Frequency-domain Near-infrared Spectroscopy Research Articles

Maximizing the Reliability and Precision of Measures of Prefrontal Cortical Oxygenation Using Frequency-Domain Near-Infrared Spectroscopy.

Frequency-domain near-infrared spectroscopy (FD-NIRS) has been used for non-invasive assessment of cortical oxygenation since the late 1990s. However, there is limited research demonstrating clinical validity and general reproducibility. To address this limitation, recording duration for adequate validity and within- and between-day reproducibility of prefrontal cortical oxygenation was evaluated. To assess validity, a reverse analysis of 10-min-long measurements (n = 52) at different recording durations (1-10-min) was quantified via coefficients of variation and Bland-Altman plots. To assess within- and between-day within-subject reproducibility, participants (n = 15) completed 2-min measurements twice a day (morning/afternoon) for five consecutive days. While 1-min recordings demonstrated sufficient validity for the assessment of oxygen saturation (StO2) and total hemoglobin concentration (THb), recordings ≥4 min revealed greater clinical utility for oxy- (HbO) and deoxyhemoglobin (HHb) concentration. Females had lower StO2, THb, HbO, and HHb values than males, but variability was approximately equal between sexes. Intraclass correlation coefficients ranged from 0.50-0.96. The minimal detectable change for StO2 was 1.15% (95% CI: 0.336-1.96%) and 3.12 µM for THb (95% CI: 0.915-5.33 µM) for females and 2.75% (95%CI: 0.807-4.70%) for StO2 and 5.51 µM (95%CI: 1.62-9.42 µM) for THb in males. Overall, FD-NIRS demonstrated good levels of between-day reliability. These findings support the application of FD-NIRS in field-based settings and indicate a recording duration of 1 min allows for valid measures; however, data recordings of ≥4 min are recommended when feasible.

Combined frequency domain near-infrared spectroscopy and diffuse correlation spectroscopy system for comprehensive metabolic monitoring of inspiratory muscles during loading.

Mechanical ventilation (MV) is a cornerstone technology in the intensive care unit as it assists with the delivery of oxygen in critically ill patients. The process of weaning patients from MV can be long and arduous and can lead to serious complications for many patients. Despite the known importance of inspiratory muscle function in the success of weaning, current clinical standards do not include direct monitoring of these muscles. The goal of this project was to develop and validate a combined frequency domain near-infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS) system for the noninvasive characterization of inspiratory muscle response to a load. The system was fabricated by combining a custom digital FD-NIRS and DCS system. It was validated via liquid phantom titrations and a healthy volunteer study. The sternocleidomastoid (SCM), an accessory muscle of inspiration, was monitored during a short loading period in fourteen young, healthy volunteers. Volunteers performed two different respiratory exercises, a moderate load and a high load, which consisted of a one-minute baseline, a one-minute load, and a six-minute recovery period. The system has low crosstalk between absorption, reduced scattering, and flow when tested in a set of liquid titrations. Faster dynamics were observed for changes in blood flow index (), and metabolic rate of oxygen () compared with hemoglobin + myoglobin (Hb+Mb) based parameters after the onset of loads in males. Additionally, larger percent changes in , and were observed compared with Hb+Mb parameters in both males and females. There were also sex differences in baseline values of oxygenated Hb+Mb, total Hb+Mb, and tissue saturation. The dynamic characteristics of Hb+Mb concentration and blood flow were distinct during loading of the SCM, suggesting that the combination of FD-NIRS and DCS may provide a more complete picture of inspiratory muscle dynamics.

The influence of voxelotor on cerebral blood flow and oxygen extraction in pediatric sickle cell disease

AbstractVoxelotor is an inhibitor of sickle hemoglobin polymerization that is used to treat sickle cell disease. Although voxelotor has been shown to improve anemia, the clinical benefit on the brain remains to be determined. This study quantified the cerebral hemodynamic effects of voxelotor in children with sickle cell anemia (SCA) using noninvasive diffuse optical spectroscopies. Specifically, frequency-domain near-infrared spectroscopy combined with diffuse correlation spectroscopy were used to noninvasively assess regional oxygen extraction fraction (OEF), cerebral blood volume, and an index of cerebral blood flow (CBFi). Estimates of CBFi were first validated against arterial spin–labeled magnetic resonance imaging (ASL-MRI) in 8 children with SCA aged 8 to 18 years. CBFi was significantly positively correlated with ASL-MRI–measured blood flow (R2 = 0.651; P = .015). Next, a single-center, open-label pilot study was completed in 8 children with SCA aged 4 to 17 years on voxelotor, monitored before treatment initiation and at 4, 8, and 12 weeks (NCT05018728). By 4 weeks, both OEF and CBFi significantly decreased, and these decreases persisted to 12 weeks (both P < .05). Decreases in CBFi were significantly correlated with increases in blood hemoglobin (Hb) concentration (P = .025), whereas the correlation between decreases in OEF and increases in Hb trended toward significance (P = .12). Given that previous work has shown that oxygen extraction and blood flow are elevated in pediatric SCA compared with controls, these results suggest that voxelotor may reduce cerebral hemodynamic impairments.

Single-distance and dual-slope frequency-domain near-infrared spectroscopy to assess skeletal muscle hemodynamics.

