Development of parallel forms of a brief smell identification test useful for longitudinal testing.

Although there are numerous brief odor identification tests available for quantifying the ability to smell, none are available in multiple parallel forms that can be longitudinally administered without potential confounding from knowledge of prior test items. Moreover, empirical algorithms for establishing optimal test lengths have not been generally applied. In this study, we employed and compared eight machine learning algorithms to develop a set of four brief parallel smell tests employing items from the University of Pennsylvania Smell Identification Test that optimally differentiated 100 COVID-19 patients from 132 healthy controls. Among the algorithms, linear discriminant analysis (LDA) achieved the best overall performance. The minimum number of odorant test items needed to differentiate smell loss accurately was identified as eight. We validated the sensitivity of the four developed tests, whose means and variances did not differ from one another (Bradley-Blackwood test), by sequential testing an independent group of 32 subjects that included persons with smell dysfunction not due to COVID-19. These eight-item tests clearly differentiated the olfactory compromised subjects from normosmics, with areas under the ROC curve ranging from 0.79 to 0.83. Each test was correlated with the overall UPSIT scores from which they were derived. These brief smell tests can be used separately or sequentially over multiple days in a variety of contexts where longitudinal olfactory testing is needed.

Opportunities and barriers to translating the hibernation phenotype for neurocritical care.

Targeted temperature management (TTM) is standard of care for neonatal hypoxic ischemic encephalopathy (HIE). Prevention of fever, not excluding cooling core body temperature to 33°C, is standard of care for brain injury post cardiac arrest. Although TTM is beneficial, HIE and cardiac arrest still carry significant risk of death and severe disability. Mammalian hibernation is a gold standard of neuroprotective metabolic suppression, that if better understood might make TTM more accessible, improve efficacy of TTM and identify adjunctive therapies to protect and regenerate neurons after hypoxic ischemia brain injury. Hibernating species tolerate cerebral ischemia/reperfusion better than humans and better than other models of cerebral ischemia tolerance. Such tolerance limits risk of transitions into and out of hibernation torpor and suggests that a barrier to translate hibernation torpor may be human vulnerability to these transitions. At the same time, understanding how hibernating mammals protect their brains is an opportunity to identify adjunctive therapies for TTM. Here we summarize what is known about the hemodynamics of hibernation and how the hibernating brain resists injury to identify opportunities to translate these mechanisms for neurocritical care.

Near infrared spectroscopy detection of hemispheric cerebral ischemia following middle cerebral artery occlusion in rats.

Timely and sensitive in vivo estimation of ischemic stroke-induced brain infarction are necessary to guide diagnosis and evaluation of treatments' efficacy. The gold standard for estimation of the cerebral infarction volume is magnetic resonance imaging (MRI), which is expensive and not readily accessible. Measuring regional cerebral blood flow (rCBF) with Laser Doppler flowmetry (LDF) is the status quo for confirming reduced blood flow in experimental ischemic stroke models. However, rCBF reduction following cerebral artery occlusion often does not correlate with subsequent infarct volume. In the present study, we employed the continuous-wave near infrared spectroscopy (NIRS) technique to monitor cerebral oxygenation during 90 min of the intraluminal middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats (n = 8, male). The NIRS device consisted of a controller module and an optical sensor with two LED light sources and two photodiodes making up two parallel channels for monitoring left and right cerebral hemispheres. Optical intensity measurements were converted to deoxyhemoglobin (Hb) and oxyhemoglobin (HbO2) changes relative to a 2-min window prior to MCAO. Area under the curve (auc) for Hb and HbO2 was calculated for the 90-min occlusion period for each hemisphere (ipsilateral and contralateral). To obtain a measure of total ischemia, auc of the contralateral side was subtracted from the ipsilateral side resulting in ΔHb and ΔHbO2 parameters. Infarct volume (IV) was calculated by triphenyl tetrazolium chloride (TTC) staining at 24h reperfusion. Results showed a significant negative correlation (r = -0.81, p = 0.03) between ΔHb and infarct volume. In conclusion, our results show feasibility of using a noninvasive optical imaging instrument, namely NIRS, in monitoring cerebral ischemia in a rodent stroke model. This cost-effective, non-invasive technique may improve the rigor of experimental models of ischemic stroke by enabling in vivo longitudinal assessment of cerebral oxygenation and ischemic injury.

