Patients' perceptions on outcomes after mechanical thrombectomy in acute ischemic stroke.

BACKGROUND: The modified Rankin Scale (mRS) is a clinician-reported scale that measures the degree of disability in patients who suffered a stroke. Patients' perception of a meaningful recovery from severe stroke, expected value of a stroke intervention, and the effect of disparities are largely unknown. METHODS: We conducted a survey of patients, their family members, and accompanying visitors to understand their personal preferences and expectations for acute strokes potentially eligible for acute endovascular intervention using a hypothetical scenario of a severe stroke in a standardized questionnaire. RESULTS: Of 164 survey respondents, 65 (39.6%) were the patient involved, 93 (56.7%) were a family member, and six (3.7%) were accompanied visitors (friends, other). Minimally acceptable disability after a stroke intervention was considered as mRS 2 by 42 respondents (25.6%), as mRS 3 by 79 (48.2%), and as mRS 4 by 43 (26.2%) respondents. Race was associated with different views on this question (p < 0.001; Hispanic and Black patients being more likely to accept disability than Caucasian and Asian patients), while sex (p = 0.333) and age (p = 0.560) were not. Sixty-three respondents (38.4%) viewed minimally acceptable probability of improvement with an intervention as over 50%, 57 (34.8%) as 10-50%, and 44 (26.8%) as less than 10%. CONCLUSIONS: A wide range of acceptable outcomes were reported regardless of gender or age. However, race was associated with different acceptable outcome. This is an important finding to demonstrate because of the persistent racial and ethnic disparities in the utilization of endovascular therapy for acute stroke in the United States.

Preliminary experience with diffuse correlation spectroscopy in acute ischemic stroke neurointerventional procedures.

BACKGROUND: Diffuse correlation spectroscopy (DCS) is a non-invasive optical technique that enables continuous blood flow measurements in various organs, including the brain. DCS quantitatively measures blood flow from temporal fluctuations in the intensity of diffusely reflected light caused by the dynamic scattering of light from moving red blood cells within the tissue. METHODS: We performed bilateral cerebral blood flow (CBF) measurements using a custom DCS device in patients undergoing neuroendovascular interventions for acute ischemic stroke. Experimental, clinical, and imaging data were collected in a prospective manner. RESULTS: The device was successfully applied in nine subjects. There were no safety concerns or interference with the standard angiography suite or intensive care unit workflow. Six cases were selected for final analysis and interpretation. DCS measurements with photon count rates greater than 30 KHz had sufficient signal-to-noise to resolve blood flow pulsatility. We found an association between angiographic changes in cerebral reperfusion (partial or complete reperfusion established in stroke thrombectomy cases; temporary flow arrest during carotid artery stenting) and those observed intraprocedurally with CBF measurements via DCS. Limitations of the current technology included sensitivity to the interrogated tissue volume under the probe and the effect of local changes in tissue optical properties on the accuracy of CBF estimates. CONCLUSION: Our initial experience with DCS in neurointerventional procedures showed the feasibility of this non-invasive approach in providing continuous measurement of regional CBF brain tissue properties.

Dynamic cerebral autoregulation measured by diffuse correlation spectroscopy.

Dynamic cerebral autoregulation (dCA) can be derived from spontaneous oscillations in arterial blood pressure (ABP) and cerebral blood flow (CBF). Transcranial Doppler (TCD) measures CBF-velocity and is commonly used to assess dCA. Diffuse correlation spectroscopy (DCS) is a promising optical technique for non-invasive CBF monitoring, so here we aimed to validate DCS as a tool for quantifying dCA. In 33 healthy adults and 17 acute ischemic stroke patients, resting-state hemodynamic were monitored simultaneously with high-speed (20 Hz) DCS and TCD. dCA parameters were calcaulated by a transfer function analysis using a Fourier decomposition of ABP and CBF (or CBF-velocity). Strong correlation was found between DCS and TCD measured gain (magnitude of regulation) in healthy volunteers (r = 0.73, p < 0.001) and stroke patients (r = 0.76, p = 0.003). DCS-gain retained strong test-retest reliability in both groups (ICC 0.87 and 0.82, respectively). DCS and TCD-derived phase (latency of regulation) did not significantly correlate in healthy volunteers (r = 0.12, p = 0.50) but moderately correlated in stroke patients (r = 0.65, p = 0.006). DCS-derived phase was reproducible in both groups (ICC 0.88 and 0.90, respectively). High-frequency DCS is a promising non-invasive bedside technique that can be leveraged to quantify dCA from resting-state data, but the discrepancy between TCD and DCS-derived phase requires further investigation.