Non-invasive optical measurements of deep tissue (e.g., muscle) need to take into account confounding contributions from baseline and dynamic optical properties of superficial tissue (adipose tissue). Discriminate superficial and deep tissue hemodynamics using data collected with frequency-domain (FD) near-infrared spectroscopy (NIRS) in a dual-slope (DS) configuration. Experimental data were collected in vivo on the forearm of three human subjects during a 3-min arterial occlusion or 1-min venous occlusion. Theoretical data were generated using diffusion theory for two-layered media with varying values of the reduced scattering coefficient () (range: 0.5 to ) and absorption coefficient () (range: ) of the two layers, and top layer thickness (range: 2 to 8mm). Data were analyzed using diffusion theory for a homogeneous semi-infinite medium. Experimental data in vivo were consistent with simulated data for a two-layered medium with a larger in the top layer, comparable absorption changes in the top and bottom layers during venous occlusion, and smaller absorption changes in the top vs. bottom layers during arterial occlusion. The dataset generated by DS FD-NIRS may allow for discrimination of superficial and deep absorption changes in two-layered media, thus lending itself to individual measurements of hemodynamics in adipose and muscle tissue.

Cumulative brain desaturation: Time to consider brain derived parameters to measure daytime sleepiness in obstructive sleep apnea

Objective/Background: The change in cerebral hemodynamics induced by sleep apneas and hypopneas may contribute to the daytime sleepiness in patients with obstructive sleep apnea (OSA). However, previous studies failed to discovery their relationship. We propose and test a new parameter, the cumulative brain oxygen desaturation, which may contribute to OSA patient's daytime sleepiness. Patients/methods22 patients with severe OSA (apnea-hypopnea index (AHI) at diagnosis [mean ± standard deviation, std.]: 52.1 ± 21.6/h, median: 45.1/h, interquartile range: 34.4–60.2/h) were monitored by polysomnography during routine continuous positive airway pressure titration. The reductions of brain tissue oxygen saturation (StO2) in all respiratory events at baseline sleep were measured by frequency-domain near-infrared spectroscopy (NIRS). The cumulative brain desaturation was calculated as AHI times the mean StO2 desaturation (i.e., AHI×ΔStO2‾). Similarly, cumulative peripheral desaturation was also calculated, i.e., AHI×ΔSpO2‾ where ΔSpO2‾ was the mean reduction of peripheral arterial oxygen saturation (SpO2). The correlations between Epworth sleepiness scale (ESS) and AHI, ΔStO2‾, AHI×ΔStO2‾, and AHI×ΔSpO2‾ were tested, respectively. Linear regression was applied to predict ESS using AHI×ΔStO2‾ and AHI×ΔSpO2‾, with age and BMI as covariates. ResultsESS significantly correlates to the cumulative brain desaturation (Pearson's correlation coefficient: 0.68, p = 0.00056), not the other parameters. Regression analysis only finds significant association between ESS and the cumulative cerebral desaturation (p = 0.00195) but not the cumulative peripheral desaturation (p = 0.71). ConclusionsThe cumulative brain oxygen desaturation, which comprehensively combines total sleep time, the frequency of apnea and hypopnea events, and the severity of cerebral oxygen desaturation, is a new indicator for daytime sleepiness in severe OSA.

Cerebral Hemodynamics in Infants with Sickle Cell Disease Indicate Presence of Early Hemodynamic Stress