Assessment of cerebral oxygenation response to hemodialysis using near-infrared spectroscopy (NIRS): Challenges and solutions.

To date, the clinical use of functional near-infrared spectroscopy (NIRS) to detect cerebral ischemia has been largely limited to surgical settings, where motion artifacts are minimal. In this study, we present novel techniques to address the challenges of using NIRS to monitor ambulatory patients with kidney disease during approximately eight hours of hemodialysis (HD) treatment. People with end-stage kidney disease who require HD are at higher risk for cognitive impairment and dementia than age-matched controls. Recent studies have suggested that HD-related declines in cerebral blood flow might explain some of the adverse outcomes of HD treatment. However, there are currently no established paradigms for monitoring cerebral perfusion in real-time during HD treatment. In this study, we used NIRS to assess cerebral hemodynamic responses among 95 prevalent HD patients during two consecutive HD treatments. We observed substantial signal attenuation in our predominantly Black patient cohort that required probe modifications. We also observed consistent motion artifacts that we addressed by developing a novel NIRS methodology, called the HD cerebral oxygen demand algorithm (HD-CODA), to identify episodes when cerebral oxygen demand might be outpacing supply during HD treatment. We then examined the association between a summary measure of time spent in cerebral deoxygenation, derived using the HD-CODA, and hemodynamic and treatment-related variables. We found that this summary measure was associated with intradialytic mean arterial pressure, heart rate, and volume removal. Future studies should use the HD-CODA to implement studies of real-time NIRS monitoring for incident dialysis patients, over longer time frames, and in other dialysis modalities.

Near infrared spectroscopy confirms recruitment of specific lumbar extensors through neuromuscular electrical stimulation.

Background: Lumbar multifidus impairments are associated with low back pain (LBP), with sustained impairments thought to contribute to recurrence and chronicity of pain. Ability to regain muscle function can be challenging. While neuromuscular electrical stimulation (NMES) may aid in muscle function recovery, validity of its ability to selectively recruit the lumbar multifidus and provide adequate dosage for muscle overload has not been demonstrated. Near infrared spectroscopy (NIRS) can be used to determine muscle selectivity and overload during NMES and offers advantages over electromyography (EMG), which is affected by electrical interference. Objective: The aim of this study was to determine the ability of NMES to activate and overload the lumbar multifidus in isolation. Methods: EMG and NIRS were collected over the trunk extensors during standardized movements followed by delivery of NMES in 10 healthy participants. NIRS was used to determine the ability of NMES to selectively recruit the lumbar multifidus at the L5 region relative to other trunk extensors. EMG and NIRS data were then entered into a linear regression model to predict muscle activity during NMES relative to the standardized movements. Results: There was a significant correlation (r = 0.81, p < 0.001) between EMG and NIRS in the lumbar multifidus. There was significantly greater activation of lumbar multifidus compared to lumbar erector spinae using specific NMES electrode placement (p < 0.001). Conclusion: NMES can preferentially activate lumbar multifidus with potential to provide a therapeutic overload to these muscles in healthy participants. It may be a promising intervention for individuals with LBP.

Functional near-infrared spectroscopy study on tonic pain activation by cold pressor test.