Non-invasive low-cost deep tissue blood flow measurement with integrated Diffuse Speckle Contrast Spectroscopy.

Diffuse Correlation Spectroscopy (DCS) is a widely used non-invasive measurement technique to quantitatively measure deep tissue blood flow. Conventional implementations of DCS use expensive single photon counters as detecting elements and optical probes with bulky fiber optic cables. In recent years, newer approaches to blood flow measurement such as Diffuse Speckle Contrast Analysis (DSCA) and Speckle Contrast Optical Spectroscopy (SCOS), have adapted speckle contrast analysis methods to simplify deep tissue blood flow measurements using cameras and single photon counting avalanche detector arrays as detectors. Here, we introduce and demonstrate integrated Diffuse Speckle Contrast Spectroscopy (iDSCS), a novel optical sensor setup which leverages diffuse speckle contrast analysis for probe-level quantitative measurement of tissue blood flow. iDSCS uses a standard photodiode configured in photovoltaic mode to integrate photon intensity fluctuations over multiple integration durations using a custom electronic circuit, as opposed to the high frequency sampling of photon counts with DCS. We show that the iDSCS device is sensitive to deep-tissue blood flow measurements with experiments on a human forearm and compare the sensitivity and dynamic range of the device to a conventional DCS instrument. The iDSCS device features a low-cost, low-power, small form factor instrument design that will enable wireless probe-level measurements of deep tissue blood flow.

Real-time tracking of brain oxygen gradients and blood flow during functional activation.

Significance: Cerebral metabolic rate of oxygen ( CMRO 2 ) consumption is a key physiological variable that characterizes brain metabolism in a steady state and during functional activation. Aim: We aim to develop a minimally invasive optical technique for real-time measurement of CMRO 2 concurrently with cerebral blood flow (CBF). Approach: We used a pair of macromolecular phosphorescent probes with nonoverlapping optical spectra, which were localized in the intra- and extravascular compartments of the brain tissue, thus providing a readout of oxygen gradients between these two compartments. In parallel, we measured CBF using laser speckle contrast imaging. Results: The method enables computation and tracking of CMRO 2 during functional activation with high temporal resolution ( ∼ 7 Hz ). In contrast to other approaches, our assessment of CMRO 2 does not require measurements of CBF or hemoglobin oxygen saturation. Conclusions: The independent records of intravascular and extravascular partial pressures of oxygen, CBF, and CMRO 2 provide information about the physiological events that accompany neuronal activation, creating opportunities for dynamic quantification of brain metabolism.

Algorithms and instrumentation for rapid spatial frequency domain fluorescence diffuse optical imaging.

Significance: Rapid estimation of the depth and margins of fluorescence targets buried below the tissue surface could improve upon current image-guided surgery techniques for tumor resection. Aim: We describe algorithms and instrumentation that permit rapid estimation of the depth and transverse margins of fluorescence target(s) in turbid media; the work aims to introduce, experimentally demonstrate, and characterize the methodology. Approach: Spatial frequency domain fluorescence diffuse optical tomography (SFD-FDOT) technique is adapted for rapid and computationally inexpensive estimation of fluorophore target depth and lateral margins. The algorithm utilizes the variation of diffuse fluorescence intensity with respect to spatial-modulation-frequency to compute target depth. The lateral margins are determined via analytical inversion of the data using depth information obtained from the first step. We characterize method performance using fluorescent contrast targets embedded in tissue-simulating phantoms. Results: Single and multiple targets with significant lateral size were imaged at varying depths as deep as 1 cm. Phantom data analysis showed good depth-sensitivity, and the reconstructed transverse margins were mostly within ∼30 % error from true margins. Conclusions: The study suggests that the rapid SFD-FDOT approach could be useful in resection surgery and, more broadly, as a first step in more rigorous SFD-FDOT reconstructions. The experiments permit evaluation of current limitations.

