Scientific Reports volume 13, Artigo número: 8803 (2023) Citar este artigo
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A espectroscopia de correlação difusa (DCS) é uma técnica óptica que pode ser usada para caracterizar o fluxo sanguíneo no tecido. A medição da hemodinâmica cerebral surgiu como um caso de uso promissor para DD, embora as implementações tradicionais de DD exibam relação sinal-ruído (SNR) e sensibilidade cerebral abaixo do ideal para fazer medições robustas do fluxo sanguíneo cerebral em adultos. Neste trabalho, apresentamos DCS interferométrico de comprimento de onda longo (LW-iDCS), que combina o uso de um comprimento de onda de iluminação mais longo (1064 nm), multi-speckle e detecção interferométrica, para melhorar a sensibilidade cerebral e a SNR. Através da comparação direta com DCS de comprimento de onda longo baseado em detectores de fótons únicos de nanofios supercondutores, demonstramos uma melhoria aproximada de 5x no SNR em um único canal de LW-DCS nos sinais de fluxo sanguíneo medidos em seres humanos. Mostramos a equivalência do fluxo sanguíneo extraído entre LW-DCS e LW-iDCS e demonstramos a viabilidade do LW-iDCS medido a 100 Hz com uma separação fonte-detector de 3,5 cm. Esta melhoria no desempenho tem o potencial de permitir medições robustas da hemodinâmica cerebral e desbloquear novos casos de uso para espectroscopia de correlação difusa.
A espectroscopia de correlação difusa (DCS) é uma técnica óptica estabelecida que permite a medição não invasiva do fluxo sanguíneo tecidual1. Através da medição da luz difusamente retroespalhada, o DCS relaciona as flutuações temporais dos sinais coletados ao movimento das células sanguíneas através da vasculatura. O monitoramento clínico do fluxo sanguíneo à beira do leito2, especialmente o monitoramento do fluxo sanguíneo cerebral3, explodiu como um caso de uso para DD, com o DCS sendo usado para estimar métricas de perfusão cerebral durante procedimentos cirúrgicos4,5,6,7,8, autorregulação cerebral9,10, cerebrovascular reatividade11, pressão intracraniana12,13,14 e pressão crítica de fechamento15,16. Embora vários estudos incluindo o monitoramento DCS tenham sido demonstrados em populações adultas, devido a limitações na sensibilidade cerebral e na relação sinal-ruído17, a técnica padrão DCS é mais adequada para medir o fluxo sanguíneo em neonatos e crianças, onde o tecido extracerebral ( couro cabeludo e crânio) é significativamente mais fino que em adultos18,19. Para melhorar o desempenho da DD em populações adultas, muitos grupos desenvolveram modificações na DD que proporcionam melhorias na sensibilidade cerebral, na relação sinal-ruído ou em ambas. Esses métodos incluem detecção interferométrica 20,21,22,23,24,25, detecção de manchas paralelizadas 26,27,28, modulação acústico-óptica 29,30,31, métodos resolvidos de comprimento de caminho 32,33,34,35,36,37, métodos de contraste de manchas 38 ,39,40 e abordagens de comprimento de onda longo41,42. Trabalhos recentes em nosso grupo mostraram a utilidade do uso de DCS de comprimento de onda longo aplicado em 1064 nm, embora na prática para medições clínicas, os detectores comerciais atualmente disponíveis não tenham desempenho de ruído razoável para medições sensíveis a fluxo profundo (InGaAs/InP single -diodos de avalanche de fótons (SPADs))43 ou são muito volumosos para serem aplicados clinicamente (detectores de fóton único de nanofios supercondutores (SNSPD)). Para resolver esta lacuna na tecnologia de detectores, desenvolvemos DCS interferométrico de comprimento de onda longo (LW-iDCS), que aproveita todos os benefícios de trabalhar em 1064 nm e evita os aspectos negativos das tecnologias de detectores sensíveis à luz em 1064 nm usando interferométrico detecção juntamente com um sensor de câmera de varredura de linha altamente paralela (inspirado no trabalho realizado em comprimentos de onda mais curtos por Zhou et al.21,44). Neste trabalho, comparamos diretamente o desempenho de LW-DCS e LW-iDCS em um estudo piloto em seres humanos para verificar a equivalência da estimativa do fluxo sanguíneo pela nova técnica LW-iDCS e comparar a qualidade dos sinais medidos.
