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Duchenne muscular dystrophy (DMD) is an X-linked debilitating muscular disease that may decrease nitric oxide (NO) production and lead to functional muscular ischemia. Currently, the 6-minute walk test (6-MWT) and the North Star Ambulatory Assessment (NSAA) are the primary outcome measures in clinical trials, but they are severely limited by the subjective consciousness and mood of patients, and can only be used in older and ambulatory boys. This study proposed using functional near-infrared spectroscopy (fNIRS) to evaluate the dynamic changes in muscle hemodynamic responses (gastrocnemius and forearm muscle) during a 6-MWT and a venous occlusion test (VOT), respectively. Muscle oxygenation of the forearm was evaluated non-invasively before, during and after VOT in all participants (included 30 DMD patients and 30 age-matched healthy controls), while dynamic muscle oxygenation of gastrocnemius muscle during 6-MWT was determined in ambulatory participants (n = 18) and healthy controls (n = 30). The results reveal that impaired muscle oxygenation was observed during 6-MWT in DMD patients that may explain why the DMD patients walked shorter distances than healthy controls. Moreover, the results of VOT implied that worsening muscle function was associated with a lower supply of muscle oxygenation and may provide useful information on the relationship between muscular oxygen consumption and supply for the clinical diagnosis of DMD. Therefore, the method of fNIRS with VOT possesses great potential in future evaluations of DMD patients that implies a good feasibility for clinical application such as for monitoring disease severity of DMD.
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Visible-light optical coherence tomography (vis-OCT) enables retinal oximetry by measuring the oxygen saturation of hemoglobin (sO2) from within individual retinal blood vessels. The sO2 calculation requires reliable estimation of the true spectrum of backscattered light from the posterior vessel wall. Unfortunately, subject motion and image noise make averaging from multiple A-lines at the same depth position challenging, and lead to inaccurate sO2 estimation. In this study, we developed an algorithm to reliably extract the backscattered light's spectrum. We used circumpapillary scanning to sample the vessels repeatedly at the same location. A combination of cross-correlation and graph-search based segmentation extracted the posterior wall locations. Using measurements from 100 B-scans as a gold standard, we demonstrated that our method achieved highly accurate measures of sO2 with minimal bias. In addition, we also investigated how the number of repeated measurements affects the accuracy of sO2 measurement. Our method sets the stage for large-scale studies of retinal oxygenation in animals and humans.
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A novel analysis of the spatial complexity of functional connectivity (SCFC) was proposed to investigate the spatial complexity of multiple dynamic functional connectivity series in an fNIRS study, using an approach combining principal component analysis and normalized entropy. The analysis was designed to describe the complex spatial features of phase synchrony based dynamic functional connectivity (dFC), which are unexplained in traditional approaches. The feasibility and validity of this method were verified in a sample of young patients with autism spectrum disorders (ASD). Our results showed that there were information exchange deficits in the right prefrontal cortex (PFC) of children with ASD, with markedly higher interregion SCFCs between the right PFC and other brain regions than those of normal controls. Furthermore, the global SCFC was significantly higher in young patients with ASD, along with considerably higher intraregion SCFCs in the prefrontal and temporal lobes which represents more diverse information exchange in these areas. The study suggests a novel method to analyze the fNIRS required dynamic hemoglobin concentrations by using concepts of SCFC. Moreover, the clinical results extend our understanding of ASD pathology, suggesting the crucial role of the right PFC during the information exchange process.
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Functional near-infrared spectroscopy (fNIRS) is a fast-developing non-invasive functional brain imaging technology widely used in cognitive neuroscience, clinical research and neural engineering. However, it is a challenge to effectively remove the global physiological noise in the fNIRS signal. The global physiological noise in fNIRS arises from multiple physiological origins in both superficial tissues and the brain. It has complex temporal, spatial and frequency characteristics, casting significant influence on the results. In the present study, we developed a novel wavelet-based method for fNIRS global physiological noise removal. The method is data-driven and does not rely on any additional hardware or subjective noise component selection procedure. It consists of two steps. Firstly, we use wavelet transform coherence to automatically detect the time-frequency points contaminated by the global physiological noise. Secondly, we decompose the fNIRS signal by using the wavelet transform, and then suppress the wavelet energy of the contaminated time-frequency points. Finally, we transform the signal back to a time series. We validated the method by using simulation and real data at both task- and resting-state. The results showed that our method can effectively remove the global physiological noise from the fNIRS signal and improve the spatial specificity of the task activation and the resting-state functional connectivity pattern.