Lossless Compressed Sensing of Photon Counts for Fast Diffuse Correlation Spectroscopy.

Diffuse Correlation Spectroscopy (DCS), a noninvasive optical technique, measures deep tissue blood flow using avalanche photon counting modules and data acquisition devices such as FPGAs or correlator boards. Conventional DCS instruments use in-processor counter modules that consume 32 bits/channel which is inefficient for low-photon budget situations prevalent in diffuse optics. Scaling these photon counters for large-scale imaging applications is difficult due to bandwidth and processing time considerations. Here, we introduce a new, lossless compressed sensing approach for fast and efficient detection of photon counts. The compressed DCS method uses an array of binary-coded-decimal counters to record photon counts from 8 channels simultaneously as a single 32-bit number. We validate the compressed DCS approach by comparisons with conventional DCS in experiments on tissue simulating phantoms and in-vivo arm cuff occlusion. Lossless compressed DCS was implemented with 87.5% compression efficiency. In tissue simulating phantoms, it was able to accurately estimate a tissue blood flow index, with no statistically significant difference compared to conventional DCS. Compressed DCS also recorded blood flow in vivo, in human forearm, with signal-to-noise ratio and dynamic range comparable to conventional DCS. Lossless 87.5% efficient compressed sensing counting of photon counts meets and exceeds benchmarks set by conventional DCS systems, offering a low-cost alternative for fast (~100 Hz) deep tissue blood flow measurement with optics.

Comparison of functional activation responses from the auditory cortex derived using multi-distance frequency domain and continuous wave near-infrared spectroscopy.

Significance: Quantitative measurements of cerebral hemodynamic changes due to functional activation are widely accomplished with commercial continuous wave (CW-NIRS) instruments despite the availability of the more rigorous multi-distance frequency domain (FD-NIRS) approach. A direct comparison of the two approaches to functional near-infrared spectroscopy can help in the interpretation of optical data and guide implementations of diffuse optical instruments for measuring functional activation. Aim: We explore the differences between CW-NIRS and multi-distance FD-NIRS by comparing measurements of functional activation in the human auditory cortex. Approach: Functional activation of the human auditory cortex was measured using a commercial frequency domain near-infrared spectroscopy instrument for 70 dB sound pressure level broadband noise and pure tone (1000 Hz) stimuli. Changes in tissue oxygenation were calculated using the modified Beer-Lambert law (CW-NIRS approach) and the photon diffusion equation (FD-NIRS approach). Results: Changes in oxygenated hemoglobin measured with the multi-distance FD-NIRS approach were about twice as large as those measured with the CW-NIRS approach. A finite-element simulation of the functional activation problem was performed to demonstrate that tissue oxygenation changes measured with the CW-NIRS approach is more accurate than that with multi-distance FD-NIRS. Conclusions: Multi-distance FD-NIRS approaches tend to overestimate functional activation effects, in part due to partial volume effects.

Fast diffuse correlation spectroscopy with a low-cost, fiber-less embedded diode laser.

Diffuse correlation spectroscopy (DCS), a popular optical technique for fast noninvasive measurement of blood flow, is commonly implemented using expensive fiber-coupled long coherence length laser systems. Here, we report the development of a portable and fiber-less approach that can be used as a low-cost alternative to illuminate tissue in DCS instruments. We validate the accuracy and noise characteristics of the fiber-less DCS laser source, by comparisons against traditional DCS light sources, with experiments on controlled tissue-simulating phantoms and in humans.

Cerebral Blood Flow Response During Bolus Normal Saline Infusion After Ischemic Stroke.