Functional near-infrared spectroscopy (fNIRS) has recently been suggested for monitoring cortical hemodynamic response to experimental and clinical acute pain. However, the hemodynamic response to a tonic, noxious cold stimulus, and its relation with subjective pain sensation is not fully characterized. We investigated the relationship between pain threshold and tolerance and the evoked hemodynamic response to cold pressor tests (CPTs) at varying intensities and explored the gender effect. Twenty-one healthy individuals (10 males and 11 females) performed four CPTs at 1°C, 5°C, 10°C, and 15°C. Deoxyhemoglobin (HHb) and oxyhemoglobin ([Formula: see text]) were measured continuously on the forehead by two "far" and two "near" channels in addition to pain scores, threshold, and tolerance. We found a significant within-subject correlation between pain threshold and the immediate [Formula: see text] response at the right frontal region. Gender difference and asymmetrical activation were observed in the "far" channels but not the "near" channels, suggesting a hemispheric preference in response to noxious cold stimuli. No gender difference was found in pain threshold, tolerance, or scores. This research adds to the body of literature suggesting the use of fNIRS for bedside assessment of pain in addition to behavioral and subjective measures for comprehensive, multimodal pain management.

Application of functional data analysis in classification and clustering of functional near-infrared spectroscopy signal in response to noxious stimuli.

We introduce the application of functional data analysis (fDA) on functional near-infrared spectroscopy (fNIRS) signals for the development of an accurate and clinically practical assessment method of pain perception. We used the cold pressor test to induce different levels of pain in healthy subjects while the fNIRS signal was recorded from the frontal regions of the brain. We applied fDA on the collected fNIRS data to convert discrete samples into continuous curves. This method enabled us to represent the curves as a linear combination of basis functions. We utilized bases coefficients as features that represent the shape of the signals (as opposed to extracting defined features from signal) and used them to train a support vector machine to classify the signals based on the level of induced pain. We achieved 94% of accuracy to classify low-pain and high-pain signals. Moreover applying hierarchical clustering on the coefficients, we found three clusters in the data which represented low-pain (one cluster) and high-pain groups (two clusters) with an accuracy of 91.2%. The center of these clusters can represent the prototype fNIRS response of that pain level.

Cerebral reactivity in migraine patients measured with functional near-infrared spectroscopy.

BACKGROUND: There are two major theories describing the pathophysiology of migraines. Vascular theory explains that migraines resulted from vasodilation of meningeal vessels irritating the trigeminal nerves and causing pain. More recently, a neural theory of migraine has been proposed, which suggests that cortical hyperexcitability leads to cortical spreading depression (CSD) causing migraine-like symptoms. Chronic migraine requires prophylactic therapy. When oral agents fail, there are several intravenous agents that can be used. Understanding underlying causes of migraine pain would help to improve efficacy of migraine medications by changing their mechanism of action. Yet to date no study has been made to investigate the link between vascular changes in response to medications for migraine versus pain improvements. Functional near-infrared spectroscopy (NIRS) has been used as an inexpensive, rapid, non-invasive and safe technique to monitor cerebrovascular dynamics. METHOD: In this study, a multi-distance near-infrared spectroscopy device has been used to investigate the cortical vascular reactivity of migraine patients in response to drug infusions and its possible correlation with changes in pain experienced. We used the NIRS on 41 chronic migraine patients receiving three medications: magnesium sulfate, valproate sodium, and dihydroergotamine (DHE). Patients rated their pain on a 1-10 numerical scale before and after the infusion. RESULTS: No significant differences were observed between the medication effects on vascular activity from near channels measuring skin vascularity. However, far channels--indicating cortical vascular activity--showed significant differences in both oxyhemoglobin and total hemoglobin between medications. DHE is a vasoconstrictor and decreased cortical blood volume in our experiment. Magnesium sulfate has a short-lived vasodilatory effect and increased cortical blood volume in our experiment. Valproate sodium had no significant effect on blood volume. Nonetheless, all three reduced patients' pain based on self-report and no significant link was observed between changes in cortical vascular reactivity and improvement in migraine pain as predicted by the vascular theory of migraine. CONCLUSION: NIRS showed the potential to be a useful tool in the clinical setting for monitoring the vascular reactivity of individual patients to various migraine and headache medications.

Functional data analysis view of functional near infrared spectroscopy data.