3.5 mm center-to-center distance), 1 single mode fiber for short-separation DCS (5 mm) and several co-localized long-separation detection fibers: 4 single mode fibers (LW-DCS), and 7 multimode detection fibers (LW-iDCS). A high coherence (lc > 10 km), fiber (MFD 6.6 µm) laser source emitting ~ 125 mW at 1064 nm (RFLM-125-0-1064, NP Photonics) was fusion spliced (S185HS Fusion Splicer, Fitel) to a 90:10, polarization maintaining fused fiber coupler (MFD 6.6 µm, PN1064R2A1, Thorlabs). The 10% arm of the coupler was used as the input for a fiber amplifier (MAKO-AMP1064, Cybel), and was connected via an FC/APC connector. The amplifier output fiber (MFD 10 µm) was fusion spliced to the input of a 50:50, 105 µm, multimode fused fiber coupler (TW1064R5A1B, Thorlabs). The two outputs of the fiber coupler were spliced to two 105 µm multimode source fibers connected to the probe. The light was amplified to allow for two MPE limited spots54 (1 W/cm2 at 1064 nm, 3.6 mm spot size diameter, 102 mW each spot) to increase the achievable signal-to-noise ratio. The 90% output arm of the polarization maintaining coupler was connected to the reference arm input of the LW-iDCS interferometer. All spliced connections were confirmed by the fusion splicer to have losses less than 0.03 dB./p> 50%. (B) For this maneuver, as expected, the systemic physiology was not significantly affected by the tightening of the tourniquet on the forehead./p> 3.5 mm apart could be used, allowing for an even higher SNR for high quality pulsatile blood flow measurements. The SNR of the LW-iDCS measurement seen in the high-speed pulsatile measurements was 4.5× the SNR of the SNSPD LW-DCS measurement when making single channel comparisons, representing an enabling improvement to the quality of blood flow measured. In the context of the DCS systems currently used for translational research, this improvement is especially significant considering that even the single illumination SNSPD LW-DCS has an SNR gain of 16× over conventional DCS42, and that measurements at 3.5 cm are not feasible with conventional NIR DCS. The use of a camera which is sensitive to light at 1064 nm takes advantage of both the higher number of photons per mode as compared to traditional NIR wavelengths as well as the slower decay of the autocorrelation function. For cerebral blood flow measurements made at long source-detector separations, the autocorrelation decay for traditional NIR DCS can happen in 1–10 s of microseconds, and a significant portion of the decay could be missed if not sampled quickly enough. The use of both heterodyne detection, measuring the slower decaying \({g}_{1}\left(\tau \right)\) as opposed to \({g}_{2}\left(\tau \right)\), and 1064 nm relaxes the sampling rate needed to effectively sample the correlation function. The longer source-detector separation achievable with these advanced DCS systems enables measurements with reduced sensitivity to the upper tissue layers relative to the sensitivity of currently applied DCS systems in the traditional NIR wavelength range (explored in the supplement). The decreased sensitivity to extracerebral signals is greatly beneficial to DCS measurements, especially in clinical applications where systemic physiological fluctuations are more likely to occur and the timing of relevant cerebral hemodynamic changes is not as well defined. We also see good agreement with the estimated noise performance given by Monte Carlo simulation (Figure S3). Additionally, the cost of the system is greatly reduced compared to LW-DCS based on SNSPDs. For this implementation of the LW-iDCS system, the detector used is ~ 7× less expensive (~ $25 k total, camera + frame grabber: ~ $20 k, assorted lenses, opto-mechanics, and fibers: ~ $5 k) as compared to the SNSPDs (~ $180 k total, cryostat: ~ $100 k, individual nanowire detectors: ~ $20 k each). The LW-iDCS cart-based system is also more mobile than the SNSPD based LW-DCS system. These improvements in cost, SNR, and mobility are promising for the clinical usability of LW-iDCS measurements of CBF in adults. The signal processing approach used to extract the correlation function from the raw data stream points to potential pitfalls in the development of iDCS instruments using multimode fiber and free space interferometers though. The motion of fibers and vibrations in the environment have the potential to corrupt the iDCS signals, however, these challenges are manageable, and the use of the custom data analysis pipeline, described in supplementary information, was successful in removing artifacts from the data. The use of a weighted fitting approach allowed for equivalent blood flow indices to be fit from both the LW-DCS and LW-iDCS correlation functions, evidenced by the results shown in Fig. 3C and D. While the results presented matched well, investigation of the generalizability of the weighting factor selected in this study is warranted given the influence that tissue layer thicknesses, optical properties, and ratios of scalp and brain blood flow are known to have on fitting autocorrelation functions67,68. Another challenge posed by the implementation of massively parallel multi-speckle detection is the raw data rate of the instruments. Recent publications on massively parallelized detection have quoted raw data rates between 0.24 GB/s (0.864 TB/hr) and 9.0 GB/s (32.4 TB/hr)22,25,26,27,28,44,69. For clinical blood flow measurements, these data rates could result in untenably large data files, though real time processing utilizing GPUs or FPGAs have been explored as a solution to address this challenge28,69. The increased SNR provided by the LW-iDCS instrument presented here enabled high sensitivity to the cerebral blood flow signal as well as a high rate of BFi calculation. These factors will be highly enabling for the clinical translation of DCS as a noninvasive cerebral blood flow monitor./p>
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