GOALS: We quantified cerebral blood flow response to a 500 cc bolus of 0.9%% normal saline (NS) within 96 hours of acute ischemic stroke (AIS) using diffuse correlation spectroscopy (DCS). MATERIALS AND METHODS: Subjects with AIS in the anterior, middle, or posterior cerebral artery territory were enrolled within 96 hours of symptom onset. DCS measured relative cerebral blood flow (rCBF) in the bilateral frontal lobes for 15 minutes at rest (baseline), during a 30-minute infusion of 500 cc NS (bolus), and for 15 minutes after completion (post-bolus). Mean rCBF for each time period was calculated for individual subjects and median rCBF for the population was compared between time periods. Linear regression was used to evaluate for associations between rCBF and clinical features. RESULTS: Among 57 subjects, median rCBF (IQR) increased relative to baseline in the ipsilesional hemisphere by 17% (-2.0%, 43.1%), P< 0.001, and in the contralesional hemisphere by 13.3% (-4.3%, 36.0%), P < .004. No significant associations were found between ipsilesional changes in rCBF and age, race, infarct size, infarct location, presence of large vessel stenosis, NIH stroke scale, or symptom duration. CONCLUSION: A 500 cc bolus of .9% NS produced a measurable increase in rCBF in both the affected and nonaffected hemispheres. Clinical features did not predict rCBF response.

Laser safety in fiber-optic monitoring of spinal cord hemodynamics: a preclinical evaluation.

The prevention and treatment of spinal cord injury are focused upon the maintenance of spinal cord blood flow, yet no technology exists to monitor spinal cord ischemia. We recently demonstrated continuous monitoring of spinal cord ischemia with diffuse correlation and optical spectroscopies using an optical probe. Prior to clinical translation of this technology, it is critically important to demonstrate the safety profile of spinal cord exposure to the required light. To our knowledge, this is the first report of in situ safety testing of such a monitor. We expose the spinal cord to laser light utilizing a custom fiber-optic epidural probe in a survival surgery model (11 adult Dorset sheep). We compare the tissue illumination from our instrument with the American National Standards Institute maximum permissible exposures. We experimentally evaluate neurological and pathological outcomes of the irradiated sheep associated with prolonged exposure to the laser source and evaluate heating in ex vivo spinal cord samples. Spinal cord tissue was exposed to light levels at ∼18 × the maximum permissible exposure for the eye and ∼ ( 1 / 3 ) × for the skin. Multidisciplinary testing revealed no functional neurological sequelae, histopathologic evidence of laser-related injury to the spinal cord, or significant temperature changes in ex vivo samples. Low tissue irradiance and the lack of neurological, pathological, and temperature changes upon prolonged exposure to the laser source offer evidence that spinal cord tissues can be monitored safely with near-infrared optical probes placed within the epidural space.

Dynamic autoregulation of cerebral blood flow measured non-invasively with fast diffuse correlation spectroscopy.

Cerebral autoregulation (CA) maintains cerebral blood flow (CBF) in the presence of systemic blood pressure changes. Brain injury can cause loss of CA and resulting dysregulation of CBF, and the degree of CA impairment is a functional indicator of cerebral tissue health. Here, we demonstrate a new approach to noninvasively estimate cerebral autoregulation in healthy adult volunteers. The approach employs pulsatile CBF measurements obtained using high-speed diffuse correlation spectroscopy (DCS). Rapid thigh-cuff deflation initiates a chain of responses that permits estimation of rates of dynamic autoregulation in the cerebral microvasculature. The regulation rate estimated with DCS in the microvasculature (median: 0.26 s-1, inter quartile range: 0.19 s-1) agrees well (R = 0.81, slope = 0.9) with regulation rates measured by transcranial Doppler ultrasound (TCD) in the proximal vasculature (median: 0.28 s-1, inter quartile range: 0.10 s-1). We also obtained an index of systemic autoregulation in concurrently measured scalp microvasculature. Systemic autoregulation begins later than cerebral autoregulation and exhibited a different rate (0.55 s-1, inter quartile range: 0.72 s-1). Our work demonstrates the potential of diffuse correlation spectroscopy for bedside monitoring of cerebral autoregulation in the microvasculature of patients with brain injury.

Noninvasive optical monitoring of critical closing pressure and arteriole compliance in human subjects.