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Optical imaging of brain activity has mostly employed genetically manipulated mice, which cannot be translated to clinical human usage. Observation of brain activity directly is challenging due to the difficulty in delivering dyes and other agents through the blood brain barrier (BBB). Using fluorescence imaging, we have demonstrated the feasibility of delivering the near-infrared voltage-sensitive dye (VSD) IR-780 perchlorate to the brain tissue through pharmacological techniques, via an adenosine agonist (regadenoson). Comparison of VSD fluorescence of mouse brains without and with regadenoson showed significantly increased residence time of the fluorescence signal in the latter case, indicative of VSD diffusion into the brain tissue. Dose and timing of regadenoson were varied to optimize BBB permeability for VSD delivery.
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In the present paper we propose an implementation of the Kalman filter algorithm, which allows simultaneous recovery of the absorption coefficient, the reduced scattering coefficient and the thicknesses of multi-layered turbid media, with the deepest layer taken as semi-infinite. The approach is validated by both Monte Carlo simulations and experiments, showing good results in structures made up of four layers. As it is a Bayesian algorithm, prior knowledge can be included to improve the accuracy of the retrieved unknowns. One of the most promising applications of this approach is the capability of real-time monitoring of living organs by near infrared spectroscopy. In particular, determination of blood perfusion in the adult head is one of the desired goals, allowing continuous control of stroke patients. This demands accurate measurement of the optical properties, especially absorption, of the head layers, from scalp to the cortex.
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[This corrects the article on p. 543 in vol. 9, PMID: 29552392.].
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The purpose of this study is to investigate cerebral cortex activation during active movement and passive movement by using a functional near-infrared spectroscopy (fNIRS). Tasks were the flexion/extension of the right hand finger by active movement and passive movement. Oxy-hemoglobin concentration changes calculated from fNIRS and analyzed the activation and connectivity so as to understand dynamical brain relationship. The results demonstrated that the brain activation in passive movements is similar to motor execution. During active movement, the estimated causality patterns showed significant causality value from the supplementary motor area (SMA) to the primary motor cortex (M1). During the passive movement, the causality from the primary somatosensory cortex (S1) to the primary motor cortex (M1) was stronger than active movement. These results demonstrated that active and passive movements had a direct effect on the cerebral cortex but the stimulus pathway of active and passive movement is different. This study may contribute to better understanding how active and passive movements can be expressed into cortical activation by means of fNIRS.
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Widefield optical imaging of neuronal populations over large portions of the cerebral cortex in awake behaving animals provides a unique opportunity for investigating the relationship between brain function and behavior. In this paper, we demonstrate that the temporal characteristics of calcium dynamics obtained through widefield imaging can be utilized to infer the corresponding behavior. Cortical activity in transgenic calcium reporter mice (n=6) expressing GCaMP6f in neocortical pyramidal neurons is recorded during active whisking (AW) and no whisking (NW). To extract features related to the temporal characteristics of calcium recordings, a method based on visibility graph (VG) is introduced. An extensive study considering different choices of features and classifiers is conducted to find the best model capable of predicting AW and NW from calcium recordings. Our experimental results show that temporal characteristics of calcium recordings identified by the proposed method carry discriminatory information that are powerful enough for decoding behavior.
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We created an auto-para viewer, an autofluorescence imaging device, to localize the parathyroid glands during thyroidectomy using an inexpensive Raspberry Pi. A special emission filter in the auto-para viewer was designed to pass 1/100 of visible light and nearly all infrared light longer than 808 nm. With this emission filter, we simultaneously acquired an autofluorescence image of the parathyroid and a visible light image of the surrounding surgical field. The auto-para viewer displayed four times brighter autofluorescence of the parathyroid glands compared to the background tissues without operating room light. Additionally, it showed two times brighter autofluorescence than the background tissues simultaneously showing the surgical field illuminated by the visible light from the operating room light. The NOIR camera, using the auto-para viewer, could reduce the camera's exposure time so the parathyroid glands to be viewed in real-time, which is expected to prevent unintentional damage to the parathyroid gland during thyroidectomy.
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Accurate, quantitative assessment of retinal blood oxygen saturation (sO2 ) may provide a useful early indicator of pathophysiology in several ocular diseases. Here, with visible-light optical coherence tomography (OCT), we demonstrate an automated spectroscopic retinal oximetry algorithm to measure the sO2 within the retinal arteries (A-sO2 ) and veins (V-sO2 ) in rats by automatically detecting the vascular posterior boundary on cross-sectional structural OCT. The algorithm was validated in vitro with flow phantoms and in vivo in rats by comparing the sO2 results, respectively, to those obtained using a blood gas analyzer and pulse oximetry. We also investigated the response of oxygen extraction (A-V sO2 ), including inter-session reproducibility, at different inhaled oxygen concentrations.