Introduction: One of the most severe complications of sickle cell disease (SCD) is ischemic brain injury, caused by a combination of decreased oxygen transport delivery related to intravascular vaso-occlusion of sickle erythrocytes and/or cerebral vasculopathy. While newborn screening programs diagnose SCD shortly after birth, routine risk assessment for stroke typically starts with transcranial ultrasound doppler (TCD) at two years of age or later. Yet, little is known about how SCD affects cerebral hemodynamics during infancy, a crucial period for brain development. To address this gap, we used advanced quantitative near-infrared spectroscopy (qNIRS) to non-invasively monitor cerebral tissue hemoglobin concentration (HbT), oxygenation (SO 2), oxygen extraction fraction (cFTOE), blood flow (CBF), and oxygen metabolism (CMRO 2) in infants with SCD. Abnormal CBF and cFTOE indicate hemodynamic stress that may increase stroke risk. Our study aims to investigate the effects of SCD on cerebral oxygen transport in infancy and its associations with age and blood hemoglobin concentration (HgB). Methods: This is a subgroup analysis of a prospective, observational neuroimaging study of SCD at Boston Children's Hospital (NCT 04166526). Inclusion criteria of this subgroup are SCD patients age less than 24 months old at the time of enrollment who are not receiving chronic transfusions. Families read and signed informed consent before participating in research activities. Measurements were conducted with the patients' normally scheduled hematology appointments at Boston Children's Hospital. During each measurement session, bilateral frontal regions of the head were measured up to six times for 30 seconds each. qNIRS variables were compared with literature values obtained with the same optical technologies from a cohort of typically developed infants around 1 year old, equivalent to the median age in this study 1. Correlation analysis was used to analyze qNIRS variables with age and HgB from clinical lab tests. Results: To date, 8 (F/M: 4/4; HbSS/HbS/B +-thalassemia/HbSC: 6/1/1) patients were enrolled with a total of 16 measurements. The meanSD age at measurement was 11.5 5.23 months and the median (IQR) HgB was 9.4 (8.9-10) g/dL. Seven (44%) measurements were performed while patients were receiving treatment with hydroxyurea. There was no difference in HgB in the groups with and without hydroxyurea, though the treatment group was older (mean age: 15.4 vs 8.4 months, P=0.002). Group averages of qNIRS variables are summarized Table 1. Average cFTOE was 0.53 ± 0.07, significantly higher than the reference value of 0.32 (mean difference: 0.21, P&amp;lt;0.001), while the cohort's mean SO 2 of 45.78 ± 7.13% was significantly lower than the reference value of 68% (mean difference: -22.2, P&amp;lt;0.001). Furthermore, cFTOE inversely correlated with HgB (r= -0.63, P=0.04) while SO 2 increased with HgB (r= 0.63, P=0.04). HbT and cerebral blood volume (CBV) were also significantly lower than the reference values (mean difference of -24.8 μM and -0.75 ml/100g, P&amp;lt;0.001 and P&amp;lt;0.02, respectively) and positively correlated with age (r=0.51 and 0.57, P=0.04). CBF did not correlate with either age or HgB. Hemodynamic variables did not differ between groups with and without hydroxyurea, except for HbT and CBV likely secondary to the cohort age difference. Taken together, this suggests that CBF compensatory mechanisms were insufficient to prevent elevated oxygen extraction. Summary: These preliminary results suggest that inadequate oxygen transport to the brain secondary to SCD evokes a compensatory increase in cFTOE starting in early infancy. The progressive hemodynamic stress to brain health during the period of the brain's greatest growth and metabolic demand for oxygen is concerning because of the potential for injury as compensatory mechanisms become exhausted. Hydroxyurea did not reduce this stress, but may have prevented further declines. Recruitment is ongoing to increase the size of the cohort and to continue following patients' trajectories with age. We demonstrated the potential of qNIRS as biomarkers of cerebral hemodynamic compensation to determine when intervention is necessary and evaluate the effectiveness of a chosen intervention in individual patients. 1. Franceschini, M. A. et al. Assessment of infant brain development with frequency-domain near-infrared spectroscopy. Pediatr Res 61, 546-551, 2007.

Exploring Near Infrared Spectroscopy As a Tool for Monitoring Tissue Hemodynamics for Patients with Sickle Cell Disease

Sickle cell disease (SCD) is a genetic disorder that has higher prevalence in people of African ancestry. In the United States, SCD affects about 100,000 people and 1 in 365 African Americans. Sickled red blood cells (RBCs) have a shorter life span and are rigid, causing chronic hemolytic anemia and vaso-occlusive crises. There is a need for accessible diagnostic and monitoring technologies to characterize hemodynamic health, especially for patients with SCD. Near infrared spectroscopy (NIRS) is a noninvasive optical technique that uses light in the near infrared range (650 - 900 nm) to gain information from tissue absorption and light scattering. The purpose of this study is to show that NIRS is sensitive to differences in tissue hemodynamics between patients with SCD and healthy population. We enrolled adults (age ≥ 18 years) of African descent who were not recently transfused under protocol NCT05604547. Baseline hemodynamics and day-to-day variability were quantified in 10 SCD patients with HbSS (six male, four female) and six healthy, ethnically matched participants (four male, two female). We assessed participants with affixed transmission speckle analysis (ATSA) and a dual system frequency domain-NIRS (FD-NIRS) with diffuse correlation spectroscopy (DCS) device to measure blood flow and hemoglobin concentration. Participants underwent a respiratory challenge, three sets of breath holds, with the optical probe on their forehead. Then, the participants underwent a vascular occlusion challenge, a three-minute brachial blood pressure cuff occlusion at 200 mmHg, with the optical probe on their forearm. We also measured skin and adipose tissue thickness (SATT) of the forearm site with ultrasound. Two of the healthy control participants were excluded from the skeletal muscle analysis due to SATT &amp;gt; 8 mm. A Mann-Whitney significance test was used to evaluate the results. From these measurements, we acquired the concentration of oxygenated (O 2Hb), deoxygenated (HHb), and total hemoglobin (tHb); blood flow index (BFi); and tissue oxygen saturation (StO 2) for cerebral and skeletal muscle. The cerebral StO 2 in the SCD cohort was lower than the control group, 55.5 ± 7.4% versus 66.9 ± 2.5% (p = 0.003), respectively. Skeletal muscle StO 2 in the SCD cohort was lower than that in control, 59.2 ± 5.8% versus 66.4 ± 6.7%, respectively, but the difference was not significant (p = 0.19). The muscle O 2Hb in the SCD cohort was lower compared to control: 32.7 ± 6.5 µM versus 51.0 ± 9.2 µM (p = 0.01), respectively. The muscle tHb had a similar trend, with the SCD cohort measuring 55.8 ± 12.0 µM and the control group measuring 76.5 ± 9.0 µM (p = 0.03). The SCD cohort was also found to have lower overall muscle BFi, averaging 5.37 x 10 -9 ± 3.47 x 10 -9 cm/s, whereas the control group had an average of 1.90 x 10 -8 ± 1.33 x 10 -8 cm/s (p = 0.004). We also calculated hemodynamic markers, such as components of the occlusion recovery. The post-occlusion O 2Hb recovery slope for the SCD cohort was 0.31 ± 0.19 µM/s compared with control group at 1.56 ± 0.75 µM/s (p = 0.004). The goal of this study is to compare baseline vascular hemodynamics between patients with SCD and ethnically matched healthy controls. This study is ongoing and preliminary data analysis suggests impaired cardiovascular health in SCD subjects. The cerebral StO 2, muscle O 2Hb, and tHb in the SCD cohort is hypothesized to be a result of the reduced ability of sickled RBC to carry oxygen. There was a significant difference in the cerebral StO 2 but not in the skeletal muscle StO 2, suggesting that there are more dynamic changes seen in the brain than the muscle. This is consistent with previous work using commercial, continuous-wave NIRS systems for a SCD cohort (Barriteau et al. 2022) that also reported significantly lower cerebral StO 2 and lower trending, but not significant, muscle StO 2 values.The post-occlusion O 2Hb recovery upslope is hypothesized to be slower for the SCD cohort due to reduced endothelial function. We plan to assess repeatability of intra-individual NIRS parameters and to compare the non-invasive hemodynamic metrics to clinical markers, such as blood Hb and echocardiogram. These preliminary results indicate that NIRS is sensitive to changes in hemodynamic variations between SCD patients and healthy controls and, therefore, has the potential to serve as a point-of-care technology for individualized clinical management for patients with SCD.