Functional near infrared spectroscopy (fNIRS) is a powerful tool for the study of oxygenation and hemodynamics of living tissues. Despite the continuous nature of the processes generating the data, analysis of fNIRS data has been limited to discrete-time methods. We propose a technique, namely functional data analysis (fDA), that converts discrete samples to continuous curves. We used fNIRS data collected on forehead during a cold pressor test (CPT) from 20 healthy subjects. Using functional principal component analysis, oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) curves were decomposed into several components based on variability across the subjects. Each component corresponded to an experimental condition and provided qualitative and quantitative information of the shape and weight of that component. Furthermore, we applied functional canonical correlation analysis to investigate the interaction between Hb and HbO2 curves. We showed that the variation of Hb and HbO2 was positively correlated during the CPT, with a "far" channel on right forehead showing a smaller and faster HbO2 variation than Hb. This research suggests the fDA platform for the analysis of fNIRS data, which solves problem of high dimensionality, enables study of response dynamics, enhances characterization of the evoked response, and may improve design of future fNIRS experiments.

Accurate optical parameter extraction procedure for broadband near-infrared spectroscopy of brain matter.

Modeling behavior of broadband (30 to 1000 MHz) frequency modulated near-infrared (NIR) photons through a phantom is the basis for accurate extraction of optical absorption and scattering parameters of biological turbid media. Photon dynamics in a phantom are predicted using both analytical and numerical simulation and are related to the measured insertion loss (IL) and insertion phase (IP) for a given geometry based on phantom optical parameters. Accuracy of the extracted optical parameters using finite element method (FEM) simulation is compared to baseline analytical calculations from the diffusion equation (DE) for homogenous brain phantoms. NIR spectroscopy is performed using custom-designed, broadband, free-space optical transmitter (Tx) and receiver (Rx) modules that are developed for photon migration at wavelengths of 680, 780, and 820 nm. Differential detection between two optical Rx locations separated by 0.3 cm is employed to eliminate systemic artifacts associated with interfaces of the optical Tx and Rx with the phantoms. Optical parameter extraction is achieved for four solid phantom samples using the least-square-error method in MATLAB (for DE) and COMSOL (for FEM) simulation by fitting data to measured results over broadband and narrowband frequency modulation. Confidence in numerical modeling of the photonic behavior using FEM has been established here by comparing the transmission mode's experimental results with the predictions made by DE and FEM for known commercial solid brain phantoms.

Hemodynamic response to repeated noxious cold pressor tests measured by functional near infrared spectroscopy on forehead.

The objective of this research was to assess the utility of a simple near infrared spectroscopy (NIRS) technology for objective assessment of the hemodynamic response to acute pain. For this exploration, we used functional near infrared spectroscopy (fNIRS) to measure the hemodynamic response on the forehead during three trials of a cold pressor test (CPT) in 20 adults. To measure hemodynamic changes at the superficial tissues as well as the intracranial tissues, two configurations of 'far' and 'near' source-detector separations were used. We identified two features that were found to be fairly consistent across all subjects. The first feature was the change of total hemoglobin (THb) concentration in a given condition divided by the duration of that condition [Formula: see text]. Statistical analyses revealed that during the first CPT trial [Formula: see text] significantly changed from its baseline value in all channels. Also, adaptation to repeated CPTs was observed in both [Formula: see text] parameter and the reported post-stimulus pain rating scores. The second feature was the difference between the maximum and the minimum of the evoked changes in the THb concentration (ΔTHb). A significant correlation was observed between the post-stimulus pain rating score and ΔTHb at all channels. An asymmetrical activity was observed only at the 'far' channels. These results suggest that fNIRS can potentially be used as a reliable technique for the assessment of the hemodynamic response to tonic pain induced by the CPT.

Highly sensitive detection of HER2 extracellular domain in the serum of breast cancer patients by piezoelectric microcantilevers.