The critical closing pressure ( CrCP) of the cerebral circulation depends on both tissue intracranial pressure and vasomotor tone. CrCP defines the arterial blood pressure ( ABP) at which cerebral blood flow approaches zero, and their difference ( ABP - CrCP) is an accurate estimate of cerebral perfusion pressure. Here we demonstrate a novel non-invasive technique for continuous monitoring of CrCP at the bedside. The methodology combines optical diffuse correlation spectroscopy (DCS) measurements of pulsatile cerebral blood flow in arterioles with concurrent ABP data during the cardiac cycle. Together, the two waveforms permit calculation of CrCP via the two-compartment Windkessel model for flow in the cerebral arterioles. Measurements of CrCP by optics (DCS) and transcranial Doppler ultrasound (TCD) were carried out in 18 healthy adults; they demonstrated good agreement (R = 0.66, slope = 1.14 ± 0.23) with means of 11.1 ± 5.0 and 13.0 ± 7.5 mmHg, respectively. Additionally, a potentially useful and rarely measured arteriole compliance parameter was derived from the phase difference between ABP and DCS arteriole blood flow waveforms. The measurements provide evidence that DCS signals originate predominantly from arteriole blood flow and are well suited for long-term continuous monitoring of CrCP and assessment of arteriole compliance in the clinic.

Non-Invasive Respiratory Impedance Enhances Cerebral Perfusion in Healthy Adults.

Optimization of cerebral blood flow (CBF) is the cornerstone of clinical management in a number of neurologic diseases, most notably ischemic stroke. Intrathoracic pressure influences cardiac output and has the potential to impact CBF. Here, we aim to quantify cerebral hemodynamic changes in response to increased respiratory impedance (RI) using a non-invasive respiratory device. We measured cerebral perfusion under varying levels of RI (6 cm H2O, 9 cm H2O, and 12 cm H2O) in 20 healthy volunteers. Simultaneous measurements of microvascular CBF and middle cerebral artery mean flow velocity (MFV), respectively, were performed with optical diffuse correlation spectroscopy and transcranial Doppler ultrasound. At a high level of RI, MFV increased by 6.4% compared to baseline (p = 0.004), but changes in cortical CBF were non-significant. In a multivariable linear regression model accounting for end-tidal CO2, RI was associated with increases in both MFV (coefficient: 0.49, p < 0.001) and cortical CBF (coefficient: 0.13, p < 0.001), although the magnitude of the effect was small. Manipulating intrathoracic pressure via non-invasive RI was well tolerated and produced a small but measurable increase in cerebral perfusion in healthy individuals. Future studies in acute ischemic stroke patients with impaired cerebral autoregulation are warranted in order to assess whether RI is feasible as a novel non-invasive therapy for stroke.

Fast blood flow monitoring in deep tissues with real-time software correlators.

We introduce, validate and demonstrate a new software correlator for high-speed measurement of blood flow in deep tissues based on diffuse correlation spectroscopy (DCS). The software correlator scheme employs standard PC-based data acquisition boards to measure temporal intensity autocorrelation functions continuously at 50 - 100 Hz, the fastest blood flow measurements reported with DCS to date. The data streams, obtained in vivo for typical source-detector separations of 2.5 cm, easily resolve pulsatile heart-beat fluctuations in blood flow which were previously considered to be noise. We employ the device to separate tissue blood flow from tissue absorption/scattering dynamics and thereby show that the origin of the pulsatile DCS signal is primarily flow, and we monitor cerebral autoregulation dynamics in healthy volunteers more accurately than with traditional instrumentation as a result of increased data acquisition rates. Finally, we characterize measurement signal-to-noise ratio and identify count rate and averaging parameters needed for optimal performance.

Pressure modulation algorithm to separate cerebral hemodynamic signals from extracerebral artifacts.