Temporal Pattern of Cortical Hypoxia in Multiple Sclerosis and Its Significance on Neuropsychological and Clinical Measures of Disability.

Multiple sclerosis (MS) is a degenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal damage. It has been hypothesized that hypoxia plays a role in the pathogenesis of MS. This study was undertaken to investigate the reproducibility of non-invasively measured cortical microvascular hemoglobin oxygenation (St O2 ) using frequency domain near-infrared spectroscopy (fdNIRS), investigate its temporal pattern of hypoxia in people with MS (pwMS), and its relationship with neurocognitive function and mood. We investigated the reproducibility of fdNIRS measurements. We measured cortical hypoxia in pwMS, and the relationships between St O2 , neurocognitive function, fatigue, and measures of physical disability. Furthermore, we cataloged the temporal pattern of St O2 measured at 1-week intervals for 4 weeks, and at 8 weeks and ~1 year. We show that fdNIRS parameters were highly reproducible in 7 healthy control participants measured over 6 days (p > 0.05). There was low variability between and within subjects. In line with our previous findings, we show that 33% of pwMS (n = 88) have cortical microvascular hypoxia. Over 8 weeks and at ~1 year, St O2 values for normoxic and hypoxic groups did not change significantly. There was no significant association between cognitive function and St O2 . This conclusion should be revisited as only a small proportion of the relapsing-remitting MS group (21%) was cognitively impaired. The fdNIRS parameters have high reproducibility and repeatability, and we have demonstrated that hypoxia in MS is a chronic condition, lasting at least a year. The results show a weak relationship between cognitive functioning and oxygenation, indicating future study is required. ANN NEUROL 2023;94:1067-1079.

The impact of central and obstructive respiratory events on cerebral oxygenation in adults with sleep disordered breathing

Obstructive sleep apnea (OSA) and central sleep apnea (CSA) are two main types of sleep disordered breathing (SDB). While the changes in cerebral hemodynamics triggered by OSA events have been well studied using near-infrared spectroscopy (NIRS), they are essentially unknown in CSA in adults. Therefore, in this study, we compared the changes in cerebral oxygenation between OSA and CSA events in adult patients using NIRS. Cerebral tissue oxygen saturation (StO2) in 13 severe SDB patients who had both CSA and OSA events was measured using frequency-domain NIRS. The changes in cerebral StO2 desaturation and blood volume (BV) in the first hour of natural sleep were compared between different types of respiratory events (i.e., 277 sleep hypopneas, 161 OSAs and 113 CSAs) with linear mixed-effect models controlling for confounders. All respiratory events occurred during non-rapid eye movement (NREM) sleep. We found that apnea events induced greater cerebral desaturations and BV fluctuations compared to hypopneas, but there was no difference between OSA and CSA. These results suggest that cerebral autoregulation in our patients are still capable to counteract the pathomechanisms of apneas, in particularly the negative intrathoracic pressure (ITP) caused by OSA events. Otherwise larger BV fluctuations in OSA compared to CSA should be observed due to the negative ITP that reduces cardiac stroke volume and leads to lower systematic blood supply. Our study suggests that OSA and CSA may have similar impact on cerebral oxygenation during NREM sleep in adult patients with SDB.

Evaluating feasibility of functional near-infrared spectroscopy in dolphins.