Rapid and sensitive detection of serum tumor biomarkers are needed to monitor cancer patients for disease progression. Highly sensitive piezoelectric microcantilever sensors (PEMS) offer an attractive tool for biomarker detection; however, their utility in the complex environment encountered in serum has yet to be determined. As a proof of concept, we have functionalized PEMS with antibodies that specifically bind to HER2, a biomarker (antigen) that is commonly overexpressed in the blood of breast cancer patients. The function and sensitivity of these anti-HER2 PEMS biosensors was initially assessed using recombinant HER2 spiked into human serum. Their ability to detect native HER2 present in the serum of breast cancer patients was then determined. We have found that the anti-HER2 PEMS were able to accurately detect both recombinant and naturally occurring HER2 at clinically relevant levels (>2 ng/mL). This indicates that PEMS-based biosensors provide a potentially effective tool for biomarker detection.

A rapid method to regenerate piezoelectric microcantilever sensors (PEMS).

Piezoelectric microcantilever sensors (PEMS) can be sensitive tools for the detection of proteins and cells in biological fluids. However, currently available PEMS can only be used a single time or must be completely stripped and refunctionalized prior to subsequent uses. Here we report the successful use of an alternative regeneration protocol employing high salt concentrations to remove the target, leaving the functional probe immobilized on the microcantilever surface. Our model system employed the extracellular domain (ECD) of recombinant human Epidermal Growth Factor Receptor (EGFR) as the probe and anti-human EGFR polyclonal antibodies as the target. We report that high concentrations of MgCl2 dissociated polyclonal antibodies specifically bound to EGFR ECD immobilized on the sensor surface without affecting its bioactivity. This simple regeneration protocol both minimized the time required to re-conjugate the probe and preserved the density of probe immobilized on PEMS surface, yielding identical biosensor sensitivity over a series of assays.

Near infrared wound monitor helps clinical assessment of diabetic foot ulcers.

BACKGROUND: The efficacy of using diffuse near infrared spectroscopy (NIRS) in predicting wound healing in diabetic foot ulcers was demonstrated by conducting a pilot human study. METHOD: Sixteen chronic diabetic wounds were followed and assessed for subsurface oxyhemoglobin concentration using the NIRS device. Weekly measurements were conducted until there was wound closure, limb amputation, or 20 completed visits without healing. Wound size and degree of wound contraction were measured by image analysis of digital photographs, and results were compared to NIRS results. RESULTS: In the 16 patients followed, seven wounds healed, six limbs were amputated, and three wounds remained opened after 20 visits. Initial values of subsurface hemoglobin concentration, in all wounds, were higher than in nonwound control sites. Healed wounds exhibited a consistent reduction of hemoglobin concentration several weeks prior to closure, and the absolute hemoglobin concentration approached the value at the control site. In wounds that did not heal or ended in amputations, the hemoglobin concentration remained elevated throughout the study. A negative slope for the rate of change of hemoglobin concentration was indicative of healing across all wounds. CONCLUSIONS: Evaluation of diabetic foot ulcers using NIRS may provide an effective and more complete measurement of wound healing compared to current clinical approaches.

Prediction of wound healing in human diabetic foot ulcers by diffuse near-infrared spectroscopy: a pilot study.

A human study was conducted in which the efficacy of in vivo diffuse near-infrared (NIR) spectroscopy was demonstrated in predicting wound healing in diabetic foot ulcers. Sixteen chronic diabetic wounds were followed and assessed for subsurface oxy-hemoglobin concentration using the NIR device. Weekly measurements were conducted until there was wound closure, limb amputation, or 20 completed visits without healing. Digital photography measured wound size, and the degree of wound contraction was compared with the NIR results. In the 16 patients followed, seven wounds healed, six limbs were amputated, and three wounds remained opened after 20 visits. The initial values in subsurface hemoglobin concentration in all wounds were higher than the nonwound control sites. Healed wounds showed a consistent reduction of hemoglobin concentration several weeks before closure that approached control site values. In wounds that did not heal or resulted in amputation of the limb, the hemoglobin concentration remained elevated. In some cases, these nonhealing wounds appeared to be improving clinically. A negative slope for the rate of change of hemoglobin concentration was indicative of healing across all wounds. In conclusion, evaluation of wounds using NIR may provide an effective measurement of wound healing. NIR spectroscopy can determine wound healing earlier than that visibly assessed by current clinical approaches.