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Light sheet fluorescence microscopy offers considerable potential to the cellular neuroscience community as it makes it possible to image extensive areas of neuronal structures, such as axons or dendrites, with a low light budget, thereby minimizing phototoxicity. However, the shallow depth of a light sheet, which is critical for achieving high contrast, well resolved images, adds a significant challenge if fast functional imaging is also required, as multiple images need to be collected across several image planes. Consequently, fast functional imaging of neurons is typically restricted to a small tissue volume where part of the neuronal structure lies within the plane of a single image. Here we describe a method by which fast functional imaging can be achieved across a much larger tissue volume; a custom-built light sheet microscope is presented that includes a synchronized galvo mirror and electrically tunable lens, enabling high speed acquisition of images across a configurable depth. We assess the utility of this technique by acquiring fast functional Ca2+ imaging data across a neuron's dendritic arbour in mammalian brain tissue.
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The high rate of drug attrition caused by cardiotoxicity is a major challenge for drug development. Here, we developed a reflective lens-free imaging (RLFI) approach to non-invasively record in vitro cell deformation in cardiac monolayers with high temporal (169 fps) and non-reconstructed spatial resolution (352 µm) over a field-of-view of maximally 57 mm2. The method is compatible with opaque surfaces and silicon-based devices. Further, we demonstrated that the system can detect the impairment of both contractility and fast excitation waves in cardiac monolayers. Additionally, the RLFI device was implemented on a CMOS-based microelectrode array to retrieve multi-parametric information of cardiac cells, thereby offering more in-depth analysis of drug-induced (cardiomyopathic) effects for preclinical cardiotoxicity screening applications.
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Dynamic optical data from a series of sampling intervals can be used for quantitative analysis to obtain meaningful kinetic parameters of probe in vivo. The sampling schemes may affect the quantification results of dynamic fluorescence imaging. Here, we investigate the influence of different sampling schemes on the quantification of binding potential (BP) with theoretically simulated and experimentally measured data. Three groups of sampling schemes are investigated including the sampling starting point, sampling sparsity, and sampling uniformity. In the investigation of the influence of the sampling starting point, we further summarize two cases by considering the missing timing sequence between the probe injection and sampling starting time. Results show that the mean value of BP exhibits an obvious growth trend with an increase in the delay of the sampling starting point, and has a strong correlation with the sampling sparsity. The growth trend is much more obvious if throwing the missing timing sequence. The standard deviation of BP is inversely related to the sampling sparsity, and independent of the sampling uniformity and the delay of sampling starting time. Moreover, the mean value of BP obtained by uniform sampling is significantly higher than that by using the non-uniform sampling. Our results collectively suggest that a suitable sampling scheme can help compartmental modeling of dynamic fluorescence imaging provide more accurate results and simpler operations.
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Multiscale entropy (MSE) analysis is a novel entropy-based analysis method for quantifying the complexity of dynamic neural signals and physiological systems across multiple temporal scales. This approach may assist in elucidating the pathophysiologic mechanisms of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). Using resting-state fNIRS imaging, we recorded spontaneous brain activity from 31 healthy controls (HC), 27 patients with aMCI, and 24 patients with AD. The quantitative analysis of MSE revealed that reduced brain signal complexity in AD patients in several networks, namely, the default, frontoparietal, ventral and dorsal attention networks. For the default and ventral attention networks, the MSE values also showed significant positive correlations with cognitive performances. These findings demonstrated that the MSE-based analysis method could serve as a novel tool for fNIRS study in characterizing and understanding the complexity of abnormal cortical signals in AD cohorts.
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Understanding how neural circuits control behavior requires monitoring a large population of neurons with high spatial resolution and volume rate. Here we report an axicon-based Bessel beam module with continuously adjustable depth of focus (CADoF), that turns frame rate into volume rate by extending the excitation focus in the axial direction while maintaining high lateral resolutions. Cost-effective and compact, this CADoF Bessel module can be easily integrated into existing two-photon fluorescence microscopes. Simply translating one of the relay lenses along its optical axis enabled continuous adjustment of the axial length of the Bessel focus. We used this module to simultaneously monitor activity of spinal projection neurons extending over 60 µm depth in larval zebrafish at 50 Hz volume rate with adjustable axial extent of the imaged volume.