Using functional near-infrared spectroscopy (fNIRS) in bottlenose dolphins (Tursiops truncatus) could help to understand how echolocating animals perceive their environment and how they focus on specific auditory objects, such as fish, in noisy marine settings. To test the feasibility of near-infrared spectroscopy (NIRS) in medium-sized marine mammals, such as dolphins, we modeled the light propagation with computational tools to determine the wavelengths, optode locations, and separation distances that maximize sensitivity to brain tissue. Using frequency-domain NIRS, we measured the absorption and reduced scattering coefficient of dolphin sculp. We assigned muscle, bone, and brain optical properties from the literature and modeled light propagation in a spatially accurate and biologically relevant model of a dolphin head, using finite-element modeling. We assessed tissue sensitivities for a range of wavelengths (600 to 1700nm), source-detector distances (50 to 120mm), and animal sizes (juvenile model 25% smaller than adult). We found that the wavelengths most suitable for imaging the brain fell into two ranges: 700 to 900nm and 1100 to 1150nm. The optimal location for brain sensing positioned the center point between source and detector 30 to 50mm caudal of the blowhole and at an angle 45deg to 90deg lateral off the midsagittal plane. Brain tissue sensitivity comparable to human measurements appears achievable only for smaller animals, such as juvenile bottlenose dolphins or smaller species of cetaceans, such as porpoises, or with source-detector separations in adult dolphins. Brain measurements in juvenile or subadult dolphins, or smaller dolphin species, may be possible using specialized fNIRS devices that support optode separations of . We speculate that many measurement repetitions will be required to overcome hemodynamic signals originating predominantly from the muscle layer above the skull. NIRS measurements of muscle tissue are feasible today with source-detector separations of 50mm, or even less.

How does obstructive sleep apnea alter cerebral hemodynamics?

We aimed to characterize the cerebral hemodynamic response to obstructive sleep apnea/hypopnea events, and evaluate their association to polysomnographic parameters. The characterization of the cerebral hemodynamics in obstructive sleep apnea (OSA) may add complementary information to further the understanding of the severity of the syndrome beyond the conventional polysomnography. Severe OSA patients were studied during night sleep while monitored by polysomnography. Transcranial, bed-side diffuse correlation spectroscopy (DCS) and frequency-domain near-infrared diffuse correlation spectroscopy (NIRS-DOS) were used to follow microvascular cerebral hemodynamics in the frontal lobes of the cerebral cortex. Changes in cerebral blood flow (CBF), total hemoglobin concentration (THC), and cerebral blood oxygen saturation (StO2) were analyzed. We considered 3283 obstructive apnea/hypopnea events from sixteen OSA patients (Age (median, interquartile range) 57 (52-64.5); females 25%; AHI (apnea-hypopnea index) 84.4 (76.1-93.7)). A biphasic response (maximum/minimum followed by a minimum/maximum) was observed for each cerebral hemodynamic variable (CBF, THC, StO2), heart rate and peripheral arterial oxygen saturation (SpO2). Changes of the StO2 followed the dynamics of the SpO2, and were out of phase from the THC and CBF. Longer events were associated with larger CBF changes, faster responses and slower recoveries. Moreover, the extrema of the response to obstructive hypopneas were lower compared to apneas (p < .001). Obstructive apneas/hypopneas cause profound, periodic changes in cerebral hemodynamics, including periods of hyper- and hypo-perfusion and intermittent cerebral hypoxia. The duration of the events is a strong determinant of the cerebral hemodynamic response, which is more pronounced in apnea than hypopnea events.

Review of recent advances in frequency-domain near-infrared spectroscopy technologies [Invited].

Over the past several decades, near-infrared spectroscopy (NIRS) has become a popular research and clinical tool for non-invasively measuring the oxygenation of biological tissues, with particular emphasis on applications to the human brain. In most cases, NIRS studies are performed using continuous-wave NIRS (CW-NIRS), which can only provide information on relative changes in chromophore concentrations, such as oxygenated and deoxygenated hemoglobin, as well as estimates of tissue oxygen saturation. Another type of NIRS known as frequency-domain NIRS (FD-NIRS) has significant advantages: it can directly measure optical pathlength and thus quantify the scattering and absorption coefficients of sampled tissues and provide direct measurements of absolute chromophore concentrations. This review describes the current status of FD-NIRS technologies, their performance, their advantages, and their limitations as compared to other NIRS methods. Significant landmarks of technological progress include the development of both benchtop and portable/wearable FD-NIRS technologies, sensitive front-end photonic components, and high-frequency phase measurements. Clinical applications of FD-NIRS technologies are discussed to provide context on current applications and needed areas of improvement. The review concludes by providing a roadmap toward the next generation of fully wearable, low-cost FD-NIRS systems.

Brain hypoxia, neurocognitive impairment, and quality of life in people post-COVID-19

