cerebral perfusion pressure (CPP)-induced changes in CA. Here, we performed preclinical experiments with controlled changes in CPP while simultaneously measuring NIRS and DCS at rest. We observed changes in arterial oxygen saturation (~10%) and arterial blood volume (~50%) with CPP, two variables often assumed to be constant in CMRO2 estimations. Hence, we propose a general mathematical model that accounts for these variations when estimating CMRO2 and validate its use for CA monitoring on our experimental data. We observed significant changes in the various oxygenation parameters, including the coupling ratio (CMRO2/blood flow) between regions of autoregulation and dysregulation. Our work provides an appropriate model and preliminary experimental evidence for the use of NIRS- and DCS-based tissue oxygenation and metabolism metrics for non-invasive diagnosis of CA health in CPP-altering neuropathologies.

Significance: Longitudinal tracking of hemodynamic changes in the breast has shown potential for neoadjuvant chemotherapy (NAC) outcome prediction. Spatial frequency domain imaging (SFDI) could be suitable for frequent monitoring of shallow breast tumors, but strong sensitivity to superficial absorbers presents a challenge. Aim: We investigated the efficacy of a two-layer SFDI inverse model that accounts for varying melanin concentration in the skin to improve discrimination of optical properties of deep tissue of the breast. Approach: Hemodynamic changes in response to localized breast compression were measured in 13 healthy volunteers using a handheld SFDI device. Epidermis optical thickness was determined based on spectral fitting of the model output and used to calculate subcutaneous optical properties. Results: Optical properties from a homogeneous model yielded physiologically unreasonable absorption and scattering coefficients for highly pigmented volunteers. The two-layer model compensated for the effect of melanin and yielded properties in the expected range for healthy breast. Extracted epidermal optical thickness was higher for higher Fitzpatrick types. Compression induced a decrease in total hemoglobin consistent with tissue blanching. Conclusions: The handheld SFDI device and two-layer model show potential for imaging hemodynamic responses that potentially could help predict efficacy of NAC in patients of varying skin tones.

Significance: Electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) are both commonly used methodologies for neuronal source reconstruction. While EEG has high temporal resolution (millisecond-scale), its spatial resolution is on the order of centimeters. On the other hand, in comparison to EEG, fNIRS, or diffuse optical tomography (DOT), when used for source reconstruction, can achieve relatively high spatial resolution (millimeter-scale), but its temporal resolution is poor because the hemodynamics that it measures evolve on the order of several seconds. This has important neuroscientific implications: e.g., if two spatially close neuronal sources are activated sequentially with only a small temporal separation, single-modal measurements using either EEG or DOT alone would fail to resolve them correctly. Aim: We attempt to address this issue by performing joint EEG and DOT neuronal source reconstruction. Approach: We propose an algorithm that utilizes DOT reconstruction as the spatial prior of EEG reconstruction, and demonstrate the improvements using simulations based on the ICBM152 brain atlas. Results: We show that neuronal sources can be reconstructed with higher spatiotemporal resolution using our algorithm than using either modality individually. Further, we study how the performance of the proposed algorithm can be affected by the locations of the neuronal sources, and how the performance can be enhanced by improving the placement of EEG electrodes and DOT optodes. Conclusions: We demonstrate using simulations that two sources separated by 2.3-3.3 cm and 50 ms can be recovered accurately using the proposed algorithm by suitably combining EEG and DOT, but not by either in isolation. We also show that the performance can be enhanced by optimizing the electrode and optode placement according to the locations of the neuronal sources.

Finger pulse oximetry traditionally assumes a semi-infinite, homogenous media where the wavelength dependent differential pathlength is assumed or calibrated for. We developed an algorithm which does not require this assumption.

This project was funded as part of the Department for Business, Energy and Industrial Strategy Offshore Energy Strategic Environmental Assessment Programme. Supplementary funding supporting J.C.M. and P.L.T. was provided by the US Office of Naval Research (ONR) grant nos N00014-18-1-2062 and N00014-20-1-2709. Supplementary funding supporting J.K. and A.R. was provided by the US Office of Naval Research (ONR) grant no. N00014-19-1-1223. Assistance in funding for acquisition of the fNIRS system was provided by SMRU Consulting's 10th Anniversary Award. Sensory ecology and physiology of free-ranging animals is challenging to study but underpins our understanding of decision making in the wild. Existing non-invasive human biomedical technology offers tools that could be harnessed to address these challenges. Functional near-infrared spectroscopy (fNIRS), a wearable, non-invasive biomedical imaging technique measures oxy- and deoxyhemoglobin concentration changes that can be used to detect localised neural activation in the brain. We tested the efficacy of fNIRS to detect cortical activation in grey seals (Halichoerus grypus) and identify regions of the cortex associated with different senses (vision, hearing and touch). Activation of specific cerebral areas in seals was detected by fNIRS in responses to light (vision), sound (hearing) and whisker stimulation (touch). Physiological parameters, including heart and breathing rate, were also extracted from the fNIRS signal, which allowed neural and physiological responses to be monitored simultaneously. This is the first time fNIRS has been used to detect cortical activation in a non-domesticated or laboratory animal. Since fNIRS is non-invasive and wearable, this study demonstrates its potential as a tool to quantitatively investigate sensory perception and brain function while simultaneously recording physiological dynamics that allow calculation of heart rate, tissue and arterial oxygen saturation of haemoglobin, respectively, perfusion changes and breathing rate in free-ranging animals. Postprint

Vascular impedance is a frequency dependent quantity relating a vascular compartment's flow dynamics to pressure changes. Although vascular impedance has been investigated in larger arteries, probing smaller arterioles using similar techniques has been difficult due to their small cross-sectional area. Here we show how vascular impedance can be quantified based on pulsatile data from cerebral measurements using diffuse correlation spectroscopy (DCS) as well as near-infrared spectroscopy (NIRS). Results from head of bed tilting in healthy volunteers will be presented, showing that quantification of vascular impedance is possible. Applications and the relationship to cerebral autoregulation will be discussed.

Cerebral blood flow regulation is impaired in many diseases and treatment based on optimizing blood flow regulation is promising for patient outcome, but may require intracranial pressure (ICP) to be known. We have recently developed a non-invasive alternative based on a combination of near-infrared spectroscopy and diffuse correlation spectroscopy. This talk will summarize the optical imaging setup, experimental procedures, and data analysis. Data from non-human primates as well as clinical data from pediatric critical care patients will be presented. We will further present data on neurovascular coupling during ICP changes, suggesting a link between blood flow regulation and neuronal activity.