Array lead zirconate titanate/glass piezoelectric microcantilevers for real-time detection of Bacillus anthracis with 10 spores/ml sensitivity and 1/1000 selectivity in bacterial mixtures.

An array of three identical piezoelectric microcantilever sensors (PEMSs) consisting of a lead zirconate titanate layer bonded to a glass layer was fabricated and examined for simultaneous, in situ, real-time, all-electrical detection of Bacillus anthracis (BA) spores in an aqueous suspension using the first longitudinal extension mode of resonance. With anti-BA antibody immobilized on the sensor surfaces all three PEMS exhibited identical BA detection resonance frequency shifts at all tested concentrations, 10-10(7) spores/ml with a standard deviation of less than 10%. The detection concentration limit of 10 spores/ml was about two orders of magnitude lower than would be permitted by flexural peaks. In blinded-sample testing, the array PEMS detected BA in three samples containing BA: (1) 3.3x10(3) spores/ml, (2) a mixture of 3.3x10(3) spores/ml and 3.3x10(5) S. aureus (SA) and P. aeruginosa (PA) per ml, and (3) a mixture of 3.3x10(3) spores/ml with 3.3x10(6) SA+PA/ml. There was no response to a sample containing only 3.3x10(6) SA+PA/ml. These results illustrate the sensitivity, specificity, reusability, and reliability of array PEMS for in situ, real-time detection of BA spores.

Noninvasive assessment of diabetic foot ulcers with diffuse photon density wave methodology: pilot human study.

A pilot human study is conducted to evaluate the potential of using diffuse photon density wave (DPDW) methodology at near-infrared (NIR) wavelengths (685 to 830 nm) to monitor changes in tissue hemoglobin concentration in diabetic foot ulcers. Hemoglobin concentration is measured by DPDW in 12 human wounds for a period ranging from 10 to 61 weeks. In all wounds that healed completely, gradual decreases in optical absorption coefficient, oxygenated hemoglobin concentration, and total hemoglobin concentration are observed between the first and last measurements. In nonhealing wounds, the rates of change of these properties are nearly zero or slightly positive, and a statistically significant difference (p<0.05) is observed in the rates of change between healing and nonhealing wounds. Differences in the variability of DPDW measurements over time are observed between healing and nonhealing wounds, and this variance may also be a useful indicator of nonhealing wounds. Our results demonstrate that DPDW methodology with a frequency domain NIR device can differentiate healing from nonhealing diabetic foot ulcers, and indicate that it may have clinical utility in the evaluation of wound healing potential.

Changes in optical properties of tissue during acute wound healing in an animal model.

Changes of optical properties of wound tissue in hairless rats were quantified by diffuse photon density wave methodology at near-infrared frequencies. The diffusion equation for semi-infinite media was used to calculate the absorption and scattering coefficients based on measurements of phase and amplitude with a frequency domain device. There was an increase in the absorption and scattering coefficients and a decrease in blood saturation of the wounds compared with the nonwounded sites. The changes correlated with the healing stage of the wound. The data obtained were supported by immunohistochemical analysis of wound tissue. These results verified now by two independent animal studies could suggest a noninvasive method to detect the progress of wound healing.

Correlation of near infrared absorption and diffuse reflectance spectroscopy scattering with tissue neovascularization and collagen concentration in a diabetic rat wound healing model.

The objective of this paper was to correlate optical changes of tissue during wound healing measured by near infrared (NIR) and diffuse reflectance spectroscopy (DRS) with histologic changes in an animal model. Amplitude and phase of scattered light were obtained in a diabetic rat and control model and biopsies were taken for blood vessel ingrowth and collagen concentration. NIR absorption coefficient correlated with blood vessel ingrowth over time, in both the control and diabetic animals. DRS data correlated with collagen concentration. Previous publications by this group documented only the NIR changes during the wound healing process but this is the first reported correlation with histology data. The ability to correlate DRS scattering with collagen concentration during healing is another important and novel finding. This technology may play an important role clinically in assessing the efficacy of wound healing agents in diabetics.