ObjectiveSystemic hypoxia occurs in COVID-19 infection; however, it is unknown if cerebral hypoxia occurs in convalescent individuals. We have evidence from other conditions associated with central nervous system inflammation that hypoxia may occur in the brain. If so, hypoxia could reduce the quality of life and brain function. This study was undertaken to assess if brain hypoxia occurs in individuals after recovery from acute COVID-19 infection and if this hypoxia is associated with neurocognitive impairment and reduced quality of life.MethodsUsing frequency-domain near-infrared spectroscopy (fdNIRS), we measured cerebral tissue oxygen saturation (StO2) (a measure of hypoxia) in participants who had contracted COVID-19 at least 8 weeks prior to the study visit and healthy controls. We also conducted neuropsychological assessments and health-related quality of life assessments, fatigue, and depression.ResultsFifty-six percent of the post-COVID-19 participants self-reported having persistent symptoms (from a list of 18), with the most reported symptom being fatigue and brain fog. There was a gradation in the decrease of oxyhemoglobin between controls, and normoxic and hypoxic post-COVID-19 groups (31.7 ± 8.3 μM, 27.8 ± 7.0 μM and 21.1 ± 7.2 μM, respectively, p = 0.028, p = 0.005, and p = 0.081). We detected that 24% of convalescent individuals’ post-COVID-19 infection had reduced StO2 in the brain and that this relates to reduced neurological function and quality of life.InterpretationWe believe that the hypoxia reported here will have health consequences for these individuals, and this is reflected in the correlation of hypoxia with greater symptomology. With the fdNIRS technology, combined with neuropsychological assessment, we may be able to identify individuals at risk of hypoxia-related symptomology and target individuals that are likely to respond to treatments aimed at improving cerebral oxygenation.

Associations between neurological examination at term-equivalent age and cerebral hemodynamics and oxygen metabolism in infants born preterm.

Infants born at 29-36 weeks gestational age (GA) are at risk of experiencing neurodevelopmental challenges. We hypothesize that cerebral hemodynamics and oxygen metabolism measured by bedside optical brain monitoring are potential biomarkers of brain development and are associated with neurological examination at term-equivalent age (TEA). Preterm infants (N = 133) born 29-36 weeks GA and admitted in the neonatal intensive care unit were enrolled in this prospective cohort study. Combined frequency-domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) were used from birth to TEA to measure cerebral hemoglobin oxygen saturation and an index of microvascular cerebral blood flow (CBF i ) along with peripheral arterial oxygen saturation (SpO2). In combination with hemoglobin concentration in the blood, these parameters were used to derive cerebral oxygen extraction fraction (OEF) and an index of cerebral oxygen metabolism (CMRO2i ). The Amiel-Tison and Gosselin Neurological Assessment was performed at TEA. Linear regression models were used to assess the associations between changes in FDNIRS-DCS parameters from birth to TEA and GA at birth. Logistic regression models were used to assess the associations between changes in FDNIRS-DCS parameters from birth to TEA and neurological examination at TEA. Steeper increases in CBF i (p < 0.0001) and CMRO2i (p = 0.0003) were associated with higher GA at birth. Changes in OEF, CBF i , and CMRO2i from birth to TEA were not associated with neurological examination at TEA. In this population, cerebral FDNIRS-DCS parameters were not associated with neurological examination at TEA. Larger increases in CBF i and CMRO2i from birth to TEA were associated with higher GA. Non-invasive bedside FDNIRS-DCS monitoring provides cerebral hemodynamic and metabolic parameters that may complement neurological examination to assess brain development in preterm infants.

Dual-slope imaging of cerebral hemodynamics with frequency-domain near-infrared spectroscopy.

This work targets the contamination of optical signals by superficial hemodynamics, which is one of the chief hurdles in non-invasive optical measurements of the human brain. To identify optimal source-detector distances for dual-slope (DS) measurements in frequency-domain (FD) near-infrared spectroscopy (NIRS) and demonstrate preferential sensitivity of DS imaging to deeper tissue (brain) versus superficial tissue (scalp). Theoretical studies (in-silico) based on diffusion theory in two-layered and in homogeneous scattering media. In-vivo demonstrations of DS imaging of the human brain during visual stimulation and during systemic blood pressure oscillations. The mean distance (between the two source-detector distances needed for DS) is the key factor for depth sensitivity. In-vivo imaging of the human occipital lobe with FD NIRS and a mean distance of 31mm indicated: (1)greater hemodynamic response to visual stimulation from FD phase versus intensity, and from DS versus single-distance (SD); (2)hemodynamics from FD phase and DS mainly driven by blood flow, and hemodynamics from SD intensity mainly driven by blood volume. DS imaging with FD NIRS may suppress confounding contributions from superficial hemodynamics without relying on data at short source-detector distances. This capability can have significant implications for non-invasive optical measurements of the human brain.

Reduced Cerebrovascular Oxygenation in Individuals with Post-Acute COVID-19 Syndrome (PACS) ("long COVID").

There is evidence that hypoxia occurs in the brain of some individuals who contracted the COVID-19 disease. Furthermore, it has been widely reported that about 13% of individuals who contracted the COVID-19 disease report persistent symptoms after the acute infection stage (>2months post-acute infection). This is termed post-acute COVID-19 syndrome (PACS) or ("long COVID"). In this study, we aimed to determine if hypoxia measured non-invasively with frequency domain near-infrared spectroscopy (fdNIRS) occurs in asymptomatic and symptomatic individuals with post-acute COVID-19 disease. We show that 26% of our symptomatic group, measured on average 9.6months post-acute COVID-19 disease, were hypoxic and 12% of the asymptomatic group, measured on average 2.5months post-acute infection, were hypoxic. Our study indicates that fdNIRS measure of hypoxia in the brain may be a useful tool to identify individuals that are likely to respond to treatments targeted at reducing inflammation and improving oxygenation.

BIAN: A Multilayer Microfluidic-Based Tissue-Mimicking Phantom for Near-Infrared Imaging.