We introduce and validate a pressure measurement paradigm that reduces extracerebral contamination from superficial tissues in optical monitoring of cerebral blood flow with diffuse correlation spectroscopy (DCS). The scheme determines subject-specific contributions of extracerebral and cerebral tissues to the DCS signal by utilizing probe pressure modulation to induce variations in extracerebral blood flow. For analysis, the head is modeled as a two-layer medium and is probed with long and short source-detector separations. Then a combination of pressure modulation and a modified Beer-Lambert law for flow enables experimenters to linearly relate differential DCS signals to cerebral and extracerebral blood flow variation without a priori anatomical information. We demonstrate the algorithm's ability to isolate cerebral blood flow during a finger-tapping task and during graded scalp ischemia in healthy adults. Finally, we adapt the pressure modulation algorithm to ameliorate extracerebral contamination in monitoring of cerebral blood oxygenation and blood volume by near-infrared spectroscopy.

Intraoperative near-infrared fluorescence imaging and spectroscopy identifies residual tumor cells in wounds.

Surgery is the most effective method to cure patients with solid tumors, and 50% of all cancer patients undergo resection. Local recurrences are due to tumor cells remaining in the wound, thus we explore near-infrared (NIR) fluorescence spectroscopy and imaging to identify residual cancer cells after surgery. Fifteen canines and two human patients with spontaneously occurring sarcomas underwent intraoperative imaging. During the operation, the wounds were interrogated with NIR fluorescence imaging and spectroscopy. NIR monitoring identified the presence or absence of residual tumor cells after surgery in 14/15 canines with a mean fluorescence signal-to-background ratio (SBR) of ∼16 . Ten animals showed no residual tumor cells in the wound bed (mean SBR<2 , P<0.001 ). None had a local recurrence at >1-year follow-up. In five animals, the mean SBR of the wound was >15 , and histopathology confirmed tumor cells in the postsurgical wound in four/five canines. In the human pilot study, neither patient had residual tumor cells in the wound bed, and both remain disease free at >1.5-year follow up. Intraoperative NIR fluorescence imaging and spectroscopy identifies residual tumor cells in surgical wounds. These observations suggest that NIR imaging techniques may improve tumor resection during cancer operations.

Calibration of diffuse correlation spectroscopy blood flow index with venous-occlusion diffuse optical spectroscopy in skeletal muscle.

We investigate and assess the utility of a simple scheme for continuous absolute blood flow monitoring based on diffuse correlation spectroscopy (DCS). The scheme calibrates DCS using venous-occlusion diffuse optical spectroscopy (VO-DOS) measurements of arm muscle tissue at a single time-point. A calibration coefficient (γ) for the arm is determined, permitting conversion of DCS blood flow indices to absolute blood flow units, and a study of healthy adults (N=10) is carried out to ascertain the variability of γ. The average DCS calibration coefficient for the right (i.e., dominant) arm was γ=(1.24±0.15)×10(8) (mL·100 mL(−1)·min(−1))/(cm(2)/s). However, variability can be significant and is apparent in our site-to-site and day-to-day repeated measurements. The peak hyperemic blood flow overshoot relative to baseline resting flow was also studied following arm-cuff ischemia; excellent agreement between VO-DOS and DCS was found (R(2)=0.95, slope=0.94±0.07, mean difference=−0.10±0.45). Finally, we show that incorporation of subject-specific absolute optical properties significantly improves blood flow calibration accuracy.

Modified Beer-Lambert law for blood flow.

We develop and validate a Modified Beer-Lambert law for blood flow based on diffuse correlation spectroscopy (DCS) measurements. The new formulation enables blood flow monitoring from temporal intensity autocorrelation function data taken at single or multiple delay-times. Consequentially, the speed of the optical blood flow measurement can be substantially increased. The scheme facilitates blood flow monitoring of highly scattering tissues in geometries wherein light propagation is diffusive or non-diffusive, and it is particularly well-suited for utilization with pressure measurement paradigms that employ differential flow signals to reduce contributions of superficial tissues.

Diffuse correlation spectroscopy for measurement of cerebral blood flow: future prospects.

Diffuse correlation spectroscopy (DCS) is an emerging optical modality used to measure cortical cerebral blood flow. This outlook presents a brief overview of the technology, summarizing the advantages and limitations of the method, and describing its recent applications to animal, adult, and infant cohorts. At last, the paper highlights future applications where DCS may play a pivotal role individualizing patient management and enhancing our understanding of neurovascular coupling, activation, and brain development.