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Measurement of sub-clinical atopic dermatitis (AD) is important for determining how long therapies should be continued after clinical clearance of visible AD lesions. An important biomarker of sub-clinical AD is epidermal hypertrophy, the structural measures of which often make optical coherence tomography (OCT) challenging due to the lack of a clearly delineated dermal-epidermal junction in AD patients. Alternatively, angiographic OCT measurements of vascular depth and morphology may represent a robust biomarker for quantifying the severity of clinical and sub-clinical AD. To investigate this, angiographic data sets were acquired from 32 patients with a range of AD severities. Deeper vascular layers within skin were found to correlate with increasing clinical severity. Furthermore, for AD patients exhibiting no clinical symptoms, the superficial plexus depth was found to be significantly deeper than healthy patients at both the elbow (p = 0.04) and knee (p<0.001), suggesting that sub-clinical changes in severity can be detected. Furthermore, the morphology of vessels appeared altered in patients with severe AD, with significantly different vessel diameter, length, density and fractal dimension. These metrics provide valuable insight into the sub-clinical severity of the condition, allowing the effects of treatments to be monitored past the point of clinical remission.
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Focused ultrasound (FUS) in combination with microbubbles temporally and locally increases the permeability of the blood-brain barrier (BBB) for facilitating drug delivery. However, the temporary effects of FUS on the brain microstructure and microcirculation need to be addressed. We used label-free optical coherence tomography (OCT) and OCT angiography (OCTA) to investigate the morphological and microcirculation changes in mouse brains due to FUS exposure at different power levels. Additionally, the recovery progress of the induced effects was studied. The results show that FUS exposure causes cerebral vessel dilation and can be identified and quantitatively analyzed via OCT/OCTA. Micro-hemorrhages can be detected when an excessive FUS exposure power is applied, causing the degradation of OCTA signal owing to strong scattering by leaked red blood cells (RBCs) and weaker backscattered intensity from RBCs in vessels. The vessel dilation effect due to FUS exposure was found to abate in several hours. This study demonstrates that the FUS-induced cerebral transiently dilated effects can be in-vivo differentiated and monitored with OCTA, and shows the feasibility of using OCT/OCTA as a novel tool for long-time monitoring of cerebral vascular dynamics during FUS-BBB opening process.
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Vascular supply is a critical component of the tumor microenvironment (TME) and is essential for tumor growth and metastasis, yet the endogenous genetic modifiers that impact vascular function in the TME are largely unknown. To identify the host TME modifiers of tumor vascular function, we combined a novel genetic mapping strategy [Consomic Xenograft Model] with near-infrared (NIR) fluorescence imaging and multiparametric analysis of pharmacokinetic modeling. To detect vascular flow, an intensified cooled camera based dynamic NIR imaging system with 785 nm laser diode based excitation was used to image the whole-body fluorescence emission of intravenously injected indocyanine green dye. Principal component analysis was used to extract the spatial segmentation information for the lungs, liver, and tumor regions-of-interest. Vascular function was then quantified by pK modeling of the imaging data, which revealed significantly altered tissue perfusion and vascular permeability that were caused by host genetic modifiers in the TME. Collectively, these data demonstrate that NIR fluorescent imaging can be used as a non-invasive means for characterizing host TME modifiers of vascular function that have been linked with tumor risk, progression, and response to therapy.
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Myocardial infarction (MI) leads to cardiomyocyte loss, impaired cardiac function, and heart failure. Molecular genetic analyses of myocardium in mouse models of ischemic heart disease have provided great insight into the mechanisms of heart regeneration, which is promising for novel therapies after MI. Although biomechanical factors are considered an important aspect in cardiomyocyte proliferation, there are limited methods for mechanical assessment of the heart in the mouse MI model. This prevents further understanding the role of tissue biomechanics in cardiac regeneration. Here we report optical coherence elastography (OCE) of the mouse heart after MI. Surgical ligation of the left anterior descending coronary artery was performed to induce an infarction in the heart. Two OCE methods with assessment of the direction-dependent elastic wave propagation and the spatially resolved displacement damping provide complementary analyses of the left ventricle. In comparison with sham, the infarcted heart features a fibrotic scar region with reduced elastic wave velocity, decreased natural frequency, and less mechanical anisotropy at the tissue level at the sixth week post-MI, suggesting lower and more isotropic stiffness. Our results indicate that OCE can be utilized for nondestructive biomechanical characterization of MI in the mouse model, which could serve as a useful tool in the study of heart repair.