Near-infrared spectroscopy (NIRS) is a non-invasive optical method for monitoring cerebral oxygenation. Changes in regional blood flow and oxygenation due to neurovascular coupling are important biomarkers of neuronal activation. So far, there has been little research on multilayer tissue phantoms with tuneable blood flow, blood volume, and optical properties to simulate local changes in oxygenation at different depths. The aim of this study is to design, fabricate and characterize a complex dynamic phantom based on multilayer microfluidics with controllable blood flow, blood volume, and optical properties for testing NIRS instruments. We developed a phantom prototype with two microfluidic chips embedded at two depths inside a solid silicone phantom to mimic the vessels in the scalp and in the cortex. To simulate the oxygenation and perfusion of tissue, a solution with blood-like optical properties was sent into the microchannels by a pump with a programmable pressure controller. The pressure adjusted the volume of the microfluidic chips representing a distension of blood vessels. The optical changes in the superficial and deep layers were measured by a commercially available frequency domain NIRS instrument. The NIRS successfully detected the changes in light intensity elicited by the changes in the pressure input to the two layers. In conclusion, the microfluidics-based imaging phantom was successfully designed and fabricated and mimics brain functional activity. This technique has great potential for testing other optical devices, e.g., diffuse correlation spectroscopy, pulse oximetry, and optical coherence tomography.

Infradian Rhythms in Cerebrovascular Oxygenation and Blood Volume in Humans at Rest: A 5-Year Study.

All parameters of human physiology show chronobiological variability. While circadian (cycle length~24h) rhythms of the neuronal, hemodynamic and metabolic aspects of human brain activity are increasingly being explored, infradian (cycle length>24h) rhythms are largely unexplored. We investigated if cerebrovascular oxygen saturation (StO2) and blood volume ([tHb]) values measured over many years in many subjects during resting show infradian rhythmicity. Absolute StO2 and [tHb] values (median over a 5 min resting-phase while sitting) were measured in 220 healthy subjects (age: 24.7±3.6years, 87 males, 133 females) 2-4 times on different days over the right and left frontal lobe (FL) and occipital lobe (OL) by employing frequency-domain NIRS as part of different systemic physiology augmented functional near-infrared spectroscopy, SPA-fNIRS, studies. The data set consisted of 708 single measurements performed over a timespan of 5years (2017-2021). General additive models (GAM) and cosinor modelling were used to analyze the data. The GAM analysis revealed (i) a non-linear trend in the StO2 and [tHb] values over the 5-year span, (ii) a circannual (cycle length~12months) rhythm in StO2 at the FL (amplitude (A): 3.4%, acrophase (φ): June) and OL (A: 1.5%, φ: May) as well as in [tHb] at the OL (A: 1.2μM, bathyphase (θ): June), and (iii) a circasemiannual (cycle length~6months) rhythm in [tHb] at the FL (A: 2.7μM, φ: March and September, respectively). Furthermore, the circannual oscillations of StO2 (at the FL) and [tHb] (at the OL) were statistically significantly correlated with the day length, outdoor temperature, humidity and air pressure. We conclude that absolute values of StO2 and [tHb] show chronobiological variability on the group-level with a long-term nonlinear trend as well as circannual/circasemiannual rhythmicity. These rhythms need to be taken into account when defining reference values for StO2 and [tHb] and may correlate with the variability of cerebrovascular disease incidents over the year.

Cerebral Metabolic Stress Improves after Voxelotor Treatment in Pediatric Sickle Cell Disease

Introduction In sickle cell disease (SCD), hemoglobin S rapidly forms intracellular polymers in the deoxygenated state, resulting in red blood cell sickling, hemolysis, and vaso-occlusion. These changes alter cerebral perfusion and dramatically increase risk for neurocognitive deficits and stroke (Bush et al., 2014; Wang et al., 2021). Voxelotor (Oxbryta®) is an inhibitor of HbS polymerization that has been shown to significantly improve anemia and reduce hemolysis in sickle cell disease. However, it is unknown whether these changes are accompanied by improvements in perfusion and reductions in cerebral metabolic stress. Here we employ two novel optical techniques known as frequency-domain near-infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) to non-invasively monitor regional changes in oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) as markers of cerebral metabolic stress in a pilot cohort of children with SCD beginning voxelotor. Our primary objective was to test the hypothesis that voxelotor decreases CBF, OEF, and CMRO2 from pre-treatment levels. We also explored the relationship between CBF, OEF, and CMRO2 and hemoglobin. Methods Children ages 4 to 17 years old with SCD (HbSS or HbS-thalassemia) were enrolled at Children's Healthcare of Atlanta. Participants who met study criteria started open label voxelotor at recommended dose. Participants were monitored prior to treatment initiation, as well as at weeks 4, 8, and 12 weeks. At each study visit, laboratory measurements of anemia (CBC, Retic) and FDNIRS/DCS measurements of regional cerebral blood flow, oxygen extraction fraction, and oxygen metabolism were made (Lee et al., 2022). Transcranial Doppler ultrasound (TCD, middle cerebral artery, internal carotid artery, and carotid bifurcations) along with markers of hemolysis (LDH, T.Bili) were performed at weeks 0 and 12. Paired Wilcoxon signed-rank tests were used to test whether all measures were significantly different from pre-treatment levels. Linear mixed-effects regression models with random-intercept at the patient level were used to examine the association of the relative change in each outcome measure (OEF, CBF, and CMRO2) from pre-treatment levels and delta changes in laboratory data. These models were two-level and accounted for repeated measures nested within each patient. Results Ten of the 12 recruited patients met study criteria. All patients were HbSS on stable dose of hydroxyurea (Table 1). Following initiation of voxelotor, the median (interquartile range, IQR) blood hemoglobin levels increased by 1.2 (0.4, 1.5) g/dL at week 4 (p=0.023); these increases persisted at weeks 8 and 12. Bilirubin was significantly decreased at week 12 (p=0.008), and LDH increased, although the trend was not statistically significant (p=0.24). While TCD velocities were unchanged at week 12, significant decreases in OEF, CBF, and CMRO2 were observed by week 4 (all p < 0.05) that persisted at weeks 8 and 12 (Table 2). Across all time points, relative changes in OEF, CBF, and CMRO2 from pre-treatment levels were inversely associated with changes in hemoglobin (p = 0.0015, 0.071, and 0.020, respectively). Discussion Non-invasive FDNIRS/DCS was used to successfully measure changes in regional cerebral blood flow and oxygen utilization in response to treatment with voxelotor. Results suggest that voxelotor treatment in children with SCD reduces cerebral metabolic stress by improving oxygen delivery to the tissue. Work is ongoing to validate these measurements with MRI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Non-Invasive Optical Characterization of Tissue Hemodynamics in Sickle Cell Patients Undergoing Treatment with Isoquercetin

Sickle Cell Disease (SCD) is an inherited hemoglobin disorder which causes a mutation in the β subunit of hemoglobin (HbA), thus producing hemoglobin S (HbS) (Williams and Thein, 2018). When HbS is deoxygenated, red blood cells (RBC) can polymerize, which promotes increased rigidity and microvascular occlusions. The presence of mutated HbS increases the likelihood of recurrent venous thromboembolism (VTE). There is an unmet need for real-time, non-invasive methods of assessing microvascular hemodynamics and endothelial dysfunction. Near-Infrared Spectroscopy (NIRS), is a non-invasive, optical technique which measures tissue absorption and scattering between 650-1100 nm in subcutaneous tissue. NIRS has the capability to quantitatively measure the concentration of oxy- and deoxy- hemoglobin as well as blood flow. To determine the sensitivity of NIRS to changes in hemodynamics in SCD patients, we evaluated a cohort of SCD patients undergoing treatment with Isoquercetin (IQ), a flavonoid antithrombotic agent, and correlated the findings with D-dimer, a marker for blood clot degradation. We recruited a sub-cohort of 17 of 46 patients participating in a randomized, double-blind, placebo-controlled trial of IQ and performed an optical hemodynamic assessment at baseline and 4 weeks post-treatment. We used the commercial, multi-modal NIRS device (MetaOx, ISS Inc) which combines frequency-domain NIRS (FD-NIRS) and diffuse correlation spectroscopy (DCS) to acquire optical markers of tissue composition and blood flow, respectively. NIRS testing included resting baseline measurements and a brachial cuff occlusion. As seen in Figure 1A, a blood pressure cuff was wrapped around the bicep and the NIRS probe was placed on the ipsilateral forearm muscle. The challenge consisted of a 3-minute baseline, 3-minute cuff occlusion at 200 mmHg, and a 3-minute recovery. The decay constant τc of the intensity autocorrelation function g2(τ), which is an indicator of the bulk displacement of scattering particles (i.e. RBCs) in the forearm, was fitted from the DCS data. We compared the mean τc during the last 30s of the occlusion to D-dimer levels for all 17 patients at baseline and at 4 weeks follow up. Following a data quality review, 8 patients had NIRS data for baseline and follow up visits. D-dimer levels were 1.875 mcg/mL ± 0.869 mcg/mL at baseline and 1.449 mcg/mL ± 0.874 mcg/mL at 4 weeks follow up. Among the 8 patients with good quality data, 5/8 showed an average decrease in τc by 0.424 ms at 4 weeks follow up and an average decrease in D-dimer levels by 0.768 mcg/mL. The patient in Figure 1B showed 42.0% decrease in τc and 46.6% decrease in D-dimer levels from baseline to 4 weeks follow up. 2/8 patients showed an increase in τc by an average of 0.139 ms and an average increase in D-dimer levels by 0.320 mcg/mL. 1/8 patient showed a decrease in the τc with no change in D-dimer levels. We found that 7/8 patients with baseline and follow up visits had matching trends between D-dimer levels and τc. As demonstrated, a larger τc signified less movement of scattering particles, such as RBCs, due to increased blood coagulation. The remaining 9/17 patients had data from one visit of acceptable quality and were excluded from this analysis. The results of this initial analysis demonstrate autocorrelation decay time could be a promising metric that is reflective of blood coagulation and rheology. While this analysis focused on the changes observed in optical blood flow markers, further work will be performed to both expand upon this analysis and to integrate the compositional data acquired from the FD-NIRS portion of the measurements. NIRS can potentially complement traditional blood biomarkers when assessing anti-thrombotic effects of SCD treatments, such as Isoquercetin. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal